U.S. patent application number 16/543196 was filed with the patent office on 2020-05-07 for methods of treating bladder cancer.
The applicant listed for this patent is Abraxis BioScience, LLC. Invention is credited to Neil P. DESAI.
Application Number | 20200138793 16/543196 |
Document ID | / |
Family ID | 51581053 |
Filed Date | 2020-05-07 |
United States Patent
Application |
20200138793 |
Kind Code |
A1 |
DESAI; Neil P. |
May 7, 2020 |
METHODS OF TREATING BLADDER CANCER
Abstract
The present invention provides methods and compositions for
treating bladder cancer, including metastatic bladder cancer and
non-muscle-invasive bladder cancer, by administering a composition
comprising nanoparticles that comprise mTOR inhibitor and
optionally an albumin.
Inventors: |
DESAI; Neil P.; (Pacific
Palisades, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abraxis BioScience, LLC |
Summit |
NJ |
US |
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Family ID: |
51581053 |
Appl. No.: |
16/543196 |
Filed: |
August 16, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15938952 |
Mar 28, 2018 |
10413531 |
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16543196 |
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14772725 |
Sep 3, 2015 |
9962373 |
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PCT/US14/26564 |
Mar 13, 2014 |
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15938952 |
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61786175 |
Mar 14, 2013 |
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61786167 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 35/04 20180101; A61K 31/436 20130101; A61P 37/04 20180101;
A61K 9/0019 20130101; A61P 13/10 20180101; A61K 9/5169 20130101;
A61K 2039/585 20130101; A61K 45/06 20130101; A61P 43/00 20180101;
A61K 9/0034 20130101; A61K 39/04 20130101; A61K 31/436 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/436 20060101
A61K031/436; A61K 39/04 20060101 A61K039/04; A61K 45/06 20060101
A61K045/06; A61K 9/00 20060101 A61K009/00; A61K 9/51 20060101
A61K009/51 |
Claims
1-26. (canceled)
27. A method of treating non-muscle invasive bladder cancer (NMIBC)
in an individual, comprising administering to the individual an
effective amount of nanoparticles comprising a limus drug and an
albumin.
28. The method of claim 27, wherein the NMIBC is refractory to
treatment with BCG, mitomycin C, or interferon.
29. The method of claim 27, wherein the nanoparticle composition is
administered intravesicularly.
30. The method of claim 27, wherein the nanoparticle composition is
administered at a frequency of at least once weekly.
31. The method of claim 27, wherein the dose of limus drug in the
nanoparticle composition is about 5 to about 500 mg.
32. The method of claim 31, wherein the dose of limus drug in the
nanoparticle composition is about 30 to about 400 mg.
33. The method of claim 31, wherein the nanoparticle composition is
administered at a volume of about 20 to about 150 ml.
34. The method of claim 31, wherein the nanoparticle composition is
administered intravesicularly, and wherein the composition is
retained in the bladder for about 30 minutes to about 4 hours.
35. The method of claim 27, wherein the composition is administered
with an effective amount of a second therapeutic agent.
36. The method of claim 35, the second therapeutic agent is an
immunotherapeutic agent.
37. The method of claim 35, wherein the second therapeutic agent is
selected from the group consisting of an alkylating agent, an
anthracycline antibiotic, an antimetabolite, an indolequinone, a
taxane, and a platinum-based agent.
38. The method of claim 37, wherein the second therapeutic agent is
selected from the group consisting of mitomycin, epirubicin,
doxorubicin, valrubicin, gemcitabine, apaziquone, docetaxel,
paclitaxel, and cisplatin.
39. The method of claim 27, wherein the limus drug is
sirolimus.
40. The method of claim 39, wherein the nanoparticles in the
composition have an average diameter of no greater than about 200
nm.
41. The method of claim 39, wherein the limus drug in the
nanoparticles is coated with albumin.
42. The method of claim 27, wherein the bladder cancer is a high
grade bladder cancer.
43. The method of claim 27, wherein the individual is human.
44. The method of claim 27, wherein the individual is selected for
treatment based on the level of one of more of: p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p'73, c-myc, and
cyclin D1.
45. The method of claim 44, further comprising determining the
level of one of more of: p-S6K, pAKT, p-4EBP1, Ki67, p53, p63,
Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1 prior to
treatment.
46. The method of claim 44, further comprising selecting the
individual for treatment based on a high level of one or more of:
p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p'73,
c-myc, and cyclin D1.
Description
RELATED APPLICATIONS
[0001] This application claims priority benefit to U.S. Provisional
Application No. 61/786,167, entitled "Methods of Treating Bladder
Cancer," filed Mar. 14, 2013 and U.S. Provisional Application No.
61/786,175, entitled "Methods of Treating Bladder Cancer," filed
Mar. 14, 2013, the contents of each of which are incorporated by
reference herein in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to methods and compositions
for the treatment of bladder cancer by administering compositions
comprising nanoparticles that comprise a limus drug and an
albumin.
BACKGROUND
[0003] In the US, bladder cancer is the fourth most common type of
cancer in men and the ninth most common cancer in women. Smoking
and age are the main known risk factors, with nearly 90% of
patients over age of 55. In 2011, it is estimated that there will
be 69,250 new cases in the US, resulting in 14,990 deaths.
Non-muscle invasive bladder cancer (NMIBC) begins and stays in the
cells lining the bladder without growing into the deeper main
muscle layer of the bladder, and accounts for the majority (70-80%)
of patients diagnosed with bladder cancer (stages Ta, T1, or CIS).
Approximately 30% of patients present with muscle-invasive disease
(stages T2-T4). Bladder cancer has the highest recurrence rate of
any malignancy. Although NMIBC is a relatively benign disease, it
recurs in 50-70% of patients, of which 10-20% would eventually
progress to high-grade muscle-invasive disease. Furthermore, the
disease is also characterized by having a large pool of patients
who have been previously diagnosed and are still undergoing
treatment for unresolved tumors; more than 1 million patients in
the US and Europe are estimated to be affected by the disease.
[0004] The high-grade muscle invasive disease is typically treated
with radical cystectomy or a combination of radiation therapy and
chemotherapy. However, even after treatment the tumor usually
remains and patients are at risk of tumor progression, leading to a
shortened life expectancy or death from metastatic disease.
Approximately 350,000 patients in the US and EU are currently
undergoing treatment for unresolved tumors.
[0005] NMIBC is typically treated with intravesicular BCG, which
elicits a nonspecific local immune response against the tumor
cells. BCG elicits a nonspecific massive local inflammatory
reaction in the bladder wall, and elevated appearance of cytokines
can be detected in the urine of BCG-treated patients. BCG is
internalized by antigen-presenting cells, such as macrophages, but
also by urothelial tumor cells, which result in an altered gene
expression of these cells. Additionally, none of the available
chemotherapeutic agents, including gemcitabine, cisplatin, and
valrubicin, that are currently explored in clinical trials for
treating bladder cancer are targeted therapeutics.
[0006] Sirolimus (INN/USAN), also known as rapamycin, is an
immunosuppressant drug used to prevent rejection in organ
transplantation; it is especially useful in kidney transplants. It
prevents activation of T cells and B cells by inhibiting their
response to interleukin-2 (IL-2). The mode of action of sirolimus
is to bind the cytosolic protein FK-binding protein 12 (FKBP12),
and the sirolimus-FKBP12 complex in turn inhibits the mammalian
target of sirolimus (mTOR) pathway by directly binding the mTOR
Complex1 (mTORC1).
[0007] Albumin-based nanoparticle compositions have been developed
as a drug delivery system for delivering substantially water
insoluble drugs. See, for example, U.S. Pat. Nos. 5,916,596;
6,506,405; 6,749,868, and 6,537,579, 7,820,788, and 7,923,536.
Abraxane.RTM., an albumin stabilized nanoparticle formulation of
paclitaxel, was approved in the United States in 2005 and
subsequently in various other countries for treating metastatic
breast cancer. It was recently approved for treating non-small cell
lung cancer in the United States, and has also shown therapeutic
efficacy in various clinical trials for treating difficult-to-treat
cancers such as bladder cancer and melanoma. Albumin derived from
human blood has been used for the manufacture of Abraxane.RTM. as
well as various other albumin-based nanoparticle compositions.
[0008] The disclosures of all publications, patents, patent
applications and published patent applications referred to herein
are hereby incorporated herein by reference in their entirety.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides methods of treating bladder
cancer in an individual, comprising administering to the individual
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug). In some
embodiments, there is provided a method of treating bladder cancer
in an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, the
limus drug is sirolimus. In some embodiments, the albumin is human
albumin (such as human serum albumin). In some embodiments, the
nanoparticles comprise sirolimus coated with albumin. In some
embodiments, the average particle size of the nanoparticles in the
nanoparticle composition is no more than about 200 nm (such as no
greater than about 150 nm). In some embodiments, the composition
comprises the albumin stabilized nanoparticle formulation of
sirolimus (Nab-sirolimus). In some embodiments, the composition is
Nab-sirolimus.
[0010] In some embodiments, there is provided a method of treating
bladder cancer in an individual, comprising administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug is coated with the albumin. In some embodiments, there
is provided a method of treating bladder cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the average particle size of the nanoparticles in
the nanoparticle composition is no greater than about 200 nm (such
as less than about 150 nm). In some embodiments, there is provided
a method of treating bladder cancer in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug is coated with the albumin, and
wherein the average particle size of the nanoparticles in the
nanoparticle composition is no greater than about 200 nm (such as
no greater than about 150 nm). In some embodiments, there is
provided a method of treating bladder cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising Nab-sirolimus. In some embodiments, there is
provided a method of treating bladder cancer in an individual,
comprising administering to the individual an effective amount of
Nab-sirolimus.
[0011] In some embodiments, the composition is administered
intravenously. In some embodiments, the composition is administered
intravesicularly (for example via urethral catheterization).
[0012] Also provided are combination therapy methods for treating
bladder cancer. For example, in some embodiments, there is provided
a method of treating bladder cancer in an individual, comprising
administering to the individual (a) an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug); and (b) an effective amount of another
agent (such as BCG). In some embodiments, there is provided a
method of treating bladder cancer in an individual, comprising
administering to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and
albumin; and (b) an effective amount of another agent (such as
BCG). The nanoparticle composition and the other agent can be
administered simultaneously or sequentially. In some embodiments,
the nanoparticle composition and the other agent are administered
concurrently. In some embodiments, the limus drug is sirolimus. In
some embodiments, the albumin is human serum albumin. In some
embodiments, the nanoparticles comprise sirolimus coated with
albumin. In some embodiments, the average particle size of the
nanoparticles in the nanoparticle composition is no more than about
200 nm (such as no greater than about 200 nm). In some embodiments,
the composition comprises the albumin stabilized nanoparticle
formulation of sirolimus (Nab-sirolimus). In some embodiments, the
composition is Nab-sirolimus.
[0013] In some embodiments, the method is carried out in a
neoadjuvant setting. In some embodiments, the method is carried out
in an adjuvant setting. In some embodiments, the method is carried
out after resection of visible tumor in the bladder.
[0014] Bladder cancer that can be treated with methods described
herein include, but are not limited to, metastatic bladder cancer,
non-muscle-invasive bladder cancer, or bladder cancer that is
refractory to a standard therapy (such as Bacillus Calmette-Guerin
(BCG)) or recurrent after the standard therapy. In some
embodiments, the bladder cancer is BCG-refractory
non-muscle-invasive bladder cancer. In some embodiments, the
bladder cancer is platinum-refractory bladder cancer. In some
embodiments, the bladder cancer is platinum-refractory metastatic
urothelial carcinoma. In some embodiments, the treatment is first
line treatment. In some embodiments, the treatment is second line
treatment.
[0015] In some embodiments, there is provided a method of treating
bladder cancer in an individual, comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, there is provided a method of treating
non-muscle-invasive bladder cancer in an individual, comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the individual has progressed from an
earlier therapy for bladder cancer. In some embodiments, the
individual is refractory to an earlier therapy for bladder cancer.
In some embodiments, the individual has recurrent bladder cancer.
In some embodiments, there is provided a method of treating a
BCG-refractory non-muscle-invasive bladder cancer in an individual,
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the amount of the nanoparticle
composition is about 5 mg to about 500 mg, including for example
about 30 mg to about 400 mg (such as about 100 mg). In some
embodiments, the nanoparticle composition is administered
weekly.
[0016] Also provided are methods of treating bladder cancer
according to any one of the methods described above, wherein the
treatment is based on the level of one or more biomarkers.
[0017] The methods described herein can be used for any one or more
of the following purposes: alleviating one or more symptoms of
bladder cancer, delaying progressing of bladder cancer, shrinking
tumor size in bladder cancer patient, inhibiting bladder cancer
tumor growth, prolonging overall survival, prolonging disease-free
survival, prolonging time to bladder disease progression,
preventing or delaying bladder cancer metastasis, reducing (such as
eradiating) preexisting bladder cancer metastasis, reducing
incidence or burden of preexisting bladder cancer metastasis,
preventing recurrence of bladder cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides methods and compositions for
treating bladder cancer by administering a composition comprising
nanoparticles comprising an mTOR inhibitor (hereinafter also
referred to as "mTOR nanoparticle composition"). In some
embodiments, the composition comprises a limus drug and an albumin
(hereinafter also referred to as "limus nanoparticle composition").
Also provided are compositions (such as pharmaceutical
compositions), medicine, kits, and unit dosages useful for the
methods described herein.
Definitions
[0019] As used herein, "treatment" or "treating" is an approach for
obtaining beneficial or desired results including clinical results.
For purposes of this invention, beneficial or desired clinical
results include, but are not limited to, one or more of the
following: alleviating one or more symptoms resulting from the
disease, diminishing the extent of the disease, stabilizing the
disease (e.g., preventing or delaying the worsening of the
disease), preventing or delaying the spread (e.g., metastasis) of
the disease, preventing or delaying the recurrence of the disease,
reducing recurrence rate of the disease, delay or slowing the
progression of the disease, ameliorating the disease state,
providing a remission (partial or total) of the disease, decreasing
the dose of one or more other medications required to treat the
disease, delaying the progression of the disease, increasing the
quality of life, and/or prolonging survival. Also encompassed by
"treatment" is a reduction of pathological consequence of bladder
cancer. The methods of the invention contemplate any one or more of
these aspects of treatment.
[0020] The term "individual" refers to a mammal and includes, but
is not limited to, human, bovine, horse, feline, canine, rodent, or
primate.
[0021] As used herein, an "at risk" individual is an individual who
is at risk of developing bladder cancer. An individual "at risk"
may or may not have detectable disease, and may or may not have
displayed detectable disease prior to the treatment methods
described herein. "At risk" denotes that an individual has one or
more so-called risk factors, which are measurable parameters that
correlate with development of bladder cancer, which are described
herein. An individual having one or more of these risk factors has
a higher probability of developing cancer than an individual
without these risk factor(s).
[0022] "Adjuvant setting" refers to a clinical setting in which an
individual has had a history of bladder cancer, and generally (but
not necessarily) been responsive to therapy, which includes, but is
not limited to, surgery (e.g., surgery resection), radiotherapy,
and chemotherapy. However, because of their history of bladder
cancer, these individuals are considered at risk of development of
the disease. Treatment or administration in the "adjuvant setting"
refers to a subsequent mode of treatment. The degree of risk (e.g.,
when an individual in the adjuvant setting is considered as "high
risk" or "low risk") depends upon several factors, most usually the
extent of disease when first treated.
[0023] "Neoadjuvant setting" refers to a clinical setting in which
the method is carried out before the primary/definitive
therapy.
[0024] As used herein, "delaying" the development of bladder cancer
means to defer, hinder, slow, retard, stabilize, and/or postpone
development of the disease. This delay can be of varying lengths of
time, depending on the history of the disease and/or individual
being treated. As is evident to one skilled in the art, a
sufficient or significant delay can, in effect, encompass
prevention, in that the individual does not develop the disease. A
method that "delays" development of bladder cancer is a method that
reduces probability of disease development in a given time frame
and/or reduces the extent of the disease in a given time frame,
when compared to not using the method. Such comparisons are
typically based on clinical studies, using a statistically
significant number of subjects. Bladder cancer development can be
detectable using standard methods, including, but not limited to,
computerized axial tomography (CAT scan), Magentic Resonance
Imaging (MRI), ultrasound, clotting tests, arteriography, biopsy,
urine cytology, and cystoscopy. Development may also refer to
bladder cancer progression that may be initially undetectable and
includes occurrence, recurrence, and onset.
[0025] As used herein, by "combination therapy" is meant that a
first agent be administered in conjunction with another agent. "In
conjunction with" refers to administration of one treatment
modality in addition to another treatment modality, such as
administration of a nanoparticle composition described herein in
addition to administration of the other agent to the same
individual. As such, "in conjunction with" refers to administration
of one treatment modality before, during, or after delivery of the
other treatment modality to the individual.
[0026] The term "effective amount" used herein refers to an amount
of a compound or composition sufficient to treat a specified
disorder, condition or disease such as ameliorate, palliate,
lessen, and/or delay one or more of its symptoms. In reference to
bladder cancer, an effective amount comprises an amount sufficient
to cause a tumor to shrink and/or to decrease the growth rate of
the tumor (such as to suppress tumor growth) or to prevent or delay
other unwanted cell proliferation in bladder cancer. In some
embodiments, an effective amount is an amount sufficient to delay
development of bladder cancer. In some embodiments, an effective
amount is an amount sufficient to prevent or delay recurrence. In
some embodiments, an effective amount is an amount sufficient to
reduce recurrence rate in the individual. An effective amount can
be administered in one or more administrations. In the case of
bladder cancer, the effective amount of the drug or composition
may: (i) reduce the number of bladder cancer cells; (ii) reduce
tumor size; (iii) inhibit, retard, slow to some extent and
preferably stop bladder cancer cell infiltration into peripheral
organs; (iv) inhibit (i.e., slow to some extent and preferably
stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or
delay occurrence and/or recurrence of tumor; (vii) reducing
recurrence rate of tumor, and/or (viii) relieve to some extent one
or more of the symptoms associated with bladder cancer.
[0027] The term "simultaneous administration," as used herein,
means that a first therapy and second therapy in a combination
therapy are administered with a time separation of no more than
about 15 minutes, such as no more than about any of 10, 5, or 1
minutes. When the first and second therapies are administered
simultaneously, the first and second therapies may be contained in
the same composition (e.g., a composition comprising both a first
and second therapy) or in separate compositions (e.g., a first
therapy in one composition and a second therapy is contained in
another composition).
[0028] As used herein, the term "sequential administration" means
that the first therapy and second therapy in a combination therapy
are administered with a time separation of more than about 15
minutes, such as more than about any of 20, 30, 40, 50, 60, or more
minutes. Either the first therapy or the second therapy may be
administered first. The first and second therapies are contained in
separate compositions, which may be contained in the same or
different packages or kits.
[0029] As used herein, the term "concurrent administration" means
that the administration of the first therapy and that of a second
therapy in a combination therapy overlap with each other.
[0030] As used herein, by "pharmaceutically acceptable" or
"pharmacologically compatible" is meant a material that is not
biologically or otherwise undesirable, e.g., the material may be
incorporated into a pharmaceutical composition administered to a
patient without causing any significant undesirable biological
effects or interacting in a deleterious manner with any of the
other components of the composition in which it is contained.
Pharmaceutically acceptable carriers or excipients have preferably
met the required standards of toxicological and manufacturing
testing and/or are included on the Inactive Ingredient Guide
prepared by the U.S. Food and Drug administration.
[0031] It is understood that aspect and embodiments of the
invention described herein include "consisting" and/or "consisting
essentially of" aspects and embodiments.
[0032] Reference to "about" a value or parameter herein includes
(and describes) variations that are directed to that value or
parameter per se. For example, description referring to "about X"
includes description of "X".
[0033] As used herein and in the appended claims, the singular
forms "a," "or," and "the" include plural referents unless the
context clearly dictates otherwise.
Methods of Treating Bladder Cancer
[0034] The present invention provides methods of treating bladder
cancer in an individual (such as human) comprising administering to
the individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug).
In some embodiments, the invention provides methods of treating
bladder cancer in an individual (e.g., human) comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0035] "mTOR inhibitor" used herein refers to inhibitors of mTOR.
mTOR is a serine/threonine-specific protein kinase downstream of
the phosphatidylinositol 3-kinase (PBK)/Akt (protein kinase B)
pathway, and a key regulator of cell survival, proliferation,
stress, and metabolism. mTOR pathway dysregulation has been found
in many human carcinomas, and mTOR inhibition produced substantial
inhibitory effects on tumor progression. mTOR inhibitors described
herein include, but are not limited to, BEZ235 (NVP-BEZ235),
everolimus (also known as RAD001 and sold under the trademarks
Zortress.RTM., Certican.RTM., and Afinitor.RTM.), rapamycin (also
known as sirolimus and sold under the trademark Rapamune.RTM.),
AZD8055, temsirolimus (also known as CCI-779 and sold under the
trademark Torisel.RTM.), PI-103, Ku-0063794, INK 128, AZD2014,
NVP-BGT226, PF-04691502, CH5132799, GDC-0980 (RG7422), Torin 1,
WAY-600, WYE-125132, WYE-687, GSK2126458, PF-05212384 (PKI-587),
PP-121, OSI-027, Palomid 529, PP242, XL765, GSK1059615, WYE-354,
and eforolimus (also known as ridaforolimus or deforolimus).
[0036] In some embodiments, the mTOR inhibitor is a limus drug,
which includes sirolimus and its analogues. Examples of limus drugs
include, but are not limited to, temsirolimus (CCI-779), everolimus
(RAD001), ridaforolimus (AP-23573), deforolimus (MK-8669),
zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506). In
some embodiments, the limus drug is selected from the group
consisting of temsirolimus (CCI-779), everolimus (RAD001),
ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus
(ABT-578), pimecrolimus, and tacrolimus (FK-506).
[0037] In some embodiments, the bladder cancer is a low grade
bladder cancer. In some embodiments, the bladder cancer is a high
grade bladder cancer. In some embodiments, the bladder cancer is
invasive. In some embodiments, the bladder cancer is non-invasive.
In some embodiments, the bladder cancer is non-muscle invasive.
[0038] In some embodiments, the bladder cancer is transitional cell
carcinoma or urothelial carcinoma (such as metastatic urothelial
carcinoma), including, but not limited to, papillary tumors and
flat carcinomas. In some embodiments, the bladder cancer is
metastatic urothelial carcinoma. In some embodiments, the bladder
cancer is urothelial carcinoma of the bladder. In some embodiments,
the bladder cancer is urothelial carcinoma of the ureter. In some
embodiments, the bladder cancer is urothelial carcinoma of the
urethra. In some embodiments, the bladder cancer is urothelial
carcinoma of the renal pelvis.
[0039] In some embodiments, the bladder cancer is squamous cell
carcinoma. In some embodiments, the bladder cancer is non-squamous
cell carcinoma. In some embodiments, the bladder cancer is
adenocarcinoma. In some embodiments, the bladder cancer is small
cell carcinoma.
[0040] In some embodiments, the bladder cancer is early stage
bladder cancer, non-metastatic bladder cancer, non-invasive bladder
cancer, non-muscle-invasive bladder cancer, primary bladder cancer,
advanced bladder cancer, locally advanced bladder cancer (such as
unresectable locally advanced bladder cancer), metastatic bladder
cancer, or bladder cancer in remission. In some embodiments, the
bladder cancer is localized resectable, localized unresectable, or
unresectable. In some embodiments, the bladder cancer is a high
grade, non-muscle-invasive cancer that has been refractory to
standard intra-bladder infusion (intravesicular) therapy.
[0041] The methods provided herein can be used to treat an
individual (e.g., human) who has been diagnosed with or is
suspected of having bladder cancer. In some embodiments, the
individual is human. In some embodiments, the individual is at
least about any of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,
80, or 85 years old. In some embodiments, the individual is male.
In some embodiments, the individual is female. In some embodiments,
the individual has undergone a tumor resection. In some
embodiments, the individual has refused surgery. In some
embodiments, the individual is medically inoperable. In some
embodiments, the individual is at a clinical stage of Ta, Tis, T1,
T2, T3a, T3b, or T4 bladder cancer. In some embodiments, the
individual is at a clinical stage of Tis, CIS, Ta, or T1.
[0042] In some embodiments, the individual is a human who exhibits
one or more symptoms associated with bladder cancer. In some
embodiments, the individual is at an early stage of bladder cancer.
In some embodiments, the individual is at an advanced stage of
bladder cancer. In some of embodiments, the individual is
genetically or otherwise predisposed (e.g., having a risk factor)
to developing bladder cancer. Individuals at risk for bladder
cancer include, e.g., those having relatives who have experienced
bladder cancer, and those whose risk is determined by analysis of
genetic or biochemical markers. In some embodiments, the individual
is positive for SPARC expression (for example based on
immunohistochemistry (IHC) standard). In some embodiments, the
individual is negative for SPARC expression. In some embodiments,
the individual has a mutation in FGFR2. In some embodiments, the
individual has a mutation in p53. In some embodiments, the
individual has a mutation in MIB-1. In some embodiments, the
individual has a mutation in one or more of FEZ1/LZTS1, PTEN,
CDKN2A/MTS1/P6, CDKN2B/INK4B/P15, TSC1, DBCCR1, HRAS1, ERBB2, or
NF1. In some embodiments, the individual has mutation in both p53
and PTEN.
[0043] The present invention for example provides in some
embodiments methods of treatment bladder cancer in an individual
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a lumus drug), wherein the treatment is based on the
mutation status of one or more of FEZ1/LZTS1, PTEN, CDKN2A/MTS1/P6,
CDKN2B/INK4B/P15, TSC1, DBCCR1, HRAS1, ERBB2, or NF1. In some
embodiments, there is provided a method of treating bladder cancer
in an individual comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug), wherein the
individual is selected for treatment based on the mutation status
of one or more of FEZ1/LZTS1, PTEN, CDKN2A/MTS1/P6,
CDKN2B/INK4B/P15, TSC1, DBCCR1, HRAS1, ERBB2, or NF1. In some
embodiments, there is provided a method of selecting (including
identifying) an individual having bladder cancer for treating with
a composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), wherein the method comprises determining
the mutation status of one or more of FEZ1/LZTS1, PTEN,
CDKN2A/MTS1/P6, CDKN2B/INK4B/P15, TSC1, DBCCR1, HRAS1, ERBB2, or
NF1. The mutation status of one or more of FEZ1/LZTS1, PTEN,
CDKN2A/MTS1/P6, CDKN2B/INK4B/P15, TSC1, DBCCR1, HRAS1, ERBB2, or
NF1 can also be useful for determining any of the following: (a)
probable or likely suitability of an individual to initially
receive treatment(s); (b) probable or likely unsuitability of an
individual to initially receive treatment(s); (c) responsiveness to
treatment; (d) probable or likely suitability of an individual to
continue to receive treatment(s); (e) probable or likely
unsuitability of an individual to continue to receive treatment(s);
(f) adjusting dosage; (g) predicting likelihood of clinical
benefits.
[0044] In some embodiments, the individual has a partial or
complete monosomy (such as monosomy 9). In some embodiments, the
individual has a deletion in chromosome 11p. In some embodiments,
the individual has a deletion in chromosome 13q. In some
embodiments, the individual has a deletion in chromosome 17p. In
some embodiments, the individual has a deletion in chromosome 1p.
In some embodiments, the individual as a chromosome loss of
8p12-22.
[0045] In some embodiments, the individual overexpresses p73,
c-myc, or cyclin D1.
[0046] The methods provided herein may be practiced in an adjuvant
setting. In some embodiments, the method is practiced in a
neoadjuvant setting, i.e., the method may be carried out before the
primary/definitive therapy. In some embodiments, the method is used
to treat an individual who has previously been treated. In some
embodiments, the individual has not previously been treated. In
some embodiments, the method is used as a first line therapy. In
some embodiments, the method is used as a second line therapy.
[0047] In some embodiments, the individual has been previously
treated for bladder cancer (also referred to as the "prior
therapy"). In some embodiments, individual has been previously
treated with a standard therapy for bladder cancer. In some
embodiments, the prior standard therapy is treatment with BCG. In
some embodiments, the prior standard therapy is treatment with
mitomycin C. In some embodiments, the prior standard therapy is
treatment with interferon (such as interferon-.alpha.). In some
embodiments, the individual has bladder cancer in remission,
progressive bladder cancer, or recurrent bladder cancer. In some
embodiments, the individual is resistant to treatment of bladder
cancer with other agents (such as platinum-based agents, BCG,
mitomycin C, or interferon). In some embodiments, the individual is
initially responsive to treatment of bladder cancer with other
agents (such as platinum-based agents, or BCG) but has progressed
after treatment.
[0048] In some embodiments, the individual has recurrent bladder
cancer (such as a bladder cancer at the clinical stage of Ta, Tis,
T1, T2, T3a, T3b, or T4) after a prior therapy (such as prior
standard therapy, for example treatment with BCG). For example, the
individual may be initially responsive to the treatment with the
prior therapy, but develops bladder cancer after about any of about
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, or 60 months upon
the cessation of the prior therapy.
[0049] In some embodiments, the individual is refractory to a prior
therapy (such as prior standard therapy, for example treatment with
BCG).
[0050] In some embodiments, the individual has progressed on the
prior therapy (such as prior standard therapy, for example
treatment with BCG) at the time of treatment. For example, the
individual has progressed within any of about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 months upon treatment with the prior
therapy.
[0051] In some embodiments, the individual is resistant to the
prior therapy (such as prior standard therapy, for example
treatment with BCG).
[0052] In some embodiments, the individual is unsuitable to
continue with the prior therapy (such as prior standard therapy,
for example treatment with BCG), for example due to failure to
respond and/or due to toxicity.
[0053] In some embodiments, the individual is non-responsive to the
prior therapy (such as prior standard therapy, for example
treatment with BCG).
[0054] In some embodiments, the individual is partially responsive
to the prior therapy (such as prior standard therapy, for example
treatment with BCG), or exhibits a less desirable degree of
responsiveness.
[0055] In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug) and an albumin. In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising intravesicularly administering (for
example via urethral catheterization) to the individual an
effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug) and an albumin,
wherein the mTOR inhibitor (such as a limus drug) in the
nanoparticles is coated with the albumin. In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising intravesicularly administering
(for example via urethral catheterization) to the individual an
effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug) and an albumin,
wherein the nanoparticles have an average particle size of no
greater than about 200 nm (such as no greater than about 150 nm).
In some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug)
and an albumin, wherein the nanoparticles comprise the mTOR
inhibitor (such as a limus drug) coated with albumin, and wherein
the nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug)
and human albumin, wherein the nanoparticles comprise the mTOR
inhibitor (such as a limus drug) coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and the mTOR inhibitor (such as a limus drug) in the
composition is about 9:1 or less (such as about 9:1 or about 8:1).
In some embodiments, the mTOR inhibitor (i.e., the mTOR inhibitor
in the mTOR nanoparticle composition) is administered at a dose of
about 5 mg to about 500 mg (including for example about 30 mg to
about 400 mg, such as about 100 mg). In some embodiments, the limus
nanoparticle composition is administered weekly. In some
embodiments, the composition is administered weekly for 6 weeks,
optionally followed by monthly maintenance thereafter.
[0056] In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin. In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm). In some embodiments, there is provided a method
of treating bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising intravesicularly administering
(for example via urethral catheterization) to the individual an
effective amount of a composition comprising Nab-sirolimus. In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of Nab-sirolimus. In some
embodiments, the limus drug (i.e., limus drug in the limus
nanoparticle composition) is administered at a dose of about 5 mg
to about 500 mg (including for example about 30 mg to about 400 mg,
such as about 100 mg). In some embodiments, the limus nanoparticle
composition is administered weekly. In some embodiments, the
composition is administered weekly for 6 weeks, optionally followed
by monthly maintenance thereafter. In some embodiments, the
composition is administered with about 30 minutes to about 4 hours,
such as about 1 hour to about 2 hours of retention in the
bladder.
[0057] In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, there is provided a
method of treating non-muscle invasive bladder cancer in an
individual (e.g., human) comprising administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, there
is provided a method of treating non-muscle invasive bladder cancer
in an individual (e.g., human) comprising administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, there is provided a method of treating non-muscle
invasive bladder cancer in an individual (e.g., human) comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm). In some embodiments, there is provided a method
of treating non-muscle invasive bladder cancer in an individual
(e.g., human) comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising sirolimus and human albumin, wherein the nanoparticles
comprise sirolimus coated with the human albumin, wherein the
nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, there is provided a method
of treating non-muscle invasive bladder cancer in an individual
(e.g., human) comprising administering to the individual an
effective amount of a composition comprising Nab-sirolimus. In some
embodiments, there is provided a method of treating non-muscle
invasive bladder cancer in an individual (e.g., human) comprising
administering to the individual an effective amount of
Nab-sirolimus. In some embodiments, the limus drug is administered
at a dose of about 5 mg to about 500 mg (including for example
about 30 mg to about 400 mg, such as about 100 mg). In some
embodiments, the limus nanoparticle composition is administered
weekly. In some embodiments, the composition is administered weekly
for 6 weeks, optionally followed by monthly maintenance
thereafter.
[0058] In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, there is provided a
method of treating non-muscle invasive bladder cancer in an
individual (e.g., human) comprising intravesicularly administering
(for example via urethral catheterization) to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, there
is provided a method of treating non-muscle invasive bladder cancer
in an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, there is provided a method of treating non-muscle
invasive bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm). In some embodiments, there is provided a method
of treating non-muscle invasive bladder cancer in an individual
(e.g., human) comprising intravesicularly administering (for
example via urethral catheterization) to the individual an
effective amount of a composition comprising nanoparticles
comprising sirolimus and human albumin, wherein the nanoparticles
comprise sirolimus coated with the human albumin, wherein the
nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, there is provided a method
of treating non-muscle invasive bladder cancer in an individual
(e.g., human) comprising intravesicularly administering (for
example via urethral catheterization) to the individual an
effective amount of a composition comprising Nab-sirolimus. In some
embodiments, there is provided a method of treating non-muscle
invasive bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of
Nab-sirolimus. In some embodiments, the limus drug is administered
at a dose of about 5 mg to about 500 mg (including for example
about 30 mg to about 400 mg, such as about 100 mg). In some
embodiments, the limus nanoparticle composition is administered
weekly. In some embodiments, the composition is administered weekly
for 6 weeks, optionally followed by monthly maintenance
thereafter.
[0059] In some embodiments, there is provided a method of treating
BCG-refractory bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, there is provided a
method of treating BCG-refractory bladder cancer in an individual
(e.g., human) comprising intravesicularly administering (for
example via urethral catheterization) to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, there
is provided a method of treating BCG-refractory bladder cancer in
an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, there is provided a method of treating BCG-refractory
bladder cancer in an individual (e.g., human) comprising
intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, there is provided a method of treating
BCG-refractory bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm). In some embodiments, there is provided a method
of treating BCG-refractory bladder cancer in an individual (e.g.,
human) comprising intravesicularly administering (for example via
urethral catheterization) to the individual an effective amount of
a composition comprising nanoparticles comprising sirolimus and
human albumin, wherein the nanoparticles comprise sirolimus coated
with the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1). In some embodiments,
there is provided a method of treating BCG-refractory bladder
cancer in an individual (e.g., human) comprising intravesicularly
administering (for example via urethral catheterization) to the
individual an effective amount of a composition comprising
Nab-sirolimus. In some embodiments, there is provided a method of
treating BCG-refractory bladder cancer in an individual (e.g.,
human) comprising intravesicularly administering (for example via
urethral catheterization) to the individual an effective amount of
Nab-sirolimus. In some embodiments, the limus drug is administered
at a dose of about 5 mg to about 500 mg (including for example
about 30 mg to about 400 mg, such as about 100 mg). In some
embodiments, the limus nanoparticle composition is administered
weekly. In some embodiments, the composition is administered weekly
for 6 weeks, optionally followed by monthly maintenance
thereafter.
[0060] In some embodiments, there is provided a method of treating
metastatic bladder cancer (such as metastatic urothelial carcinoma)
in an individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug).
In some embodiments, there is provided a method of treating
metastatic bladder cancer (such as metastatic urothelial carcinoma)
in an individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, there is provided a method of treating metastatic
bladder cancer (such as metastatic urothelial carcinoma) in an
individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, there is provided a method of treating metastatic
bladder cancer (such as metastatic urothelial carcinoma) in an
individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and albumin and having an
average diameter of no greater than about 200 nm. In some
embodiments, there is provided a method of treating metastatic
bladder cancer (such as metastatic urothelial carcinoma) in an
individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug coated with albumin and
having an average diameter of no greater than about 200 nm. In some
embodiments, there is provided a method of treating metastatic
bladder cancer (such as metastatic urothelial carcinoma) in an
individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
nanoparticles comprising sirolimus coated with human albumin and
having an average diameter of no greater than about 150 (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, there is provided a method of treating metastatic
bladder cancer (such as metastatic urothelial carcinoma) in an
individual, comprising intravenously administering to the
individual an effective amount of a composition comprising
Nab-sirolimus. In some embodiments, there is provided a method of
treating metastatic bladder cancer (such as metastatic urothelial
carcinoma) in an individual, comprising intravenously administering
to the individual an effective amount of Nab-sirolimus. In some
embodiments, the treatment is second line treatment.
[0061] In some embodiments, there is provided a method of treating
a platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug).
In some embodiments, there is provided a method of treating a
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, there is provided a method of treating
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, there is provided a method of treating
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and albumin and having an
average diameter of no greater than about 200 nm. In some
embodiments, there is provided a method of treating
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug coated with albumin and
having an average diameter of no greater than about 200 nm. In some
embodiments, there is provided a method of treating
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus coated with human albumin and
having an average diameter of no greater than about 200 nm, wherein
the weight ratio of human albumin and sirolimus in the composition
is about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, there is provided a method of treating
platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of a composition comprising
Nab-sirolimus. In some embodiments, there is provided a method of
treating platinum-refractory bladder cancer (such as metastatic
platinum-refractory bladder cancer, for example metastatic
platinum-refractory urothelial carcinoma) in an individual,
comprising administering (such as intravenously administering) to
the individual an effective amount of Nab-sirolimus.
[0062] The methods described herein are useful for various aspects
of bladder cancer treatment. In some embodiments, there is provided
a method of inhibiting bladder cancer cell proliferation (such as
bladder cancer tumor growth) in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, at least about 10% (including for
example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or
100%) cell proliferation is inhibited. In some embodiments, the
limus drug is sirolimus. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravenous
administration. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravesicular
administration. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, the composition comprises nanoparticles having an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising a
limus drug coated with albumin, wherein the nanoparticles have an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising
sirolimus coated with human albumin, wherein the nanoparticles have
an average diameter of no greater than about 150 nm (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, the composition comprises Nab-sirolimus. In some
embodiments, the composition is Nab-sirolimus.
[0063] In some embodiments, there is provided a method of
preventing local recurrence (e.g., recurrence of tumor after
resection) in an individual having bladder cancer, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, at least about 10% (including for
example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or
100%) metastasis is inhibited. In some embodiments, the limus drug
is sirolimus. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravenous
administration. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravesicular
administration. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, the composition comprises nanoparticles having an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising a
limus drug coated with albumin, wherein the nanoparticles have an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising
sirolimus coated with human albumin, wherein the nanoparticles have
an average diameter of no greater than about 150 nm (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, the composition comprises Nab-sirolimus. In some
embodiments, the composition is Nab-sirolimus.
[0064] In some embodiments, there is provided a method of
inhibiting bladder cancer tumor metastasis in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, at least about 10% (including for
example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or
100%) metastasis is inhibited. In some embodiments, a method of
inhibiting metastasis to lymph node is provided. In some
embodiments, a method of inhibiting metastasis to the lung is
provided. In some embodiments, the limus drug is sirolimus. In some
embodiments, the limus drug in the nanoparticle in the composition
is administered by intravenous administration. In some embodiments,
the limus drug in the nanoparticle in the composition is
administered by intravesicular administration. In some embodiments,
the composition comprises nanoparticles comprising a limus drug
coated with albumin. In some embodiments, the composition comprises
nanoparticles having an average diameter of no greater than about
200 nm. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin, wherein
the nanoparticles have an average diameter of no greater than about
200 nm. In some embodiments, the composition comprises
nanoparticles comprising sirolimus coated with human albumin,
wherein the nanoparticles have an average diameter of no greater
than about 150 nm (such as no greater than about 120 nm, for
example about 100 nm), wherein the weight ratio of human albumin
and sirolimus in the composition is about 9:1 or less (such as
about 9:1 or about 8:1). In some embodiments, the composition
comprises Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0065] In some embodiments, there is provided a method of reducing
(such as eradiating) pre-existing bladder cancer tumor metastasis
(such as pulmonary metastasis or metastasis to the lymph node) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, at
least about 10% (including for example at least about any of 20%,
30%, 40%, 60%, 70%, 80%, 90%, or 100%) metastasis is reduced. In
some embodiments, a method of reducing metastasis to lymph node is
provided. In some embodiments, a method of reducing metastasis to
the lung is provided. In some embodiments, the limus drug is
sirolimus. In some embodiments, the limus drug in the nanoparticle
in the composition is administered by intravenous administration.
In some embodiments, the limus drug in the nanoparticle in the
composition is administered by intravesicular administration. In
some embodiments, the composition comprises nanoparticles
comprising a limus drug coated with albumin. In some embodiments,
the composition comprises nanoparticles having an average diameter
of no greater than about 200 nm. In some embodiments, the
composition comprises nanoparticles comprising a limus drug coated
with albumin, wherein the nanoparticles have an average diameter of
no greater than about 200 nm. In some embodiments, the composition
comprises nanoparticles comprising sirolimus coated with human
albumin, wherein the nanoparticles have an average diameter of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1). In some embodiments, the composition
comprises Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0066] In some embodiments, there is provided a method of reducing
incidence or burden of preexisting bladder cancer tumor metastasis
(such as pulmonary metastasis or metastasis to the lymph node) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, the
limus drug is sirolimus. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravenous
administration. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravesicular
administration. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, the composition comprises nanoparticles having an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising a
limus drug coated with albumin, wherein the nanoparticles have an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising
sirolimus coated with human albumin, wherein the nanoparticles have
an average diameter of no greater than about 150 nm (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, the composition comprises Nab-sirolimus. In some
embodiments, the composition is Nab-sirolimus.
[0067] In some embodiments, there is provided a method of reducing
bladder cancer tumor size in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the tumor size is reduced at least
about 10% (including for example at least about any of 20%, 30%,
40%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, the limus
drug is sirolimus. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravenous
administration. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravesicular
administration. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, the composition comprises nanoparticles having an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising a
limus drug coated with albumin, wherein the nanoparticles have an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising
sirolimus coated with human albumin, wherein the nanoparticles have
an average diameter of no greater than about 150 nm (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1).
[0068] In some embodiments, there is provided a method of
prolonging time to disease progression of bladder cancer in an
individual, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin. In some embodiments, the method prolongs the
time to disease progression by at least any of 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 weeks. In some embodiments, the limus drug is
sirolimus. In some embodiments, the limus drug in the nanoparticle
in the composition is administered by intravenous administration.
In some embodiments, the limus drug in the nanoparticle in the
composition is administered by intravesicular administration. In
some embodiments, the composition comprises nanoparticles
comprising a limus drug coated with albumin. In some embodiments,
the composition comprises nanoparticles having an average diameter
of no greater than about 200 nm. In some embodiments, the
composition comprises nanoparticles comprising a limus drug coated
with albumin, wherein the nanoparticles have an average diameter of
no greater than about 200 nm. In some embodiments, the composition
comprises nanoparticles comprising sirolimus coated with human
albumin, wherein the nanoparticles have an average diameter of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1). In some embodiments, the composition
comprises Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0069] In some embodiments, there is provided a method of
prolonging survival of an individual having bladder cancer,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method prolongs the survival of
the individual by at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 18, or 24 month. In some embodiments, the limus drug is
sirolimus. In some embodiments, the limus drug in the nanoparticle
in the composition is administered by intravenous administration.
In some embodiments, the limus drug in the nanoparticle in the
composition is administered by intravesicular administration. In
some embodiments, the composition comprises nanoparticles
comprising a limus drug coated with albumin. In some embodiments,
the composition comprises nanoparticles having an average diameter
of no greater than about 200 nm. In some embodiments, the
composition comprises nanoparticles comprising a limus drug coated
with albumin, wherein the nanoparticles have an average diameter of
no greater than about 200 nm. In some embodiments, the composition
comprises nanoparticles comprising sirolimus coated with human
albumin, wherein the nanoparticles have an average diameter of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1). In some embodiments, the composition
comprises Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0070] In some embodiments, there is provided a method of
alleviating one or more symptoms in an individual having bladder
cancer, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravenous
administration. In some embodiments, the limus drug in the
nanoparticle in the composition is administered by intravesicular
administration. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin. In some
embodiments, the composition comprises nanoparticles having an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising a
limus drug coated with albumin, wherein the nanoparticles have an
average diameter of no greater than about 200 nm. In some
embodiments, the composition comprises nanoparticles comprising
sirolimus coated with human albumin, wherein the nanoparticles have
an average diameter of no greater than about 150 nm (such as no
greater than about 120 nm, for example about 100 nm), wherein the
weight ratio of human albumin and sirolimus in the composition is
about 9:1 or less (such as about 9:1 or about 8:1). In some
embodiments, the composition comprises Nab-sirolimus. In some
embodiments, the composition is Nab-sirolimus.
[0071] In some embodiments, there is provided a method of
suppression the progression of CIS (carcinoma in situ) lesions in
an individual having bladder cancer, comprising administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, the limus drug in the nanoparticle in the composition
is administered by intravenous administration. In some embodiments,
the limus drug in the nanoparticle in the composition is
administered by intravesicular administration. In some embodiments,
the composition comprises nanoparticles comprising a limus drug
coated with albumin. In some embodiments, the composition comprises
nanoparticles having an average diameter of no greater than about
200 nm. In some embodiments, the composition comprises
nanoparticles comprising a limus drug coated with albumin, wherein
the nanoparticles have an average diameter of no greater than about
200 nm. In some embodiments, the composition comprises
nanoparticles comprising sirolimus coated with human albumin,
wherein the nanoparticles have an average diameter of no greater
than about 150 nm (such as no greater than about 120 nm, for
example about 100 nm), wherein the weight ratio of human albumin
and sirolimus in the composition is about 9:1 or less (such as
about 9:1 or about 8:1). In some embodiments, the composition
comprises Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus.
[0072] Also provided are pharmaceutical compositions comprising
nanoparticles comprising an mTOR inhibitor (such as limus drug, for
example sirolimus) for use in any of the methods of treating
bladder cancer described herein. In some embodiments, the
compositions comprise nanoparticles comprising an mTOR inhibitor
(such as limus drug, for example sirolimus) and albumin (such as
human albumin).
Methods of Combination Therapy
[0073] The present invention also provides combination therapy
methods for treating bladder cancer. Thus, in some embodiments, the
individual being treated with the mTOR nanoparticle composition is
also subjected to a second therapy. In some embodiments, the second
therapy is surgery, radiation, immunotherapy, and/or chemotherapy.
It is understood that reference to and description of methods of
treating bladder cancer above is exemplary and that the description
applies equally to and includes methods of treating bladder cancer
using combination therapy.
[0074] In some embodiments, the method comprises administering the
mTOR inhibitor nanoparticle composition (such as a limus
nanoparticle composition) and at least another agent. In some
embodiments, the nanoparticle composition and the other agent
(including the specific therapeutic agents described herein) are
administered simultaneously. When the drugs are administered
simultaneously, the drug in the nanoparticles and the other agent
may be contained in the same composition (e.g., a composition
comprising both the nanoparticles and the other agent) or in
separate compositions (e.g., the nanoparticles are contained in one
composition and the other agent is contained in another
composition). In some embodiments, the nanoparticle composition and
the other agent are administered sequentially. Either the
nanoparticle composition or the other agent may be administered
first. The nanoparticle composition and the other agent are
contained in separate compositions, which may be contained in the
same or different packages. In some embodiments, the administration
of the nanoparticle composition and the other agent are concurrent,
i.e., the administration period of the nanoparticle composition and
that of the other agent overlap with each other.
[0075] In some embodiments, the method comprises administration of
an mTOR nanoparticle composition (such as a limus nanoparticle
composition) in combination with an immunotherapy (such as
administration of an immunotherapeutic agent). Suitable
immunotherapeutic agents that can be combined with the mTOR
nanoparticle composition (such as a limus nanoparticle composition)
include, but are not limited to, BCG, interferons, and other immune
stimulatory cytokines.
[0076] Thus, the present application in some embodiments provides a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug); and (b) an
immunotherapeutic agent. Thus, the present application in some
embodiments provides a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin; and (b) an immunotherapeutic agent. In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; and (b) an immunotherapeutic agent. In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); and (b) an immunotherapeutic agent. In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles comprise a limus drug coated with albumin, and
wherein the nanoparticles have an average particle size of no
greater than about 200 nm (such as no greater than about 150 nm);
and (b) an immunotherapeutic agent. In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); and (b) an immunotherapeutic agent. In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising Nab-sirolimus; and (b) an immunotherapeutic
agent. In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus; and (b) an immunotherapeutic
agent. In some embodiments, the bladder cancer is non-muscle
invasive bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory bladder cancer. In some embodiments, the bladder
cancer is BCG-refractory non-muscle invasive bladder cancer.
[0077] In some embodiments, the other agent is BCG (Bacillus
Calmette-Guerin), a live attenuated form of Mycobacterium bovis. In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug); and (b) an effective amount of BCG. In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin; and (b) an effective amount of BCG. In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; and (b) an effective amount of BCG. In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); and (b) an effective amount of BCG. In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles comprise a limus drug coated with albumin, and
wherein the nanoparticles have an average particle size of no
greater than about 200 nm (such as no greater than about 150 nm);
and (b) an effective amount of BCG. In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); and (b) an effective amount of BCG. In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising Nab-sirolimus; and (b) an effective amount
of BCG. In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus; and (b) an effective amount
of BCG. In some embodiments, the bladder cancer is non-muscle
invasive bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory bladder cancer. In some embodiments, the bladder
cancer is BCG-refractory non-muscle invasive bladder cancer.
[0078] In some embodiments, there is provided a method of treating
bladder cancer (such as non-muscle invasive bladder cancer) in an
individual (e.g., human) comprising intravesicularly administering
(for example via urethral catheterization) to the individual (a) an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the dose of the
limus drug in the composition is about 5 mg to about 500 mg (such
as about 30 mg to about 400 mg, for example about 100 mg); and (b)
an effective amount of BCG, wherein the dose of BCG is about 8 mg
to about 100 mg (such as about 25 mg to about 85 mg, for example
about 80 mg). In some embodiments, there is provided a method of
treating bladder cancer (such as non-muscle invasive bladder
cancer) in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin, wherein the dose of the limus drug in the composition
is about 5 mg to about 500 mg (such as about 30 to about 400 mg,
for example about 100 mg); and (b) an effective amount of BCG,
wherein the dose of BCG is about 8 mg to about 100 mg (such as
about 25 mg to about 85 mg, for example about 80 mg). In some
embodiments, there is provided a method of treating bladder cancer
(such as non-muscle invasive bladder cancer) in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm), wherein the
dose of the limus drug in the composition is about 5 mg to about
500 mg (such as about 30 mg to about 400 mg, for example about 100
mg); and (b) an effective amount of BCG, wherein the dose of BCG is
about 8 mg to about 100 mg (such as about 25 mg to about 85 mg, for
example about 80 mg). In some embodiments, there is provided a
method of treating bladder cancer (such as non-muscle invasive
bladder cancer) in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm), wherein the dose of the limus drug in
the composition is about 5 mg to about 500 mg (such as about 30 mg
to about 400 mg, for example about 100 mg); and (b) an effective
amount of BCG, wherein the dose of BCG is about 8 mg to about 100
mg (such as about 25 mg to about 85 mg, for example about 80 mg).
In some embodiments, there is provided a method of treating bladder
cancer (such as non-muscle invasive bladder cancer) in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1) wherein the dose of
the sirolimus in the composition is about 5 mg to about 500 mg
(such as about 30 mg to about 400 mg, for example about 100 mg);
and (b) an effective amount of BCG, wherein the dose of BCG is
about 8 mg to about 100 mg (such as about 25 mg to about 85 mg, for
example about 80 mg). In some embodiments, there is provided a
method of treating bladder cancer (such as non-muscle invasive
bladder cancer) in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising Nab-sirolimus, wherein the dose
of the limus drug in the composition is about 5 mg to about 500 mg
(such as about 30 to about 400 mg, for example about 100 mg); and
(b) an effective amount of BCG, wherein the dose of BCG is about 8
mg to about 100 mg (such as about 25 mg to about 85 mg, for example
about 80 mg). In some embodiments, there is provided a method of
treating bladder cancer (such as non-muscle invasive bladder
cancer) in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) administering to the individual (a) an effective
amount of Nab-sirolimus, wherein the dose of the limus drug in the
composition is about 5 mg to about 500 mg (such as about 30 to
about 400 mg, for example about 100 mg); and (b) an effective
amount of BCG, wherein the dose of BCG is about 8 mg to about 100
mg (such as about 25 mg to about 85 mg, for example about 80 mg).
In some embodiments, the bladder cancer is non-muscle invasive
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory bladder cancer. In some embodiments, the bladder
cancer is BCG-refractory non-muscle invasive bladder cancer.
[0079] In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1), wherein the dose of
the sirolimus in the composition is about 5 mg to about 500 mg
(such as about 30 mg to about 400 mg, for example about 100 mg)
weekly; and (b) an effective amount of BCG, wherein the dose of BCG
is about 8 mg to about 100 mg (such as about 25 mg to about 85 mg,
for example about 80 mg) weekly. In some embodiments, there is
provided a method of treating bladder cancer (such as non-muscle
invasive bladder cancer) in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising Nab-sirolimus, wherein the dose
of the limus drug in the composition is about 5 mg to about 500 mg
(such as about 30 mg to about 400 mg, for example about 100 mg)
weekly; and (b) an effective amount of BCG, wherein the dose of BCG
is about 8 mg to about 100 mg (such as about 25 mg to about 85 mg,
for example about 80 mg) weekly. In some embodiments, there is
provided a method of treating bladder cancer (such as non-muscle
invasive bladder cancer) in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus, wherein the dose of the limus
drug in the composition is about 5 mg to about 500 mg (such as
about 30 mg to about 400 mg, for example about 100 mg) weekly; and
(b) an effective amount of BCG, wherein the dose of BCG is about 8
mg to about 100 mg (such as about 25 mg to about 85 mg, for example
about 80 mg) weekly. In some embodiments, the nanoparticle
composition and/or BCG are provided in a volume of about 20-ml to
about 150 ml (such as about 50 ml). In some embodiments, the
nanoparticle composition and/or BCG are retained in the bladder for
about 30 minutes to about 4 hours (such as about 30 minutes).
[0080] In some embodiments, the methods of combination therapy
described herein comprise administration of an interferon, such as
interferon a, with or without BCG.
[0081] Thus, for example, in some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug); (b) an
effective amount of an interferon (such as interferon .alpha.). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin; (b) an effective amount of an interferon (such as
interferon .alpha.). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the limus drug in
the nanoparticles is coated with the albumin; (b) an effective
amount of an interferon (such as interferon .alpha.). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); (b) an effective amount of an interferon (such as interferon
.alpha.). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm); (b) an effective amount of an
interferon (such as interferon a). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); (b) an effective amount of an
interferon (such as interferon .alpha.). In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
Nab-sirolimus; (b) an effective amount of an interferon (such as
interferon .alpha.). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) administering to the
individual (a) an effective amount of Nab-sirolimus; (b) an
effective amount of an interferon (such as interferon .alpha.). In
some embodiments, the bladder cancer is non-muscle invasive bladder
cancer. In some embodiments, the bladder cancer is BCG-refractory
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory non-muscle invasive bladder cancer.
[0082] In some embodiments, there is provided a method of treating
bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug); (b) an effective amount of BCG;
and (c) an effective amount of an interferon (such as interferon
.alpha.). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin; (b) an effective amount of BCG; and (c) an
effective amount of an interferon (such as interferon .alpha.). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; (b) an effective amount of BCG; and (c) an effective
amount of an interferon (such as interferon .alpha.). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); (b) an effective amount of BCG; and (c) an effective amount of
an interferon (such as interferon .alpha.). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm); (b) an effective amount of BCG; and (c) an
effective amount of an interferon (such as interferon .alpha.). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1); (b) an effective
amount of BCG; and (c) an effective amount of an interferon (such
as interferon .alpha.). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising Nab-sirolimus; (b)
an effective amount of BCG; and (c) an effective amount of an
interferon (such as interferon .alpha.). In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization))
administering to the individual (a) an effective amount of
Nab-sirolimus; (b) an effective amount of BCG; and (c) an effective
amount of an interferon (such as interferon .alpha.). In some
embodiments, the bladder cancer is non-muscle invasive bladder
cancer. In some embodiments, the bladder cancer is BCG-refractory
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory non-muscle invasive bladder cancer.
[0083] In some embodiments, there is provided a method of treating
bladder cancer in an individual, comprising administering to the
individual a) an effective amount of at least another therapeutic
agent. In some embodiments, the other therapeutic agent is selected
from the group consisting of an alkylating agent, an anthracycline
antibiotic, a DNA crosslinking agent, an antimetabolite, an
indolequinone, a taxane, or a platinum-based agent. In some
embodiments, the other therapeutic agent is selected from the group
consisting of mitomycin, epirubicin, doxorubicin, valrubicin,
gemcitabine, apaziquone, docetaxel, paclitaxel, and cisplatin.
[0084] In some embodiments, the other agent to be administered in
combination with the mTOR nanoparticle composition (such as the
limus nanoparticle composition) is an alkylating agent. Thus, for
example, in some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug); and (b) an effective amount of an
alkylating agent (such as mitomycin). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin; and (b) an
effective amount of an alkylating agent (such as mitomycin). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; and (b) an effective amount of an alkylating agent
(such as mitomycin). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm); and (b) an effective amount of an
alkylating agent (such as mitomycin). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles comprise a limus drug coated with albumin, and
wherein the nanoparticles have an average particle size of no
greater than about 200 nm (such as no greater than about 150 nm);
and (b) an effective amount of an alkylating agent (such as
mitomycin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising
sirolimus and human albumin, wherein the nanoparticles comprise
sirolimus coated with the human albumin, wherein the nanoparticles
have an average particle size of no greater than about 150 nm (such
as no greater than about 120 nm, for example about 100 nm), wherein
the weight ratio of human albumin and sirolimus in the composition
is about 9:1 or less (such as about 9:1 or about 8:1); and (b) an
effective amount of an alkylating agent (such as mitomycin). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising Nab-sirolimus; and (b) an effective amount
of an alkylating agent (such as mitomycin). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) administering to the individual (a) an effective
amount of Nab-sirolimus; and (b) an effective amount of an
alkylating agent (such as mitomycin). In some embodiments, the
bladder cancer is non-muscle invasive bladder cancer. In some
embodiments, the bladder cancer is BCG-refractory bladder cancer.
In some embodiments, the bladder cancer is BCG-refractory
non-muscle invasive bladder cancer.
[0085] In some embodiments, the other agent to be administered in
combination with the mTOR nanoparticle composition (such as the
limus nanoparticle composition) is a DNA crosslinking agent. Thus,
for example, in some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug); and (b) an effective amount of a
DNA crosslinking agent (such as mitomycin). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin; and (b) an effective amount of a DNA crosslinking agent
(such as mitomycin). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the limus drug in
the nanoparticles is coated with the albumin; and (b) an effective
amount of a DNA crosslinking agent (such as mitomycin). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); and (b) an effective amount of a DNA crosslinking agent (such
as mitomycin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm); and (b) an effective amount of a DNA
crosslinking agent (such as mitomycin). In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); and (b) an effective amount of a DNA
crosslinking agent (such as mitomycin). In some embodiments, there
is provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
Nab-sirolimus; and (b) an effective amount of a DNA crosslinking
agent (such as mitomycin). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) administering to the
individual (a) an effective amount of Nab-sirolimus; and (b) an
effective amount of an alkylating agent (such as mitomycin). In
some embodiments, the bladder cancer is non-muscle invasive bladder
cancer. In some embodiments, the bladder cancer is BCG-refractory
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory non-muscle invasive bladder cancer.
[0086] In some embodiments, there is provided a method of treating
non-muscle invasive bladder cancer in an individual (e.g., human)
comprising intravesicularly administering (for example via urethral
catheterization) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1), wherein the dose of
the sirolimus in the composition is about 5 mg to about 500 mg
(such as about 30 mg to about 400 mg, for example about 100 mg)
weekly; and (b) an effective amount of an alkylating agent (such as
mitomycin), wherein the dose of the alkylating agent (such as
mitomycin) is about 8 mg to about 100 mg (such as about 25 mg to
about 50 mg, for example about 40 mg) weekly. In some embodiments,
there is provided a method of treating bladder cancer (such as
non-muscle invasive bladder cancer) in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising Nab-sirolimus,
wherein the dose of the limus drug in the composition is about 5 mg
to about 500 mg (such as about 30 mg to about 400 mg, for example
about 100 mg) weekly; and (b) an effective amount of an alkylating
agent (such as mitomycin), wherein the dose of the alkylating agent
(such as mitomycin) is about 8 mg to about 100 mg (such as about 25
mg to about 50 mg, for example about 40 mg) weekly. In some
embodiments, there is provided a method of treating bladder cancer
(such as non-muscle invasive bladder cancer) in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization))
administering to the individual (a) an effective amount of
Nab-sirolimus, wherein the dose of the limus drug in the
composition is about 5 mg to about 500 mg (such as about 30 mg to
about 400 mg, for example about 100 mg) weekly; and (b) an
effective amount of an alkylating agent (such as mitomycin),
wherein the dose of the alkylating agent (such as mitomycin) is
about 8 mg to about 100 mg (such as about 25 mg to about 50 mg, for
example about 40 mg) weekly. In some embodiments, the nanoparticle
composition and/or the alkylating agent (such as mitomycin) are
provided in a volume of about 20-ml to about 150 ml (such as about
50 ml). In some embodiments, the nanoparticle composition and/or
BCG are retained in the bladder for about 30 minutes to about 4
hours (such as about 30 minutes). In some embodiments, the bladder
cancer is non-muscle invasive bladder cancer. In some embodiments,
the bladder cancer is BCG-refractory bladder cancer. In some
embodiments, the bladder cancer is BCG-refractory non-muscle
invasive bladder cancer.
[0087] In some embodiments, the other agent is an anthracycline
antibiotic. Thus, for example, in some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug);
and (b) an effective amount of an anthracycline (such as epirubicin
and/or doxorubicin, or valrubicin). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin; and (b) an
effective amount of an anthracycline (such as epirubicin and/or
doxorubicin, or valrubicin). In some embodiments, there is provided
a method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the limus drug in
the nanoparticles is coated with the albumin; and (b) an effective
amount of an anthracycline (such as epirubicin and/or doxorubicin,
or valrubicin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm); and (b) an effective amount of an anthracycline
(such as epirubicin and/or doxorubicin, or valrubicin). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm); and (b) an effective amount of an anthracycline
(such as epirubicin and/or doxorubicin, or valrubicin). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1); and (b) an effective
amount of an anthracycline (such as epirubicin and/or doxorubicin,
or valrubicin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising Nab-sirolimus; and (b) an
effective amount of an anthracycline (such as epirubicin and/or
doxirubicin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus; and (b) an effective amount
of an anthracycline (such as epirubicin and/or doxorubicin, or
valrubicin). In some embodiments, the bladder cancer is non-muscle
invasive bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory bladder cancer. In some embodiments, the bladder
cancer is BCG-refractory non-muscle invasive bladder cancer.
[0088] In some embodiments, the other agent is an antimetabolite.
Thus, for example, in some embodiments, there is provided a method
of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin; and (b) an effective amount
of an antimetabolite (such as gemcitabine). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug); and (b) an effective amount of an
antimetabolite (such as gemcitabine). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin; and (b)
an effective amount of an antimetabolite (such as gemcitabine). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); and (b) an effective amount of an antimetabolite (such as
gemcitabine). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm); and (b) an effective amount of an
antimetabolite (such as gemcitabine). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); and (b) an effective amount of an
antimetabolite (such as gemcitabine). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
Nab-sirolimus; and (b) an effective amount of an antimetabolite
(such as gemcitabine). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) administering to the
individual (a) an effective amount of Nab-sirolimus; and (b) an
effective amount of an antimetabolite (such as gemcitabine). In
some embodiments, the bladder cancer is non-muscle invasive bladder
cancer. In some embodiments, the bladder cancer is BCG-refractory
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory non-muscle invasive bladder cancer. In some
embodiments, the antimetabolite (such as gemcitabine) is
administered weekly, for example by weekly intravesicular
administration at the dose of 2 grams in 50 ml, each with about 30
minutes to about 4 hours, for example about 1 hour to about 2 hours
of retention time in the bladder. In some embodiments, the
antimetabolite (such as gemcitabine) is administered immediately
before or after the administration of the nanoparticle
composition.
[0089] In some embodiments, the other agent is a taxane. Suitable
taxanes include, but are not limited to, paclitaxel and docetaxel.
The taxane can be provided in nanoparticle forms. In some
embodiments, the second agent is Abraxane.RTM.. Thus, for example,
in some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug); and (b) an effective amount of a taxane
(such as paclitaxel or docetaxel). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin; and (b) an
effective amount of a taxane (such as paclitaxel or docetaxel). In
some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; and (b) an effective amount of a taxane (such as
paclitaxel or docetaxel). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm); and (b) an effective amount of a
taxane (such as paclitaxel or docetaxel). In some embodiments,
there is provided a method of treating bladder cancer in an
individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, and wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm); and (b) an effective amount of a taxane (such
as paclitaxel or docetaxel). In some embodiments, there is provided
a method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising sirolimus and human albumin, wherein the nanoparticles
comprise sirolimus coated with the human albumin, wherein the
nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1); and (b) an effective amount of a taxane (such as
paclitaxel or docetaxel). In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising Nab-sirolimus; and
(b) an effective amount of a taxane (such as paclitaxel or
docetaxel). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus; and (b) an effective amount
of a taxane (such as paclitaxel or docetaxel). In some embodiments,
the bladder cancer is non-muscle invasive bladder cancer. In some
embodiments, the bladder cancer is BCG-refractory bladder cancer.
In some embodiments, the bladder cancer is BCG-refractory
non-muscle invasive bladder cancer.
[0090] In some embodiments, the other agent is a platinum-based
agent. Thus, for example, in some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) to the individual (a)
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug); and (b) an
effective amount of a platinum-based agent (such as carboplatin or
cisplatin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin; and (b) an effective amount of a
platinum-based agent (such as carboplatin or cisplatin). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin; and (b) an effective amount of a platinum-based agent
(such as carboplatin or cisplatin). In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm); and (b) an
effective amount of a platinum-based agent (such as carboplatin or
cisplatin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm); and (b) an effective amount of a
platinum-based agent (such as carboplatin or cisplatin). In some
embodiments, there is provided a method of treating bladder cancer
in an individual (e.g., human) comprising administering (such as
intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
the human albumin, wherein the nanoparticles have an average
particle size of no greater than about 150 nm (such as no greater
than about 120 nm, for example about 100 nm), wherein the weight
ratio of human albumin and sirolimus in the composition is about
9:1 or less (such as about 9:1 or about 8:1); and (b) an effective
amount of a platinum-based agent (such as carboplatin or
cisplatin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising Nab-sirolimus; and (b) an
effective amount of a platinum-based agent (such as carboplatin or
cisplatin). In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) administering to the individual (a)
an effective amount of Nab-sirolimus; and (b) an effective amount
of a platinum-based agent (such as carboplatin or cisplatin). In
some embodiments, the bladder cancer is non-muscle invasive bladder
cancer. In some embodiments, the bladder cancer is BCG-refractory
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory non-muscle invasive bladder cancer.
[0091] The methods described herein may comprise administration of
a limus nanoparticle composition in combination with two or more
other agents. These two or more other agents may be of the same or
different classes. For example, in some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug);
(b) an effective amount of BCG; and (c) an effective amount of
mitomycin. In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual (a) an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin; (b) an effective amount of BCG; and (c) an
effective amount of mitomycin. In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin; (b) an
effective amount of BCG; and (c) an effective amount of mitomycin.
In some embodiments, there is provided a method of treating bladder
cancer in an individual (e.g., human) comprising administering
(such as intravesicularly administering (for example via urethral
catheterization)) to the individual (a) an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm); (b) an effective amount of BCG; and (c) an effective amount of
mitomycin. In some embodiments, there is provided a method of
treating bladder cancer in an individual (e.g., human) comprising
administering (such as intravesicularly administering (for example
via urethral catheterization)) to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles comprise a limus
drug coated with albumin, and wherein the nanoparticles have an
average particle size of no greater than about 200 nm (such as no
greater than about 150 nm); (b) an effective amount of BCG; and (c)
an effective amount of mitomycin. In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with the human albumin,
wherein the nanoparticles have an average particle size of no
greater than about 150 nm (such as no greater than about 120 nm,
for example about 100 nm), wherein the weight ratio of human
albumin and sirolimus in the composition is about 9:1 or less (such
as about 9:1 or about 8:1); (b) an effective amount of BCG; and (c)
an effective amount of mitomycin. In some embodiments, there is
provided a method of treating bladder cancer in an individual
(e.g., human) comprising administering (such as intravesicularly
administering (for example via urethral catheterization)) to the
individual (a) an effective amount of a composition comprising
Nab-sirolimus; (b) an effective amount of BCG; and (c) an effective
amount of mitomycin. In some embodiments, there is provided a
method of treating bladder cancer in an individual (e.g., human)
comprising administering (such as intravesicularly administering
(for example via urethral catheterization)) administering to the
individual (a) an effective amount of Nab-sirolimus; (b) an
effective amount of BCG; and (c) an effective amount of mitomycin.
In some embodiments, the bladder cancer is non-muscle invasive
bladder cancer. In some embodiments, the bladder cancer is
BCG-refractory bladder cancer. In some embodiments, the bladder
cancer is BCG-refractory non-muscle invasive bladder cancer.
Use of Biomarkers
[0092] The present application further provides methods of
treatments (such as any of the treatment methods described above)
based on the expression of one or more biomarkers. Biomarkers
useful for methods described herein include, but are not limited
to, p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC,
p73, c-myc, and cyclin D1. In some embodiments, the biomarker is
selected from the group consisting of p-S6K, pAKT, p-4EBP1, Ki67,
p53, p63, Stathmin, Tau, SPARC, p73, c-myc, TSC1, and cyclin
D1.
[0093] PS6k encodes a member of the RSK (ribosomal s6 kinase)
family of serine/threonine kinases. This kinase contains 2
non-identical kinase catalytic domains and phosphorylates several
residues of the S6 ribosomal protein. The kinase activity of this
protein leads to an increase in protein synthesis and cell
proliferation.
[0094] Akt, also known as Protein Kinase B (PKB), is a
serine/threonine-specific protein kinase that plays a key role in
multiple cellular processes, including, e.g., glucose metabolism,
apoptosis, cell proliferation, transcription and cell
migration.
[0095] p4EBP1 is a member of a family of translation repressor
proteins. p4EBP1 directly interacts with eukaryotic translation
initiation factor 4E (eIF4E), which is a limiting component of the
multi-subunit complex that recruits 40S ribosomal subunits to the
5' end of mRNAs. Interaction of this protein with eIF4E inhibits
complex assembly and represses translation. It has been shown that
mTOR signals downstream to at least S6K1 and 4EBP1/eIF4E, which
themselves function in translational control to regulate mammalian
cell size (Fingar et al. (2002) Genes Dev. 16: 1472-1487).
[0096] The Ki-67 protein (also known as MKI67) is a cellular marker
for proliferation (Wu et al. (2003) Dev. Cell 5: 723-34). During
interphase, Ki-67 can be exclusively detected within the cell
nucleus, whereas in mitosis most of the protein is relocated to the
surface of the chromosomes. Ki-67 is present during all active
phases of the cell cycle (G1, S, G2, and mitosis), but is absent
from resting cells (G0).
[0097] p53 (also known as protein 53 or tumor protein 53), is a
tumor suppressor protein that in humans is encoded by the TP53
gene. p53 is a transcription factor that is crucial in
multicellular organisms, where it regulates the cell cycle and,
thus, functions as a tumor suppressor that is involved in
preventing cancer. p63 (also known as TP63) is a member of the p53
family of transcription factors. p63 -/- mice have several
developmental defects which include the lack of limbs and other
tissues, such as teeth and mammary glands, which develop as a
result of interactions between mesenchyme and epithelium. In
humans, mutations in the TP63 gene are associated with
ectrodactyly-ectodermal dysplasia-cleft syndrome, Hay-Wells
syndrome, cleft lip/palate syndrome 3 (EEC3); ectrodactyly (also
known as split-hand/foot malformation 4 (SHFM4));
ankyloblepharon-ectodermal defects-cleft lip/palate, ADULT syndrome
(acro-dermato-ungual-lacrimal-tooth), limb-mammary syndrome,
Rap-Hodgkin syndrome (RHS), and orofacial cleft 8. p73 (or TP73)
was first identified as a homologue of p53. The protein product of
p73 induces cell cycle arrest or apoptosis. Accordingly, p73 is
classified as a tumor suppressor. However unlike p53, p73 is
infrequently mutated in cancers.
[0098] Stathmin 1/oncoprotein 18, also known as STMN1, is a highly
conserved 17 kDa protein that regulates microtubule dynamics.
Stathmin forms a complex with dimeric .alpha.,.beta.-tubulin to
form a ternary complex called the T2S complex. When stathmin
sequesters tubulin into the T2S complex, tubulin becomes
non-polymerizable. As a result, microtubule assembly is inhibited.
Through this mechanism, stathmin promotes microtubule
disassembly.
[0099] Tau proteins are highly soluble microtubule-associated
proteins (MAPs). In humans, these proteins are mostly found in
neurons compared to non-neuronal cells. For example, tau proteins
are expressed in central nervous system astrocytes and
oligodendrocytes. One of tau's main functions is to modulate the
stability of axonal microtubules and promote tubulin assembly into
microtubules. Six tau isoforms exist in human brain tissue.
[0100] The Myc (c-Myc) gene encodes a transcription factor that
activates expression of many genes through binding on Enhancer Box
sequences (E-boxes) and recruiting histone acetyltransferases
(HATs). Accordingly, Myc also functions to regulate global
chromatin structure. Myc is activated upon various mitogenic
signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By
modifying the expression of its target genes, Myc activation
results in numerous biological effects. Myc plays roles in driving
cell proliferation, regulating cell growth and apoptosis, and
regulating differentiation and stem cell self-renewal.
[0101] Cyclin D1 encodes the regulatory subunit of a holoenzyme
that phosphorylates and inactivates the retinoblastoma protein and
promotes progression through the G1-S phase of the cell cycle.
Amplification or overexpression of cyclin D1 plays pivotal roles in
the development of a subset of human cancers including parathyroid
adenoma, breast cancer, colon cancer, lymphoma, melanoma, and
prostate cancer. Of the three D-type cyclins, each of which binds
cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that
is predominantly associated with human tumorigenesis and cellular
metastases.
[0102] SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a
matricellular protein upregulated in several aggressive cancers.
See Porter et al., J. Histochem. Cytochem. 1995; 43:791. The human
SPARC gene encodes a 303 amino acid SPARC proteins, while mature
SPARC is a 285 amino acid glycoprotein. After cleavage of the
signal sequence a 32-kD secreted form is produced which migrates at
43 kD on SDA-PAGE because of glycosylation.
[0103] TSC1 (also referred to as Hamartin or tuberous sclerosis 1)
is a peripheral membrane protein implicated as a tumor suppressor.
It forms a complex with TSC2 that regulates mTORC1 signaling and
may be also involved in vesicular transport and docking.
[0104] Thus, the present invention in some embodiments provides a
method of treating bladder cancer in an individual (such as human)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), wherein the individual is selected for
treatment based on the level of one or more of: p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73, c-myc, and
cyclin D1. In some embodiments, the individual is selected for
treatment based on the level of one of more of: p-S6K, pAKT,
p-4EBP1, and Ki67. In some embodiments, there is provided a method
of treating bladder cancer in an individual (such as human)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), wherein the individual is selected for
treatment based on the level of one or more of: p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73, c-myc, TSC1,
and cyclin D1. In some embodiments, the individual is selected for
treatment based on the level of TSC1. In some embodiments, the
method comprises administering to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin. In some embodiments, the method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin. In some embodiments, the method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, the method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles comprise a limus drug coated with albumin, wherein
the nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm). In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising sirolimus and human albumin, wherein the nanoparticles
comprise sirolimus coated with human albumin, wherein the
nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0105] As used herein, "based upon" or "based on" include
assessing, determining, or measuring the individual's
characteristics as described herein (and preferably selecting an
individual suitable for receiving treatment). When a biomarker is
used as a basis for selection, assessing (or aiding in assessing),
measuring, or determining method of treatment as described herein,
the biomarker is measured before and/or during treatment, and the
values obtained are used by a clinician in assessing any of the
following: (a) probable or likely suitability of an individual to
initially receive treatment(s); (b) probable or likely
unsuitability of an individual to initially receive treatment(s);
(c) responsiveness to treatment; (d) probable or likely suitability
of an individual to continue to receive treatment(s); (e) probable
or likely unsuitability of an individual to continue to receive
treatment(s); (f) adjusting dosage; or (g) predicting likelihood of
clinical benefits.
[0106] Thus, the present invention in some embodiments provides a
method of treating bladder cancer in an individual (such as human)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), wherein the individual is selected for
treatment based on a high level of one or more of: p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73, c-myc, and
cyclin D1. In some embodiments, the individual is selected for
treatment based on a high level of one of more of: p-S6K, pAKT,
p-4EBP1, and Ki67. In some embodiments, the method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0107] In some embodiments, there is provided a method of treating
bladder cancer in an individual (such as human) comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), wherein the individual has a high level of
one or more of: p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin,
Tau, SPARC, p73, c-myc, and cyclin D1. In some embodiments, the
individual has a high level of one of more of: p-S6K, pAKT,
p-4EBP1, and Ki67. In some embodiments, the method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0108] In some embodiments, there is provided a method of treating
bladder cancer in an individual (such as human) comprising: a)
determining the level of one or more biomarkers selected from the
group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin,
Tau, SPARC, p73, c-myc, and cyclin D1 in the individual; and b)
selecting the individual for treatment based on the individual
having a high level of one of more of the biomarkers, wherein the
treatment method comprises administering to the individual an
effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug). In some
embodiments, the individual is selected for treatment based on the
individual having a high level of one of more biomarkers selected
from the group consisting of p-S6K, pAKT, p-4EBP1, and Ki67. In
some embodiments, the method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the limus drug in
the nanoparticles is coated with the albumin. In some embodiments,
the method comprises administering to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin, wherein the nanoparticles have an average
particle size of no greater than about 200 nm (such as no greater
than about 150 nm). In some embodiments, the method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0109] In some embodiments, there is provided a method of treating
bladder cancer in an individual (such as human) comprising: a)
selecting the individual for treatment based on the individual
having a high level of one of more of the biomarkers selected from
the group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63,
Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1 in the individual;
b) administering to the selected individual an effective amount of
a composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, the individual is
selected for treatment based on the individual having a high level
of one of more biomarkers selected from the group consisting of
p-S6K, pAKT, p-4EBP1, and Ki67. In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0110] In some embodiments, there is provided a method of treating
bladder cancer in an individual (such as human) comprising: a)
determining the level of one or more biomarkers selected from the
group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin,
Tau, SPARC, p73, c-myc, and cyclin D1 in the individual; and b)
selecting the individual for treatment based on the individual
having a high level of one of more of the biomarkers, c)
administering to the selected individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, the individual is
selected for treatment based on the individual having a high level
of one of more biomarkers selected from the group consisting of
p-S6K, pAKT, p-4EBP1, and Ki67. In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the method further comprises
administering to the individual an effective amount of another
agent (such as BCG and/or mitomycin).
[0111] In some embodiments, there is provided a method of assessing
whether an individual with bladder cancer is more likely to respond
to a treatment comprising administering to the selected individual
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug), the method
comprising assessing the level of one or more biomarkers selected
from the group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63,
Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1 in the individual;
wherein a low level of one or more of the biomarkers indicates that
the individual is less likely to respond to the treatment, wherein
a high level of one of more of the biomarkers indicates that the
individual is more likely to respond to the treatment. In some
embodiments, the method further comprises selecting the individual
for treatment based on the individual having a high level of one of
more of the biomarkers. In some embodiments, the method further
comprises administering to the selected individual an effective
amount of a composition comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug). In some embodiments, the
individual is selected for treatment based on the individual having
a high level of one of more biomarkers selected from the group
consisting of p-S6K, pAKT, p-4EBP1, and Ki67. In some embodiments,
the treatment method comprises administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin. In some embodiments, the
treatment method comprises administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the limus drug in
the nanoparticles is coated with the albumin. In some embodiments,
the treatment method comprises administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
have an average particle size of no greater than about 200 nm (such
as no greater than about 150 nm). In some embodiments, the
treatment method comprises administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a limus drug and an albumin, wherein the nanoparticles
comprise a limus drug coated with albumin, wherein the
nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm). In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the treatment method further
comprises administering to the individual an effective amount of
another agent (such as BCG and/or mitomycin).
[0112] In some embodiments, there is provided a method of
determining whether an individual with bladder cancer has responded
to a treatment comprising administering to the selected individual
an effective amount of a composition comprising nanoparticles
comprising an mTOR inhibitor (such as a limus drug), the method
comprising assessing the level of one or more biomarkers selected
from the group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63,
Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1 in the individual
prior to and after the treatment; wherein a decreased level of one
or more of the biomarkers after the treatment indicates that the
individual has responded to the treatment. In some embodiments, the
method further comprises continue to administer to the individual
who has responded to the treatment an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug). In some embodiments, the method comprises
adjusting the dosage of the mTOR nanoparticle composition. In some
embodiments, the biomarker is selected from the group consisting of
p-S6K, pAKT, p-4EBP1, and Ki67. In some embodiments, the treatment
method comprises administering to the individual an effective
amount of a composition comprising nanoparticles comprising a limus
drug and an albumin. In some embodiments, the treatment method
comprises administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin. In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
human albumin, wherein the nanoparticles have an average particle
size of no greater than about 150 nm (such as no greater than about
120 nm, for example about 100 nm), wherein the weight ratio of
human albumin and sirolimus in the composition is about 9:1 or less
(such as about 9:1 or about 8:1). In some embodiments, the
composition comprises Nab-sirolimus. In some embodiments, the
composition is Nab-sirolimus. In some embodiments, the composition
is Nab-sirolimus. In some embodiments, the treatment method further
comprises administering to the individual an effective amount of
another agent (such as BCG and/or mitomycin).
[0113] In some embodiments, there is provided a method of treating
an individual having bladder cancer, comprising (i) administering
to the individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug),
(ii) assessing the level of one or more biomarkers selected from
the group consisting of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63,
Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1 in the individual
after the treatment; (iii) comparing the levels of the one or more
biomarkers with the level of the biomarkers prior to the treatment,
and (iv) continue to administer to the individual an effective
amount of a composition comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug) if the individual has a decreased
level of one or more of the biomarkers after the treatment. In some
embodiments, the method comprises adjusting the dosage of the mTOR
nanoparticle composition. In some embodiments, the biomarker is
selected from the group consisting of p-S6K, pAKT, p-4EBP1, and
Ki67. In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin. In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the limus drug in the nanoparticles is coated with
the albumin. In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles have an average particle size of
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin, wherein the nanoparticles comprise a limus drug coated
with albumin, wherein the nanoparticles have an average particle
size of no greater than about 200 nm (such as no greater than about
150 nm). In some embodiments, the treatment method comprises
administering to the individual an effective amount of a
composition comprising nanoparticles comprising sirolimus and human
albumin, wherein the nanoparticles comprise sirolimus coated with
human albumin, wherein the nanoparticles have an average particle
size of no greater than about 150 nm (such as no greater than about
120 nm, for example about 100 nm), wherein the weight ratio of
human albumin and sirolimus in the composition is about 9:1 or less
(such as about 9:1 or about 8:1). In some embodiments, the
composition comprises Nab-sirolimus. In some embodiments, the
composition is Nab-sirolimus. In some embodiments, the composition
is Nab-sirolimus. In some embodiments, the treatment method further
comprises administering to the individual an effective amount of
another agent (such as BCG and/or mitomycin).
[0114] In some embodiments, there is provided a method of treating
an individual having bladder cancer, comprising: (i) assessing the
level of one or more biomarkers selected from the group consisting
of p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73,
c-myc, and cyclin D1 in the individual prior to treatment; (ii)
administering to the individual an effective amount of a
composition comprising nanoparticles comprising an mTOR inhibitor
(such as a limus drug), (iii) assessing the level of one or more
biomarkers selected from the group consisting of p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73, c-myc, and
cyclin D1 in the individual after the treatment; (iv) comparing the
levels of the one or more biomarkers with the level of the
biomarkers prior to the treatment, and (v) continue to administer
to the individual an effective amount of a composition comprising
nanoparticles comprising an mTOR inhibitor (such as a limus drug)
if the individual has a decreased level of one or more of the
biomarkers after the treatment. In some embodiments, the method
comprises adjusting the dosage of the mTOR nanoparticle
composition. In some embodiments, the biomarker is selected from
the group consisting of p-S6K, pAKT, p-4EBP1, and Ki67. In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin. In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
limus drug in the nanoparticles is coated with the albumin. In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm). In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a limus drug and an albumin, wherein the
nanoparticles comprise a limus drug coated with albumin, wherein
the nanoparticles have an average particle size of no greater than
about 200 nm (such as no greater than about 150 nm). In some
embodiments, the treatment method comprises administering to the
individual an effective amount of a composition comprising
nanoparticles comprising sirolimus and human albumin, wherein the
nanoparticles comprise sirolimus coated with human albumin, wherein
the nanoparticles have an average particle size of no greater than
about 150 nm (such as no greater than about 120 nm, for example
about 100 nm), wherein the weight ratio of human albumin and
sirolimus in the composition is about 9:1 or less (such as about
9:1 or about 8:1). In some embodiments, the composition comprises
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the composition is
Nab-sirolimus. In some embodiments, the treatment method further
comprises administering to the individual an effective amount of
another agent (such as BCG and/or mitomycin).
[0115] The methods described herein in some embodiments comprise
determining the levels of one or more biomarkers in an individual.
In some embodiments, the level is the activity level of a biomarker
in a sample. In some embodiments the level is an expression level.
In some embodiments the level is a measure of a protein present in
a cell (for example the surface of a cell), a sample, or a tumor.
In some embodiments, the level is based on a mutation or
polymorphism in the biomarker gene that correlates with the protein
or mRNA level of a biomarker. In some embodiments, the level is the
protein expression level. In some embodiments, the level is the
mRNA level.
[0116] Levels of biomarker in an individual may be determined based
on a sample (e.g., sample from the individual or reference sample).
In some embodiments, the sample is from a tissue, organ, cell, or
tumor. In some embodiments, the sample is a biological sample. In
some embodiments, the biological sample is a biological fluid
sample or a biological tissue sample. In further embodiments, the
biological fluid sample is a bodily fluid. Bodily fluids include,
but are not limited to, blood, urine, lymph, saliva, semen,
peritoneal fluid, cerebrospinal fluid, breast milk, and pleural
effusion. In some embodiments, the sample is a blood sample which
includes, for example, platelets, lymphocytes, polymorphonuclear
cells, macrophages, and erythrocytes. In some embodiments, the
sample is a urine sample.
[0117] In some embodiments, the sample is a tumor tissue, normal
tissue adjacent to said tumor, normal tissue distal to said tumor,
blood sample, or other biological sample. In some embodiments, the
sample is a fixed sample. Fixed samples include, but are not
limited to, a formalin fixed sample, a paraffin-embedded sample, or
a frozen sample. In some embodiments, the sample is a biopsy
containing cancer cells. In some embodiments, the sample is a
biopsy sample obtained from a cystoscopy. In some embodiments, the
sample is a biopsy sample obtained from a trans urethral resection
of the bladder tumor (TURBT). In a further embodiment, the biopsy
is a fine needle aspiration of bladder cancer cells. In a further
embodiment, the biopsy is laparoscopy obtained bladder cancer
cells. In some embodiments, the biopsied cells are centrifuged into
a pellet, fixed, and embedded in paraffin. In some embodiments, the
biopsied cells are flash frozen. In some embodiments, the biopsied
cells are mixed with an antibody that recognizes the biomarker. In
some embodiments, a biopsy is taken to determine whether an
individual has cancer and is then used as a sample. In some
embodiments, the sample comprises surgically obtained tumor cells.
In some embodiments, samples may be obtained at different times
than when the determining of biomarker levels occurs.
[0118] In some embodiments, the sample comprises a circulating
metastatic bladder cancer cell. In some embodiments, the sample is
obtained by sorting bladder circulating tumor cells (CTCs) from
blood. In a further embodiment, the CTCs have detached from a
primary tumor and circulate in a bodily fluid. In yet a further
embodiment, the CTCs have detached from a primary tumor and
circulate in the bloodstream. In a further embodiment, the CTCs are
an indication of metastasis.
[0119] In some embodiments, the level of one biomarker (such as
p-S6K) is determined. In some embodiments, the levels of two or
more biomarkers are determined; for example, one or more biomarkers
selected from the group consisting of p-S6K, pAKT, p-4EBP1, and
Ki67 can be determined. The one or more biomarkers include, for
example, at least two or more biomarkers, at least three or more
biomarkers, at least four or more biomarkers, at least five or more
biomarkers, or at least six or more biomarkers described herein. In
some embodiments, the one or more biomarkers include p-S6K.
[0120] In some embodiments, the protein expression level of the
biomarker is determined. In some embodiments, the mRNA level of the
biomarker is determined. In some embodiments, the level of the
biomarker is determined by an immunohistochemistry method.
[0121] The levels of a biomarker may be a high level or a low level
as compared to a control sample. In some embodiments, the level of
the biomarker in an individual is compared to the level of the
biomarker in a control sample. In some embodiments the level of the
biomarker in a subject is compared to the level of the biomarker in
multiple control samples. In some embodiments, multiple control
samples are used to generate a statistic that is used to classify
the level of the biomarker in an individual with cancer.
[0122] In some embodiments, the DNA copy number is determined, and
a high DNA copy number for the gene encoding the biomarker (for
example a high DNA copy number as compared to a control sample) is
indicative of a high level of the biomarker.
[0123] The classification or ranking of the biomarker level (i.e.,
high or low) may be determined relative to a statistical
distribution of control levels. In some embodiments, the
classification or ranking is relative to a control sample obtained
from the individual. In some embodiment the levels of the biomarker
(such as p-S6K) is classified or ranked relative to a statistical
distribution of control levels. In some embodiments, the level of
the biomarker (such as p-S6K1) is classified or ranked relative to
the level from a control sample obtained from the subject.
[0124] Control samples can be obtained using the same sources and
methods as non-control samples. In some embodiments, the control
sample is obtained from a different individual (for example an
individual not having cancer and/or an individual sharing similar
ethnic, age, and gender identity). In some embodiments when the
sample is a tumor tissue sample, the control sample may be a
non-cancerous sample from the same individual. In some embodiments,
multiple control samples (for example from different individuals)
are used to determine a range of levels of biomarkers in a
particular tissue, organ, or cell population. In some embodiments,
the control sample is a cultured tissue or cell that has been
determined to be a proper control. In some embodiments, the control
is a cell that does not express the biomarker. In some embodiments,
a clinically accepted normal level in a standardized test is used
as a control level for determining the biomarker level. In some
embodiments, the reference level of biomarker (e.g., p-S6K1) in the
subject is classified as high, medium or low according to a scoring
system, such as an immunohistochemistry-based scoring system. In
some embodiments, the reference level of biomarker (e.g., p-S6K1)
in the subject is classified as a low sample when the score is less
than or equal to the overall median score.
[0125] In some embodiments, the biomarker level is determined by
measuring the level of a biomarker in an individual and comparing
to a control or reference (e.g., the median level for the given
patient population or level of a second individual). For example,
if the level of a biomarker (e.g., p-S6K1) for the single
individual is determined to be above the median level of the
patient population, that individual is determined to have a high
level of the biomarker. Alternatively, if the level of a biomarker
for the single individual is determined to be below the median
level of the patient population, that individual is determined to
have a low level of the biomarker. In some embodiments, the
individual is compared to a second individual and/or a patient
population which is responsive to treatment. In some embodiments,
the individual is compared to a second individual and/or a patient
population which is not responsive to treatment. In any of the
embodiments herein, the levels can be determined by measuring the
level of a nucleic acid encoding a biomarker (e.g., p-S6K1). For
example, if the level of an mRNA encoding a biomarker for the
single individual is determined to be above the median level of the
patient population, that individual is determined to have a high
level of an mRNA encoding the biomarker. Alternatively, if the
level of mRNA encoding the biomarker for the single individual is
determined to be below the median level of the patient population,
that individual is determined to have a low level of an mRNA
encoding the biomarker.
[0126] In some embodiments, the reference level of a biomarker is
determined by obtaining a statistical distribution of biomarker
levels.
[0127] In some embodiments, bioinformatics methods are used for the
determination and classification of the levels of the biomarker.
Numerous alternative bioinformatics approaches have been developed
to assess gene set expression profiles using gene expression
profiling data. Methods include but are not limited to those
described in Segal, E. et al. Nat. Genet. 34:66-176 (2003); Segal,
E. et al. Nat. Genet. 36:1090-1098 (2004); Barry, W. T. et al.
Bioinformatics 21:1943-1949 (2005); Tian, L. et al. Proc Nat'l Acad
Sci USA 102:13544-13549 (2005); Novak B A and Jain A N.
Bioinformatics 22:233-41 (2006); Maglietta R et al. Bioinformatics
23:2063-72 (2007); Bussemaker H J, BMC Bioinformatics 8 Suppl 6:S6
(2007).
[0128] In some embodiments, mRNA level is determined, and a low
level is an mRNA level less than about 1.1, 1.2, 1.3, 1.5, 1.7, 2,
2.2, 2.5, 2.7, 3, 5, 7, 10, 20, 50, 70, 100, 200, 500, 1000 times
or less than 1000 times to that of what is considered as clinically
normal or to the level obtained from a control. In some
embodiments, high level is an mRNA level more than about 1.1, 1.2,
1.3, 1.5, 1.7, 2, 2.2, 2.5, 2.7, 3, 5, 7, 10, 20, 50, 70, 100, 200,
500, 1000 times or more than 1000 times to that of what is
considered as clinically normal or to the level obtained from a
control.
[0129] In some embodiments, protein expression level is determined,
for example by immunohistochemistry. For example, the criteria for
low or high levels can be made based on the number of positive
staining cells and/or the intensity of the staining, for example by
using an antibody that specifically recognizes the biomarker
protein (e.g., p-S6K). In some embodiments, the level is low if
less than about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or
50% cells have positive staining. In some embodiments, the level is
low if the staining is 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, or 50% less intense than a positive control staining.
[0130] In some embodiments, the level is high if more than about
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, cells
have positive staining. In some embodiments, the level is high if
the staining is as intense as positive control staining. In some
embodiments, the level is high if the staining is 80%, 85%, or 90%
as intense as positive control staining.
[0131] In some embodiments, strong staining, moderate staining, and
weak staining are calibrated levels of staining, wherein a range is
established and the intensity of staining is binned within the
range. In some embodiments, strong staining is staining above the
75th percentile of the intensity range, moderate staining is
staining from the 25th to the 75th percentile of the intensity
range, and low staining is staining is staining below the 25th
percentile of the intensity range. In some aspects one skilled in
the art, and familiar with a particular staining technique, adjusts
the bin size and defines the staining categories.
[0132] Further provided herein are methods of directing treatment
of a bladder cancer by delivering a sample to a diagnostic lab for
determination of biomarker levels; providing a control sample with
a known level of a biomarker; providing an antibody to a biomarker
(e.g., p-S6K1 antibody); subjecting the sample and control sample
to binding by the antibody, and/or detecting a relative amount of
antibody binding, wherein the level of the sample is used to
provide a conclusion that a patient should receive a treatment with
any one of the methods described herein.
[0133] Also provided herein are methods of directing treatment of a
disease, further comprising reviewing or analyzing data relating to
the presence (or level) of a biomarker (e.g., p-S6K1) in a sample;
and providing a conclusion to an individual about the likelihood or
suitability of the individual to respond to a treatment, a health
care provider or a health care manager, the conclusion being based
on the review or analysis of data. In one aspect of the invention a
conclusion is the transmission of the data over a network.
Dosing and Method of Administering the Nanoparticle
Compositions
[0134] The dose of the mTOR nanoparticles (such as a limus
nanoparticle compositions) administered to an individual (such as a
human) may vary with the particular composition, the mode of
administration, and the type of bladder cancer being treated. In
some embodiments, the amount of the composition is effective to
result in an objective response (such as a partial response or a
complete response). In some embodiments, the amount of the mTOR
nanoparticle composition (such as a limus nanoparticle composition)
is sufficient to result in a complete response in the individual.
In some embodiments, the amount of the mTOR nanoparticle
composition (such as a limus nanoparticle composition) is
sufficient to result in a partial response in the individual. In
some embodiments, the amount of the mTOR nanoparticle composition
(such as a limus nanoparticle composition) administered (for
example when administered alone) is sufficient to produce an
overall response rate of more than about any of 20%, 30%, 40%, 50%,
60%, or 64% among a population of individuals treated with the mTOR
nanoparticle composition (such as a limus nanoparticle
composition). Responses of an individual to the treatment of the
methods described herein can be determined, for example, based on
RECIST levels, cystoscopy (with or without biopsy), biopsy,
cytology, and CT imaging.
[0135] In some embodiments, the amount of the mTOR nanoparticle
composition (such as a limus nanoparticle composition) is
sufficient to produce a negative biopsy in the individual. In some
embodiments, the amount of the mTOR nanoparticle composition (such
as a limus nanoparticle composition) is sufficient to produce a
response (partial or complete) based on urine cytology. In some
embodiments, the amount of the mTOR nanoparticle composition (such
as a limus nanoparticle composition) is sufficient to produce both
a negative biopsy and a response (partial or complete) based on
urine cytology.
[0136] In some embodiments, the amount of the mTOR nanoparticle
composition (such as a limus nanoparticle composition) is not
sufficient to cause systemic toxicity, such as cystitis, hematuria,
dysuria, urinary retension, urinary frequency/urgency, or bladder
spasm.
[0137] In some embodiments, the amount of the composition is
sufficient to prolong progress-free survival of the individual. In
some embodiments, the amount of the composition is sufficient to
prolong overall survival of the individual. In some embodiments,
the amount of the composition (for example when administered alone)
is sufficient to produce clinical benefit of more than about any of
50%, 60%, 70%, or 77% among a population of individuals treated
with the mTOR nanoparticle composition (such as a limus
nanoparticle composition).
[0138] In some embodiments, the amount of the composition is an
amount sufficient to decrease the size of a tumor, decrease the
number of cancer cells, or decrease the growth rate of a tumor by
at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
95% or 100% compared to the corresponding tumor size, number of
bladder cancer cells, or tumor growth rate in the same subject
prior to treatment or compared to the corresponding activity in
other subjects not receiving the treatment. Standard methods can be
used to measure the magnitude of this effect, such as in vitro
assays with purified enzyme, cell-based assays, animal models, or
human testing.
[0139] In some embodiments, the amount of the mTOR inhibitor (such
as a limus drug, for example sirolimus) in the composition is below
the level that induces a toxicological effect (i.e., an effect
above a clinically acceptable level of toxicity) or is at a level
where a potential side effect can be controlled or tolerated when
the composition is administered to the individual.
[0140] In some embodiments, the amount of the composition is close
to a maximum tolerated dose (MTD) of the composition following the
same dosing regime. In some embodiments, the amount of the
composition is more than about any of 80%, 90%, 95%, or 98% of the
MTD.
[0141] In some embodiments, the amount of an mTOR inhibitor (such
as a limus drug, e.g., sirolimus) in the composition is included in
any of the following ranges: about 0.1 mg to about 1000 mg, about
0.1 mg to about 2.5 mg, about 0.5 mg to about 5 mg, about 5 mg to
about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20
mg, about 20 mg to about 25 mg, about 20 mg to about 50 mg, about
25 mg to about 50 mg, about 50 mg to about 75 mg, about 50 mg to
about 100 mg, about 75 mg to about 100 mg, about 100 mg to about
125 mg, about 125 mg to about 150 mg, about 150 mg to about 175 mg,
about 175 mg to about 200 mg, about 200 mg to about 225 mg, about
225 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg
to about 350 mg, about 350 mg to about 400 mg, about 400 mg to
about 450 mg, or about 450 mg to about 500 mg, about 500 mg to
about 600 mg, about 600 mg to about 700 mg, about 700 mg to about
800 mg, about 800 mg to about 900 mg, or about 900 mg to about 1000
mg. In some embodiments, the amount of an mTOR inhibitor (such as a
limus drug, e.g., sirolimus) in the effective amount of the
composition (e.g., a unit dosage form) is in the range of about 5
mg to about 500 mg, such as about 30 mg to about 400 mg, 30 mg to
about 300 mg, or about 50 mg to about 200 mg. In some embodiments,
the amount of an mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) in the effective amount of the composition (e.g., a unit
dosage form) is in the range of about 150 mg to about 500 mg,
including for example, about 150 mg, about 225 mg, about 250 mg,
about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400
mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In
some embodiments, the concentration of the mTOR inhibitor (such as
a limus drug, e.g., sirolimus) in the composition is dilute (about
0.1 mg/ml) or concentrated (about 100 mg/ml), including for example
any of about 0.1 to about 50 mg/ml, about 0.1 mg/ml to about 20
mg/ml, about 1 mg/ml to about 10 mg/ml, about 2 mg/ml to about 8
mg/ml, about 4 mg/ml to about 6 mg/ml, or about 5 mg/ml. In some
embodiments, the concentration of the mTOR inhibitor (such as a
limus drug, e.g., sirolimus) is at least about any of 0.5 mg/ml,
1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml,
7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml,
30 mg/ml, 40 mg/ml, or 50 mg/ml.
[0142] In some embodiments of any of the above aspects, the amount
of an mTOR inhibitor (such as a limus drug, e.g., sirolimus) in the
composition includes at least about any of 1 mg/kg, 2.5 mg/kg, 3.5
mg/kg, 5 mg/kg, 6.5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg,
25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55
mg/kg, or 60 mg/kg. In various embodiments, the effective amount of
an mTOR inhibitor (such as a limus drug, e.g., sirolimus) in the
composition includes less than about any of 350 mg/kg, 300 mg/kg,
250 mg/kg, 200 mg/kg, 150 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 20
mg/kg, 10 mg/kg, 7.5 mg/kg, 6.5 mg/kg, 5 mg/kg, 3.5 mg/kg, 2.5
mg/kg, or 1 mg/kg of an mTOR inhibitor (such as a limus drug, e.g.,
sirolimus).
[0143] Exemplary dosing frequencies for the administration of the
nanoparticle compositions include, but are not limited to, daily,
every two days, every three days, every four days, every five days,
every six days, weekly without break, three out of four weeks, once
every three weeks, once every two weeks, or two out of three weeks.
In some embodiments, the composition is administered about once
every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6
weeks, or once every 8 weeks. In some embodiments, the composition
is administered at least about any of 1.times., 2.times., 3.times.,
4.times., 5.times., 6.times., or 7.times. (i.e., daily) a week. In
some embodiments, the intervals between each administration are
less than about any of 6 months, 3 months, 1 month, 20 days, 15,
days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days,
7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some
embodiments, the intervals between each administration are more
than about any of 1 month, 2 months, 3 months, 4 months, 5 months,
6 months, 8 months, or 12 months. In some embodiments, there is no
break in the dosing schedule. In some embodiments, the interval
between each administration is no more than about a week. In some
embodiments, the composition is administered weekly. In some
embodiments, the composition is administered twice every week.
[0144] The administration of the composition can be extended over
an extended period of time, such as from about a month up to about
seven years. In some embodiments, the composition is administered
over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months. In some
embodiments, the composition is administered weekly for 6 weeks,
optionally followed by monthly maintenance thereafter.
[0145] In some embodiments, the individual is treated for at least
about any of one, two, three, four, five, six, seven, eight, nine,
or ten treatment cycles.
[0146] The mTOR nanoparticle composition (such as a limus
nanoparticle composition) can be administered to an individual
(such as human) via various routes, including, for example,
intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral,
inhalation, intravesicular, intramuscular, intra-tracheal,
subcutaneous, intraocular, intrathecal, transmucosal, and
transdermal. In some embodiments, sustained continuous release
formulation of the composition may be used. In some embodiments,
the composition is administered intravenously. In some embodiments,
the composition is administered intravesicularly. In some
embodiments, the composition is administered intraarterially. In
some embodiments, the composition is administered
intraperitoneally.
[0147] In some embodiments when the limus nanoparticle composition
is administered intravesicularly, the dosage of an mTOR inhibitor
(such as a limus drug, e.g., sirolimus) in a nanoparticle
composition can be in the range of about 30 mg to about 400 mg in
volume of about 20 ml to about 150 ml, for example retained in the
bladder for about 30 minutes to about 4 hours. In some embodiments,
the nanoparticle composition is retained in the bladder for about
30 minutes to about 4 hours, including for example about 30 minutes
to about 1 hour, about 1 hour to about 2 hours, about 2 hours to
about 3 hours, or about 3 hours to about 4 hours.
[0148] In some embodiments, the dosage of an mTOR inhibitor (such
as a limus drug, e.g., sirolimus) is about 100 mg to about 400 mg,
for example about 100 mg, about 200 mg, about 300 mg, or about 400
mg. In some embodiments, the limus drug is administered at about
100 mg weekly, about 200 mg weekly, about 300 mg weekly, about 100
mg twice weekly, or about 200 mg twice weekly. In some embodiments,
the administration is further followed by a monthly maintenance
dose (which can be the same or different from the weekly
doses).
[0149] In some embodiments when the limus nanoparticle composition
is administered intravenously, the dosage of an mTOR inhibitor
(such as a limus drug, e.g., sirolimus) in a nanoparticle
composition can be in the range of about 30 mg to about 400 mg. The
compositions described herein allow infusion of the composition to
an individual over an infusion time that is shorter than about 24
hours. For example, in some embodiments, the composition is
administered over an infusion period of less than about any of 24
hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30
minutes, 20 minutes, or 10 minutes. In some embodiments, the
composition is administered over an infusion period of about 30
minutes to about 40 minutes.
Modes of Administration of Combination Therapies
[0150] The dosing regimens described in the section above apply to
both monotherapy and combination therapy settings. The modes of
administration for combination therapy methods are further
described below.
[0151] In some embodiments, the nanoparticle composition and the
other agent (including the specific chemotherapeutic agents
described herein) are administered simultaneously. When the drugs
are administered simultaneously, the drug in the nanoparticles and
the other agent may be contained in the same composition (e.g., a
composition comprising both the nanoparticles and the other agent)
or in separate compositions (e.g., the nanoparticles are contained
in one composition and the other agent is contained in another
composition).
[0152] In some embodiments, the nanoparticle composition and the
other agent are administered sequentially. Either the nanoparticle
composition or the other agent may be administered first. The
nanoparticle composition and the other agent are contained in
separate compositions, which may be contained in the same or
different packages.
[0153] In some embodiments, the administration of the nanoparticle
composition and the other agent are concurrent, i.e., the
administration period of the nanoparticle composition and that of
the other agent overlap with each other. In some embodiments, the
nanoparticle composition is administered for at least one cycle
(for example, at least any of 2, 3, or 4 cycles) prior to the
administration of the other agent. In some embodiments, the other
agent is administered for at least any of one, two, three, or four
weeks. In some embodiments, the administrations of the nanoparticle
composition and the other agent are initiated at about the same
time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
In some embodiments, the administrations of the nanoparticle
composition and the other agent are terminated at about the same
time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
In some embodiments, the administration of the other agent
continues (for example for about any one of 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, or 12 months) after the termination of the
administration of the nanoparticle composition. In some
embodiments, the administration of the other agent is initiated
after (for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, or 12 months) the initiation of the administration of
the nanoparticle composition. In some embodiments, the
administrations of the nanoparticle composition and the other agent
are initiated and terminated at about the same time. In some
embodiments, the administrations of the nanoparticle composition
and the other agent are initiated at about the same time and the
administration of the other agent continues (for example for about
any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after
the termination of the administration of the nanoparticle
composition. In some embodiments, the administration of the
nanoparticle composition and the other agent stop at about the same
time and the administration of the other agent is initiated after
(for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months) the initiation of the administration of the
nanoparticle composition.
[0154] In some embodiments, the administration of the nanoparticle
composition and the other agent are non-concurrent. For example, in
some embodiments, the administration of the nanoparticle
composition is terminated before the other agent is administered.
In some embodiments, the administration of the other agent is
terminated before the nanoparticle composition is administered. The
time period between these two non-concurrent administrations can
range from about two to eight weeks, such as about four weeks.
[0155] The dosing frequency of the drug-containing nanoparticle
composition and the other agent may be adjusted over the course of
the treatment, based on the judgment of the administering
physician. When administered separately, the drug-containing
nanoparticle composition and the other agent can be administered at
different dosing frequency or intervals. For example, the
drug-containing nanoparticle composition can be administered
weekly, while a chemotherapeutic agent can be administered more or
less frequently. In some embodiments, sustained continuous release
formulation of the drug-containing nanoparticle and/or
chemotherapeutic agent may be used. Various formulations and
devices for achieving sustained release are known in the art. A
combination of the administration configurations described herein
can also be used.
[0156] The nanoparticle composition and the other agent can be
administered using the same route of administration or different
routes of administration. In some embodiments (for both
simultaneous and sequential administrations), the limus drug in the
nanoparticle composition and the other agent are administered at a
predetermined ratio. For example, in some embodiments, the ratio by
weight of the limus drug in the nanoparticle composition and the
other agent is about 1 to 1. In some embodiments, the weight ratio
may be between about 0.001 to about 1 and about 1000 to about 1, or
between about 0.01 to about 1 and 100 to about 1. In some
embodiments, the ratio by weight of the limus drug in the
nanoparticle composition and the other agent is less than about any
of 100:1, 50:1, 30:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1,
and 1:1 In some embodiments, the ratio by weight of the limus drug
in the nanoparticle composition and the other agent is more than
about any of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 30:1,
50:1, 100:1. Other ratios are contemplated.
[0157] The doses required for the limus drug and/or the other agent
may (but not necessarily) be lower than what is normally required
when each agent is administered alone. Thus, in some embodiments, a
subtherapeutic amount of the drug in the nanoparticle composition
and/or the other agent is administered. "Subtherapeutic amount" or
"subtherapeutic level" refer to an amount that is less than the
therapeutic amount, that is, less than the amount normally used
when the drug in the nanoparticle composition and/or the other
agent are administered alone. The reduction may be reflected in
terms of the amount administered at a given administration and/or
the amount administered over a given period of time (reduced
frequency).
[0158] In some embodiments, enough chemotherapeutic agent is
administered so as to allow reduction of the normal dose of the
drug in the nanoparticle composition required to effect the same
degree of treatment by at least about any of 5%, 10%, 20%, 30%,
50%, 60%, 70%, 80%, 90%, or more. In some embodiments, enough drug
in the nanoparticle composition is administered so as to allow
reduction of the normal dose of the other agent required to effect
the same degree of treatment by at least about any of 5%, 10%, 20%,
30%, 50%, 60%, 70%, 80%, 90%, or more.
[0159] In some embodiments, the dose of both the limus drug in the
nanoparticle composition and the other agent are reduced as
compared to the corresponding normal dose of each when administered
alone. In some embodiments, both the limus drug in the nanoparticle
composition and the other agent are administered at a
subtherapeutic, i.e., reduced, level. In some embodiments, the dose
of the nanoparticle composition and/or the other agent is
substantially less than the established maximum toxic dose (MTD).
For example, the dose of the nanoparticle composition and/or the
other agent is less than about 50%, 40%, 30%, 20%, or 10% of the
MTD.
[0160] A combination of the administration configurations described
herein can be used. The combination therapy methods described
herein may be performed alone or in conjunction with another
therapy, such as chemotherapy, radiation therapy, surgery, hormone
therapy, gene therapy, immunotherapy, chemoimmunotherapy, hepatic
artery-based therapy, cryotherapy, ultrasound therapy, liver
transplantation, local ablative therapy, radiofrequency ablation
therapy, photodynamic therapy, and the like. Additionally, a person
having a greater risk of developing the bladder cancer may receive
treatments to inhibit and/or delay the development of the
disease.
[0161] The other agent described herein can be administered to an
individual (such as human) via various routes, such as
parenterally, including intravenous, intra-arterial,
intraperitoneal, intrapulmonary, oral, inhalation, intravesicular,
intramuscular, intra-tracheal, subcutaneous, intraocular,
intrathecal, or transdermal. In some embodiments, the other agent
is administrated intravenously. In some embodiments, the
nanoparticle composition is administered orally.
[0162] The dosing frequency of the other agent can be the same or
different from that of the nanoparticle composition. Exemplary
frequencies are provided above. As further example, the other agent
can be administered three times a day, two times a day, daily, 6
times a week, 5 times a week, 4 times a week, 3 times a week, two
times a week, weekly. In some embodiments, the other agent is
administered twice daily or three times daily. Exemplary amounts of
the other agent include, but are not limited to, any of the
following ranges: about 0.5 mg to about 5 mg, about 5 mg to about
10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg,
about 20 mg to about 25 mg, about 20 mg to about 50 mg, about 25 mg
to about 50 mg, about 50 mg to about 75 mg, about 50 mg to about
100 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg,
about 125 mg to about 150 mg, about 150 mg to about 175 mg, about
175 mg to about 200 mg, about 200 mg to about 225 mg, about 225 mg
to about 250 mg, about 250 mg to about 300 mg, about 300 mg to
about 350 mg, about 350 mg to about 400 mg, about 400 mg to about
450 mg, or about 450 mg to about 500 mg. For example, the other
agent can be administered at a dose of about 1 mg/kg to about 200
mg/kg (including for example about 1 mg/kg to about 20 mg/kg, about
20 mg/kg to about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about
60 mg/kg to about 80 mg/kg, about 80 mg/kg to about 100 mg/kg,
about 100 mg/kg to about 120 mg/kg, about 120 mg/kg to about 140
mg/kg, about 140 mg/kg to about 200 mg/kg).
[0163] In some embodiments the other agent is BCG. In some
embodiments, the dose of BCG is about 1 mg to about 5 mg, about 5
mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about
30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg,
about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg
to about 80 mg, about 80 mg to about 90 mg. In some embodiments,
the dose of BCG is about 1.times.10.sup.5 CFU/ml to about
1.times.10.sup.7 CFU/ml, including for example about
1-8.times.10.sup.6 CFU/ml, such as about 2.times.10.sup.6, about
3.times.10.sup.6, about 4.times.10.sup.6, about 5.times.10.sup.6,
about 6.times.10.sup.6, about 7.times.10.sup.6, or about
8.times.10.sup.6 CFU/ml. In some embodiments, the BCG is
administered intravesicularly. In some embodiments, the BCG is
administered weekly. In some embodiments, the amount of limus drug
useful for combination with the BCG is about 5 mg to about 500 mg,
including for example about 30 mg to about 400 mg, such as about
100 mg to about 200 mg.
[0164] In some embodiments, the amount of the mTOR inhibitor (such
as limus drug, e.g., sirolimus) in the nanoparticle composition is
between about 5 mg to about 500 mg and the amount of the other
agent is about 1 mg/kg to about 200 mg/kg (including for example
about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to about 40 mg/kg,
about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to about 80 mg/kg,
about 80 mg/kg to about 100 mg/kg, about 100 mg/kg to about 120
mg/kg, about 120 mg/kg to about 140 mg/kg, about 140 mg/kg to about
200 mg/kg). In some embodiments, the amount of 1 mTOR inhibitor
(such as limus drug, e.g., sirolimus) in the nanoparticle
composition is between about 30 mg to about 400 mg and the amount
of the other agent is about 1 mg/kg to about 200 mg/kg (including
for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to
about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to
about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg
to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140
mg/kg to about 200 mg/kg). In some embodiments, the amount of mTOR
inhibitor (such as limus drug, e.g., sirolimus) in the nanoparticle
composition is between about 100 mg to about 200 mg and the amount
of the other agent is about 1 mg/kg to about 200 mg/kg (including
for example about 1 mg/kg to about 20 mg/kg, about 20 mg/kg to
about 40 mg/kg, about 40 mg/kg to about 60 mg/kg, about 60 mg/kg to
about 80 mg/kg, about 80 mg/kg to about 100 mg/kg, about 100 mg/kg
to about 120 mg/kg, about 120 mg/kg to about 140 mg/kg, about 140
mg/kg to about 200 mg/kg).
[0165] In some embodiments, the appropriate doses of other agents
are approximately those already employed in clinical therapies
wherein the other agent are administered alone or in combination
with other agents.
Nanoparticle Compositions
[0166] The nanoparticle compositions described herein comprise
nanoparticles comprising (in various embodiments consisting
essentially of) an mTOR inhibitor (such as a limus drug, for
example sirolimus). The nanoparticles may further comprise a
carrier protein (e.g., an albumin such as human serum albumin or
human albumin). Nanoparticles of poorly water soluble drugs have
been disclosed in, for example, U.S. Pat. Nos. 5,916,596;
6,506,405; 6,749,868, 6,537,579, 7,820,788, and also in U.S. Pat.
Pub. Nos. 2006/0263434, and 2007/0082838; PCT Patent Application
WO08/137148, each of which is incorporated by reference in their
entirety.
[0167] In some embodiments, the composition comprises nanoparticles
with an average or mean diameter of no greater than about 1000
nanometers (nm), such as no greater than about (or less than about)
any of 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm. In some
embodiments, the average or mean diameters of the nanoparticles is
no greater than about 200 nm (such as no greater than about 150
nm). In some embodiments, the average or mean diameters of the
nanoparticles is no greater than about 150 nm. In some embodiments,
the average or mean diameters of the nanoparticles is no greater
than about 100 nm. In some embodiments, the average or mean
diameter of the nanoparticles is about 20 nm to about 400 nm. In
some embodiments, the average or mean diameter of the nanoparticles
is about 40 nm to about 200 nm. In some embodiments, the
nanoparticles are sterile-filterable.
[0168] In some embodiments, the nanoparticles in the composition
described herein have an average diameter of no greater than about
200 nm, including for example no greater than about any one of 190,
180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm.
In some embodiments, at least about 50% (for example at least about
any one of 60%, 70%, 80%, 90%, 95%, or 99%) of the nanoparticles in
the composition have a diameter of no greater than about 200 nm,
including for example no greater than about any one of 190, 180,
170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm. In
some embodiments, at least about 50% (for example at least any one
of 60%, 70%, 80%, 90%, 95%, or 99%) of the nanoparticles in the
composition fall within the range of about 20 nm to about 400 nm,
including for example about 20 nm to about 200 nm, about 40 nm to
about 200 nm, about 30 nm to about 180 nm, about 40 nm to about 150
nm, about 50 nm to about 120 nm, and about 60 nm to about 100
nm.
[0169] In some embodiments, the carrier protein (e.g., an albumin)
has sulfhydryl groups that can form disulfide bonds. In some
embodiments, at least about 5% (including for example at least
about any one of 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%,
or 90%) of carrier protein (e.g., an albumin) in the nanoparticle
portion of the composition are crosslinked (for example crosslinked
through one or more disulfide bonds).
[0170] In some embodiments, the nanoparticles comprising the mTOR
inhibitor (such as a limus drug, e.g., sirolimus) are coated with a
carrier protein (e.g., an albumin such as human albumin or human
serum albumin). In some embodiments, the composition comprises an
mTOR inhibitor (such as a limus drug, for example sirolimus) in
both nanoparticle and non-nanoparticle forms (e.g., in the form of
solutions or in the form of soluble carrier protein/nanoparticle
complexes), wherein at least about any one of 50%, 60%, 70%, 80%,
90%, 95%, or 99% of the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) in the composition are in nanoparticle form. In some
embodiments, the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) in the nanoparticles constitutes more than about any one
of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticles by
weight. In some embodiments, the nanoparticles have a non-polymeric
matrix. In some embodiments, the nanoparticles comprise a core of
an mTOR inhibitor (such as a limus drug, for example sirolimus)
that is substantially free of polymeric materials (such as
polymeric matrix).
[0171] In some embodiments, the composition comprises a carrier
protein (e.g., an albumin) in both nanoparticle and
non-nanoparticle portions of the composition, wherein at least
about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the
carrier protein (e.g., an albumin) in the composition are in
non-nanoparticle portion of the composition.
[0172] In some embodiments, the weight ratio of an albumin (such as
human albumin or human serum albumin) and a mTOR inhibitor in the
nanoparticle composition is about 18:1 or less, such as about 15:1
or less, for example about 10:1 or less. In some embodiments, the
weight ratio of an albumin (such as human albumin or human serum
albumin) and an mTOR inhibitor (such as a limus drug, for example
sirolimus) in the composition falls within the range of any one of
about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to
about 13:1, about 4:1 to about 12:1, about 5:1 to about 10:1. In
some embodiments, the weight ratio of an albumin and an mTOR
inhibitor (such as a limus drug, for example sirolimus) in the
nanoparticle portion of the composition is about any one of 1:2,
1:3, 1:4, 1:5, 1:9, 1:10, 1:15, or less. In some embodiments, the
weight ratio of the albumin (such as human albumin or human serum
albumin) and the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) in the composition is any one of the following: about
1:1 to about 18:1, about 1:1 to about 15:1, about 1:1 to about
12:1, about 1:1 to about 10:1, about 1:1 to about 9:1, about 1:1 to
about 8:1, about 1:1 to about 7:1, about 1:1 to about 6:1, about
1:1 to about 5:1, about 1:1 to about 4:1, about 1:1 to about 3:1,
about 1:1 to about 2:1, about 1:1 to about 1:1.
[0173] In some embodiments, the nanoparticle composition comprises
one or more of the above characteristics.
[0174] The nanoparticles described herein may be present in a dry
formulation (such as lyophilized composition) or suspended in a
biocompatible medium. Suitable biocompatible media include, but are
not limited to, water, buffered aqueous media, saline, buffered
saline, optionally buffered solutions of amino acids, optionally
buffered solutions of proteins, optionally buffered solutions of
sugars, optionally buffered solutions of vitamins, optionally
buffered solutions of synthetic polymers, lipid-containing
emulsions, and the like.
[0175] In some embodiments, the pharmaceutically acceptable carrier
comprises a carrier protein (e.g., an albumin such as human albumin
or human serum albumin). Examples of suitable carrier proteins
include proteins normally found in blood or plasma, which include,
but are not limited to, an albumin, immunoglobulin including IgA,
lipoproteins, apolipoprotein B, .alpha.-acid glycoprotein,
.beta.-2-macroglobulin, thyroglobulin, transferrin, fibronectin,
factor VII, factor VIII, factor IX, factor X, and the like. In some
embodiments, the carrier protein is non-blood protein, such as
casein, .alpha.-lactalbumin, .beta.-lactoglobulin. The proteins may
either be natural in origin or synthetically prepared. In some
embodiments, the protein is an albumin, such as human albumin or
human serum albumin. In some embodiments, the albumin is a
recombinant albumin.
[0176] Human serum albumin (HSA) is a highly soluble globular
protein of M.sub.r 65K and consists of 585 amino acids. HSA is the
most abundant protein in the plasma and accounts for 70-80% of the
colloid osmotic pressure of human plasma. The amino acid sequence
of HSA contains a total of 17 disulfide bridges, one free thiol
(Cys 34), and a single tryptophan (Trp 214). Intravenous use of HSA
solution has been indicated for the prevention and treatment of
hypovolumic shock (see, e.g., Tullis, JAMA, 237: 355-360, 460-463,
(1977)) and Houser et al., Surgery, Gynecology and Obstetrics, 150:
811-816 (1980)) and in conjunction with exchange transfusion in the
treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson,
Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)). Other
albumins are contemplated, such as bovine serum albumin. Use of
such non-human albumins could be appropriate, for example, in the
context of use of these compositions in non-human mammals, such as
the veterinary (including domestic pets and agricultural context).
Human serum albumin (HSA) has multiple hydrophobic binding sites (a
total of eight for fatty acids, an endogenous ligand of HSA) and
binds a diverse set of drugs, especially neutral and negatively
charged hydrophobic compounds (Goodman et al., The Pharmacological
Basis of Therapeutics, 9th ed, McGraw-Hill New York (1996)). Two
high affinity binding sites have been proposed in subdomains IIA
and IIIA of HSA, which are highly elongated hydrophobic pockets
with charged lysine and arginine residues near the surface which
function as attachment points for polar ligand features (see, e.g.,
Fehske et al., Biochem. Pharmcol., 30, 687-92 (198a), Vorum, Dan.
Med. Bull., 46, 379-99 (1999), Kragh-Hansen, Dan. Med. Bull., 1441,
131-40 (1990), Curry et al., Nat. Struct. Biol., 5, 827-35 (1998),
Sugio et al., Protein. Eng., 12, 439-46 (1999), He et al., Nature,
358, 209-15 (199b), and Carter et al., Adv. Protein. Chem., 45,
153-203 (1994)). Sirolimus and propofol have been shown to bind HSA
(see, e.g., Paal et al., Eur. J. Biochem., 268(7), 2187-91 (200a),
Purcell et al., Biochim. Biophys. Acta, 1478(a), 61-8 (2000),
Altmayer et al., Arzneimittelforschung, 45, 1053-6 (1995), and
Garrido et al., Rev. Esp. Anestestiol. Reanim., 41, 308-12 (1994)).
In addition, docetaxel has been shown to bind to human plasma
proteins (see, e.g., Urien et al., Invest. New Drugs, 14(b), 147-51
(1996)).
[0177] The carrier protein (e.g., an albumin such as human albumin
or human serum albumin) in the composition generally serves as a
carrier for the mTOR inhibitor, i.e., the albumin in the
composition makes the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) more readily suspendable in an aqueous medium or helps
maintain the suspension as compared to compositions not comprising
a carrier protein. This can avoid the use of toxic solvents (or
surfactants) for solubilizing the mTOR inhibitor, and thereby can
reduce one or more side effects of administration of the mTOR
inhibitor (such as a limus drug, e.g., sirolimus) into an
individual (such as a human). Thus, in some embodiments, the
composition described herein is substantially free (such as free)
of surfactants, such as Cremophor (or polyoxyethylated castor oil,
including Cremophor EL.RTM. (BASF)). In some embodiments, the
nanoparticle composition is substantially free (such as free) of
surfactants. A composition is "substantially free of Cremophor" or
"substantially free of surfactant" if the amount of Cremophor or
surfactant in the composition is not sufficient to cause one or
more side effect(s) in an individual when the nanoparticle
composition is administered to the individual. In some embodiments,
the nanoparticle composition contains less than about any one of
20%, 15%, 10%, 7.5%, 5%, 2.5%, or 1% organic solvent or surfactant.
In some embodiments, the carrier protein is an albumin. In some
embodiments, the albumin is human albumin or human serum albumin.
In some embodiments, the albumin is recombinant albumin.
[0178] The amount of a carrier protein such as an albumin in the
composition described herein will vary depending on other
components in the composition. In some embodiments, the composition
comprises a carrier protein such as an albumin in an amount that is
sufficient to stabilize the mTOR inhibitor (such as a limus drug,
e.g., sirolimus) in an aqueous suspension, for example, in the form
of a stable colloidal suspension (such as a stable suspension of
nanoparticles). In some embodiments, the carrier protein such as an
albumin is in an amount that reduces the sedimentation rate of the
mTOR inhibitor (such as a limus drug, e.g., sirolimus) in an
aqueous medium. For particle-containing compositions, the amount of
the carrier protein such as an albumin also depends on the size and
density of nanoparticles of the mTOR inhibitor.
[0179] An mTOR inhibitor (such as a limus drug, for example
sirolimus) is "stabilized" in an aqueous suspension if it remains
suspended in an aqueous medium (such as without visible
precipitation or sedimentation) for an extended period of time,
such as for at least about any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The
suspension is generally, but not necessarily, suitable for
administration to an individual (such as human). Stability of the
suspension is generally (but not necessarily) evaluated at a
storage temperature (such as room temperature (such as
20-25.degree. C.) or refrigerated conditions (such as 4.degree.
C.)). For example, a suspension is stable at a storage temperature
if it exhibits no flocculation or particle agglomeration visible to
the naked eye or when viewed under the optical microscope at 1000
times, at about fifteen minutes after preparation of the
suspension. Stability can also be evaluated under accelerated
testing conditions, such as at a temperature that is higher than
about 40.degree. C.
[0180] In some embodiments, the carrier protein (e.g., an albumin)
is present in an amount that is sufficient to stabilize the mTOR
inhibitor (such as a limus drug, e.g., sirolimus) in an aqueous
suspension at a certain concentration. For example, the
concentration of the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) in the composition is about 0.1 mg/ml to about 100
mg/ml, including for example any of about 0.1 mg/ml to about 50
mg/ml, about 0.1 mg/ml to about 20 mg/ml, about 1 mg/ml to about 10
mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 mg/ml to about 6
mg/ml, or about 5 mg/ml. In some embodiments, the concentration of
the mTOR inhibitor (such as a limus drug, e.g., sirolimus) is at
least about any of 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml,
5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20
mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, and 50 mg/ml. In some
embodiments, the carrier protein (e.g., an albumin) is present in
an amount that avoids use of surfactants (such as Cremophor), so
that the composition is free or substantially free of surfactant
(such as Cremophor).
[0181] In some embodiments, the composition, in liquid form,
comprises from about 0.1% to about 50% (w/v) (e.g. about 0.5%
(w/v), about 5% (w/v), about 10% (w/v), about 15% (w/v), about 20%
(w/v), about 30% (w/v), about 40% (w/v), or about 50% (w/v)) of
carrier protein (e.g., an albumin). In some embodiments, the
composition, in liquid form, comprises about 0.5% to about 5% (w/v)
of carrier protein (e.g., an albumin).
[0182] In some embodiments, the weight ratio of a carrier protein
(e.g., an albumin) to the mTOR inhibitor (such as a limus drug,
e.g., sirolimus) in the nanoparticle composition is such that a
sufficient amount of mTOR inhibitor binds to, or is transported by,
the cell. While the weight ratio of a carrier protein (e.g., an
albumin) to mTOR inhibitor will have to be optimized for different
carrier protein (e.g., an albumin) and mTOR inhibitor combinations,
generally the weight ratio of carrier protein (e.g., an albumin),
to mTOR inhibitor (such as a limus drug, e.g., sirolimus) (w/w) is
about 0.01:1 to about 100:1, about 0.02:1 to about 50:1, about
0.05:1 to about 20:1, about 0.1:1 to about 20:1, about 1:1 to about
18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1
to about 10:1, about 5:1 to about 9:1, or about 9:1. In some
embodiments, the carrier protein (e.g., an albumin) to mTOR
inhibitor weight ratio is about any of 18:1 or less, 15:1 or less,
14:1 or less, 13:1 or less, 12:1 or less, 11:1 or less, 10:1 or
less, 9:1 or less, 8:1 or less, 7:1 or less, 6:1 or less, 5:1 or
less, 4:1 or less, and 3:1 or less. In some embodiments, the
carrier protein is an albumin. In some embodiments, the weight
ratio of the albumin (such as human albumin or human serum albumin)
to the mTOR inhibitor in the composition is any one of the
following: about 1:1 to about 18:1, about 1:1 to about 15:1, about
1:1 to about 12:1, about 1:1 to about 10:1, about 1:1 to about 9:1,
about 1:1 to about 8:1, about 1:1 to about 7:1, about 1:1 to about
6:1, about 1:1 to about 5:1, about 1:1 to about 4:1, about 1:1 to
about 3:1, about 1:1 to about 2:1, about 1:1 to about 1:1.
[0183] In some embodiments, the carrier protein (e.g., an albumin)
allows the composition to be administered to an individual (such as
human) without significant side effects. In some embodiments, the
carrier protein (e.g., an albumin such as human serum albumin or
human albumin) is in an amount that is effective to reduce one or
more side effects of administration of the mTOR inhibitor (such as
a limus drug, e.g., sirolimus) to a human. The term "reducing one
or more side effects" of administration of the mTOR inhibitor (such
as a limus drug, e.g., sirolimus) refers to reduction, alleviation,
elimination, or avoidance of one or more undesirable effects caused
by the mTOR inhibitor, as well as side effects caused by delivery
vehicles (such as solvents that render the limus drugs suitable for
injection) used to deliver the mTOR inhibitor. Such side effects
include, for example, myelosuppression, neurotoxicity,
hypersensitivity, inflammation, venous irritation, phlebitis, pain,
skin irritation, peripheral neuropathy, neutropenic fever,
anaphylactic reaction, venous thrombosis, extravasation, and
combinations thereof. These side effects, however, are merely
exemplary and other side effects, or combination of side effects,
associated with limus drugs (such as sirolimus) can be reduced.
[0184] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) and an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) and an albumin (such as human
albumin or human serum albumin), wherein the nanoparticles have an
average diameter of no greater than about 150 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) and an albumin (such as human
albumin or human serum albumin), wherein the nanoparticles have an
average diameter of no greater than about 150 nm (for example about
100 nm). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising sirolimus and
human albumin (such as human serum albumin), wherein the
nanoparticles have an average diameter of no greater than about 150
nm (for example about 100 nm).
[0185] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) and an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm, wherein
the weight ratio of the albumin and the mTOR inhibitor in the
composition is no greater than about 9:1 (such as about 9:1 or
about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising an mTOR
inhibitor (such as a limus drug, for example sirolimus) and an
albumin (such as human albumin or human serum albumin), wherein the
nanoparticles have an average diameter of no greater than about 150
nm, wherein the weight ratio of the albumin and the mTOR inhibitor
in the composition is no greater than about 9:1 (such as about 9:1
or about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising an mTOR
inhibitor (such as a limus drug, for example sirolimus) and an
albumin (such as human albumin or human serum albumin), wherein the
nanoparticles have an average diameter of about 150 nm, wherein the
weight ratio of the albumin and the mTOR inhibitor in the
composition is no greater than about 9:1 (such as about 9:1 or
about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising sirolimus and
human albumin (such as human serum albumin), wherein the
nanoparticles have an average diameter of no greater than about 150
nm (for example about 100 nm), wherein the weight ratio of albumin
and sirolimus inhibitor in the composition is about 9:1 or about
8:1.
[0186] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) coated with an albumin
(such as human albumin or human serum albumin). In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) coated with an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) coated with an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 150 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) coated with an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 150 nm (for
example about 100 nm). In some embodiments, the nanoparticle
compositions described herein comprises nanoparticles comprising
sirolimus coated with human albumin (such as human serum albumin),
wherein the nanoparticles have an average diameter of no greater
than about 150 nm (for example about 100 nm).
[0187] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) coated with an albumin
(such as human albumin or human serum albumin), wherein the weight
ratio of the albumin and the mTOR inhibitor in the composition is
no greater than about 9:1 (such as about 9:1 or about 8:1). In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) coated with an albumin (such as
human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm, wherein
the weight ratio of the albumin and the mTOR inhibitor in the
composition is no greater than about 9:1 (such as about 9:1 or
about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising an mTOR
inhibitor (such as a limus drug, for example sirolimus) coated with
an albumin (such as human albumin or human serum albumin), wherein
the nanoparticles have an average diameter of no greater than about
150 nm, wherein the weight ratio of the albumin and the mTOR
inhibitor in the composition is no greater than about 9:1 (such as
about 9:1 or about 8:1). In some embodiments, the nanoparticle
compositions described herein comprises nanoparticles comprising an
mTOR inhibitor (such as a limus drug, for example sirolimus) coated
with an albumin (such as human albumin or human serum albumin),
wherein the nanoparticles have an average diameter of about 150 nm,
wherein the weight ratio of the albumin and the mTOR inhibitor in
the composition is no greater than about 9:1 (such as about 9:1 or
about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising sirolimus
coated with human albumin (such as human serum albumin), wherein
the nanoparticles have an average diameter of no greater than about
150 nm (for example about 100 nm), wherein the weight ratio of
albumin and the sirolimus in the composition is about 9:1 or about
8:1.
[0188] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) stabilized by an albumin
(such as human albumin or human serum albumin). In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) stabilized by an albumin (such
as human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) stabilized by an albumin (such
as human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 150 nm. In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) stabilized by an albumin (such
as human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 150 nm (for
example about 100 nm). In some embodiments, the nanoparticle
compositions described herein comprises nanoparticles comprising
sirolimus stabilized by human albumin (such as human serum
albumin), wherein the nanoparticles have an average diameter of no
greater than about 150 nm (for example about 100 nm).
[0189] In some embodiments, the nanoparticle compositions described
herein comprises nanoparticles comprising an mTOR inhibitor (such
as a limus drug, for example sirolimus) stabilized by an albumin
(such as human albumin or human serum albumin), wherein the weight
ratio of the albumin and the mTOR inhibitor in the composition is
no greater than about 9:1 (such as about 9:1 or about 8:1). In some
embodiments, the nanoparticle compositions described herein
comprises nanoparticles comprising an mTOR inhibitor (such as a
limus drug, for example sirolimus) stabilized by an albumin (such
as human albumin or human serum albumin), wherein the nanoparticles
have an average diameter of no greater than about 200 nm, wherein
the weight ratio of the albumin and the mTOR inhibitor in the
composition is no greater than about 9:1 (such as about 9:1 or
about 8:1). In some embodiments, the nanoparticle compositions
described herein comprises nanoparticles comprising an mTOR
inhibitor (such as a limus drug, for example sirolimus) stabilized
by an albumin (such as human albumin or human serum albumin),
wherein the nanoparticles have an average diameter of no greater
than about 150 nm, wherein the weight ratio of the albumin and the
mTOR inhibitor in the composition is no greater than about 9:1
(such as about 9:1 or about 8:1). In some embodiments, the
nanoparticle compositions described herein comprises nanoparticles
comprising an mTOR inhibitor (such as a limus drug, for example
sirolimus) stabilized by an albumin (such as human albumin or human
serum albumin), wherein the nanoparticles have an average diameter
of about 150 nm, wherein the weight ratio of the albumin and the
mTOR inhibitor in the composition is no greater than about 9:1
(such as about 9:1 or about 8:1). In some embodiments, the
nanoparticle compositions described herein comprises nanoparticles
comprising sirolimus stabilized by human albumin (such as human
serum albumin), wherein the nanoparticles have an average diameter
of no greater than about 150 nm (for example about 100 nm), wherein
the weight ratio of albumin and the sirolimus in the composition is
about 9:1 or about 8:1.
[0190] In some embodiments, the nanoparticle composition comprises
Nab-sirolimus. In some embodiments, the nanoparticle composition is
Nab-sirolimus. Nab-sirolimus is a formulation of sirolimus
stabilized by human albumin USP, which can be dispersed in directly
injectable physiological solution. The weight ratio of human
albumin and sirolimus is about 8:1 to about 9:1. When dispersed in
a suitable aqueous medium such as 0.9% sodium chloride injection or
5% dextrose injection, Nab-sirolimus forms a stable colloidal
suspension of sirolimus. The mean particle size of the
nanoparticles in the colloidal suspension is about 100 nanometers.
Since HSA is freely soluble in water, Nab-sirolimus can be
reconstituted in a wide range of concentrations ranging from dilute
(0.1 mg/ml sirolimus) to concentrated (20 mg/ml sirolimus),
including for example about 2 mg/ml to about 8 mg/ml, or about 5
mg/ml.
[0191] Methods of making nanoparticle compositions are known in the
art. For example, nanoparticles containing mTOR inhibitor (such as
a limus drug, e.g., sirolimus) and carrier protein (e.g., an
albumin such as human serum albumin or human albumin) can be
prepared under conditions of high shear forces (e.g., sonication,
high pressure homogenization, or the like). These methods are
disclosed in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405;
6,749,868, 6,537,579 and 7,820,788 and also in U.S. Pat. Pub. Nos.
2007/0082838, 2006/0263434 and PCT Application WO08/137148.
[0192] Briefly, the mTOR inhibitor (such as a limus drug, e.g.,
sirolimus) is dissolved in an organic solvent, and the solution can
be added to a carrier protein solution such as an albumin solution.
The mixture is subjected to high pressure homogenization. The
organic solvent can then be removed by evaporation. The dispersion
obtained can be further lyophilized. Suitable organic solvent
include, for example, ketones, esters, ethers, chlorinated
solvents, and other solvents known in the art. For example, the
organic solvent can be methylene chloride or chloroform/ethanol
(for example with a ratio of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3,
1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1).
mTOR Inhibitor
[0193] The methods described herein in some embodiments comprise
administration of nanoparticle compositions of mTOR inhibitors.
"mTOR inhibitor" used herein refers to an inhibitor of mTOR. mTOR
is a serine/threonine-specific protein kinase downstream of the
phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)
pathway, and a key regulator of cell survival, proliferation,
stress, and metabolism. mTOR pathway dysregulation has been found
in many human carcinomas, and mTOR inhibition produced substantial
inhibitory effects on tumor progression.
[0194] The mammalian target of rapamycin (mTOR) (also known as
mechanistic target of rapamycin or FK506 binding protein
12-rapamycin associated protein 1 (FRAP1)) is an atypical
serine/threonine protein kinase that is present in two distinct
complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2).
mTORC1 is composed of mTOR, regulatory-associated protein of mTOR
(Raptor), mammalian lethal with SEC13 protein 8 (MLST8), PRAS40 and
DEPTOR (Kim et al. (2002). Cell 110: 163-75; Fang et al. (2001).
Science 294 (5548): 1942-5). mTORC1 integrates four major signal
inputs: nutrients (such as amino acids and phosphatidic acid),
growth factors (insulin), energy and stress (such as hypoxia and
DNA damage). Amino acid availability is signaled to mTORC1 via a
pathway involving the Rag and Ragulator (LAMTOR1-3) Growth factors
and hormones (e.g. insulin) signal to mTORC1 via Akt, which
inactivates TSC2 to prevent inhibition of mTORC1. Alternatively,
low ATP levels lead to the AMPK-dependent activation of TSC2 and
phosphorylation of raptor to reduce mTORC1 signaling proteins.
[0195] Active mTORC1 has a number of downstream biological effects
including translation of mRNA via the phosphorylation of downstream
targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy
(Atg13, ULK1), ribosome biogenesis, and activation of transcription
leading to mitochondrial metabolism or adipogenesis. Accordingly,
mTORC1 activity promotes either cellular growth when conditions are
favorable or catabolic processes during stress or when conditions
are unfavorable.
[0196] mTORC2 is composed of mTOR, rapamycin-insensitive companion
of mTOR (RICTOR), G.beta.L, and mammalian stress-activated protein
kinase interacting protein 1 (mSIN1). In contrast to mTORC1, for
which many upstream signals and cellular functions have been
defined (see above), relatively little is known about mTORC2
biology. mTORC2 regulates cytoskeletal organization through its
stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42,
and protein kinase C .alpha. (PKC.alpha.). It had been observed
that knocking down mTORC2 components affects actin polymerization
and perturbs cell morphology (Jacinto et al. (2004). Nat. Cell
Biol. 6, 1122-1128; Sarbassov et al. (2004). Curr. Biol. 14,
1296-1302). This suggests that mTORC2 controls the actin
cytoskeleton by promoting protein kinase C.alpha. (PKC.alpha.)
phosphorylation, phosphorylation of paxillin and its relocalization
to focal adhesions, and the GTP loading of RhoA and Rac1. The
molecular mechanism by which mTORC2 regulates these processes has
not been determined.
[0197] In some embodiments, the mTOR inhibitor is an inhibitor of
mTORC1. In some embodiments, the mTOR inhibitor is an inhibitor of
mTORC2.
[0198] In some embodiments, the mTOR inhibitor is a limus drug,
which includes sirolimus and its analogues. Examples of limus drugs
include, but are not limited to, temsirolimus (CCI-779), everolimus
(RAD001), ridaforolimus (AP-23573), deforolimus (MK-8669),
zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506). In
some embodiments, the limus drug is selected from the group
consisting of temsirolimus (CCI-779), everolimus (RAD001),
ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus
(ABT-578), pimecrolimus, and tacrolimus (FK-506).
[0199] In some embodiments, the mTOR inhibitor is sirolimus.
Sirolimus is macrolide antibiotic that complexes with FKBP-12 and
inhibits the mTOR pathway by binding mTORC1.
[0200] In some embodiments, the mTOR inhibitor is selected from the
group consisting of sirolimus (rapamycin), BEZ235 (NVP-BEZ235),
everolimus (also known as RAD001 and sold under the trademarks
Zortress.RTM., Certican.RTM., and Afinitor.RTM.), AZD8055,
temsirolimus (also known as CCI-779 and sold under the trademark
Torisel.RTM.), PI-103, Ku-0063794, INK 128, AZD2014, NVP-BGT226,
PF-04691502, CH5132799, GDC-0980 (RG7422), Torin 1, WAY-600,
WYE-125132, WYE-687, GSK2126458, PF-05212384 (PKI-587), PP-121,
OSI-027, Palomid 529, PP242, XL765, GSK1059615, WYE-354, and
eforolimus (also known as ridaforolimus or deforolimus).
[0201] BEZ235 (NVP-BEZ235) is an imidazoquilonine derivative that
is an mTORC1 catalytic inhibitor (Roper J, et al. PLoS One, 2011,
6(9), e25132). Everolimus is the 40-O-(2-hydroxyethyl) derivative
of rapamycin and binds the cyclophilin FKBP-12, and this complex
also mTORC1. AZD8055 is a small molecule that inhibits the
phosphorylation of mTORC1 (p70S6K and 4E-BP1). Temsirolimus is a
small molecule that forms a complex with the FK506-binding protein
and prohibits the activation of mTOR when it resides in the
mTORC1complex. PI-103 is a small molecule that inhibits the
activation of the rapamycin-sensitive (mTORC1) complex (Knight et
al. (2006) Cell. 125: 733-47). KU-0063794 is a small molecule that
inhibits the phosphorylation of mTORC1 at Ser2448 in a
dose-dependent and time-dependent manner. INK 128, AZD2014,
NVP-BGT226, CH5132799, WYE-687, and are each small molecule
inhibitors of mTORC1. PF-04691502 inhibits mTORC1 activity.
GDC-0980 is an orally bioavailable small molecule that inhibits
Class I PI3 Kinase and TORC1. Torin 1 is a potent small molecule
inhibitor of mTOR. WAY-600 is a potent, ATP-competitive and
selective inhibitor of mTOR. WYE-125132 is an ATP-competitive small
molecule inhibitor of mTORC1. GSK2126458 is an inhibitor of mTORC1.
PKI-587 is a highly potent dual inhibitor of PI3K.alpha.,
PI3K.gamma. and mTOR. PP-121 is a multi-target inhibitor of PDGFR,
Hck, mTOR, VEGFR2, Src and Abl. OSI-027 is a selective and potent
dual inhibitor of mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM,
respectively. Palomid 529 is a small molecule inhibitor of mTORC1
that lacks affinity for ABCB1/ABCG2 and has good brain penetration
(Lin et al. (2013) Int J Cancer DOI: 10.1002/ijc.28126 (e-published
ahead of print). PP242 is a selective mTOR inhibitor. XL765 is a
dual inhibitor of mTOR/PI3k for mTOR, p110.alpha., p110.beta.,
p110.gamma. and p110.delta.. GSK1059615 is a novel and dual
inhibitor of PI3K.alpha., PI3K.beta., PI3K.delta., PI3K.gamma. and
mTOR. WYE-354 inhibits mTORC1 in HEK293 cells (0.2 .mu.M-5 .mu.M)
and in HUVEC cells (10 nM-1 .mu.M). WYE-354 is a potent, specific
and ATP-competitive inhibitor of mTOR. Deforolimus (Ridaforolimus,
AP23573, MK-8669) is a selective mTOR inhibitor.
Other Components in the Nanoparticle Compositions
[0202] The nanoparticles described herein can be present in a
composition that include other agents, excipients, or stabilizers.
For example, to increase stability by increasing the negative zeta
potential of nanoparticles, certain negatively charged components
may be added. Such negatively charged components include, but are
not limited to bile salts of bile acids consisting of glycocholic
acid, cholic acid, chenodeoxycholic acid, taurocholic acid,
glycochenodeoxycholic acid, taurochenodeoxycholic acid, litocholic
acid, ursodeoxycholic acid, dehydrocholic acid and others;
phospholipids including lecithin (egg yolk) based phospholipids
which include the following phosphatidylcholines:
palmitoyloleoylphosphatidylcholine,
palmitoyllinoleoylphosphatidylcholine,
stearoyllinoleoylphosphatidylcholine
stearoyloleoylphosphatidylcholine,
stearoylarachidoylphosphatidylcholine, and
dipalmitoylphosphatidylcholine. Other phospholipids including
L-.alpha.-dimyristoylphosphatidylcholine (DMPC),
dioleoylphosphatidylcholine (DOPC), distearyolphosphatidylcholine
(DSPC), hydrogenated soy phosphatidylcholine (HSPC), and other
related compounds. Negatively charged surfactants or emulsifiers
are also suitable as additives, e.g., sodium cholesteryl sulfate
and the like.
[0203] In some embodiments, the composition is suitable for
administration to a human. In some embodiments, the composition is
suitable for administration to a mammal such as, in the veterinary
context, domestic pets and agricultural animals. There are a wide
variety of suitable formulations of the nanoparticle composition
(see, e.g., U.S. Pat. Nos. 5,916,596 and 6,096,331). The following
formulations and methods are merely exemplary and are in no way
limiting. Formulations suitable for oral administration can consist
of (a) liquid solutions, such as an effective amount of the
compound dissolved in diluents, such as water, saline, or orange
juice, (b) capsules, sachets or tablets, each containing a
predetermined amount of the active ingredient, as solids or
granules, (c) suspensions in an appropriate liquid, and (d)
suitable emulsions. Tablet forms can include one or more of
lactose, mannitol, corn starch, potato starch, microcrystalline
cellulose, acacia, gelatin, colloidal silicon dioxide,
croscarmellose sodium, talc, magnesium stearate, stearic acid, and
other excipients, colorants, diluents, buffering agents, moistening
agents, preservatives, flavoring agents, and pharmacologically
compatible excipients. Lozenge forms can comprise the active
ingredient in a flavor, usually sucrose and acacia or tragacanth,
as well as pastilles comprising the active ingredient in an inert
base, such as gelatin and glycerin, or sucrose and acacia,
emulsions, gels, and the like containing, in addition to the active
ingredient, such excipients as are known in the art.
[0204] Examples of suitable carriers, excipients, and diluents
include, but are not limited to, lactose, dextrose, sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose, water, saline solution,
syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc,
magnesium stearate, and mineral oil. The formulations can
additionally include lubricating agents, wetting agents,
emulsifying and suspending agents, preserving agents, sweetening
agents or flavoring agents.
[0205] Formulations suitable for parenteral administration include
aqueous and non-aqueous, isotonic sterile injection solutions,
which can contain anti-oxidants, buffers, bacteriostats, and
solutes that render the formulation compatible with the blood of
the intended recipient, and aqueous and non-aqueous sterile
suspensions that can include suspending agents, solubilizers,
thickening agents, stabilizers, and preservatives. The formulations
can be presented in unit-dose or multi-dose sealed containers, such
as ampules and vials, and can be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid excipient, for example, water, for injections, immediately
prior to use. Extemporaneous injection solutions and suspensions
can be prepared from sterile powders, granules, and tablets of the
kind previously described. Injectable formulations are
preferred.
[0206] In some embodiments, the composition is formulated to have a
pH range of about 4.5 to about 9.0, including for example pH ranges
of any of about 5.0 to about 8.0, about 6.5 to about 7.5, and about
6.5 to about 7.0. In some embodiments, the pH of the composition is
formulated to no less than about 6, including for example no less
than about any of 6.5, 7, or 8 (such as about 8). The composition
can also be made to be isotonic with blood by the addition of a
suitable tonicity modifier, such as glycerol.
Kits, Medicines, and Compositions
[0207] The invention also provides kits, medicines, compositions,
and unit dosage forms for use in any of the methods described
herein.
[0208] Kits of the invention include one or more containers
comprising limus drug-containing nanoparticle compositions (or unit
dosage forms and/or articles of manufacture) and/or another agent
(such as the agents described herein), and in some embodiments,
further comprise instructions for use in accordance with any of the
methods described herein. The kit may further comprise a
description of selection an individual suitable or treatment.
Instructions supplied in the kits of the invention are typically
written instructions on a label or package insert (e.g., a paper
sheet included in the kit), but machine-readable instructions
(e.g., instructions carried on a magnetic or optical storage disk)
are also acceptable.
[0209] For example, in some embodiments, the kit comprises a) a
composition comprising nanoparticles comprising mTOR inhibitor
(such as a limus drug) and an albumin (such as human serum
albumin), and b) instructions for administering the nanoparticle
composition for treatment of bladder cancer. In some embodiments,
the kit comprises a) a composition comprising nanoparticles
comprising mTOR inhibitor (such as a limus drug) and an albumin
(such as human serum albumin), b) an effective amount of another
agent, wherein the other agent inhibits microtubule disassembly,
and c) instructions for administering (such as administering
intravesicularly or intravenously) the nanoparticle composition and
the other agents for treatment of bladder cancer. The nanoparticles
and the other agents can be present in separate containers or in a
single container. For example, the kit may comprise one distinct
composition or two or more compositions wherein one composition
comprises nanoparticles and one composition comprises another
agent.
[0210] The kits of the invention are in suitable packaging.
Suitable packaging include, but is not limited to, vials, bottles,
jars, flexible packaging (e.g., seled Mylar or plastic bags), and
the like. Kits may optionally provide additional components such as
buffers and interpretative information. The present application
thus also provides articles of manufacture, which include vials
(such as sealed vials), bottles, jars, flexible packaging, and the
like.
[0211] The instructions relating to the use of the nanoparticle
compositions generally include information as to dosage, dosing
schedule, and route of administration for the intended treatment.
The containers may be unit doses, bulk packages (e.g., multi-dose
packages) or sub-unit doses. For example, kits may be provided that
contain sufficient dosages of the mTOR inhibitor (such as a limus
drug, e.g., sirolimus) as disclosed herein to provide effective
treatment of an individual for an extended period, such as any of a
week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks,
3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7
months, 8 months, 9 months, or more. Kits may also include multiple
unit doses of the mTOR inhibitor (such as a limus drug) and
pharmaceutical compositions and instructions for use and packaged
in quantities sufficient for storage and use in pharmacies, for
example, hospital pharmacies and compounding pharmacies.
[0212] Also provided are medicines, compositions, and unit dosage
forms useful for the methods described herein. In some embodiments,
there is provided a medicine (or composition) for use in treating
bladder cancer, comprising nanoparticles comprising an mTOR
inhibitor (such as a limus drug) and an albumin (such as human
serum albumin). In some embodiments, there is provided a medicine
(or composition or a unit dosage form) for use in treating bladder
cancer in conjunction with another agent, comprising nanoparticles
comprising a limus drug and an albumin (such as human serum
albumin), wherein the other agent inhibits microtubule disassembly.
In some embodiments, there is provided a medicine (or composition
or a unit dosage form) for use in treating bladder cancer,
comprising nanoparticles comprising a limus drug and an albumin
(such as human serum albumin) and another agent, wherein the other
agent inhibits microtubule disassembly.
Exemplary Embodiments
[0213] The present application in some embodiments provides a
method of treating bladder cancer in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a limus drug and an
albumin.
[0214] In some embodiments according to (e.g., as applied to) the
method above, the nanoparticle composition is administered
intravesicularly.
[0215] In some embodiments according to (e.g., as applied to) any
one of the methods above, the bladder cancer is non-muscle-invasive
bladder cancer.
[0216] In some embodiments according to (e.g., as applied to) any
one of the methods above, the bladder cancer is refractory to
treatment with BCG, mitomycin C, or interferon.
[0217] In some embodiments according to (e.g., as applied to) any
one of the methods above, the nanoparticle composition is
administered at least once weekly.
[0218] In some embodiments according to (e.g., as applied to) any
one of the methods above, the dose of limus drug in the
nanoparticle composition is about 5 mg to about 500 mg (such as
about 30 mg to about 400 mg.
[0219] In some embodiments according to (e.g., as applied to) any
one of the methods above, the nanoparticle composition is
administered at a volume of about 20 ml to about 150 ml.
[0220] In some embodiments according to (e.g., as applied to) any
one of the methods above, the nanoparticle composition is
administered intravesicularly, and wherein the composition is
retained in the bladder for about 30 minutes to about 4 hours.
[0221] In some embodiments according to (e.g., as applied to) any
one of the methods above, further comprising administering an
effective amount of a second therapeutic agent.
[0222] In some embodiments according to (e.g., as applied to) any
one of the methods above, the second therapeutic agent is an
immunotherapeutic agent, such as BCG. In some embodiments, the BCG
is administered intravesicularly, e.g., at the dose of about 8 mg
to about 100 mg.
[0223] In some embodiments according to (e.g., as applied to) any
one of the methods above, the method further comprises
administering to the individual a therapeutic agent. In some
embodiments, the therapeutic agent is selected from the group
consisting of an alkylating agent, an anthracycline antibiotic, an
antimetabolite, an indolequinone, a taxane, and a platinum-based
agent. In some embodiments, the therapeutic agent is selected from
the group consisting of mitomycin, epirubicin, doxorubicin,
valrubicin, gemcitabine, apaziquone, docetaxel, paclitaxel, and
cisplatin.
[0224] In some embodiments according to (e.g., as applied to) any
one of the methods above, the limus drug is sirolimus.
[0225] In some embodiments according to (e.g., as applied to) any
one of the methods above, the nanoparticles in the composition have
an average diameter of no greater than about 200 nm.
[0226] In some embodiments according to (e.g., as applied to) any
one of the methods above, the limus drug in the nanoparticles are
coated with albumin.
[0227] In some embodiments according to (e.g., as applied to) any
one of the methods above, the bladder cancer is urothelial
carcinoma.
[0228] In some embodiments according to (e.g., as applied to) any
one of the methods above, the bladder cancer is a high grade
bladder cancer.
[0229] In some embodiments according to (e.g., as applied to) any
one of the methods above, the individual is human.
[0230] In some embodiments according to (e.g., as applied to) any
one of the methods above, the individual is selected for treatment
based on the level of one of more of: p-S6K, pAKT, p-4EBP1, Ki67,
p53, p63, Stathmin, Tau, SPARC, p73, c-myc, and cyclin D1.
[0231] In some embodiments according to (e.g., as applied to) any
one of the methods above, further comprising determining the level
of one of more of: p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin,
Tau, SPARC, p73, c-myc, and cyclin D1 prior to treatment. In some
embodiments, the method further comprises selecting the individual
for treatment based on a high level of one or more of: p-S6K, pAKT,
p-4EBP1, Ki67, p53, p63, Stathmin, Tau, SPARC, p73, c-myc, and
cyclin D1.
[0232] In some embodiments according to (e.g., as applied to) any
one of the methods above, further comprising determining the level
of one of more of: p-S6K, pAKT, p-4EBP1, Ki67, p53, p63, Stathmin,
Tau, SPARC, p73, c-myc, and cyclin D1 after the treatment.
[0233] Those skilled in the art will recognize that several
embodiments are possible within the scope and spirit of this
invention. The invention will now be described in greater detail by
reference to the following non-limiting examples. The following
examples further illustrate the invention but, of course, should
not be construed as in any way limiting its scope.
EXAMPLES
Example 1
Phase 1 Clinical Trial for Establishing the Maximum Delivered Dose
(MDD) and Safety of Nab-Sirolimus (mTOR Inhibitor) for
Intravesicular Treatment of BCG-Refractory Non-Muscle Invasive
Bladder Cancer (NMIBC)
[0234] Patients with BCG-refractory NMIBC receive Nab-sirolimus
intravesicularly by sterile urethral catheterization following
resection of visible tumors during cystoscopy. This study enrolls
15 patients, 3 per cohort: 100 mg/week, 100 mg 2.times./week (total
weekly dose 200 mg), 300 mg/week, 200 mg 2.times./week (total
weekly dose 400 mg), and 400 mg/week for 6 weeks of treatment. For
each treatment, nab-sirolimus is reconstituted with 100 ml 0.9%
sodium chloride. Patients are instructed to keep the drug in the
bladder for 2 hours before voiding. If a National Cancer Institute
Common Toxicity Criteria (NCI CTC) v3.0 grade 2 local toxicity
develops, treatment is delayed for 1 dose and resume if the
toxicity resolves to grade 1 or less. A DLT (dose limiting
toxicity) is considered any grade 3 or 4 event, and the patient is
immediately removed from the trial. Dose escalation follows the 3+3
rule to establish the MDD. Six weeks after the last treatment,
patients undergo a cystoscopy and biopsy. A complete response (CR)
is defined as a cancer-negative biopsy at the 6-week
post-treatment.
[0235] If a patient has a CR, the patient receives additional
monthly maintenance instillations at the maximum dose that
particular patient received. Cystoscopic examinations are every 3
months, and the patient will receive therapy until disease
progression for a maximum of 6 additional instillations.
[0236] Systemic and local bladder toxicities are monitored
throughout treatment and maintenance therapy.
[0237] Collection and Processing of Samples: Physical exams and
collection of urine and blood samples are performed at enrollment,
treatment days, end of treatment, and 6-week follow up. Biopsies of
tumor and normal bladder tissue are taken pretreatment, once during
treatment prior to day 14 dosing, and at the 6-week post-treatment
cystoscopy.
[0238] Analysis: At each visit, patients are monitored for local
bladder toxicity as defined by the NCI CTC v3.0. At every visit,
patients' vitals (weight, blood pressure, and pulse) and updated
medical history are obtained. Urine samples are checked by dipstick
for pH and sent to the laboratory for analysis. Four hours after
the nab-sirolimus treatment, blood samples are taken for analysis
of serum sirolimus levels. Complete blood count, basic metabolic
panel, hepatic functional panel, lipid panel, and coagulation
profile are checked for signs of systemic toxicity.
Example 2
Efficacy of the Combination of Intravesicular Nab-Sirolimus and BCG
in a Genetically Engineered Mouse Model of Bladder Cancer
[0239] This preclinical study uses an animal model of progressive
bladder cancer. These genetically engineered mice have a targeted
deletion of p53 and PTEN in the bladder epithelium. This combined
deletion of p53 and PTEN in the bladder epithelium after the
delivery of Adeno-Cre results in CIS development at .about.6 weeks
after injection, resembling the human disease. Thus, we initiate
treatment at 6 weeks after Adeno-Cre injection. We use only female
mice in our study as an angiocatheter can be easily passed through
the urethra compared to male mice whose urethras are more
convoluted.
[0240] Surgery: After adequate sedation is achieved with
inhalational anesthesia, a lubricated angiocatheter (24G) is passed
through the urethra. The bladder is irrigated with sterile PBS to
ensure return of urine and thus, proper positioning in the bladder.
Urine will be removed and discarded. Treatment will be delivered
via the angiocatheter and into the bladder. Silk suture (5-0) is
secured around the urethra to prevent intravesicular treatment from
being expelled. Suture remains in place be until a treatment time
of 2 hours is achieved.
[0241] Doses: A preliminary in vitro study determines if
Nab-sirolimus has any effect on BCG viability. A pilot study is
performed to determine tolerable dosage of single agents and
combination therapy. We start with a BCG dose of 2.times.10.sup.6
CFU/ml based on the clinically used dose (1-8.times.10.sup.6
CFU/ml), and the dose used in a previous preclinical study with
BCG-based combination therapy. For Nab-sirolimus, we start with an
initial intravesicular dose of 15 mg/kg. After the conclusion of
the pilot study, we establish the specific study dose in mice
(n=15/group). Treatment duration is 6 weeks. The single agent
cohort undergoes once weekly treatments of either BCG or
nab-sirolimus, with a total indwell time of 2 hours. The
combination cohort receives BCG on Monday, then Nab-sirolimus on
Thursday. A control group receives vehicle once weekly. Biweekly
weights are utilized to assess drug toxicity. Mice with body weight
loss of 10-15% or sick appearance is euthanized for humane reasons.
As an endpoint, if the tumor is greater than 1.5 cm, the mice is
euthanized.
[0242] Collection and Processing of Samples: Periodic
ultrasonography will be performed prior to treatment and every 2
weeks thereafter to monitor presence of tumor and tumor size.
Throughout the course of the preclinical trial, we observe the mice
for any physical signs of distress or loss of body weight (10-15%),
which could indicate toxicity or infection.
[0243] Analysis: All surviving mice are sacrificed after 6 weeks of
intravesicular treatment for evaluation of bladder size, weight,
and immunohistochemistry (IHC) analysis. IHC analysis includes
hematoxylin and eosin (H&E) staining, markers of the mTOR
pathway (pS6, p-AKT, p-4EBP1), and markers of immune cells (to
identify macrophages, dendritic cells, T-cells, etc).
Example 3
Evaluation of the Systemic and Target Tissue Drug Exposure of
Intravesicular Nab-Sirolimus in Patients with NMIBC
[0244] During phase 1/2 clinical trials, blood samples are taken 4
hours after nab-sirolimus administration, collected in EDTA-treated
tubes, and stored at -80.degree. C. until analysis. The bladder
tissue biopsy samples for measuring sirolimus levels (5 samples per
patient) are taken via cystoscopy just prior to dosing on day 14.
The tissue samples are collected into 15 ml cryovials, flash frozen
on dry ice, and stored at -80.degree. C. until analysis.
[0245] Analysis: Sirolimus levels in serum and in bladder tissue
samples are measured by liquid chromatography/mass spectrometry
(LC/MS). Sirolimus concentrations in the target bladder tissue are
correlated with clinical efficacy data, and pharmacodynamic
biomarkers to help establish effective biological dose.
Example 4
Evaluation of Target Biomarker Suppression and Other Relevant
Molecular Markers in Patient Tissue Samples
[0246] We evaluate the activated mTOR levels at baseline and at
6-week post-treatment, which help to determine the clinical value
for pretreatment screening of patient population. Demonstration of
mTOR pathway suppression following treatment can provide clear
indication of the specificity and efficacy of nab-sirolimus and
potentially predict clinical response. Several biomarkers are
particular relevant to the mTOR pathway (p-S6K, p-AKT, p-4EBP1),
and bladder cancer (Ki67) and will be examined. P-S6 is a biomarker
of mTOR pathway activation, which is expected to be reduced when
mTOR activity is inhibited. Ki67 is a cellular marker for
proliferation and is elevated in bladder cancer. Following
inhibition of mTORC1 by sirolimus and its analogues, the p-Akt is
increased through feedback activation with mTORC2, which may result
in side effects and resistance of sirolimus treatment. Other
potential molecular markers would include p53, p63, Stathmin, Tau,
Ki67, and SPARC.
[0247] Collection and Processing of Samples: Prior to treatment,
tumor and normal tissues samples are collected by resection of
visible tumors during cystoscopy. Additional normal tissue samples
(and tumor samples if available) are collected prior to the 14-day
treatment and at 6-weeks post-treatment cystoscopy. The samples are
immediately frozen and sectioned.
[0248] Analysis: The samples are analyzed by immunohistochemistry
(H&E staining, and with antibodies against p-S6K, p-AKT,
p-4EBP1, etc). The slides are scored by a pathologist for staining
intensity of different biomarkers. Quantification of proliferating
cells are done as described previously. The biomarker status at
baseline and during treatment are correlated with clinical
responses with Fisher's exact test to investigate the predictive
value of these biomarkers for NMIBC patients treated with
intravesicular Nab-sirolimus therapy.
Example 5
Phase 2 Clinical Study to Evaluate the Efficacy, Safety, and
Potential Predictive Biomarkers of Intravesicular Nab-Sirolimus in
BCG-Refractory NMIBC
[0249] Research Design: The clinical phase 1 dose escalation study
is expanded into this clinical phase 2 study with up to 29 patients
enrolled at the MDD to evaluate the utility of nab-sirolimus in the
treatment of BCG-refractory NMIBC as measured by rate of complete
responders. We enroll 10 patients in the first stage (Simon 2-stage
method). If 2 or more patients respond, we enroll an additional 19
in the second stage. If only 1 or no response is observed in the
first stage, we terminate the study for lack of efficacy. Based on
our operating characteristic of 5% type I error and 20% type II
error, the number of patients that is expected to be enrolled will
be 15 on average with a maximum total of 29 in order to
sufficiently power the study. Patient treatment protocol is the
same as the phase 1 study. If a patient has a CR, the patient
receive additional monthly maintenance instillations at the MDD.
Cystoscopic examinations will be performed every 3 months, and the
patient continue therapy until disease progression or for a maximum
6 additional instillations. Patients are monitored for local and
systemic toxicities throughout the study and maintenance
therapy.
[0250] Collection and Processing of Samples: Patient tumor and
normal bladder tissue samples are taken prior to, during, and after
treatment. Blood and urine samples will also be taken at multiple
time points as described preciously.
[0251] Analysis: Patient samples are evaluated following procedures
described above. A CR is defined as a cancer-negative biopsy at the
6-week post-treatment cystoscopy. Safety assessment is per standard
NCI criteria.
Example 6
Phase 2 Clinical Study to Evaluate the Efficacy, Safety, and
Potential Predictive Biomarkers of Intravesicular Nab-Sirolimus
Plus BCG in BCG-Refractory NMIBC
[0252] Research Design: BCG is dosed at the clinically used weekly
intravesicular dose of 81 mg BCG in 50 ml saline. BCG can also be
used at half or one third of the standard 81 mg dose. With the
established MDD of Nab-sirolimus, up to 20 patients are treated
with a combination of intravesicular nab-sirolimus plus BCG.
Patient enrollment and statistical considerations are similar to
the study above, with 2 stages of enrollment. Scheduling of the
combination treatment (drugs given together or sequentially) are
determined from Example 2.
[0253] Collection and Processing of Samples: Patient tumor and
bladder tissue samples are taken prior to, during, and after
treatment. Blood and urine samples (for cytokine levels as
indicators of local immune response) are also taken at multiple
time points.
[0254] Analysis: Patient samples are evaluated following procedures
listed above. Patients are evaluated for efficacy by cystoscopy and
biopsy 6 weeks post-treatment. A CR is defined as a cancer-negative
biopsy at the 6-week post-treatment cystoscopy.
Example 7
Phase 2 Clinical Study to Evaluate the Efficacy and Safety of
Intravesicular Nab-Sirolimus and Mitomycin C Combination in
BCG-Refractory NMIBC
[0255] Design: Appropriate dose of nab-sirolimus is reconstituted
in 80-100 mL saline and administered through intravesicular
catheters for a weekly 1-2 hour treatment of 6 weeks. Mitomycin C
is dosed intravesicularly at 40 mg in 40 mL of sterile water for
injection, once weekly for 6 weeks. Up to 20 patients are treated
with a combination of intravesicular nab-sirolimus and mitomycin C.
Scheduling of the combination treatment is determined from outcomes
of Aims 1 and 3. The drugs are given sequentially on the same day,
each with 2 hours retention in the bladder. If a patient has a CR,
the patient receives additional monthly maintenance instillations
of Nab-sirolimus and mitomycin C. Cystoscopic examinations are
performed every 3 months, and the patient continue therapy until
disease progression or for a maximum 6 additional instillations.
Patients are monitored for local and systemic toxicities throughout
the study and maintenance therapy
[0256] Collection and Processing of Samples: Physical exams and
collection of urine and blood samples are performed at enrollment,
treatment days, end of treatment, and 6-week follow up. Biopsies of
tumor and normal bladder tissue will be taken by cystoscopy
pretreatment, once during treatment prior to day 14 dosing, and at
the 6-week post-treatment.
[0257] Analysis: Patient samples are evaluated following procedures
above. Patients will be evaluated for efficacy by cystoscopy and
biopsy 6 weeks post-treatment.
Example 8
Efficacy of the Combination of Nab-Sirolimus and Various Agents in
a Xenograft Model (T24) of Bladder Cancer
[0258] T24 human bladder cancer cells are cultured at 37.degree. C.
and 5% CO2 in RPMI 1640 supplemented with 10% FBS, 100 U/mL
penicillin and 100 .mu.g/mL streptomycin, 800 mg/L NaHCO3 and 3.6 g
HEPES. Male NCr nu/nu nude mice will be used. The study will
require 100 mice, 5 to 6 weeks old. Animal weight will be 20-30
grams on the day of implantation. Animals are identified by cage
number and ear punch. Approximately one hundred mice are used for
the study once the average tumor volumes reach approximately 100
mm.sup.3. The mice will be randomly assigned to 10 study groups
with 10 animals in each group prior to dosing. The study groups and
treatment schedules are listed in the Table below.
TABLE-US-00001 Group Treatment (N = 10) Dosing Schedule A Saline
weekly for 3 weeks, IV B nab-sirolimus (nab-S) 40 mg/kg, weekly for
3 weeks, IV C Mitomycin C (MMC) 1 mg/kg, weekly for 3 weeks, IP D
Cisplatin (Cis) 3 mg/kg, weekly for 3 weeks, IP E Gemcitabine (Gem)
50 mg/kg, weekly for 3 weeks, IP F Valrubicin (Val) 30 mg/kg,
weekly for 3 weeks, IP G MMC + nab-S Mitomycin C administered
immediately prior to nab-S H Cis + nab-S Cisplatin administered
immediately prior to nab-S I Gem + nab-S Gemcitabine administered
immediately prior to nab-S J Val + nab-S Valrubicin administered
immediately prior to nab-S
[0259] To compare the antitumor activity of the combination
treatment versus single agents, 10 treatment groups with mice
bearing T24 human bladder cancer xenografts are used, including
saline control, nab-sirolimus, mitomycin C, cisplatin, gemcitabine,
valrubicin, and the combination treatment groups of mitomycin C,
cisplatin, gemcitabine, or valrubicin each in combination with
nab-sirolimus. The mice are treated for 4 weeks, and the tumors are
measured with a digital caliper twice weekly until the end of
study. Animal body weights are measured twice weekly, and animals
are monitored for any physical signs of distress or significant
loss of body weight (10-15%).
[0260] Analysis: Tumor size data are analyzed for tumor growth
inhibition by each treatment regimen. Statistical analysis of tumor
growth curves are performed using ANOVA.
Example 9
Phase 2 Clinical Study to Evaluate the Efficacy and Safety of
Intravesicular Nab-Sirolimus and Gemcitabine Combination in
BCG-Refractory NMIBC
[0261] Design: Appropriate dose of nab-sirolimus is reconstituted
in 100 mL saline and administered through intravesicular catheters
for a treatment of 6 weeks. Gemcitabine is dosed intravesically at
a dose of 2 g in approx 50 ml once weekly for 6 weeks for 1-2
hours. Up to 20 patients are treated with a combination of
intravesicular nab-sirolimus and mitomycin C. The drugs are given
sequentially on the same day, each with 2 hours retention in the
bladder. If a patient has a CR, the patient receives additional
monthly maintenance instillations of Nab-sirolimus and mitomycin C.
Cystoscopic examinations are performed every 3 months, and the
patient continues therapy until disease progression or for a
maximum 6 additional instillations. Patients are monitored for
local and systemic toxicities throughout the study and maintenance
therapy
[0262] Collection and Processing of Samples: Physical exams and
collection of urine and blood samples are performed at enrollment,
treatment days, end of treatment, and 6-week follow up. Biopsies of
tumor and normal bladder tissue will be taken by cystoscopy
pretreatment, once during treatment prior to day 14 dosing, and at
the 6-week post-treatment.
[0263] Analysis: Patient samples are evaluated following procedures
above. Patients will be evaluated for efficacy by cystoscopy and
biopsy 6 weeks post-treatment.
* * * * *