U.S. patent application number 14/550509 was filed with the patent office on 2015-03-19 for methods and compositions for treating recurrent cancer.
This patent application is currently assigned to Abraxis BioScience, LLC. The applicant listed for this patent is Abraxis BioScience, LLC. Invention is credited to Neil P. DESAI, Patrick SOON-SHIONG.
Application Number | 20150079181 14/550509 |
Document ID | / |
Family ID | 39733105 |
Filed Date | 2015-03-19 |
United States Patent
Application |
20150079181 |
Kind Code |
A1 |
DESAI; Neil P. ; et
al. |
March 19, 2015 |
METHODS AND COMPOSITIONS FOR TREATING RECURRENT CANCER
Abstract
The present invention provides methods of treating recurrent
cancer (such as recurrent ovarian, peritoneal, or fallopian tube
cancer) in an individual, comprising administering to the
individual an effective amount of a composition (such as
Nab-paclitaxel or Abraxane.RTM.) comprising nanoparticles
comprising a taxane and a carrier protein.
Inventors: |
DESAI; Neil P.; (Los
Angeles, CA) ; SOON-SHIONG; Patrick; (Los Angeles,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abraxis BioScience, LLC |
Los Angeles |
CA |
US |
|
|
Assignee: |
Abraxis BioScience, LLC
Los Angeles
CA
|
Family ID: |
39733105 |
Appl. No.: |
14/550509 |
Filed: |
November 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12600991 |
May 10, 2010 |
8927019 |
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14550509 |
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Current U.S.
Class: |
424/489 ;
514/15.2; 514/449 |
Current CPC
Class: |
A61K 38/38 20130101;
A61K 47/42 20130101; A61K 47/643 20170801; A61K 9/5169 20130101;
A61P 35/00 20180101; A61P 9/14 20180101; A61K 31/337 20130101; A61K
31/282 20130101; A61K 31/555 20130101; A61K 38/38 20130101; A61K
31/337 20130101; Y10S 977/773 20130101; A61P 35/04 20180101; Y10S
977/906 20130101; A61K 47/6929 20170801; A61K 2300/00 20130101;
A61K 31/555 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/489 ;
514/449; 514/15.2 |
International
Class: |
A61K 47/42 20060101
A61K047/42; A61K 31/282 20060101 A61K031/282; A61K 47/48 20060101
A61K047/48; A61K 31/337 20060101 A61K031/337 |
Claims
1. A method of treating a recurrent ovarian, peritoneal, or
fallopian tube cancer in an individual, comprising administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a taxane and a carrier protein.
2. The method of claim 1, wherein the recurrent ovarian,
peritoneal, or fallopian cancer is platinum-sensitive.
3. The method of claim 1, wherein the individual has received a
prior platinum-based chemotherapy and has a treatment free interval
of more than about 12 months since the completion of the
platinum-based chemotherapy.
4. The method of claim 1, wherein the composition comprising
nanoparticles comprising a taxane and a carrier protein is
administered alone.
5. The method of claim 1, wherein the taxane is paclitaxel.
6. The method of claim 1, wherein the carrier protein is
albumin.
7. The method of claim 1, wherein the nanoparticles in the
composition have an average or mean diameter of less than about 200
nm.
8. The method of claim 7, wherein the composition comprising
nanoparticles comprising a taxane and a carrier protein is
Nab-paclitaxel.
9-12. (canceled)
13. A method of treating a recurrent ovarian, peritoneal, or
fallopian tube cancer in an individual, comprising administering to
the individual: a) an effective amount of a composition comprising
nanoparticles comprising a taxane and a carrier protein, and b) an
effective amount of a platinum-based agent.
14. The method of claim 13, wherein the composition comprising
nanoparticles and the platinum-based agent are concurrently
administered.
15. The method of claim 13, wherein the platinum-based agent is
carboplatin.
16. The method of claim 13, wherein the individual has received a
prior platinum-based chemotherapy and has a treatment free interval
of more than about 12 months since the completion of the
platinum-based chemotherapy.
17. The method of claim 13, wherein the taxane is paclitaxel.
18. The method of claim 13, wherein the carrier protein is
albumin.
19. The method of claim 13, wherein the nanoparticles in the
composition have an average or mean diameter of less than about 200
nm.
20. The method of claim 19, wherein the composition comprising
nanoparticles comprising a taxane and a carrier protein is
Nab-paclitaxel.
21. The method of claim 13, wherein the individual has received a
prior chemotherapy and has a treatment free interval for more about
6 months prior to the initiation of the treatment.
22. The method of claim 13, wherein the individual does not show a
symptom of hypersensitivity prior to the initiation of the
treatment.
23. The method of claim 13, wherein the individual does not show a
symptom resulting from the recurrent cancer upon completion of the
treatment.
24. The method of claim 13, wherein the individual has a reduced
CA-125 level upon completion of the treatment.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of the U.S.
Provisional Patent Application No. 60/932,750 filed on Jun. 1,
2007, the content of which is incorporated herein by reference in
its entirety.
TECHNICAL FIELD
[0002] The present invention relates to methods and compositions
for the treatment of recurrent cancer, particularly recurrent
ovarian cancer, comprising the administration of compositions
comprising nanoparticles comprising taxane and a carrier protein
(such as albumin).
BACKGROUND
[0003] Ovarian cancer forms in tissues of an ovary (one of a pair
of female reproductive glands in which the ova, or eggs, are
formed). Most ovarian cancers are either ovarian epithelial
carcinomas (cancer that begins in the cells on the surface of the
ovary) or malignant germ cell tumors (cancer that begins in egg
cells). According to the National Cancer Institute, ovarian cancer
is the seventh most common cancer, with an estimated 20,180 new
cases in 2006, but is the fourth most deadly, with an estimated
15,310 deaths in 2006.
[0004] A possible genetic contribution to ovarian cancer risk is
indicated by the increased incidence of this cancer among women
with a family history, and by the observation of rare families in
which multiple family members are affected with ovarian cancer, in
a pattern compatible with autosomal dominant inheritance of cancer
susceptibility. Formal studies of families (linkage analysis) have
subsequently proven the existence of autosomal dominant
predispositions to ovarian cancer and have led to the
identification of several highly penetrant genes as the cause of
inherited cancer risk in many cancer-prone families. Mutations in
these genes are rare in the general population and are estimated to
account for no more than 5% to 10% of ovarian cancer cases
overall.
[0005] Although reproductive, demographic, and lifestyle factors
affect risk of ovarian cancer, the single greatest ovarian cancer
risk factor is a family history of the disease. A large
meta-analysis of 15 published studies estimated an odds ratio (OR)
of 3.1 for the risk of ovarian cancer associated with at least one
first-degree relative with ovarian cancer.
[0006] Despite recent improvements, initial or first-line
chemotherapy fails to produce a remission in more than 70% of
patients with ovarian cancer. Furthermore, approximately 40-50% of
the women who do achieve a remission after first-line chemotherapy
will experience a recurrence of cancer within 3 years. Patients
with recurrent ovarian, peritoneal, or fallopian tube cancer
generally have a poor outcome with current therapies. There is a
need for effective treatment method for patients with recurrent
ovarian cancers. Preferably, the treatments overcome the
shortcomings of current drug and transplant treatments, such as
hypersensitivity reactions due to the solvent/surfactant in which
drugs are dissolved.
[0007] Many anti-proliferative agents are dissolved in a
solvent/surfactant which produces hypersensitivity reactions. Great
efforts have been invested on the development of water soluble
prodrugs and derivatives of anti-proliferative agents with higher
hydrophilic groups to enhance water solubility and thus obviate the
need for potentially toxic solvents/surfactants. Another approach
to address the problem associated with the poor water solubility of
anti-proliferative agents is the development of various
formulations such as nanoparticles, oil-in-water emulsions, and
liposomes. For example, Abraxane.RTM. is a nanoparticle composition
of paclitaxel and albumin. Nanoparticle compositions of
substantially poorly water soluble drugs and uses thereof have been
disclosed, for example, in U.S. Pat. Nos. 5,916,596; 6,096,331;
6,749,868; and 6,537,579; U.S. Patent Appln. Pub. No.
US20030199425; and PCT Application Pub. Nos. WO98/14174,
WO99/00113, WO07/027941 and WO07/027819. Administration of
Abraxane.RTM. to a patient with recurrent ovarian cancer is
described in Mida et al., Gynecologic Oncology, 100:437-438
(2006).
[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 for the treatment of
a recurrent cancer (such as a recurrent gynecological cancer) by
administering a composition comprising nanoparticles comprising a
taxane and a carrier protein (hereinafter referred to as "taxane
nanoparticle composition"). In some embodiments, there is provided
a method of treating a recurrent cancer (such as a recurrent
gynecological cancer, for example recurrent ovarian, peritoneal, or
fallopian tube cancer) in an individual, comprising administering
to the individual an effective amount of a composition comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin). In some embodiments, the
recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) is
platinum sensitive. In some embodiments, the recurrent cancer (such
as a recurrent gynecological cancer, for example recurrent ovarian,
peritoneal, or fallopian tube cancer) is platinum resistant. In
some embodiments, the recurrent cancer is a recurrent lung
cancer.
[0010] In some embodiments, the recurrent cancer is a recurrent
gynecological cancer. In some embodiments, the recurrent
gynecological cancer is a recurrent ovarian cancer (such as a
recurrent epithelial ovarian cancer). In some embodiments, the
recurrent gynecological cancer is a recurrent peritoneal cancer. In
some embodiments, the recurrent gynecological cancer is a recurrent
fallopian tube cancer (including for example papillary serous
adenocarcinomas, sarcomas, and transitional cell carcinomas). Other
recurrent gynecological cancers such as recurrent malignant mixed
mullerian tumor and serous endo can also be treated.
[0011] In some embodiments, the individual is a woman who is about
40 to about 85 years old, including for example about 60 to about
70 years old. In some embodiments, the individual has an Eastern
Cooperative Oncology Group (ECOG) performance status of 0-2 (such
as any of 0, 1, or 2) prior to the administration of the taxane
nanoparticie composition. In some embodiments, the individual has
received a prior cancer therapy (such as chemotherapy) and has a
treatment free interval for more than about any of 3, 6, or 9
months since the completion of prior chemotherapy. In some
embodiments, the individual has received a prior cancer therapy
(such as chemotherapy) and has a treatment free interval for more
than about any of 12, 18, 24, 36, or 48 months since the completion
of prior chemotherapy. In some embodiments, the prior chemotherapy
has a different mechanism of action than that of the taxane. In
some embodiments, the individual has only been treated with
platinum-based agent(s) prior to the administration of the taxane
nanoparticle composition. In some embodiments, the individual has
only been treated with one dosing regime prior to the
administration of the taxane nanoparticle composition. In some
embodiments, the individual has not previously been treated with a
taxane-based therapy.
[0012] In some embodiments, the individual has received a prior
cancer therapy (such as chemotherapy) and has a treatment free
interval for more than about any of 3, 6, or 9 months prior to the
initiation of the methods described herein. In some embodiments,
the individual has received a prior cancer therapy (such as
chemotherapy) and has a treatment free interval for more than about
any of 12, 18, 24, 36, or 48 months prior to the initiation of the
methods described herein. In some embodiments, the individual does
not show a symptom of hypersensitivity (such as neuropathy) prior
to the initiation of the methods described herein (such as within
12, 9, 6, 5, 4, 3, 2, or 1 month prior to the initiation of the
methods described herein). In some embodiments, the individual does
not show a symptom of hypersensitivity throughout the treatment
period with methods described herein. In some embodiments, the
individual does not show a symptom of hypersensitivity upon
completion of the treatment with methods described herein.
[0013] In some embodiments when the method is directed to treatment
of a recurrent ovarian, peritoneal, or fallopian tube cancer, the
individual may be confirmed of having an ovarian, peritoneal, or
fallopian tube cancer histologically or cytologically. In some
embodiments, the individual is determined to have an ovarian,
peritoneal, or fallopian tube cancer based on RECIST (Response
Evaluation Criteria in Solid Tumors). In some embodiments, the
individual has an elevated blood level of Cancer Antigen 125
(CA-125, for example a CA-125 level of more than about 40, 50, 60,
70, 80, or 90 units/ml, or about 2.times., 3.times., 4.times., or
more of that of the upper limit of a normal CA-125 level). In some
embodiments, the individual has an altered level of a marker that
is indicative of an ovarian, peritoneal, or fallopian tube
cancer.
[0014] In some embodiments, the individual satisfies at least two
of the criteria described above. For example, in some embodiments,
the individual has a measurable disease by RECIST and an elevated
blood level of CA-125. In some embodiments, the individual is
confirmed of having an ovarian cancer histologically or
cytologically and has only been treated with platinum-based
agent(s) prior to administration of the nanoparticle compositions
described above. In some embodiments, the individual satisfies at
least any of two, three, four, five, or more criteria described
above. In some embodiments, the individual satisfies all criteria
described above.
[0015] In some embodiments, the recurrent cancer (such as recurrent
ovarian cancer) is platinum-sensitive. For example, in some
embodiments, the individual has received prior platinum-based
chemotherapy and has a treatment-free interval for more than about
any of 3, 6, or 9 months since the completion of the platinum-based
chemotherapy. In some embodiments, the individual has received
prior platinum-based chemotherapy and has a treatment-free interval
for more than about any of 12, 18, 24, 36, or 48 months since the
completion of the platinum-based chemotherapy. Platinum-based
chemotherapy includes, but is not limited to, treatment with
carboplatin, cisplatin, and oxaliplatin. In some embodiments, the
platinum-based chemotherapy is treatment with carboplatin.
[0016] The methods described herein comprise administering to the
individual an effective amount of a composition comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin). In some embodiments, the taxane
nanoparticle composition is administered in conjunction with
another chemotherapeutic agent (such as a platinum-based agent).
For example, the taxane nanoparticle composition and the other
chemotherapeutic agent (such as a platinum-based agent) can be
administered sequentially, simultaneously, or concurrently. In some
embodiments, the other chemotherapeutic agent (such as
platinum-based agent) is administered in the same composition as
the nanoparticles comprising taxane and carrier protein. The other
chemotherapeutic agent (such as platinum-based agent) can also be
formulated into a nanoparticle composition as described herein.
[0017] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent. In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual a) an
effective amount of a composition comprising nanoparticles
comprising paclitaxel and an albumin (such as Abraxane.RTM.), and
b) an effective amount of a platinum-based agent. Suitable
platinum-based agents include, but are not limited to, carboplatin,
cisplatin, and oxaliplatin. In some embodiments, the platinum-based
agent is carboplatin. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent are administered
simultaneously. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent are administered
sequentially. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent is administered
concurrently.
[0018] In some embodiments, there is provided a method of treating
a recurrent ovarian cancer in an individual, comprising
administering to the individual: a) an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin), and b) an
effective amount of a platinum-based agent. In some embodiments,
there is provided a method of treating a primary peritoneal cancer
in an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent.
[0019] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent, wherein the taxane nanoparticle composition and the
platinum-based agent are administered concurrently. In some
embodiments, there is provided a method of treating a recurrent
cancer (such as a recurrent gynecological cancer, for example
recurrent ovarian, peritoneal, or fallopian tube cancer) in an
individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a paclitaxel and an albumin (such as Abraxane.RTM.), and
b) an effective amount of a platinum-based agent, wherein the
paclitaxel nanoparticle composition and the platinum-based agent
are administered concurrently.
[0020] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering (for example intravenously
or intraperitoneally) to the individual: a) an effective amount of
a composition comprising nanoparticles comprising a paclitaxel and
an albumin (such as Abraxane.RTM.), wherein the amount of the
paclitaxel in the composition is at least about 40 mg/m.sup.2
(including for example about any of 50 mg/m.sup.2, 60 mg/m.sup.2,
70 mg/m.sup.2, 80 mg/m.sup.2, 90 mg/m.sup.2, 100 mg/m.sup.2, 150
mg/m.sup.2, or 200 mg/m.sup.2); b) an effective amount of a
platinum-based agent (such as the platinum-based agent at the
amount of AUC3, AUC4, or AUC6), wherein the taxane nanoparticle
composition and the platinum-based agent are administered
concurrently. In some embodiments, the method comprises
administering a composition comprising nanoparticles comprising
paclitaxel and an albumin (such as Abraxane.RTM.) at about 100
mg/m.sup.2, three out of four weeks, and a platinum-based agent
(such as carboplatin) AUC6 every four weeks in the same treatment
cycle. In some embodiments, the method comprises administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and a platinum-based agent (such as carboplatin)
AUC5 every four weeks in the same treatment cycle. In some
embodiments, the method comprises intravenously administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and intravenously administering a platinum-based
agent (such as carboplatin) AUC5 every four weeks in the same
treatment cycle. In some embodiments, the individual is treated
with at least any of about one, two, three, four, five, six, seven,
eight, or more such treatment cycles.
[0021] In some embodiments, there is provided a method of treating
recurrent ovarian cancer, comprising intravenously administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and intravenously administering a platinum-based
agent (such as carboplatin) AUC5 (or AUC6) every four weeks in the
same treatment cycle. In some embodiments, there is provided a
method of treating primary peritoneal cancer, comprising
intravenously administering a composition comprising nanoparticles
comprising paclitaxel and an albumin (such as Abraxane.RTM.) at
about 100 mg/m.sup.2, three out of four weeks, and intravenously
administering a platinum-based agent (such as carboplatin) AUC5 (or
AUC6) every four weeks in the same treatment cycle. In some
embodiments, the individual is treated with at least any of about
one, two, three, four, five, six, seven, eight, or more such
treatment cycles.
[0022] In some embodiments, the taxane nanoparticle composition is
not administered in conjunction with a platinum-based agent, that
is, the taxane nanoparticle composition is either administered in a
monotherapy dosing regime or administered in conjunction with a
chemotherapeutic agent other than a platinum-based agent. In some
embodiments, a platinum-based agent is not administered to the
individual during the time period in which the individual is
receiving one or more doses of the taxane nanoparticle composition.
In some embodiments, the individual is not treated with a
platinum-based agent concurrently with the administration of the
taxane nanoparticle composition.
[0023] In some embodiments, the taxane nanoparticle composition can
be administered alone, that is, the taxane nanoparticle is
administered in a monotherapy dosing regime. For example, in some
embodiments, the amount of the taxane nanoparticle composition
administered alone is sufficient to result in a complete response
in the individual. In some embodiments, the amount of the taxane
nanoparticle composition administered alone is sufficient to result
in a partial response in the individual. In some embodiments, the
amount of the taxane nanoparticle composition administered alone is
sufficient to produce an overall response rate of more than about
any of 40%, 50%, 60%, or 64% among a population of individuals
treated with the taxane nanoparticle composition. In some
embodiments, the amount of taxane nanoparticle composition
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 taxane nanoparticle composition.
[0024] The taxane nanoparticle compositions described herein
comprise nanoparticles comprising taxane (such as paclitaxel) and a
carrier protein. In some embodiments, the taxane is paclitaxel,
docetaxel, ortataxel, or IDN5390. In some embodiments, the carrier
protein is albumin, such as human serum albumin. In some
embodiments, the weight ratio of the carrier protein to the taxane
in the taxane nanoparticle composition is less than about 18:1
(including for example less than about any of 15:1, 12:1, 10:1,
such as 9:1).
[0025] In some embodiments, the nanoparticles comprise the taxane
coated with a coating comprising the carrier protein (such as
albumin). In some embodiments, the coating consists essentially of
or consists of the carrier protein. In some embodiments, at least a
portion of the carrier protein in the nanoparticle portion of the
taxane nanoparticle composition is crosslinked (for example
crosslinked by disulfide bonds). In some embodiments, the
nanoparticles of the composition comprise at least 5% (including
for example at least any of 10%, 15%, 20%, or 25%) of carrier
protein that is cross-linked.
[0026] In some embodiments, the average or mean diameter of the
nanoparticles in the composition is no greater than about 200 nm.
In some embodiments, the average or mean diameter of the particles
is between about 20 nm to about 400 nm (such as about 40 nm to
about 200 nm). In some embodiments, the nanoparticles are
sterile-filterable. In some embodiments, the taxane in the
nanoparticles is amorphous. In some embodiments, the nanoparticles
are substantially free of polymeric core materials. In some
embodiments, the nanoparticles comprise a core of taxane that is
substantially free of polymeric materials (such as polymertic
matrix). In some embodiments, the nanoparticles in the composition
have a solid core. In some embodiments, the nanoparticles in the
composition have a core that is not aqueous (i.e., other than
aqueous core). In some embodiments, the nanoparticles of the
composition are substantially free of lipids. In some embodiments,
the nanoparticles of the composition are free of lipids.
[0027] In some embodiments, the composition comprises more than
about 50% (for example more than about any of 60%, 70%, 80%, 90%,
or 95%) of the taxane in nanoparticle form. In some embodiments,
the weight percentage of the taxane in the nanoparticle portion of
the taxane nanoparticle composition is at least about any of 50%,
60%, 70%, 80%, 90%, or 95% of the total weight of the nanoparticle
portion of the composition.
[0028] In some embodiments, the composition is administered at
least about any of once every three weeks, once every two weeks,
once a week, twice a week, three times a week, four times a week,
five times a week, six times a week, or daily. Other exemplary
dosing frequencies include, but are not limited to, weekly, two out
of three weeks; weekly, three out of four weeks; and weekly, four
out of five weeks. In some embodiments, the composition is
administered (with or without breaks in administration cycles) for
at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or
more month(s).
[0029] In some embodiments, the composition is administered via any
of intravenous, intraperitoneal, oral or inhalational routes. In
some embodiments, the nanoparticle composition is administered with
premedication. In some embodiments, the nanoparticle composition is
administered without premedication.
[0030] The dose of the taxane in the nanoparticle composition will
depend on the type of cancer to be treated, the severity and course
of the cancer, the individual's clinical history, and the
discretion of the attending physician. Suitable dosages of the
taxane in the taxane nanoparticle compositions include, but are not
limited to, about any of 50 mg/m.sup.2, 60 mg/m.sup.2, 75
mg/m.sup.2, 80 mg/m.sup.2, 90 mg/m.sup.2, 100 mg/m.sup.2, 120
mg/m.sup.2, 125 mg/m.sup.2, 150 mg/m.sup.2, 160 mg/m.sup.2, 180
mg/m.sup.2, 200 mg/m.sup.2, 210 mg/m.sup.2, 220 mg/m.sup.2, 230
mg/m.sup.2, 240 mg/m.sup.2, 260 mg/m.sup.2, and 300 mg/m.sup.2.
Exemplary dosing schedules for the administration of the taxane
nanoparticle composition (such as paclitaxel/albumin nanoparticle
composition, for example Abraxane.RTM.) include, but are not
limited to, 260 mg/m.sup.2, every three weeks; 60-150 mg/m.sup.2,
weekly, without break, and 60-150 mg/m.sup.2, weekly, three out of
four weeks. In addition, the taxane can be administered by
following a metronomic dosing regime described herein. In some
embodiments, the method comprises administering Abraxane.RTM. at
260 mg/m.sup.2 by 30 minutes IV infusion every three weeks.
[0031] Also provided herein are compositions, kits and unit dosage
forms that are suitable for methods described herein. For example,
in some embodiments, there is provided a composition for use in the
treatment of a recurrent cancer (such as recurrent gynecological
cancer for example recurrent ovarian, peritoneal, and fallopian
tube cancer), wherein the composition comprises nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin). In some embodiments, there is provided a
composition for use in decreasing one or more symptoms resulting
from a recurrent cancer (such as recurrent gynecological cancer for
example recurrent ovarian, peritoneal, and fallopian tube cancer),
wherein the composition comprises nanoparticles comprising a taxane
(such as paclitaxel) and a carrier protein (such as albumin). In
some embodiments, there is provided a composition for use in the
treatment of a recurrent cancer (such as recurrent gynecological
cancer for example recurrent ovarian, peritoneal, and fallopian
tube cancer) in conjunction with a platinum-based agent, wherein
the composition comprises nanoparticles comprising a taxane (such
as paclitaxel), wherein the composition comprises nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin). In some embodiments, there is provided a
composition for use in decreasing one or more symptoms resulting
from a recurrent cancer (such as recurrent gynecological cancer for
example recurrent ovarian, peritoneal, and fallopian tube cancer)
in conjunction with a platinum-based agent, wherein the composition
comprises nanoparticles comprising a taxane (such as paclitaxel)
and a carrier protein (such as albumin).
[0032] These and other aspects and advantages of the present
invention will become apparent from the subsequent detailed
description and the appended claims. It is to be understood that
one, some, or all of the properties of the various embodiments
described herein may be combined to form other embodiments of the
present invention.
BRIEF DESCRIPTION OF FIGURES
[0033] FIG. 1a shows overall survival among patients plotted in
terms of months (x-axis) to proportion of survival (y-axis).
[0034] FIG. 1b shows progression free survival among patients
plotted in terms of months (x-axis) to proportion not progressed
(y-axis).
[0035] FIG. 2 shows a comparison of plasma level of paclitaxel when
Nab-paclitaxel is administered intraperitoneally or intravenously
(log-log).
[0036] FIG. 3 shows a comparison of plasma level of paclitaxel when
Nab-paclitaxel is administered intraperitoneally or intravenously
(log-linear).
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention provides methods for the treatment of
a recurrent cancer (such as recurrent gynecological cancer)
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin). Specifically,
we have shown that a composition comprising nanoparticles
comprising a taxane and a carrier protein (hereinafter designated
as a "taxane nanoparticle composition"), particularly, a
composition comprising nanoparticles comprising paclitaxel and
albumin, more particularly, a composition comprising nanoparticles
albumin bound paclitaxel ("Nab-paclitaxel"), was very active as a
single agent or in combination with a platinum-based agent
(carboplatin) in patients with platinum sensitive recurrent
gynecological cancer, including recurrent ovarian, peritoneal, or
fallopian tube cancer. The overall response rate for the treatment
was 64% and the clinical benefit rate was 77%. Complete response
was attained in about 70% patients treated with Abraxane.RTM. and
carboplatin. This demonstrates that a taxane nanoparticle
composition is particularly suitable (either as a single agent or
in combination with a platinum-based agent) for treating
platinum-sensitive recurrent cancer, particularly recurrent
gynecological cancer.
[0038] Accordingly, the present invention in one aspect provides a
method of treating a platinum-sensitive recurrent cancer comprising
administering to the individual an effective amount of a
composition (such as Nab-paclitaxel or Abraxane.RTM.) comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin). In another aspect, there is
provided a method of treating a recurrent ovarian cancer (such as
platinum-sensitive recurrent ovarian cancer) comprising
administering to the individual an effective amount of a
composition (such as Nab-paclitaxel or Abraxane.RTM.) comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin).
DEFINITIONS
[0039] As used herein, "the composition" or "compositions" includes
and is applicable to compositions of the invention. The invention
also provides pharmaceutical compositions comprising the components
described herein.
[0040] Reference to "taxane" herein applies to a taxane or its
derivatives and accordingly the invention contemplates and includes
all these variations. Reference to "taxane" is to simplify the
description and is exemplary. Taxanes include, but are not limited
to, compounds that are structurally similar to or are in the same
general chemical class such as paclitaxel (i.e., taxol), docetaxel
(i.e., taxotere), or ortataxel, and pharmaceutically acceptable
salts, derivatives, or analogs of paclitaxel, docetaxel, and
ortataxel. Taxanes are antimicrobial agents that inhibit cell
replication by promoting the assembly and stabilization of
microtubule from tubulin dimers
[0041] Unless clearly indicated otherwise, "an individual" as used
herein refers to human.
[0042] 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: decreasing 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), delay or slowing the progression of the disease,
ameliorating the disease state, decreasing the dose of one or more
other medications required to treat the disease, increasing the
quality of life, and/or prolonging survival (including overall
survival and progression free survival. In some embodiments, the
composition reduces the severity of one or more symptoms associated
with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 95%, or 100% compared to the corresponding symptom
in the same subject prior to treatment or compared to the
corresponding symptom in other subjects not receiving the
composition. Also encompassed by "treatment" is a reduction of
pathological consequence of cancer. The methods of the invention
contemplate any one or more of these aspects of treatment.
[0043] As used herein, "delaying" the development of 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 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. Cancer development can be detectable using standard
methods, such as routine physical exams or x-ray. Development may
also refer to disease progression that may be initially
undetectable and includes occurrence and onset.
[0044] "Adjuvant setting" refers to a clinical setting in which an
individual has had a history of ovarian cancer, and generally (but
not necessarily) been responsive to therapy, which includes, but is
not limited to, surgery (e.g., surgical resection), radiotherapy,
and chemotherapy. However, because of their history of the 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 (i.e.,
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.
[0045] "Neoadjuvant setting" refers to a clinical setting in which
the method is be carried out before the primary/definitive
therapy.
[0046] As used herein, an "at risk" individual is an individual who
is at risk of developing 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 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).
[0047] As used herein, by "pharmaceutically active compound" is
meant a chemical compound that induces a desired effect, e.g.,
treating, stabilizing, preventing, and/or delaying cancer.
[0048] As used herein, by "combination therapy" is meant a first
therapy that includes nanoparticles comprising nanoparticles
comprising a taxane (e.g. paclitaxel) and a carrier protein in
conjunction with a second therapy (e.g., surgery or a therapeutic
agent) useful for treating, stabilizing, preventing, and/or
delaying cancer. Administration in "conjunction with" another
compound includes administration in the same or different
composition(s), either sequentially, simultaneously, or
continuously. In some embodiments, the combination therapy
optionally includes one or more pharmaceutically acceptable
carriers or excipients, non-pharmaceutically active compounds,
and/or inert substances.
[0049] The term "effective amount" refers to an amount of a drug
effective to treat cancer in the patient. The effective amount of
the drug may reduce the number of cancer cells; reduce the tumor
size; inhibit (i.e., slow to some extent and preferably stop)
cancer cell infiltration into peripheral organs; inhibit (i.e.,
slow to some extent and preferably stop) tumor metastasis; inhibit,
to some extent, tumor growth; and/or relieve to some extent one or
more of the symptoms associated with the cancer. To the extent the
drug may prevent growth and/or kill existing cancer cells, it may
be cytostatic and/or cytotoxic. The effective amount may extend
progression free survival (e.g. as measured by Response Evaluation
Criteria for Solid Tumors, RECIST, or CA-125 changes), result in an
objective response (including a partial response or a complete
response), increase overall survival time, and/or improve one or
more symptoms of cancer (e.g. as assessed by FOSI).
[0050] As is understood in the art, an "effective amount" may be in
one or more doses, i.e., a single dose or multiple doses may be
required to achieve the desired treatment endpoint. An effective
amount may be considered in the context of administering one or
more therapeutic agents, and a nanoparticle composition (e.g., a
composition including a taxane (e.g., paclitaxel) and a carrier
protein) may be considered to be given in an effective amount if,
in conjunction with one or more other agents, a desirable or
beneficial result may be or is achieved.
[0051] 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
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.
[0052] The term "proteins" refers to polypeptides or polymers of
amino acids of any length (including full length or fragments),
which may be linear or branched, comprise modified amino acids,
and/or be interrupted by non-amino acids. The term also encompasses
an amino acid polymer that has been modified naturally or by
intervention, including, for example, disulfide bond formation,
glycosylation, lipidation, acetylation, phosphorylation, or any
other manipulation or modification. Also included within this term
are, for example, polypeptides containing one or more analogs of an
amino acid (including, for example, unnatural amino acids, etc.),
as well as other modifications known in the art. The proteins
described herein may be naturally-occurring, i.e., obtained or
derived from a natural source (e.g., blood) or synthesized (e.g.,
chemically synthesized or by synthesized by recombinant DNA
techniques). Exemplary carrier proteins are described herein.
[0053] The term "antimicrobial agent" used herein refers to an
agent that is capable of inhibiting (e.g., delaying, reducing,
slowing, and/or preventing) the growth of one or more
microorganisms. Significant microbial growth can be measured or
indicated by a number of ways known in the art, such as one or more
of the following: (i) microbial growth in a composition that is
enough to cause one or more adverse effects to an individual when
the composition is administered to the individual; (ii) more than
about 10-fold increase in microbial growth over a certain period of
time (for example over a 24 hour period) upon extrinsic
contamination (e.g., exposure to 10-10.sup.3 colony forming units
at a temperature in the range of 20 to 25.degree. C.). Other
indicia of significant microbial growth are described in U.S.
Patent Application Publication No. US20070117744 (U.S. Ser. No.
11/514,030, filed Aug. 30, 2006), which is hereby incorporated by
reference in its entirety.
[0054] "Sugar" as used herein includes, but is not limited to,
monosaccharides, disaccharides, polysaccharides, and derivatives or
modifications thereof. Suitable sugars for compositions described
herein include, for example, mannitol, sucrose, fructose, lactose,
maltose, and trehalose.
[0055] 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.
[0056] "Survival" refers to the patient remaining alive, and
includes overall survival as well as progression free survival.
[0057] "Overall survival" refers to the patient remaining alive for
a defined period of time, such as 1 year, 5 years, etc. from the
time of diagnosis or treatment.
[0058] "Progression free survival" refers to the patient remaining
alive, without the cancer progressing or getting worse.
[0059] By "prolonging survival" is meant increasing overall or
progression free survival in a treated patient relative to an
untreated patient (e.g. relative to a patient not treated with a
taxane nanoparticle composition).
[0060] As used herein, reference to "not" a value or parameter
generally means and describes "other than" a value or parameter.
For example, if a taxane is not administered, it means an agent
other than a taxane is administered.
[0061] 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".`
[0062] As used herein and in the appended claims, the singular
forms "a," "or," and "the" include plural referents unless the
context clearly dictates otherwise. It is understood that aspects
and variations of the invention described herein include
"consisting" and/or "consisting essentially of" aspects and
variations.
Methods of the Present Invention
[0063] The present invention provides methods for the treatment of
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) by
administering a composition comprising nanoparticles comprising a
taxane and a carrier protein. In some embodiments, there is
provided a method of treating a recurrent cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane and a
carrier protein. In some embodiments, the recurrent cancer is
platinum sensitive. In some embodiments, the recurrent cancer is
platinum resistant. In some embodiments, the recurrent cancer is
any of recurrent ovarian cancer, recurrent peritoneal cancer,
recurrent fallopian tube cancer, recurrent malignant mixed
mullerian tumor, and serous endo.
[0064] In some embodiments, there is provided a method of treating
a recurrent ovarian, peritoneal, or fallopian tube cancer in an
individual, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a
taxane and a carrier protein. In some embodiments, there is
provided a method of treating a platinum-sensitive recurrent
ovarian, peritoneal, or fallopian tube cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane and a
carrier protein. In some embodiments, the recurrent cancer is a
recurrent ovarian cancer (such as a recurrent epithelial ovarian
cancer). In some embodiments, the recurrent cancer is a recurrent
peritoneal cancer. In some embodiments, the recurrent cancer is a
recurrent fallopian tube cancer (including for example papillary
serous adenocarcinomas, sarcomas, and transitional cell
carcinomas).
[0065] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received a prior
chemotherapy and has a treatment free interval for more about any
of 3, 6, 9 months since the completion of prior chemotherapy. In
some embodiments, there is provided a method of treating a
recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received a prior
chemotherapy and has a treatment free interval for more about any
of 12, 18, 24, 36, or 48 months since the completion of prior
chemotherapy. In some embodiments, the prior chemotherapy has a
different mechanism of action than that of the taxane-based
therapy. In some embodiments, the individual has only been treated
with platinum-based agent(s) prior to the administration of the
taxane nanoparticle composition. In some embodiments, the
individual has only been treated with one dosing regime prior to
the administration of the taxane nanoparticle composition. In some
embodiments, the individual has not previously been treated with a
taxane-based therapy.
[0066] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received prior
platinum-based chemotherapy and has a treatment free interval for
more than about any of 3, 6, 9 months since the completion of the
platinum-based chemotherapy. In some embodiments, there is provided
a method of treating a recurrent cancer (such as a recurrent
gynecological cancer for example recurrent ovarian, peritoneal, or
fallopian tube cancer) in an individual, comprising administering
to the individual an effective amount of a composition comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin), wherein the individual has
received prior platinum-based chemotherapy and has a treatment free
interval for more than about any of 12, 18, 24, 36, or 38 months
since the completion of the platinum-based chemotherapy. In some
embodiments, the method further comprises administering to the
individual an effective amount of a platinum-based agent (such as
carboplatin). In some embodiments, the composition comprising
nanoparticles comprising a taxane and a carrier protein is not
administered in conjunction with a platinum agent, that is, the
composition comprising nanoparticles comprising a taxane and a
carrier protein is either administered alone or administered in
conjunction with a chemotherapeutic agent other than a
platinum-based agent.
[0067] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received a prior
chemotherapy and has a treatment free interval for more about any
of 3, 6, 9 months prior to the initiation of the treatment method
with the taxane nanoparticle composition. In some embodiments,
there is provided a method of treating a recurrent cancer (such as
a recurrent gynecological cancer for example recurrent ovarian,
peritoneal, or fallopian tube cancer) in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin), wherein the
individual has received a prior chemotherapy and has a treatment
free interval for more about any of 12, 18, 24, 36, or 48 months
prior to the initiation of the treatment method with the taxane
nanoparticle composition. In some embodiments, the prior
chemotherapy has a different mechanism of action than that of the
taxane-based therapy. In some embodiments, the individual has only
been treated with platinum-based agent(s) prior to the
administration of the taxane nanoparticle composition. In some
embodiments, the individual has only been treated with one dosing
regime prior to the administration of the taxane nanoparticle
composition. In some embodiments, the individual has not previously
been treated with a taxane-based therapy.
[0068] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received prior
platinum-based chemotherapy and has a treatment free interval for
more than about any of 3, 6, 9 months prior to the initiation of
the treatment method with the taxane nanoparticle composition. In
some embodiments, there is provided a method of treating a
recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual has received prior
platinum-based chemotherapy and has a treatment free interval for
more than about any of 12, 18, 24, 36, or 38 months prior to the
initiation of the treatment method with the taxane nanoparticle
composition. In some embodiments, the method further comprises
administering to the individual an effective amount of a
platinum-based agent. In some embodiments, the composition
comprising nanoparticles comprising a taxane and a carrier protein
is not administered in conjunction with a platinum agent, that is,
the composition comprising nanoparticles comprising a taxane and a
carrier protein is either administered alone or administered in
conjunction with a chemotherapeutic agent other than a
platinum-based agent.
[0069] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual does not show a symptom
of hypersensitivity (such as neuropathy) prior to the initiation of
the treatment method with the taxane nanoparticle composition. In
some embodiments, there is provided a method of treating a
recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the individual does not show a symptom
of hypersensitivity throughout the treatment period. In some
embodiments, there is provided a method of treating a recurrent
cancer (such as a recurrent gynecological cancer for example
recurrent ovarian, peritoneal, or fallopian tube cancer) in an
individual, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a
taxane (such as paclitaxel) and a carrier protein (such as
albumin), wherein the individual does not show symptoms of
hypersensitivity upon completion of the treatment.
[0070] In some embodiments, the composition comprising
nanoparticles comprising a taxane and a carrier protein is
administered alone. For example, in some embodiments, there is
provided a method of treating a recurrent cancer (such as a
recurrent gynecological cancer for example recurrent ovarian,
peritoneal, or fallopian tube cancer) in an individual, comprising
administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin), wherein the
amount of the composition administered to the individual alone is
effective to result in a complete response in the individual. In
some embodiments, there is provided a method of treating a
recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the amount of the composition
administered to the individual alone is effective to result in a
partial response in the individual.
[0071] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the amount of the composition
administered to the individual alone is sufficient to produce an
overall response rate of more than about any of 40%, 50%, 60%, or
64% among a population of individuals treated with the composition.
In some embodiments, there is provided a method of treating a
recurrent cancer (such as a recurrent gynecological cancer for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the amount of the composition
administered to the individual 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 composition.
[0072] In some embodiments, the method comprises administering to
the individual an effective amount of a composition comprising
nanoparticles comprising paclitaxel and albumin. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein average or mean diameter of the
nanoparticles in the composition is less than about 200 nm. In some
embodiments, the method comprises administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), wherein the nanoparticles comprise taxane coated
with a coating comprising the carrier protein. In some embodiments,
the method comprises administering to the individual an effective
amount of a Nab-paclitaxel (such as Abraxane.RTM.). For example, in
some embodiments, there is provided a method of treating a
platinum-sensitive recurrent ovarian, peritoneal, or fallopian tube
cancer in the individual, comprising administering to the
individual an effective amount of Nab-paclitaxel or
Abraxane.RTM..
[0073] In some embodiments, there is provided a method of treating
a recurrent ovarian, peritoneal, or fallopian tube cancer (such as
a platinum-resistant ovarian, peritoneal, or fallopian tube cancer)
in an individual, comprising administering to the individual about
50 mg/m.sup.2 to about 300 mg/m.sup.2 (including for example about
260 mg/m.sup.2) Nab-paclitaxel or Abraxane.RTM.. In some
embodiments, the Nab-paclitaxel or Abraxane.RTM. is administered
every three weeks. In some embodiments, the Nab-paclitaxel or
Abraxane.RTM. is administered intravenously (such as by i.v.
infusion over a period of about 30 minutes or less). In some
embodiments, the Nab-paclitaxel or Abraxane.RTM. is administered
intraperitoneally.
[0074] The methods of the present invention are useful for any one
or more of the following (and thus in various embodiments can
achieve and/or include any one or more of the following): 1)
decreasing one or more symptoms resulting from recurrent cancer
(such as recurrent gynecological cancer for example recurrent
ovarian, peritoneal, and fallopian tube cancer); 2) increasing
overall response rate of a recurrent cancer (such as recurrent
gynecological cancer for example recurrent ovarian, peritoneal, and
fallopian tube cancer); 3) increasing partial response rate of a
recurrent cancer (such as recurrent gynecological cancer for
example recurrent ovarian, peritoneal, and fallopian tube cancer);
4) increasing complete response rate of a recurrent cancer (such as
recurrent gynecological cancer for example recurrent ovarian,
peritoneal, and fallopian tube cancer); 5) delaying disease
progression of an individual with a recurrent cancer (such as
recurrent gynecological cancer for example recurrent ovarian,
peritoneal, and fallopian tube cancer); 6) increasing the quality
of life in an individual with recurrent cancer (such as recurrent
gynecological cancer for example recurrent ovarian, peritoneal, and
fallopian tube cancer); 7) prolonging overall survival of an
individual having recurrent cancer (such as recurrent gynecological
cancer for example recurrent ovarian, peritoneal, and fallopian
tube cancer); and 8) prolonging progression-free survival of an
individual having recurrent cancer (such as recurrent gynecological
cancer for example recurrent ovarian, peritoneal, and fallopian
tube cancer).
[0075] Accordingly, in some embodiments, there is provided a method
of decreasing one or more symptoms resulting from a recurrent
cancer (such as recurrent gynecological cancer for example
recurrent ovarian, peritoneal, and fallopian tube cancer),
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin). In some
embodiments, there is provided a method of decreasing one more
symptoms resulting from a recurrent cancer (such as recurrent
gynecological cancer for example recurrent ovarian, peritoneal, and
fallopian tube cancer), comprising administering to the individual
an effective amount of Nab-paclitaxel or Abraxane.RTM..
[0076] In some embodiments, there is provided a method of
increasing response rate of recurrent cancer (such as recurrent
gynecological cancer for example recurrent ovarian, peritoneal, and
fallopian tube cancer), comprising administering to the individual
an effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin). In some embodiments, there is provided a method
of increasing response rate of recurrent cancer (such as recurrent
gynecological cancer for example recurrent ovarian, peritoneal, and
fallopian tube cancer), comprising administering to the individual
an effective amount of Nab-paclitaxel or Abraxane.RTM..
[0077] In some embodiments, there is provided a method of delaying
disease progression of an individual with recurrent cancer (such as
recurrent gynecological cancer for example recurrent ovarian,
peritoneal, and fallopian tube cancer), comprising administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin). In some embodiments, there is
provided a method of delaying disease progression of an individual
with recurrent cancer (such as recurrent gynecological cancer for
example recurrent ovarian, peritoneal, and fallopian tube cancer),
comprising administering to the individual an effective amount of
Nab-paclitaxel or Abraxane.RTM..
[0078] In some embodiments, there is provided a method of
prolonging survival of an individual having recurrent cancer (such
as recurrent gynecological cancer for example recurrent ovarian,
peritoneal, and fallopian tube cancer), comprising administering to
the individual an effective amount of a composition comprising
nanoparticles comprising a taxane (such as paclitaxel) and a
carrier protein (such as albumin). In some embodiments, there is
provided a method of prolonging survival of an individual having
recurrent cancer (such as recurrent gynecological cancer for
example ovarian, peritoneal, and fallopian tube cancer), comprising
administering to the individual an effective amount of
Nab-paclitaxel or Abraxane.RTM..
[0079] In some embodiments, there is provided a method of treating
a recurrent ovarian, peritoneal, or fallopian tube cancer in an
individual, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a
taxane and a carrier protein, wherein one or more symptoms
resulting from the recurrent cancer is decreased. In some
embodiments, there is provided a method of treating a recurrent
ovarian, peritoneal, or fallopian tube cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane and a
carrier protein, wherein the individual has a partial response to
treatment upon completion of less than about any of one, two,
three, four, five, six, seven, or eight treatment cycles. In some
embodiments, there is provided a method of treating a recurrent
ovarian, peritoneal, or fallopian tube cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane and a
carrier protein, wherein the individual has a complete response to
treatment upon completion of less than about any of one, two,
three, four, five, six, seven, or eight treatment cycles. In some
embodiments, the treatment cycle is four weeks. In some
embodiments, the treatment cycle is three weeks.
[0080] In some embodiments, there is provided a method of treating
a recurrent ovarian, peritoneal, or fallopian tube cancer in an
individual, comprising administering to the individual an effective
amount of a composition comprising nanoparticles comprising a
taxane and a carrier protein, wherein the individual is disease
free for at least about any of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 14, 16, 18, 20, 22, or 24 months upon completion of the
treatment. In some embodiments, there is provided a method of
treating a recurrent ovarian, peritoneal, or fallopian tube cancer
in an individual, comprising administering to the individual an
effective amount of a composition comprising nanoparticles
comprising a taxane and a carrier protein, wherein the individual
does not show a symptom resulting from the recurrent cancer for at
least about any of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,
18, 20, 22, or 24 months upon completion of the treatment. In some
embodiments, there is provided a method of treating a recurrent
ovarian, peritoneal, or fallopian tube cancer in an individual,
comprising administering to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane and a
carrier protein, wherein the individual has a reduced CA-125 level
(such as a level below about any of 70%, 60%, 50%, 40%, 30%, 20%,
10% of the level prior to the treatment) upon completion of the
treatment. In some embodiments, the individual has a reduced CA-125
level for at least about any of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 14, 16, 18, 20, 22, or 24 months upon completion of the
treatment.
[0081] In some embodiments, there is provided a method of treating
a recurrent ovarian, peritoneal, or fallopian tube cancer in an
individual, comprising administering (for example intravenously or
intraperitoneally) to the individual an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin), wherein the
amount of the taxane per administration is at least about 50
mg/m.sup.2 (such as at least about any of 70 mg/m.sup.2, 100
mg/m.sup.2, 150 mg/m.sup.2, 200 mg/m.sup.2, or 260 mg/m.sup.2), and
wherein one or more symptoms resulting from the recurrent cancer is
decreased. In some embodiments, there is provided a method of
treating a recurrent ovarian, peritoneal, or fallopian tube cancer
in an individual, comprising administering (for example
intravenously or intraperitoneally) to the individual an effective
amount of Abraxane.RTM., wherein the amount of paclitaxel per
administration is at least about 50 mg/m.sup.2 (such as at least
about any of 70 mg/m.sup.2, 100 mg/m.sup.2, 150 mg/m.sup.2, 200
mg/m.sup.2, or 260 mg/m.sup.2), and wherein one or more symptoms
resulting from the recurrent cancer is decreased. In some
embodiments, the composition is administered once every three
weeks. In some embodiments, the composition is administered weekly.
In some embodiments, the composition is administered three out of
four weeks. In some embodiments, the individual does not show a
symptom of hypersensitivity (such as neuropathy) prior to the
initiation of the treatment. In some embodiments, the individual
does not show a symptom of hypersensitivity throughout the
treatment period. In some embodiments, the individual does not show
a symptom of hypersensitivity upon completion of the treatment.
[0082] In some embodiments, the taxane nanoparticle composition is
administered in conjunction with another chemotherapeutic agent
(such as a platinum-based agent). For example, in some embodiments,
the taxane nanoparticle composition and the other chemotherapeutic
agent (such as a platinum-based agent) are administered
simultaneously. The term "simultaneous administration," as used
herein, means that the taxane nanoparticle composition and the
other chemotherapeutic agent are administered with a time
separation of no more than about 15 minute(s), such as no more than
about any of 10, 5, or 1 minutes. When the drugs are administered
simultaneously, the taxane in the nanoparticles and the other
chemotherapeutic agent may be contained in the same composition
(e.g., a composition comprising both the nanoparticles and the
other chemotherapeutic agent) or in separate compositions (e.g.,
the nanoparticles are contained in one composition and the other
chemotherapeutic agent is contained in another composition). For
example, the taxane and the other chemotherapeutic agent may be
present in a single composition containing at least two different
nanoparticles, wherein some of the nanoparticles in the composition
comprise the taxane and a carrier protein, and some of the other
nanoparticles in the composition comprise the other
chemotherapeutic agent and a carrier protein. In some embodiments,
only the taxane is contained in nanoparticles. In some embodiments,
simultaneous administration of the drug in the nanoparticle
composition and the other chemotherapeutic agent can be combined
with supplemental doses of the taxane and/or the other
chemotherapeutic agent.
[0083] In some embodiments, the nanoparticle composition and the
other chemotherapeutic agent (such as the platinum-based agent) are
administered sequentially. The term "sequential administration" as
used herein means that the taxane in the nanoparticle composition
and the other chemotherapeutic agent 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 nanoparticle
composition or the other chemotherapeutic agent may be administered
first. The nanoparticle composition and the other chemotherapeutic
agent are contained in separate compositions, which may be
contained in the same or different packages.
[0084] In some embodiments, the administration of the nanoparticle
composition and the other chemotherapeutic agent are concurrent,
i.e., the administration period of the nanoparticle composition and
that of the other chemotherapeutic agent overlap with each other.
In some embodiments, the nanoparticle composition and the other
chemotherapeutic agent are administered in the same treatment
cycle(s).
[0085] The dosing frequency of the drug-containing nanoparticle
composition and the other chemotherapeutic 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
chemotherapeutic 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.
[0086] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent. In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual a) an
effective amount of a composition comprising nanoparticles
comprising paclitaxel and an albumin (such as Abraxane.RTM.), and
b) an effective amount of a platinum-based agent. Suitable
platinum-based agents include, but are not limited to, carboplatin,
cisplatin, and oxaliplatin. In some embodiments, the platinum-based
agent is carboplatin. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent are administered
simultaneously. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent are administered
sequentially. In some embodiments, the taxane nanoparticle
composition and the platinum-based agent is administered
concurrently.
[0087] In some embodiments, there is provided a method of treating
a recurrent ovarian cancer in an individual, comprising
administering to the individual: a) an effective amount of a
composition comprising nanoparticles comprising a taxane (such as
paclitaxel) and a carrier protein (such as albumin), and b) an
effective amount of a platinum-based agent. In some embodiments,
there is provided a method of treating a primary peritoneal cancer
in an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent.
[0088] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a taxane (such as paclitaxel) and a carrier protein
(such as albumin), and b) an effective amount of a platinum-based
agent, wherein the taxane nanoparticle composition and the
platinum-based agent are administered concurrently. In some
embodiments, there is provided a method of treating a recurrent
cancer (such as a recurrent gynecological cancer, for example
recurrent ovarian, peritoneal, or fallopian tube cancer) in an
individual, comprising administering to the individual: a) an
effective amount of a composition comprising nanoparticles
comprising a paclitaxel and an albumin (such as Abraxane.RTM.), and
b) an effective amount of a platinum-based agent, wherein the
paclitaxel nanoparticle composition and the platinum-based agent
are administered concurrently.
[0089] In some embodiments, there is provided a method of treating
a recurrent cancer (such as a recurrent gynecological cancer, for
example recurrent ovarian, peritoneal, or fallopian tube cancer) in
an individual, comprising administering (for example intravenously
or intraperitoneally) to the individual: a) an effective amount of
a composition comprising nanoparticles comprising a paclitaxel and
an albumin (such as Abraxane.RTM.), wherein the amount of the
paclitaxel in the composition is at least about 40 mg/m.sup.2
(including for example about any of 50 mg/m.sup.2, 60 mg/m.sup.2,
70 mg/m.sup.2, 80 mg/m.sup.2, 90 mg/m.sup.2, 100 mg/m.sup.2, 150
mg/m.sup.2, or 200 mg/m.sup.2); b) an effective amount of a
platinum-based agent (such as the platinum-based agent at the
amount of AUC3, AUC4, or AUC6), wherein the taxane nanoparticle
composition and the platinum-based agent are administered
concurrently. In some embodiments, the method comprises
administering a composition comprising nanoparticles comprising
paclitaxel and an albumin (such as Abraxane.RTM.) at about 100
mg/m.sup.2, three out of four weeks, and a platinum-based agent
(such as carboplatin) AUC6 every four weeks in the same treatment
cycle. In some embodiments, the method comprises administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and a platinum-based agent (such as carboplatin)
AUC5 every four weeks in the same treatment cycle. In some
embodiments, the method comprises intravenously administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and intravenously administering a platinum-based
agent (such as carboplatin) AUC5 every four weeks in the same
treatment cycle. In some embodiments, the individual is treated
with at least any of about one, two, three, four, five, six, seven,
eight, or more such treatment cycles.
[0090] In some embodiments, there is provided a method of treating
recurrent ovarian cancer, comprising intravenously administering a
composition comprising nanoparticles comprising paclitaxel and an
albumin (such as Abraxane.RTM.) at about 100 mg/m.sup.2, three out
of four weeks, and intravenously administering a platinum-based
agent (such as carboplatin) AUC5 (or AUC6) every four weeks in the
same treatment cycle. In some embodiments, there is provided a
method of treating primary peritoneal cancer, comprising
intravenously administering a composition comprising nanoparticles
comprising paclitaxel and an albumin (such as Abraxane.RTM.) at
about 100 mg/m.sup.2, three out of four weeks, and intravenously
administering a platinum-based agent (such as carboplatin) AUC5 (or
AUC6) every four weeks in the same treatment cycle. In some
embodiments, the individual is treated with at least any of about
one, two, three, four, five, six, seven, eight, or more such
treatment cycles.
Individual Having Recurrent Cancer
[0091] The present invention provides a method of treating a
recurrent cancer (such as recurrent gynecological cancer for
example recurrent ovarian, peritoneal, and fallopian tube cancer)
in an individual. A "recurrent" cancer is one which has regrown,
either at the initial site or at a distant site, after a response
to initial therapy. In some embodiments, the length of time between
the completion of initial therapy and the development of recurrent
disease is longer than about 3 month, including for example longer
than about any of 4, 5, 6, 7, 8, 9, 10, or 11 months. In some
embodiments, the length of time between the completion of initial
therapy and the development of recurrent disease is longer than
about 12 month, including for example, longer than about any of 14,
16, 18, 20, 22, 24, 36, or 48 months.
[0092] In some embodiments, the recurrent cancer is a recurrent
gynecological cancer. "Gynecologic cancer" used herein refers to a
cancer originating in the female reproductive organs. It includes
cancers of the cervix, fallopian tubes, ovaries, uterus, vagina and
vulva. In some embodiments, the recurrent cancer is a recurrent
ovarian cancer. In some embodiments, the cancer is ovarian
epithelial cancer. Exemplary ovarian epithelial cancer histological
classifications include: serous cystomas (e.g., serous benign
cystadenomas, serous cystadenomas with proliferating activity of
the epithelial cells and nuclear abnormalities but with no
infiltrative destructive growth, or serous cystadenocarcinomas),
mucinous cystomas (e.g., mucinous benign cystadenomas, mucinous
cystadenomas with proliferating activity of the epithelial cells
and nuclear abnormalities but with no infiltrative destructive
growth, or mucinous cystadenocarcinomas), endometrioid tumors
(e.g., endometrioid benign cysts, endometrioid tumors with
proliferating activity of the epithelial cells and nuclear
abnormalities but with no infiltrative destructive growth, or
endometrioid adenocarcinomas), clear cell (mesonephroid) tumors
(e.g., begin clear cell tumors, clear cell tumors with
proliferating activity of the epithelial cells and nuclear
abnormalities but with no infiltrative destructive growth, or clear
cell cystadenocarcinomas), unclassified tumors that cannot be
allotted to one of the above groups, or other malignant tumors.
[0093] In some embodiments, the recurrent cancer is a recurrent
ovarian germ cell tumor. Exemplary histologic subtypes include
dysgerminomas or other germ cell tumors (e.g., endodermal sinus
tumors such as hepatoid or intestinal tumors, embryonal carcinomas,
olyembryomas, choriocarcinomas, teratomas, or mixed form tumors).
Exemplary teratomas are immature teratomas, mature teratomas, solid
teratomas, and cystic teratomas (e.g., dermoid cysts such as mature
cystic teratomas, and dermoid cysts with malignant transformation).
Some teratomas are monodermal and highly specialized, such as
struma ovarii, carcinoid, struma ovarii and carcinoid, or others
(e.g., malignant neuroectodermal and ependymomas).
[0094] In some embodiments, the recurrent cancer is a recurrent
peritoneal cancer. In some embodiments, the recurrent cancer is a
recurrent fallopian tube cancer (including for example papillary
serous adenocarcinomas, sarcomas, and transitional cell
carcinomas). Other recurrent cancers such as recurrent malignant
mixed mullerian tumor and serous endo can also be treated.
[0095] Recurrence of ovarian, peritoneal, or fallopian tube cancer
can be determined, for example, based on bimanual pelvic
examinations, serial measurements of CA-125 or other tumor markers,
one or more imaging studies reassessments, and second-look
laparotomy. Imaging studies such as CT, PET, or a CT/PET
combination can also be used. In some embodiments, recurrence of
ovarian, peritoneal, or fallopian tube cancer can be determined
based on Response Evaluation Criteria in Solid Tumors (RECIST).
[0096] "Individual" used herein refers to human. In some
embodiments, the individual is a woman who is about 40 to about 85
years old, including for example about 60 to about 70 years old. In
some embodiments, the individual has an Eastern Cooperative
Oncology Group (ECOG) performance status of 0-2 (such as any of 0,
1, or 2) prior to the administration of the taxane nanoparticle
composition. In some embodiments, the individual has received a
prior chemotherapy and has a treatment free interval for more than
about any of 3, 6, or 9 months since the completion of prior
chemotherapy. In some embodiments, the individual has received a
prior chemotherapy and has a treatment free interval for more than
about any of 12, 18, 24, 36, or 48 months since the completion of
prior chemotherapy. In some embodiments, the prior chemotherapy has
a different mechanism of action than that of the taxane. In some
embodiments, the individual has only been treated with
platinum-based agent(s) prior to the administration of the taxane
nanoparticle composition. In some embodiments, the individual has
only been treated with one dosing regime prior to the
administration of the taxane nanoparticle composition. In some
embodiments, the individual has not previously been treated with a
taxane-based therapy.
[0097] In some embodiments, when the method is directed to
treatment of a recurrent ovarian, peritoneal, or fallopian tube
cancer, the individual is confirmed of having an ovarian,
peritoneal, or fallopian tube cancer histologically or
cytologically. In some embodiments, the individual is determined to
have an ovarian, peritoneal, or fallopian tube cancer based on
RECIST. In some embodiments, the individual has an elevated blood
level of Cancer Antigen 125 (CA-125, for example a CA-125 level of
more than about 40, 50, 60, 70, 80, or 90 units/ml, or about
2.times., 3.times., 4.times., or more of that of the upper limit of
a normal CA-125 level). In some embodiments, the individual has an
altered expression level of another marker that is indicative of a
recurrent ovarian, peritoneal, and fallopian tube cancer.
[0098] The individual being treated may have one or more risk
factors associated with a higher probability of developing ovarian,
peritoneal, and fallopian tube cancer. These risk factors include,
but are not limited to, age, sex, race, diet, history of previous
disease, presence of precursor disease, genetic (i.e., hereditary)
considerations, and environmental exposure. In some embodiments,
the individual may be a human who is genetically or otherwise
predisposed to developing ovarian, peritoneal, and fallopian tube
cancer, particularly recurrent ovarian, peritoneal, and fallopian
tube cancer.
[0099] Individuals at risk for ovarian, peritoneal, and fallopian
tube cancer include, for example, those having relatives who have
experienced this disease, and those whose risk is determined by
analysis of genetic or biochemical markers. For example, the
individual may be a human who has a gene, genetic mutation, or
polymorphism associated with ovarian cancer (e.g., BRCA1 or BRCA2)
or has one or more extra copies of a gene associated with ovarian
cancer (e.g., one or more extra copies of the HER2 gene). In some
embodiments, the individual is HER2 positive. In some embodiments,
the individual is HER2 negative. In some embodiments, the ovarian
cancer is associated with basal cell nevus (Gorlin) syndrome,
multiple endocrine neoplasia type 1 (MEN1), or hereditary
nonpolyposis colon cancer (HNPCC).
[0100] In some embodiments, the individual satisfies at least two
of the criteria described above. For example, in some embodiments,
the individual has a measurable disease by RECIST and an elevated
blood level of CA-125. In some embodiments, the individual is
confirmed of having an ovarian cancer histologically or
cytologically and has only been treated with platinum-based
agent(s) prior to administration of the nanoparticle compositions
described above. In some embodiments, the individual satisfies at
least any of two, three, four, five, or more criteria described
above. In some embodiments, the individual satisfies all criteria
described above.
[0101] In some embodiments, the recurrent cancer is platinum
sensitive. For example, in some embodiments, the individual has
received prior platinum-based chemotherapy and has a treatment-free
interval for more than about any of 3, 6, or 9 months since the
completion of the platinum-based chemotherapy. In some embodiments,
the individual has received prior platinum-based chemotherapy and
has a treatment-free interval for more than about any of 12, 18,
24, 36, or 48 months since the completion of the platinum-based
chemotherapy. In some embodiments, the recurrent cancer is a
platinum-sensitive ovarian cancer. In some embodiments, the
recurrent cancer is a platinum-sensitive peritoneal cancer. In some
embodiments, the recurrent cancer is a platinum-sensitive fallopian
tube cancer.
[0102] In some embodiments, the recurrent cancer (such as a
recurrent ovarian, peritoneal, or fallopian tube cancer) is
platinum resistant. By "platinum-resistant" cancer is meant that
the individual with cancer has progressed while receiving
platinum-based chemotherapy (i.e. the patient is "platinum
refractory").
[0103] By "platinum-based chemotherapy" is intended to mean therapy
with one or more platinum-based chemotherapeutic agents, optionally
in combination with one or more other chemotherapeutic agents. A
"platinum-based chemotherapeutic agent" comprises an organic
compound which contains platinum as an integral part of the
molecule. These agents are believed to inhibit cell growth by
forming reactive platinum complexes which form intrastrand and
interstrand cross-linking of DNA molecules and inhibit DNA
synthesis. Examples of platinum-based chemotherapeutic agents
include carboplatin, cisplatin, and oxaliplatinum. In some
embodiments, the platinum-based chemotherapy comprises treatment
with only platinum-based agents. In some embodiments, the
platinum-based chemotherapy comprises treatment with
carboplatin.
Dosing and Method of Administration
[0104] The amount of the inventive composition administered to an
individual (such as a human) may vary with the particular
composition, the method of administration, and the particular type
of recurrent cancer being treated. The amount should be sufficient
to produce a desirable beneficial effect. For example, 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 taxane
nanoparticle composition is sufficient to result in a complete
response in the individual. In some embodiments, the amount of the
taxane nanoparticle composition is sufficient to result in a
partial response in the individual. In some embodiments, the amount
of the taxane nanoparticle composition administered (for example
when administered alone) is sufficient to produce an overall
response rate of more than about any of 40%, 50%, 60%, or 64% among
a population of individuals treated with the taxane nanoparticle
composition. Responses of an individual to the treatment of the
methods described herein can be determined, for example, based on
RECIST or CA-125 level. For example, when CA-125 is used, a
complete response can be defined as a return to a normal range
value of at least 28 days from the pretreatment value. A particle
response can be defined as a sustained over 50% reduction from the
pretreatment value.
[0105] In some embodiments, the amount of the composition is
sufficient to prolong progress-free survival of the individual (for
example as measured by RECIST or CA-125 changes). 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 along) 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 taxane nanoparticle composition.
[0106] In some embodiments, the amount of the taxane (e.g.,
paclitaxel) 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. 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.
[0107] In some embodiments, the amount of a taxane (e.g.,
paclitaxel) in the composition is included in any of the following
ranges: about 0.5 to about 5 mg, about 5 to about 10 mg, about 10
to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg,
about 20 to about 50 mg, about 25 to about 50 mg, about 50 to about
75 mg, about 50 to about 100 mg, about 75 to about 100 mg, about
100 to about 125 mg, about 125 to about 150 mg, about 150 to about
175 mg, about 175 to about 200 mg, about 200 to about 225 mg, about
225 to about 250 mg, about 250 to about 300 mg, about 300 to about
350 mg, about 350 to about 400 mg, about 400 to about 450 mg, or
about 450 to about 500 mg. In some embodiments, the amount of a
taxane (e.g., paclitaxel) or derivative thereof 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
300 mg or about 50 mg to about 200 mg. In some embodiments, the
concentration of the taxane (e.g., paclitaxel) 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
to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to
about 8 mg/ml, about 4 to about 6 mg/ml, about 5 mg/ml. In some
embodiments, the concentration of the taxane (e.g., paclitaxel) 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.
[0108] Exemplary effective amounts of a taxane (e.g., paclitaxel)
in the nanoparticle composition include, but are not limited to,
about any of 25 mg/m.sup.2, 30 mg/m.sup.2, 50 mg/m.sup.2, 60
mg/m.sup.2, 75 mg/m.sup.2, 80 mg/m.sup.2, 90 mg/m.sup.2, 100
mg/m.sup.2, 120 mg/m.sup.2, 125 mg/m.sup.2, 150 mg/m.sup.2, 160
mg/m.sup.2, 175 mg/m.sup.2, 180 mg/m.sup.2, 200 mg/m.sup.2, 210
mg/m.sup.2, 220 mg/m.sup.2, 250 mg/m.sup.2, 260 mg/m.sup.2, 300
mg/m.sup.2, 350 mg/m.sup.2, 400 mg/m.sup.2, 500 mg/m.sup.2, 540
mg/m.sup.2, 750 mg/m.sup.2, 1000 mg/m.sup.2, or 1080 mg/m.sup.2 of
a taxane (e.g., paclitaxel). In various embodiments, the
composition includes less than about any of 350 mg/m.sup.2, 300
mg/m.sup.2, 250 mg/m.sup.2, 200 mg/m.sup.2, 150 mg/m.sup.2, 120
mg/m.sup.2, 100 mg/m.sup.2, 90 mg/m.sup.2, 50 mg/m.sup.2, or 30
mg/m.sup.2 of a taxane (e.g., paclitaxel). In some embodiments, the
amount of the taxane (e.g., paclitaxel) per administration is less
than about any of 25 mg/m.sup.2, 22 mg/m.sup.2, 20 mg/m.sup.2, 18
mg/m.sup.2, 15 mg/m.sup.2, 14 mg/m.sup.2, 13 mg/m.sup.2, 12
mg/m.sup.2, 11 mg/m.sup.2, 10 mg/m.sup.2, 9 mg/m.sup.2, 8
mg/m.sup.2, 7 mg/m.sup.2, 6 mg/m.sup.2, 5 mg/m.sup.2, 4 mg/m.sup.2,
3 mg/m.sup.2, 2 mg/m.sup.2, or 1 mg/m.sup.2. In some embodiments,
the effective amount of a taxane (e.g., paclitaxel) in the
composition is included in any of the following ranges: about 1 to
about 5 mg/m.sup.2, about 5 to about 10 mg/m.sup.2, about 10 to
about 25 mg/m.sup.2, about 25 to about 50 mg/m.sup.2, about 50 to
about 75 mg/m.sup.2, about 75 to about 100 mg/m.sup.2, about 100 to
about 125 mg/m.sup.2, about 125 to about 150 mg/m.sup.2, about 150
to about 175 mg/m.sup.2, about 175 to about 200 mg/m.sup.2, about
200 to about 225 mg/m.sup.2, about 225 to about 250 mg/m.sup.2,
about 250 to about 300 mg/m.sup.2, about 300 to about 350
mg/m.sup.2, or about 350 to about 400 mg/m.sup.2. Preferably, the
effective amount of a taxane (e.g., paclitaxel) in the composition
is about 5 to about 300 mg/m.sup.2, such as about 100 to about 150
mg/m.sup.2, about 120 mg/m.sup.2, about 130 mg/m.sup.2, or about
140 mg/m.sup.2.
[0109] In some embodiments of any of the above aspects, the
effective amount of a taxane (e.g., paclitaxel) 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, or 20 mg/kg. In
various embodiments, the effective amount of a taxane (e.g.,
paclitaxel) 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 a taxane (e.g.,
paclitaxel).
[0110] Exemplary dosing frequencies include, but are not limited
to, weekly without break; weekly, three out of four weeks; once
every three weeks; once every two weeks; weekly, 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, 12 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.
[0111] 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 taxane (e.g., paclitaxel) or derivative thereof is
administered over a period of at least one month, wherein the
interval between each administration is no more than about a week,
and wherein the dose of the taxane (e.g., paclitaxel) at each
administration is about 0.25 mg/m.sup.2 to about 75 mg/m.sup.2,
such as about 0.25 mg/m.sup.2 to about 25 mg/m.sup.2 or about 25
mg/m.sup.2 to about 50 mg/m.sup.2.
[0112] In some embodiments, the dosage of a taxane (e.g.,
paclitaxel) in a nanoparticle composition can be in the range of
5-400 mg/m.sup.2 when given on a 3 week schedule, or 5-250
mg/m.sup.2 when given on a weekly schedule. For example, the amount
of a taxane (e.g., paclitaxel) is about 60 to about 300 mg/m.sup.2
(e.g., about 260 mg/m.sup.2).
[0113] Other exemplary dosing schedules for the administration of
the nanoparticle composition (e.g., paclitaxel/albumin nanoparticle
composition) include, but are not limited to, 100 mg/m.sup.2,
weekly, without break; 75 mg/m.sup.2 weekly, 3 out of four weeks;
100 mg/m.sup.2, weekly, 3 out of 4 weeks; 125 mg/m.sup.2, weekly, 3
out of 4 weeks; 125 mg/m.sup.2, weekly, 2 out of 3 weeks; 130
mg/m.sup.2, weekly, without break; 175 mg/m.sup.2, once every 2
weeks; 260 mg/m.sup.2, once every 2 weeks; 260 mg/m.sup.2, once
every 3 weeks; 180-300 mg/m.sup.2, every three weeks; 60-175
mg/m.sup.2, weekly, without break; 20-150 mg/m.sup.2 twice a week;
and 150-250 mg/m.sup.2 twice a week. The dosing frequency of the
composition may be adjusted over the course of the treatment based
on the judgment of the administering physician.
[0114] 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.
[0115] 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.
[0116] In some embodiments, the invention provides a method of
treating cancer in an individual by parenterally administering to
the individual (e.g., a human) an effective amount of a composition
comprising nanoparticles that comprise a taxane (e.g., paclitaxel)
and a carrier protein (e.g., albumin such as human serum albumin).
The invention also provides a method of treating cancer in an
individual by intravenous, intra-arterial, intramuscular,
subcutaneous, inhalation, oral, intraperitoneal, nasally, or
intra-tracheal administering to the individual (e.g., a human) an
effective amount of a composition comprising nanoparticles that
comprise a taxane (e.g., paclitaxel) and a carrier protein (e.g.,
albumin such as human serum albumin). In some embodiments, the
route of administration is intraperitoneal. In some embodiments,
the route of administration is intravenous, intra-arterial,
intramuscular, or subcutaneous. In various embodiments, about 5 mg
to about 500 mg, such as about 30 mg to about 300 mg or about 50 to
about 500 mg, of the taxane (e.g., paclitaxel) or derivative
thereof is administered per dose. In some embodiments, the taxane
(e.g., paclitaxel) or derivative thereof is the only
pharmaceutically active agent for the treatment of cancer that is
contained in the composition. In some embodiments, the method
comprises intraperitoneally administering composition comprising
nanoparticles that comprise a taxane (e.g., paclitaxel) and a
carrier protein (e.g., albumin such as human serum albumin) at the
dose of any of about 60 m g/m.sup.2, 80 mg/m.sup.2, 100 mg/m.sup.2,
125 mg/m.sup.2, and 150 mg/m.sup.2.
[0117] Any of the compositions described herein 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
one variation of the invention, nanoparticles (such as albumin
nanoparticles) of the inventive compounds can be administered by
any acceptable route including, but not limited to, orally,
intramuscularly, transdermally, intravenously, through an inhaler
or other air borne delivery systems and the like.
[0118] In some embodiments, paclitaxel-containing nanoparticles
composition may be administered with a second therapeutic compound
and/or a second therapy. The dosing frequency of the
paclitaxel-containing nanoparticles composition and the second
compound may be adjusted over the course of the treatment based on
the judgment of the administering physician. In some embodiments,
the first and second therapies are administered simultaneously,
sequentially, or concurrently. When administered separately, the
taxane (e.g., paclitaxel)-containing nanoparticles composition and
the second compound can be administered at different dosing
frequency or intervals. For example, the taxane (e.g.,
paclitaxel)-containing nanoparticle composition can be administered
weekly, while a second compound can be administered more or less
frequently. In some embodiments, sustained continuous release
formulation of the taxane (e.g., paclitaxel)-containing
nanoparticle and/or second compound 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 be used.
[0119] When the taxane nanoparticle compositions are administered
in conjunction with another chemotherapeutic agent, the
nanoparticle composition and the other chemotherapeutic 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 taxane in the
nanoparticle composition and the other chemotherapeutic agent are
administered at a predetermined ratio. For example, in some
embodiments, the ratio by weight of the taxane in the nanoparticle
composition and the other chemotherapeutic 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
taxane in the nanoparticle composition and the other
chemotherapeutic 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 taxane in the nanoparticle
composition and the other chemotherapeutic 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.
[0120] The doses required for the taxane and/or the other
chemotherapeutic 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 chemotherapeutic agent
are 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 chemotherapeutic 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).
[0121] 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 chemotherapeutic 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.
[0122] In some embodiments, the dose of both the taxane in the
nanoparticle composition and the other chemotherapeutic agent are
reduced as compared to the corresponding normal dose of each when
administered alone. In some embodiments, both the taxane in the
nanoparticle composition and the other chemotherapeutic agent are
administered at a subtherapeutic, i.e., reduced, level. In some
embodiments, the dose of the nanoparticle composition and/or the
other chemotherapeutic agent is substantially less than the
established maximum toxic dose (MTD). For example, the dose of the
nanoparticle composition and/or the other chemotherapeutic agent is
less than about 50%, 40%, 30%, 20%, or 10% of the MTD.
Metronomic Therapy Regimes
[0123] The present invention also provides metronomic therapy
regimes for any of the methods of treatment and methods of
administration described herein. Exemplary metronomic therapy
regimes and embodiments for the use of metronomic therapy regimes
are discussed below and disclosed in U.S. Ser. No. 11/359,286,
filed Feb. 21, 2006, published as U.S. Pub. No. 2006/0263434 (such
as those described in paragraphs [0138] to [0157]), which is hereby
incorporated by reference in its entirety. In some embodiments, the
nanoparticle composition is administered over a period of at least
one month, wherein the interval between each administration is no
more than about a week, and wherein the dose of the taxane (e.g.,
paclitaxel) at each administration is about 0.25% to about 25% of
its maximum tolerated dose following a traditional dosing regime.
In some embodiments, the nanoparticle composition is administered
over a period of at least two months, wherein the interval between
each administration is no more than about a week, and wherein the
dose of the taxane (e.g., paclitaxel) at each administration is
about 1% to about 20% of its maximum tolerated dose following a
traditional dosing regime. In some embodiments, the dose of a
taxane (e.g., paclitaxel) per administration is less than about any
of 25%, 24%, 23%, 22%, 20%, 18%, 15%, 14%, 13%, 12%, 11%, 10%, 9%,
8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the maximum tolerated dose. In
some embodiments, any nanoparticle 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,
12 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, 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.
Carrier Proteins
[0124] Provided herein are also compositions comprising
nanoparticles that comprise a taxane and a carrier protein for use
in methods of treatment, methods of administration, and dosage
regimes described herein. In some embodiments, the carrier protein
is albumin. In some embodiments, the carrier protein is human serum
albumin.
[0125] Examples of suitable carrier proteins include proteins
normally found in blood or plasma, which include, but are not
limited to, albumin, immunoglobulin including IgA, lipoproteins,
apolipoprotein B, a-acid glycoprotein, .beta.-2-macroglobulin,
thyroglobulin, transferin, fibronectin, factor VII, factor VIII,
factor IX, factor X, and the like. In some embodiments, the carrier
protein is a non-blood protein, such as casein, a-lactalbumin, or
.beta.-lactoglobulin. The carrier proteins may either be natural in
origin or synthetically prepared. In some embodiments, the
pharmaceutical acceptable carrier comprises albumin, such as human
serum albumin (HSA). HSA is a highly soluble globular protein of
M.sub.r 65 K 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 disulphide bridges, one free thiol
(Cys 34), and a single tryptophan (Trp 214). 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
animals (including domestic pets and agricultural animals).
[0126] 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, 9.sup.th 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
(1981), 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 (1992), and Carter et al.,
Adv. Protein. Chem., 45, 153-203 (1994)).
[0127] The carrier protein (e.g., albumin) in the composition
generally serves as a carrier for the taxane (e.g., paclitaxel) or
derivative thereof, i.e., the carrier protein in the composition
makes the taxane (e.g., paclitaxel) or derivative thereof 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 for solubilizing
of the taxane (e.g., paclitaxel), and thereby can reduce one or
more side effects of administration of the taxane (e.g.,
paclitaxel) into an individual (e.g., human). In some embodiments,
the composition is substantially free (e.g. free) of organic
solvents or surfactants. A composition is "substantially free of
organic solvent" or "substantially free of surfactant" if the
amount of organic solvent or surfactant in the composition is not
sufficient to cause one or more side effect(s) in an individual
when the composition is administered to the individual. In some
embodiments, the nanoparticles in the composition have a solid
core. In some embodiments, the nanoparticles in the composition
have a core that is not aqueous (i.e., other than aqueous core). In
some embodiments, the nanoparticles of the composition lack a
polymeric matrix. In some embodiments, the nanoparticles of the
composition are filter sterilizable. In some embodiments, the
nanoparticles in the composition comprise at least one cross-linked
carrier protein. In some embodiments, the nanoparticles in the
composition comprise at least ten-percent of carrier protein that
is cross-linked.
[0128] The taxane (e.g., paclitaxel) is "stabilized" in an aqueous
suspension if it remains suspended in an aqueous medium (e.g.,
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 (e.g., human). Stability of the
suspension is generally (but not necessarily) evaluated at storage
temperature, such as room temperature (e.g., 20-25.degree. C.) or
refrigerated conditions (e.g., 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.
[0129] In some embodiments, the composition comprises nanoparticles
comprising (in various embodiments consisting essentially of) a
taxane (e.g., paclitaxel) and a carrier protein. When the taxane
(e.g., paclitaxel) is in a liquid form, the particles or
nanoparticles are also referred to as droplets or nanodroplets. In
some embodiments, taxane is coated with the carrier protein.
Particles (such as nanoparticles) of poorly water soluble
pharmaceutical agents have been disclosed in, for example, U.S.
Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in U.S. Pat.
App. Pub. No. 2005/0004002A1.
[0130] The amount of carrier protein in the composition described
herein will vary depending on the taxane (e.g., paclitaxel) or
derivative thereof, and other components in the composition. In
some embodiments, the composition comprises a carrier protein in an
amount that is sufficient to stabilize the taxane (e.g.,
paclitaxel) in an aqueous suspension, for example, in the form of a
stable colloidal suspension (e.g., a stable suspension of
nanoparticles). In some embodiments, the carrier protein is in an
amount that reduces the sedimentation rate of the taxane (e.g.,
paclitaxel) in an aqueous medium. The amount of the carrier protein
also depends on the size and density of particles of the taxane
(e.g., paclitaxel).
[0131] In some embodiments of any of the aspects of the invention,
the taxanes in the nanoparticles are coated with a carrier protein,
such as albumin (e.g., human serum albumin). In some embodiments,
the taxane is paclitaxel. In various embodiments, the composition
comprises more than about any of 50%, 60%, 70%, 80%, 90%, 95%, or
99% of the taxane or derivative thereof in nanoparticle form. In
some embodiments, the taxane or derivative thereof constitutes more
than about any of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the
nanoparticles by weight. In some embodiments, the nanoparticles are
substantially free of polymeric core materials. In some
embodiments, the taxane in the nanoparticles is amorphous. In some
embodiments, the taxane used for making the nanoparticle
compositions is in anhydrous form. In some embodiments, the carrier
protein (such as albumin) to a taxane weight ratio in the taxane
nanoparticle composition 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, 7.5:1 or less, 7:1 or less, 6:1
or less, 5:1 or less, 4:1 or less, or 3:1 or less. In some
embodiments, the albumin to taxane weight ratio is between about
any of 18:1 to 1:18, 10:1 to 1:10, 9:1 to 1:1, 8:1 to 1:1, 7.5:1 to
1.1, 7.1:1 to 1:1, 6:1 to 1:1, 5:1 to 1:1, 4:1 to 1:1, or 3:1 to
1:1. In some embodiments, the composition comprises a stable
aqueous suspension of particles (e.g., nanoparticles) comprising a
taxane and carrier protein (such as albumin, e.g., particles of
paclitaxel coated with albumin).
[0132] In some embodiments, the composition comprises nanoparticles
of any shape (e.g., a spherical or non-spherical shape) with an
average or mean diameter of no greater than about 1000 nanometers
(nm), such as no greater than about any of 900 nm, 800 nm, 700 nm,
600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm, 90 nm, 80 nm, 70
nm, 60 nm, or 50 nm. In some embodiments, the average or mean
diameter of the particles is no greater than about 200 nm. In some
embodiments, the composition is sterile filterable. In some
embodiments, the composition is sterile filtered. In some
embodiments, the average or mean diameter of the particles is no
greater than about 100 nm. In some embodiments, the average or mean
diameter of the particles is between about 20 to about 400 nm. In
some embodiments, the average or mean diameter of the particles is
between about 40 to about 200 nm. In some embodiments, the
particles are sterile-filterable. In some embodiments, the
composition comprises nanoparticles with a diameter of about any of
1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm,
200 nm, 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, or 50 nm. In some
embodiments, the composition comprises nanoparticles with a
diameter of between about any of 50 nm and 150 nm, 50 nm and 75 nm,
50 nm and 100 nm, 75 nm and 100 nm, 100 nm and 125 nm, 125 nm and
150 nm, 100 nm and 150 nm, 150 nm and 175 nm, or 175 nm and 200 nm.
In some embodiments, the diameter of about any of 50% or more, 65%
or more, 75% or more, 80% or more, 90% or more, 95% or more, 98% or
more, 99% or more, 99.5% or more, or 99.9% or more of the
nanoparticles can fall within the range specified. Average or mean
diameters of nanoparticles can be determined by methods known in
the art, for example laser light scattering.
[0133] The nanoparticles described herein may be present in a dry
formulation (e.g., 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.
[0134] In some embodiments, the nanoparticles do not comprise a
blood-insoluble gas or do not comprise gas-filled microbubbles.
[0135] In some embodiments, the carrier protein is present in an
effective amount to reduce one or more side effects associated with
administration of taxane to a human compared to compositions
without carrier protein. These side effects include, but are not
limited to, myelosuppression, neurotoxicity, hypersensitivity,
inflammation, venous irritation, phlebitis, pain, skin irritation,
neutropenic fever, anaphylactic reaction, hematologic toxicity, and
cerebral or neurologic toxicity, and combinations thereof. In some
embodiments, there is provided a method of reducing
hypersensitivity reactions associated with administration of the
taxane (e.g., paclitaxel), including, for example, severe skin
rashes, hives, flushing, dyspnea, tachycardia, pulmonary
hypertension (e.g., lymphoma); chest pain; black, tarry stools;
general feeling of illness, shortness of breath; swollen glands;
weight loss; yellow skin and eyes, abdominal pain; unexplained
anxiousness; bloody or cloudy urine; bone pain; chills; confusion;
convulsions (seizures); cough; decreased urge to urinate; fast,
slow, or irregular heartbeat; fever; frequent urge to urinate;
increased thirst; loss of appetite; lower back or side pain; mood
changes; muscle pain or cramps; nausea or vomiting; numbness or
tingling around lips, hands, or feet; painful or difficult
urination; rash; sore throat; sores or white spots on lips or in
mouth; swelling of hands, ankles, feet, or lower legs; swollen
glands; trouble breathing; unusual bleeding or bruising; unusual
tiredness or weakness; weakness or heaviness of legs, skin ulcer or
sores, weight gain, acne; constipation; diarrhea; difficulty in
moving; headache; loss of energy or weakness; muscle pain or
stiffness; pain; shaking or trembling; trouble sleeping; nosebleed;
and/or swelling of the face. These side effects, however, are
merely exemplary and other side effects, or combination of side
effects, associated with the taxane (e.g., paclitaxel) can be
reduced. The side effects may be immediate or delayed (such as not
occurring for a few days, weeks, months, or years after treatment
begins).
Antimicrobial Agents in Compositions
[0136] In some embodiments, the compositions of the invention also
includes an antimicrobial agent (e.g., an agent in addition to the
taxane (e.g., paclitaxel)) in an amount sufficient to significantly
inhibit (e.g., delay, reduce, slow, and/or prevent) microbial
growth in the composition for use in the methods of treatment,
methods of administration, and dosage regimes described herein.
Exemplary microbial agents and variations for the use of microbial
agents are disclosed in U.S. Ser. No. 11/514,030, filed Aug. 30,
2006 (such as those described in paragraphs [0036] to [0058]). In
some embodiments, the antimicrobial agent is a chelating agent,
such as EDTA, edetate, citrate, pentetate, tromethamine, sorbate,
ascorbate, derivatives thereof, or mixtures thereof. In some
embodiments, the antimicrobial agent is a polydentate chelating
agent. In some embodiments, the antimicrobial agent is a
non-chelating agent, such as any of sulfites, benzoic acid, benzyl
alcohol, chlorobutanol, and paraben. In some embodiments, an
antimicrobial other than the taxane discussed above is not
contained or used in the methods of treatment, methods of
administration, and dosage regimes described herein.
Sugar Containing Compositions
[0137] In some embodiments, the compositions of the invention
include a sugar for use in the methods of treatment described
herein. In some embodiments, the compositions of the invention
include both a sugar and an antimicrobial agent for use in the
methods of treatment described herein. Exemplary sugars and
variations for the use of sugars are disclosed in U.S. Ser. No.
11/514,030, filed Aug. 30, 2006 (such as those described in
paragraphs [0084] to [0090]). In some embodiments, the sugar serves
as a reconstitution enhancer which causes a lyophilized composition
to dissolve or suspend in water and/or aqueous solution more
quickly than the lyophilized composition would dissolve without the
sugar. In some embodiments, the composition is a liquid (e.g.,
aqueous) composition obtained by reconstituting or resuspending a
dry composition. In some embodiments, the concentration of sugar in
the composition is greater than about 50 mg/ml. In some
embodiments, the sugar is in an amount that is effective to
increase the stability of the taxane (e.g., paclitaxel) or
derivative thereof in the composition as compared to a composition
without the sugar. In some embodiments, the sugar is in an amount
that is effective to improve filterability of the composition as
compared to a composition without the sugar.
[0138] The sugar-containing compositions described herein may
further comprise one or more antimicrobial agents, such as the
antimicrobial agents described herein or in U.S. Ser. No.
11/514,030, filed Aug. 30, 2006. In addition to one or more sugars,
other reconstitution enhancers (such as those described in U.S.
Pat. App. Publication No. 2005/0152979, which is hereby
incorporated by reference in its entirety) can also be added to the
compositions. In some embodiments, a sugar is not contained or used
in the methods of treatment, methods of administration, and dosage
regimes described herein.
Stabilizing Agents in Compositions
[0139] In some embodiments, the compositions of the invention also
include a stabilizing agent for use in the methods of treatment,
methods of administration, and dosage regimes described herein. In
some embodiments, the compositions of the invention include an
antimicrobial agent and/or a sugar and/or a stabilizing agent for
use in the methods of treatment, methods of administration, and
dosage regimes described herein. Exemplary stabilizing agents and
variations for the use of stabilizing agents are disclosed in U.S.
Ser. No. 11/513,756, filed Aug. 30, 2006 (such as those described
in paragraphs [0038] to [0083] and [0107] to [0114]). The present
invention in another variation provides for compositions and
methods of preparation of a taxane (e.g., paclitaxel) which retain
the desirable therapeutic effects and remain physically and/or
chemically stable upon exposure to certain conditions such as
prolonged storage, elevated temperature, or dilution for parenteral
administration. The stabilizing agent includes, for example,
chelating agents (e.g., citrate, malic acid, edetate, or
pentetate), sodium pyrophosphate, and sodium gluconate. In some
embodiments, the invention provides pharmaceutical formulations of
a taxane (e.g., paclitaxel) comprising citrate, sodium
pyrophosphate, EDTA, sodium gluconate, citrate and sodium chloride,
and/. In another variation, the invention provides a composition of
a taxane, wherein the taxane (e.g., paclitaxel) used for preparing
the formulation is in an anhydrous form prior to being incorporated
into the composition.
[0140] In some embodiments, a stabilizing agent is not contained or
used in the methods of treatment, methods of administration, and
dosage regimes described herein.
Pharmaceutical Compositions and Formulations
[0141] The compositions described herein may be used in the
preparation of a formulation, such as a pharmaceutical formulation,
by combining the nanoparticle composition(s) described with a
pharmaceutical acceptable carrier, excipients, stabilizing agents
or other agent, which are known in the art, for use in the methods
of treatment, methods of administration, and dosage regimes
described herein. 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, bile acids, 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-a-dimyristoylphosphatidylcholine (DMPC),
dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine
(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.
[0142] In some embodiments, the composition is suitable for
administration to a human. There are a wide variety of suitable
formulations of the inventive composition (see, e.g., U.S. Pat.
Nos. 5,916,596 and 6,096,331, which are hereby incorporated by
reference in their entireties). The following formulations and
methods are merely exemplary and are in no way limiting.
Formulations suitable for oral administration can comprise (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, (d) suitable emulsions, and
(e) powders. 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.
[0143] 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, stabilizing agents, 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 methods of treatment, methods of
administration, and dosage regimes described herein (i.e., water)
for injection, 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.
[0144] The invention also includes formulations of nanoparticle
compositions comprising the taxane (e.g., paclitaxel) or derivative
thereof and a carrier suitable for administration by inhalation for
use in the methods of the invention. Formulations suitable for
aerosol administration comprise the inventive composition include
aqueous and non-aqueous, isotonic sterile solutions, which can
contain anti-oxidants, buffers, bacteriostats, and solutes, as well
as aqueous and non-aqueous sterile suspensions that can include
suspending agents, solubilizers, thickening agents, stabilizing
agents, and preservatives, alone or in combination with other
suitable components, which can be made into aerosol formulations to
be administered via inhalation. These aerosol formulations can be
placed into pressurized acceptable propellants, such as
dichlorodifluoromethane, propane, nitrogen, and the like. They also
can be formulated as pharmaceuticals for non-pressured
preparations, such as in a nebulizer or an atomizer.
[0145] In some embodiments, the composition is formulated to have a
pH in the 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 (e.g., about 8). The
composition can also be made to be isotonic with blood by the
addition of a suitable tonicity modifier, such as glycerol.
[0146] The nanoparticles of this invention can be enclosed in a
hard or soft capsule, can be compressed into tablets, or can be
incorporated with beverages or food or otherwise incorporated into
the diet. Capsules can be formulated by mixing the nanoparticles
with an inert pharmaceutical diluent and inserting the mixture into
a hard gelatin capsule of the appropriate size. If soft capsules
are desired, a slurry of the nanoparticles with an acceptable
vegetable oil, light petroleum or other inert oil can be
encapsulated by machine into a gelatin capsule.
[0147] Also provided are unit dosage forms comprising the
compositions and formulations described herein. These unit dosage
forms can be stored in a suitable packaging in single or multiple
unit dosages and may also be further sterilized and sealed. For
example, the pharmaceutical composition (e.g., a dosage or unit
dosage form of a pharmaceutical composition) may include (i)
nanoparticles that comprise a taxane (e.g., paclitaxel) and a
carrier protein and (ii) a pharmaceutically acceptable carrier. In
some embodiments, the pharmaceutical composition also includes one
or more other compounds (or pharmaceutically acceptable salts
thereof) that are useful for treating cancer. In various
embodiments, the amount of a taxane (e.g., paclitaxel) in the
composition is included in any of the following ranges: about 5 to
about 50 mg, about 20 to about 50 mg, about 50 to about 100 mg,
about 100 to about 125 mg, about 125 to about 150 mg, about 150 to
about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg,
about 225 to about 250 mg, about 250 to about 300 mg, about 300 to
about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg,
or about 450 to about 500 mg. In some embodiments, the amount of a
taxane (e.g., paclitaxel) or derivative thereof in the composition
(e.g., a dosage or unit dosage form) is in the range of about 5 mg
to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg
to about 200 mg, of the taxane (e.g., paclitaxel) or derivative
thereof. In some embodiments, the carrier is suitable for parental
administration (e.g., intravenous administration). In some
embodiments, the taxane (e.g., paclitaxel) or derivative thereof is
the only pharmaceutically active agent for the treatment of cancer
that is contained in the composition.
[0148] In some embodiments, the invention features a dosage form
(e.g., a unit dosage form) for the treatment of cancer comprising
(i) nanoparticles that comprise a carrier protein and a taxane
(e.g., paclitaxel), wherein the amount of a taxane (e.g.,
paclitaxel) or derivative thereof in the unit dosage from is in the
range of about 5 mg to about 500 mg, and (ii) a pharmaceutically
acceptable carrier. In some embodiments, the amount of the taxane
(e.g., paclitaxel) or derivative thereof in the unit dosage form
includes about 30 mg to about 300 mg.
[0149] Also provided are articles of manufacture comprising the
compositions, formulations, and unit dosages described herein in
suitable packaging for use in the methods of treatment, methods of
administration, and dosage regimes described herein. Suitable
packaging for compositions described herein are known in the art,
and include, for example, vials (such as sealed vials), vessels
(such as sealed vessels), ampules, bottles, jars, flexible
packaging (e.g., sealed Mylar or plastic bags), and the like. These
articles of manufacture may further be sterilized and/or
sealed.
Kits
[0150] The invention also provides kits comprising the
compositions, formulations, unit dosages, and articles of
manufacture described herein for use in the methods of treatment,
methods of administration, and dosage regimes described herein.
Kits of the invention include one or more containers comprising a
taxane (e.g., paclitaxel)-containing nanoparticle compositions
(formulations or unit dosage forms and/or articles of manufacture),
and in some embodiments, further comprise instructions for use in
accordance with any of the methods of treatment described herein.
In some embodiments, the kit comprises i) a composition comprising
nanoparticles comprising a taxane (e.g., paclitaxel) and a carrier
protein (such as albumin) and ii) instructions for administering
the nanoparticles and the other chemotherapeutic agents
simultaneously and/or sequentially, for treatment of cancer. In
various embodiments, the amount of a taxane (e.g., paclitaxel) in
the kit is included in any of the following ranges: about 5 mg to
about 20 mg, about 20 to about 50 mg, about 50 to about 100 mg,
about 100 to about 125 mg, about 125 to about 150 mg, about 150 to
about 175 mg, about 175 to about 200 mg, about 200 to about 225 mg,
about 225 to about 250 mg, about 250 to about 300 mg, about 300 to
about 350 mg, about 350 to about 400 mg, about 400 to about 450 mg,
or about 450 to about 500 mg. In some embodiments, the amount of a
taxane (e.g., paclitaxel) in the kit is in the range of about 5 mg
to about 500 mg, such as about 30 mg to about 300 mg or about 50 mg
to about 200 mg. In some embodiments, the kit includes one or more
other compounds (i.e., one or more compounds other than a taxane)
that are useful for cancer.
[0151] 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. 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 kit may further comprise a description of
selecting an individual suitable or treatment.
[0152] The present invention also provides kits comprising
compositions (or unit dosages forms and/or articles of manufacture)
described herein and may further comprise instruction(s) on methods
of using the composition, such as uses further described herein. In
some embodiments, the kit of the invention comprises the packaging
described above. In other embodiments, the kit of the invention
comprises the packaging described above and a second packaging
comprising a buffer. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, syringes, and package inserts
with instructions for performing any methods described herein.
[0153] For combination therapies of the invention, the kit may
contain instructions for administering the first and second
therapies simultaneously and/or sequentially for the effective
treatment of cancer. The first and second therapies can be present
in separate containers or in a single container. It is understood
that the kit may comprise one distinct composition or two or more
compositions wherein one composition comprises a first therapy and
one composition comprises a second therapy.
[0154] Kits may also be provided that contain sufficient dosages of
the taxane (e.g., paclitaxel) as disclosed herein to provide
effective treatment for an individual for an extended period, such
as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3
months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months
or more. Kits may also include multiple unit doses of the taxane
(e.g., paclitaxel) compositions, pharmaceutical compositions, and
formulations described herein and instructions for use and packaged
in quantities sufficient for storage and use in pharmacies, for
example, hospital pharmacies and compounding pharmacies. In some
embodiments, the kit comprises a dry (e.g., lyophilized)
composition that can be reconstituted, resuspended, or rehydrated
to form generally a stable aqueous suspension of nanoparticles
comprising a taxane (e.g., paclitaxel) and albumin (e.g., a taxane
(e.g., paclitaxel) coated with albumin).
[0155] The kits of the invention are in suitable packaging.
Suitable packaging include, but is not limited to, vials, bottles,
jars, flexible packaging (e.g., sealed Mylar or plastic bags), and
the like. Kits may optionally provide additional components such as
buffers and interpretative information.
Methods of Making the Compositions
[0156] Methods of making compositions containing carrier proteins
and poorly water soluble pharmaceutical agents are known in the
art. For example, nanoparticles containing poorly water soluble
pharmaceutical agents and carrier proteins (e.g., 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; and
6,537,579 and also in U.S. Pat. Pub. No. 2005/0004002A1, which are
each hereby incorporated by reference in their entireties.
[0157] Briefly, the taxane (e.g., paclitaxel) is dissolved in an
organic solvent. Suitable organic solvents include, for example,
ketones, esters, ethers, chlorinated solvents, and other solvents
known in the art. For example, the organic solvent can be methylene
chloride, chloroform/ethanol, or chloroform/t-butanol (for example
with a ratio of about any 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 or with a ratio
of about any of 3:7, 5:7, 4:6, 5:5, 6:5, 8:5, 9:5, 9.5:5, 5:3, 7:3,
6:4, or 9.5:0.5). The solution is added to a carrier protein (e.g.,
human serum albumin). The mixture is subjected to high pressure
homogenization (e.g., using an Avestin, APV Gaulin,
Microfluidizer.TM. such as a Microfluidizer.TM. Processor M-110EH
from Microfluidics, Stansted, or Ultra Turrax homogenizer). The
emulsion may be cycled through the high pressure homogenizer for
between about 2 to about 100 cycles, such as about 5 to about 50
cycles or about 8 to about 20 cycles (e.g., about any of 8, 10, 12,
14, 16, 18 or 20 cycles). The organic solvent can then be removed
by evaporation utilizing suitable equipment known for this purpose,
including, but not limited to, rotary evaporators, falling film
evaporators, wiped film evaporators, spray driers, and the like
that can be operated in batch mode or in continuous operation. The
solvent may be removed at reduced pressure (such as at about any of
25 mm Hg, 30 mm Hg, 40 mm Hg, 50 mm Hg, 100 mm Hg, 200 mm Hg, or
300 mm Hg). The amount of time used to remove the solvent under
reduced pressure may be adjusted based on the volume of the
formulation. For example, for a formulation produced on a 300 mL
scale, the solvent can be removed at about 1 to about 300 mm Hg
(e.g., about any of 5-100 mm Hg, 10-50 mm Hg, 20-40 mm Hg, or 25 mm
Hg) for about 5 to about 60 minutes (e.g., about any of 7, 8, 9,
10, 11, 12, 13, 14, 15 16, 18, 20, 25, or 30 minutes).
[0158] If desired, human albumin solution may be added to the
dispersion to adjust the human serum albumin to the taxane (e.g.,
paclitaxel) ratio or to adjust the concentration of the taxane
(e.g., paclitaxel) in the dispersion. For example, human serum
albumin solution (e.g., 25% w/v) can be added to adjust the human
serum albumin to a taxane (e.g., paclitaxel) ratio to about any of
18:1, 15:1 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7.5:1, 7:1, 6:1,
5:1, 4:1, or 3:1. For example, human serum albumin solution (e.g.,
25% w/v) or another solution is added to adjust the concentration
of a taxane (e.g., paclitaxel) in the dispersion to 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. The dispersion
may be serially filtered through multiple filters, such as a
combination of 1.2 .mu.M and 0.8/0.2 .mu.m filters; the combination
of 1.2 .mu.m, 0.8 .mu.m, 0.45 .mu.m, and 0.22 .mu.m filters; or the
combination of any other filters known in the art. The dispersion
obtained can be further lyophilized. The nanoparticle compositions
may be made using a batch process or a continuous process (e.g.,
the production of a composition on a large scale).
[0159] If desired, a second therapy (e.g., one or more compounds
useful for treating cancer), an antimicrobial agent, sugar, and/or
stabilizing agent can also be included in the composition. This
additional agent can either be admixed with the taxane (e.g.,
paclitaxel) and/or the carrier protein during preparation of the
taxane (e.g., paclitaxel)/carrier protein composition, or added
after the taxane (e.g., paclitaxel)/carrier protein composition is
prepared. In some embodiments, the agent is admixed with the taxane
(e.g., paclitaxel)/carrier protein composition prior to
lyophilization. In some embodiments, the agent is added to the
lyophilized pharmaceutical agent/carrier protein composition. In
some embodiments when the addition of the agent changes the pH of
the composition, the pH in the composition are generally (but not
necessarily) adjusted to a desired pH. Exemplary pH values of the
compositions include, for example, in the range of about 5 to about
8.5. In some embodiments, the pH of the composition is adjusted to
no less than about 6, including for example no less than any of
about 6.5, 7, or 8 (e.g., about 8).
[0160] Unless defined otherwise, the meanings of all technical and
scientific terms used herein are those commonly understood by one
of skill in the art to which this invention belongs. One of skill
in the art will also appreciate that any methods and materials
similar or equivalent to those described herein can also be used to
practice or test the invention.
[0161] The following Examples are provided to illustrate, but not
limit, the invention.
EXAMPLES
[0162] The examples, which are intended to be purely exemplary of
the invention and should therefore not be considered to limit the
invention in any way, also describe and detail aspects and
variations of the invention discussed above. Efforts have been made
to ensure accuracy with respect to numbers used (for example,
amounts, temperature, etc.) but some experimental errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and
pressure is at or near atmospheric.
Example 1
Exemplary Method for the Formation of Nanoparticle Compositions
with Paclitaxel and Albumin
[0163] This example provides formulations of paclitaxel/albumin.
The compositions were prepared essentially as described in U.S.
Pat. Nos. 5,439,686 and 5,916,596. Briefly, paclitaxel was
dissolved in an organic solvent (such as methylene chloride or a
chloroform/ethanol mixture), and the solution was added to a human
serum albumin solution. The mixture was homogenized for 5 minutes
at low RPM to form a crude emulsion, and then transferred into a
high pressure homogenizer. The emulsification was performed at
9000-40,000 psi while recycling the emulsion for at least 5 cycles.
The resulting system was transferred into a rotary evaporator, and
the organic solvent was rapidly removed at 40.degree. C., at
reduced pressure (30 mm Hg) for 20-30 minutes. The dispersion was
then further lyophilized for 48 hours. The resulting cake was
reconstituted to the original dispersion by addition of sterile
water or saline, which may optionally contain additional
antimicrobial agent(s).
Example 2
Evaluation of Efficacy of Nanoparticle Albumin Bound Paclitaxel
(Nab-Paclitaxel) in Treating Platinum-Sensitive Patients with
Recurrent Ovarian, Peritoneal, or Fallopian Tube Cancer
[0164] The primary objective of this study was to determine the
objective response rate in platinum-sensitive patients with
recurrent ovarian, peritoneal, or fallopian tube cancer. The study
also evaluated the progression free survival, overall survival,
quality of life during treatment, and the safety and toxicity of
the treatment in this patient population.
Patient Population Evaluated
[0165] Patients were eligible for inclusion for inclusion in this
study if she met all of the following criteria: had histologically
or cytologically confirmed epithelial cancer of the ovary,
fallopian tube or peritoneum (any stage, grade 2-3 if stage 1), had
measurable disease by RECIST or elevated CA-125 (>70) in the
absence of measurable disease, had received prior platinum-based
chemotherapy, was considered platinum sensitive (i.e., having a
treatment-free interval >6 months since completion of platinum
base chemotherapy), had an ECOG Performance Status (PS) 0-2, had a
present, existing peripheral neuropathy which was less than or
equal to Grade 1, and had signed an Institutional Review Board
approved informed consent. Patients were excluded from this study
if she met any of the following criteria: had previously untreated
stage 1, Grade 1 disease, was chemotherapy-naive, had received more
than one prior regimen or prior regimen that was not
platinum-based, had non-epithelial disease, had nonmeasurable
disease with CA-125 less than or equal to 70, had received a taxane
within 6 months of registration or any prior treatment with
Nab-paclitaxel.
Treatment Schedule
[0166] Premedication was administered at the discretion of the
treating physician. Patients received 260 mg/m.sup.2 of
Nab-paclitaxel (Abraxane.RTM.) administered IV during a 30-minute
period on Day 1 of each 21-day cycle. Successive cycles were
initiated every 3 weeks and were continued until there was evidence
of disease progression, unacceptable toxicity, or until 6 cycles.
In patients whose only disease measure was an elevated CA-125, up
to 3 cycles of treatment were to be administered at the discretion
of the treating physician before response was assessed. Patients
who achieved a CR could have received an additional 2 cycles at the
discretion of the treating physician therefore, CR patients were
eligible to receive a maximum of 8 cycles.
Assessments
[0167] Baseline: Complete medical history and physical exam,
assessment of ECOG performance status and peripheral neuropathy,
CBC, CMP, CA-125, pregnancy test (if appropriate), clinical and
radiological assessment of the sites of disease, urinalysis, ECG,
and completion FACT-O quality of life questionnaire was
determined.
[0168] During treatment (prior to the start of each cycle): brief
medical history and physical exam, assessment of ECOG performance
status and peripheral neuropathy, CBC, CMP, CA-125, pregnancy test
(if appropriate), clinical and radiological assessment of tumor
response, assessment of other sites of disease, toxicity
assessments, and completion FACT-O quality of life questionnaire.
These same assessments were made at the time that patients went off
study treatment and every 3 months for a total of 18 months after
the last dose. Responses were assessed by RECIST criteria, CA-125
criteria, or both. See Therasse P. et al., J. NCI 95:205-16 (2000).
Response assessment using RECIST followed the commonly applied
definitions.
[0169] Using CA-125, a complete response was defined as a return to
a normal range value for at least 28 days from the pretreatment
value. See Rustin et al. Clin. Cancer Res. 10(11):3919-26 (2004). A
partial response was defined as a sustained over 50% reduction from
the pretreatment value. Stable disease was defined as a sustained
greater than 50% increase in CA-125 over 28 days in the absence of
any new clinically measurable disease, after an adequate trial of
therapy. Progressive disease was defined as a sustained over 50%
increase in CA-125 or development of new clinically measurable
disease after an adequate trial of therapy. An increase was
measured from the nadir (the lowest CA-125 value since
enrollment).
[0170] Patients who discontinued due to adverse events, PD,
noncompliance, etc. were followed only for survival, additional
therapy, site and date of relapse or progression. Adverse event
data were collected for 30 days following last dose.
Patient Characteristics
[0171] The majority of enrolled patients had recurrence of disease
great than 12 months since prior platinum based chemotherapy.
TABLE-US-00001 TABLE 1 Patient characteristics. Number of Subjects
Enrolled 47 Age (Years) Median 65.4 Range 42-84 Number and
Percentage (%) of Subjects Race White 41 (87.2) Black 1 (2.1)
Hispanic 3 (6.4) Asian 1 (2.1) Indian 1 (2.1) ECOG Performance
Status* 0 38 (80.8) 1 9 (19.2) Prior Therapy ** Prior Chemotherapy
greater 43 (91.5) than or equal to 12 months Prior Chemotherapy
less 4 (8.5) than or equal to 12 months Surgery 44 (93.6) Site of
Primary Disease Epithelial ovarian 37 (78.7) Fallopian tube 1 (2.1)
Peritoneum 9 (19.2) Histological Grade GX (can not be assessed) 1
(2.1) G1 (well differentiated) 4 (8.5) G2 (moderately
differentiated) 9 (19.2) G3 (poorly differentiated) 23 (48.9)
Missing/Unknown 10 (21.3) *Assessed prior to first treatment **
Subjects may not have more than one prior chemotherapy regimen.
Status
TABLE-US-00002 [0172] TABLE 2 Patient Status. Total Number of
Subjects 47 Number and Percentage (%) of Subjects Status Alive 44
(93.6) Dead 3 (6.4) Cause of Death Progressive disease 3 Reason for
Discontinuation Normal Completion 30 (63.8) Toxicity 1 (2.1)
Patient Request/Withdrew 2 (4.2) Consent Investigator decision 3
(6.4) Recurrence 10 (21.3) Other (Coronary artery 1 (2.1) bypass
surgery) Total Cycles Received Median 6.0 Range 1-8
Response to Treatment
[0173] Overall response rates were calculated using either RECIST
or CA-125 or both, the ORR (CP+PR) was 63.2%. Three patients were
not evaluable, two were found to be ineligible after start of
treatment, and one patient was never treated. Overall survival and
progression free survival were plotted in terms of months (x-axis)
to proportion of survival or proportion not progressed (y-axis),
respectively. See FIGS. 1a and 1b.
TABLE-US-00003 TABLE 3 Patient Response Total Number of
Eligible/Treated Subjects 44 N (%) 95% Cl Best Response Complete
Response 14 (31.8) (18.1, 45.6) Partial Response 14 (31.8) (18.1,
45.6) Stable disease 14 (31.8) (18.1, 45.6) SD greater than or
equal to 6 6 months SD less than 6 moths 8 Progressive disease
.sup. 2 (4.5%) (0, 10.7) Clinical Benefit 34 (77.3) Non-evaluable 3
Time to Response (months) Median 1.8 Range 0.6-3.4 Duration of
Response (months) Median 6.5 Range 2.7-13.2 95% Cl 6.6, NA
TABLE-US-00004 TABLE 4 Best Response. By RECIST Best Response By
RECIST By CA-125 and CA-125 Complete Response 1 6 7 Partial
Response 4 3 7 Stable disease 5 2 7 SD greater than or 3 0 3 equal
to 6 months SD less than 6 moths 2 2 4 Progressive disease 1 0 1
Clinical Benefit 8 9 17
Treatment-Related Toxicity >Grade 3
[0174] There were 56 patients treated. Grade 3 neuropathy occurred
in 8.7% of patients.
TABLE-US-00005 TABLE 5 Treatment-related Grade 3-4 Toxicity in
greater than or equal to 2% of patients Adverse Event Grade 3 Grade
4 Total Total % Hematologic Leukopenia 6 0 6 13.0% Neutropenia 6 5
11 23.9% Nonhematologic Abdominal pain 1 0 1 2.2% Diarrhea 1 0 1
2.2% Fatigue 1 0 1 2.2% Neuropathy 4 0 4 8.7% Pneumonia 1 0 1 2.2%
Upper 1 0 1 2.2% respiratory tract infection Generalized 1 0 1 2.2%
weakness
TABLE-US-00006 TABLE 6 Incidences of Alopecia Alopecia Grade 1 5
(10.8%) Grade 2 35 (76.1%)
Estimated Quality of Life
[0175] The Quality of Life (FACT-O) questionnaire was completed at
baseline and before each cycle. Overall quality of life measured
decreased from baseline at the initiation of therapy. As measured
by the questionnaire, the major contributors to the initial decline
in quality of life were the functional, social, and physical well
being assessments. All measure improved at the completion of
therapy and returned to based line.
Conclusion
[0176] Nab-paclitaxel was very active as a single agent in patients
with platinum sensitive recurrent ovarian, peritoneal, or fallopian
tube cancer. The ORR was 64% and the clinical benefit rate was 77%.
Toxicities were tolerable and manageable.
Example 3
Evaluation of Efficacy of Nab-Paclitaxel Plus Carboplatin in
Treating Patients with Recurrent Platinum-Sensitive Ovarian or
Primary Peritoneal Cancer
[0177] This open-label, non-randomized study was designed to
determine the efficacy and safety of nab-paclitaxel (a 130-nm
albumin-bound particle form of paclitaxel) plus carboplatin in
patients with metastatic ovarian or primary peritoneal carcinoma
following platinum-based chemotherapy.
Methods
[0178] Eligible patients had to have either measurable disease
(based on RECIST criteria) or pretreatment CA-125 levels >2
times the upper limit of normal in the absence of measurable
disease. Patients also had to have good performance status,
adequate hepatic/renal function, peripheral neuropathy <grade 1,
and life expectancy >6 months. Patients may have received prior
chemotherapy for ovarian cancer, including taxane-containing
regimens, provided the treatment was completed at least 6 months
before enrollment. Nab-Paclitaxel 100 mg/m.sup.2 was administered
IV over 30 minutes on days 1, 8, and 15 every 28 days. Carboplatin
AUC 6 was administered IV over 1-2 hours on day 1 every 28 days.
Treatment continued for 6 cycles (or longer in the absence of
unacceptable toxicity). Planned sample size was 43 patients (39
evaluable). Efficacy was determined by changes in tumor size for
patients with measurable disease or changes in CA-125 levels for
those with non-measurable disease.
Results
[0179] To date, 10 patients have been enrolled, 2 of whom completed
2 treatment cycles; both patients had a 50% reduction in their
disease (partial response). One patient had grade 4 neutropenia;
grade 3 hematologic events were neutropenia (2 patients),
thrombocytopenia (3), and anemia (1). Severe headache and severe
nausea were reported for 2 patients each; all 4 events required
medication.
Conclusions
[0180] Preliminary results indicated that nab-paclitaxel 100 mg/m2
plus carboplatin AUC 6 will have antitumor activity in patients
with recurrent platinum-sensitive ovarian or primary peritoneal
cancer and that treatment appears to be well tolerated.
Example 3B
Abraxane.RTM. Plus Carboplatin in Patients with Recurrent
Platinum-Sensitive Ovarian or Primary Peritoneal Cancer: Evaluation
of the Response and Survival and Progression-Free Survival
[0181] The aim of this study was to evaluate the effectiveness of
Abraxane.RTM. plus carboplatin in the treatment of patients with
recurrent platinum-sensitive ovarian or primary peritoneal
cancer.
Methods
[0182] Patients with recurrent platinum-sensitive ovarian or
primary peritoneal carcinoma with measurable or biological evidence
of disease had received Abraxane.RTM. 100 mg/m.sup.2 on days 1, 8,
and 15 and carboplatin AUC 5 on day 1, every 28 days, intravenously
for six cycles. In this study of patients with advanced ovarian
cancer, an interim data analysis was conducted of the first 29 of
43 patients who had completed six cycles of treatment. Patients
were evaluated with respect to the safety, tolerability, and
antitumor effect of intravenous Abraxane.RTM. plus carboplatin.
Efficacy was measured as changes from baseline in tumor size
measured by CT using RECIST Criteria, survival, progression-free
survival, and recurrence-free survival during treatment and post
study. Safety and tolerability were monitored through adverse
events and clinical laboratory values, as well as physical
examinations during study drug dosing.
Results
[0183] Twenty-six of 29 patients completed six cycles of
chemotherapy. Complete response was attained by 20 of 29 (68.9%)
patients. Partial response based on CT evaluation was achieved by
four of 29 (13.8%) patients. In one of 29 (3.4%) patients, tumor
size increased after the second cycle and then decreased. Two of 29
(6.8%) patients progressed and discontinued treatment: one (1/29,
3.4%) discontinued treatment secondary to carboplatin toxicity and
the other (1/29, 3.4%) patient discontinued treatment secondary to
severe thrombocytopenia. Abraxane.RTM. plus carboplatin can be used
to treat recurrent platinum-sensitive ovarian or primary peritoneal
cancer effectively.
Example 4
Comparison of Pharmacokinetics of Intravenous and
Intraperitoneal
[0184] The purpose of this study was to compare the
pharmacokinetics of intravenous and intraperitoneal administration
of Nab-paclitaxel. For intravenous administration, 20 rats were
dosed with Abraxane.RTM. at 50 mg/kg. Dose volume of 10 ml/kg was
delivered intravenously via the tail vein. Blood was drawn at the
following intervals for LC/MS/MS analysis of paclitaxel: 0.0,
0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72 hr. For intraperitoneal
administration, 3 rats were dosed with Abraxane.RTM. at 50 mg/kg.
Dose volume of 10 ml/kg was delivered intraperitoneally. Blood was
drawn at the following intervals for LC/MS/MS analysis of
paclitaxel: 0.0, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72 hr.
Results
[0185] The plasma level of paclitaxel was measured by LC/MS/MS
analysis (FIG. 2 and FIG. 3). As indicated in Table 7,
intraperitoneal delivery leaded to a slow absorption of paclitaxel
into the circulation with t.sub.max occurring at .about.3 hrs. The
terminal half-lives of paclitaxel when administered
intraperitoneally or intravenously were about the same. Systemic
exposure after IP administration was .about.50% of IV (over 72
hrs), indicating substantial local intraperitoneal exposure of
drug, especially in the early phase (0-4 hrs) after administration.
There may be sustained exposure beyond 72 hrs; however, this study
was terminated at 72 hrs.
TABLE-US-00007 TABLE 7 Pharmacokinetics Parameters of Intravenous
and Intraperitoneal HL C.sub.max AUC last AUC inf % AUC (h)
T.sub.max (hr) (ng/ml) (hr * ng/ml) (hr * ng/ml) Extrapolate F (%)
IP (N = 3) 6.31 .+-. 0.20 3.33 .+-. 1.16 3207 .+-. 717 26233 .+-.
3848 26770 .+-. 3904 2.0 .+-. 1.2 53 IV (N = 20) 7.96 .+-. 4.05
0.083 .+-. 0.000 25060 .+-. 3573 50038 .+-. 6134 50146 .+-. 6137
0.2 .+-. 0.1
Example 5
Intraperitoneal Administration of Abraxane.RTM. in Recurrent
Mullerian Cancer
[0186] Intraperitoneal therapy for recurrent diseases is an area
that requires further study. The purpose of this experiment is to
determine the safety, efficacy, and maximum tolerable dose of
Nab-paclitaxel when administered intraperitoneally.
Methods
[0187] A Phase I dose-escalation trial is conducted with 6 patients
per cohort to provide sufficient pharmacokinetic data points. Every
4 weeks dosages are escalated so that the cumulative toxicity of
weekly treatment may be evaluated. When the MTD is reached, an
additional 10 patients are treated to obtain further information
about the tolerability at this dose continuously (or 3/4weeks) as
well as preliminary information regarding efficacy.
[0188] Intraperitoneal dosing of Abraxane.RTM. begins at 60
mg/m.sup.2. Doses is escalated as follows: Dose level 1: 60
mg/m.sup.2, Dose level 2: 80 mg/m.sup.2, Dose level 3: 100
mg/m.sup.2, Dose level 4: 125 mg/m.sup.2, and Dose level 5: 150
mg/m.sup.2. Ten patients are added at the DLT, and the study is
expected to accrue approximately 30-40 patients.
Patient Population
[0189] Patients are included in the study if they meet the
following criteria: having recurrent Mullerian cancer (ovarian,
peritoneal, fallopian tube, malignant mixed mullerian tumor, serous
endo), having disease <1 cm by CT/MRI or SLO, displaying
adequate heme/hepatic/renal function, and PS 0-1. Patients are
excluded based on meeting the following criteria: having a bowel
obstruction (or impending), existing intra-abdominal infection,
having significant loculations/adhesions or other contraindications
to IP port placement, existing neuropathy >grade 1, having
extraperitoneal disease, or displaying an inability to tolerate IV
paclitaxel and docetaxel, suggestive of taxane allergy.
* * * * *