U.S. patent application number 14/574082 was filed with the patent office on 2015-09-17 for treatment of cancer using hypoxia activated prodrugs.
This patent application is currently assigned to THRESHOLD PHARMACEUTICALS, INC.. The applicant listed for this patent is THRESHOLD PHARMACEUTICALS, INC.. Invention is credited to John G. Curd, Jian-Xin Duan, Charles P. Hart, Stewart Kroll, Mark Matteucci, Jessica D. Sun.
Application Number | 20150258125 14/574082 |
Document ID | / |
Family ID | 42119663 |
Filed Date | 2015-09-17 |
United States Patent
Application |
20150258125 |
Kind Code |
A1 |
Curd; John G. ; et
al. |
September 17, 2015 |
TREATMENT OF CANCER USING HYPOXIA ACTIVATED PRODRUGS
Abstract
Cancer can be treated by administration of a hypoxia-activated
prodrug, such as TH-302, alone or in combination with other
anticancer agents and/or radiation therapy. In combination therapy,
the hypoxia-activated prodrug and another anticancer agent or
radiation therapy may be administered within the same 24-hour
period, and administration of the hypoxia-activated prodrug may be
completed prior to beginning administration of the other anticancer
agent or radiation therapy.
Inventors: |
Curd; John G.; (Burlinggame,
CA) ; Kroll; Stewart; (Oakland, CA) ;
Matteucci; Mark; (Portola Valley, CA) ; Hart; Charles
P.; (Redwood City, CA) ; Duan; Jian-Xin;
(South San Francisco, CA) ; Sun; Jessica D.;
(Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THRESHOLD PHARMACEUTICALS, INC. |
South San Francisco |
CA |
US |
|
|
Assignee: |
THRESHOLD PHARMACEUTICALS,
INC.
|
Family ID: |
42119663 |
Appl. No.: |
14/574082 |
Filed: |
December 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13125303 |
Jul 27, 2011 |
8946275 |
|
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PCT/US09/61541 |
Oct 21, 2009 |
|
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14574082 |
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61244172 |
Sep 21, 2009 |
|
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61151163 |
Feb 9, 2009 |
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61150700 |
Feb 6, 2009 |
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61118368 |
Nov 26, 2008 |
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61107253 |
Oct 21, 2008 |
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Current U.S.
Class: |
424/649 ; 514/34;
514/49; 514/77 |
Current CPC
Class: |
A61K 31/675 20130101;
A61P 13/08 20180101; A61P 43/00 20180101; A61K 9/0019 20130101;
A61K 31/337 20130101; A61K 31/4985 20130101; A61K 31/7068 20130101;
A61K 31/704 20130101; A61K 31/513 20130101; A61K 31/7068 20130101;
A61K 31/555 20130101; A61K 31/519 20130101; A61K 33/24 20130101;
A61P 1/18 20180101; A61P 17/00 20180101; A61K 33/24 20130101; A61P
35/00 20180101; A61K 31/337 20130101; A61K 45/06 20130101; A61K
31/704 20130101; A61K 31/4985 20130101; A61K 47/26 20130101; A61K
31/675 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61P 1/00 20180101; A61K 31/513 20130101; A61K 31/555
20130101 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/519 20060101 A61K031/519; A61K 31/704 20060101
A61K031/704; A61K 9/00 20060101 A61K009/00; A61K 31/7068 20060101
A61K031/7068; A61K 31/555 20060101 A61K031/555; A61K 31/513
20060101 A61K031/513; A61K 31/337 20060101 A61K031/337; A61K 33/24
20060101 A61K033/24 |
Claims
1.-8. (canceled)
9. A method of treating cancer comprising administering a
therapeutically effective dose of TH-302 and a therapeutically
effective dose of an anticancer drug that is not a hypoxia
activated prodrug to a patient in need of cancer therapy, wherein
(a) the patient is in need of treatment for NSCLC, prostate cancer,
neuroendocrine cancer, anal cancer, urachal cancer, urethral
cancer, breast cancer, melanoma, or renal cell carcinoma and the
anticancer drug that is not a hypoxia activated prodrug is
docetaxel; or (b) the patient is in need of treatment for bile duct
cancer, ovarian cancer, esophageal cancer, NSCLC, ampullary cancer,
neuroendocrine cancer, soft tissue sarcoma, or thyroid cancer and
the anticancer drug that is not a hypoxia activated prodrug is
gemcitabine; or (c) the patient is in need of treatment for
esophageal cancer, pancreatic cancer, NSCLC, neuroendocrine cancer,
soft tissue sarcoma, colorectal cancer, hepatocellular carcinoma
(HCC), renal cancer, or parotid cancer and the anticancer drug that
is not a hypoxia activated prodrug is pemetrexed.
10. A method of treating cancer comprising administering TH-302 as
a single agent, wherein said TH-302 is administered intravenously
in an amount in the range of 200 mg/m.sup.2 to 700 mg/m.sup.2 to a
patient in need of cancer therapy.
11. The method of claim 10 wherein the cancer is a small cell lung
cancer.
12. The method of claim 10 wherein the cancer is melanoma.
13.-14. (canceled)
15. A method of treating cancer, said method comprising
administering to a patient in need of cancer therapy two anticancer
drugs, one a hypoxia activated prodrug (HAP) and the other an
anticancer drug that is not a HAP (non-HAP), wherein both drugs are
administered within a 24 hour period, the HAP is administered
first, and administration of the non-HAP is commenced at least
about 30 minutes and no more than 8 hours after administration of
the HAP is stopped.
16. The method of claim 15, wherein the non-HAP is administered at
least about 2 hours and no more than 4 hours after administration
of the HAP is stopped.
17. The method of claim 15, wherein the HAP is selected from
TH-302, TH-281, PR104 and AQ4N.
18. The method of claim 15, wherein the non-HAP is selected from
the group consisting of doxorubicin, gemcitabine, pemetrexed, a
platinum-containing drug, and a taxane.
19. A pharmaceutical formulation comprising TH-302 as an active
ingredient in an amount of about 50 mg/ml to about 300 mg/ml, a
nonionic surfactant in an amount effective to act as a stabilizer,
and an alcohol as a carrier.
20.-22. (canceled)
23. The pharmaceutical formulation according to claim 19, further
comprising at least one amide carrier.
Description
RELATED APPLICATIONS
[0001] This application is continuation of U.S. patent application
Ser. No. 13/125,303 (filed Jul. 27, 2011), which was filed under 35
U.S.C. .sctn.371 as a National Stage of International Application
No. PCT/US09/61541 (filed Oct. 21, 2009), which claims priority to
the following U.S. Provisional Applications: No. 61/244,172 (filed
Sep. 21, 2009); No. 61/151,163 (filed Feb. 9, 2009); No. 61/150,700
(filed Feb. 6, 2009); No. 61/118,368 (filed Nov. 26, 2008) and No.
61/107,253 (filed Oct. 21, 2008), the disclosure on each of which
are hereby incorporated in their entirety by reference.
FIELD OF THE INVENTION
[0002] The present invention provides methods and compositions for
treating cancer with hypoxia activated prodrugs administered alone
and in combination with anticancer drugs that are not hypoxically
activated and/or in combination with radiation therapy. The
invention relates to the fields of medicine, pharmacology, and
medicinal chemistry.
BACKGROUND OF THE INVENTION
[0003] Cancer is one of the major causes of human morbidity and
mortality. Cancer treatment is challenging because it is difficult
to kill cancer cells without damaging or killing normal cells.
Damaging or killing normal cells during cancer treatment causes
adverse side effects in patients and can limit the amount of
anticancer drug administered to a cancer patient. It is also
difficult to kill cancer cells in regions distant from the
vasculature where anticancer drugs fail to penetrate.
[0004] Many cancer cells are more hypoxic relative to normal cells.
Tumor hypoxia is associated with resistance to anticancer
therapies, cancer relapse, and poor prognosis. Certain drugs in
preclinical and clinical development target hypoxic cancer cells.
These drugs, called hypoxia-activated prodrugs or "HAPs" are
administered in an inactive, or prodrug, form but are activated,
and become toxic, in a hypoxic environment. PCT Pat. Pub. Nos. WO
07/002931 and WO 08/083101, each of which is incorporated herein by
reference, describe HAPs such as those having a structure defined
by Formula I, below.
##STR00001##
where Z.sub.3 is selected from the group consisting of:
##STR00002##
and X.sub.4 is Cl or Br. The compounds known as TH-302 and TH-281
are particularly promising therapeutic candidates. TH-302, known by
the chemical name
(2-bromoethyl)({[(2-bromoethyl)amino][(2-nitro-3-methylimidazol-4-yemetho-
xy]phosphoryl})amine, has the structure represented below:
##STR00003##
See Duan et al., 2008, "Potent and highly selective
hypoxia-activated achiral phosphoramidate mustards as anticancer
drugs," J Med. Chem. 51: 2412, incorporated herein by reference.
Another promising HAP is TH-281, which differs from TH-302 only in
that it has 2-chloroethyl groups instead of the 2-bromoethyl groups
present in TH-302.
[0005] There remains a need for new methods of formulating HAPs
such as TH-302 and TH-281 to improve their anticancer efficacy as
well as methods for administering them, and other HAPs, alone and
in combination with other anticancer agents, to improve cancer
therapy. The present invention meets these needs.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a stable
liquid composition comprising TH-302 or another compound of Formula
I (10 mg/mL to about 300 mg/mL), ethanol (70%-95%), a nonionic
surfactant such as TWEEN 80 (5%-10%), and optionally one or more
other agents, such as dimethylacetamide.
[0007] In another aspect, the present invention provides methods
for treating cancer in a patient with TH-302 or another compound of
Formula I, which methods comprise administering to a patient in
need of cancer therapy TH-302 or another compound of Formula I as a
single agent (i.e., in monotherapy, where no other anticancer
agents are administered during the course of therapy with TH-302 or
other compound of Formula I) at a dose in the range of 240
mg/m.sup.2 to 1 g/m.sup.2. In one embodiment, the therapeutically
effective dose is administered once per week for at least three
weeks. In one embodiment, the therapeutically effective dose is
administered once per week for three weeks, no dose is administered
during the fourth week (four weeks being one "cycle"), and this
pattern of administration is followed for one or more additional
cycles. In one embodiment, the therapeutically effective dose is
administered once every three weeks, and this pattern of
administration is followed for one or more additional cycles. In
various embodiments, the dose administered once per week is 480
mg/m.sup.2, 575 mg/m.sup.2, or 670 mg/m.sup.2. In various
embodiments, the cancer is small cell lung cancer (SCLC), including
but not limited to refractory SCLC, or melanoma. In one aspect the
invention provides a method of treating cancer by administering
TH-302 as a single agent, wherein said TH-302 is administered
intravenously in an amount in the range of 200 mg/m.sup.2 to 700
mg/m.sup.2 to a patient in need of cancer therapy, e.g., treatment
for a small cell lung cancer or melanoma.
[0008] In one aspect, the invention provides administering TH-302
monotherapy to a patient with small cell lung cancer. In some
embodiments the TH-302 is administered once per week for 3 weeks
followed by one week with no administration (e.g., days 1, 8 and 15
of a 28-day cycle). In some embodiments the TH-302 is administered
to a patient with small cell lung cancer once per week for 3 weeks
followed by one week with no administration at a dose in the range
of about 480 mg/m.sup.2-about 670 mg/m.sup.2. In some embodiments
the TH-302 is administered for at least 2, at least 3, at least 4,
at least 5, or at least 6 28-day cycles. In some embodiments the
TH-302 is administered once every three weeks (e.g., day 1 of a
21-day cycle). In some embodiments the TH-302 is administered to a
patient with small cell lung cancer once every 3 weeks at a dose in
the range of about 670 mg/m.sup.2-less than 940 mg/m.sup.2. In some
embodiments the TH-302 is administered for at least 2, at least 3,
at least 4, at least 5, or at least 6 21-day cycles.
[0009] In one aspect, the invention provides administering TH-302
monotherapy to a patient with metastatic melanoma. In some
embodiments the TH-302 is administered once per week for 3 weeks
followed by one week with no administration (e.g., days 1, 8 and 15
of a 28-day cycle). In some embodiments the TH-302 is administered
at a dose in the range of about 480 mg/m.sup.2-about 670
mg/m.sup.2, sometimes about 575 mg/m.sup.2-about 670 mg/m.sup.2. In
some embodiments the TH-302 is administered for at least 2, at
least 3, at least 4, at least 5, or at least 6, 28-day cycles.
[0010] In another aspect, the present invention provides methods
for treating cancer in which the patient is administered TH-302 (or
another compound of Formula I) in combination with an oral and/or
topical formulation of an agent to reduce or prevent mucosal and/or
skin damage.
[0011] In another aspect, the present invention provides new
methods for administering a hypoxia-activated prodrug (HAP) and a
second anticancer agent that is not a HAP. According to these
methods, the two drugs are administered noncontemporaneously, with
administration of the non-HAP drug commencing a specified time
after the completion of HAP administration.
[0012] In another aspect, the invention provides methods for
treating cancer in which a patient in need of cancer therapy is
administered TH-302 or another compound of Formula I in combination
with a non-HAP anticancer agent. In various embodiments, the
non-HAP anticancer agent is gemcitabine, docetaxel, pemetrexed, or
doxorubicin. In various embodiments, the cancer is pancreatic
cancer, prostate cancer, non-SCLC (NSCLC), or sarcoma. In one
embodiment, the cancer is pancreatic cancer and the non-HAP
anticancer agent is gemcitabine. In one embodiment, the cancer is
prostate cancer, and the non-HAP anticancer agent is docetaxel. In
one embodiment, the cancer is NSCLC, and the non-HAP anticancer
agent is docetaxel or pemetrexed. In one embodiment, the cancer is
sarcoma, and the non-HAP anticancer agent is doxorubicin.
[0013] In some aspects the invention provides a method of treating
cancer by administering a therapeutically effective dose of TH-302
and a therapeutically effective dose of an anticancer drug that is
not a hypoxia activated prodrug to a patient in need of cancer
therapy, wherein
[0014] (a) the patient is in need of treatment for NSCLC, prostate
cancer, neuroendocrine cancer, anal cancer, urachal cancer,
urethral cancer, breast cancer, melanoma, and renal cell carcinoma
and the anticancer drug that is not a hypoxia activated prodrug is
docetaxel; or
[0015] (b) the patient is in need of treatment for bile duct
cancer, ovarian cancer, esophageal cancer, pancreatic cancer,
NSCLC, ampullary cancer, neuroendocrine cancer, soft tissue
sarcoma, and thyroid cancer and the anticancer drug that is not a
hypoxia activated prodrug is gemcitabine; or
[0016] (c) the patient is in need of treatment for esophageal
cancer, pancreatic cancer, NSCLC, neuroendocrine cancer, soft
tissue sarcoma, colorectal cancer, hepatocellular carcinoma (HCC),
renal cancer, and parotid cancer and the anticancer drug that is
not a hypoxia activated prodrug is pemetrexed.
[0017] In some aspects the invention provides a method of treating
cancer by administering TH-302 and a therapeutically effective dose
of an anticancer drug that is not a hypoxia activated prodrug to a
patient in need of cancer therapy, wherein TH-302 is administered
intravenously in an amount in the range of 200 mg/m.sup.2 to 500
mg/m.sup.2 and administration of the anticancer drug that is not a
hypoxia activated prodrug begins 30 minutes to 8 hours, optionally
2 hours to 6 hours, after administration of TH-302 is
completed.
DETAILED DESCRIPTION OF THE INVENTION
[0018] This detailed description of the invention is divided into
sections for the convenience of the reader. Section I provides
definitions of certain terms used herein. Section II describes
pharmaceutical formulations of TH-302, TH-281, and other compounds
of Formula I provided by the invention. Section III describes
methods for treating cancer with TH-302, TH-281, and other
compounds of Formula I in single agent therapies (monotherapies)
provided by the invention. Section IV describes methods for
treating cancer with a HAP and non-HAP anticancer agents in
combination. Section V describes methods for treating cancer with
TH-302, TH-281, and other compounds of Formula I in combination
with non-HAP anticancer agents. Section V is followed by examples
that provide illustrative embodiments of the methods and
compositions provided by the invention.
I. DEFINITIONS
[0019] The following definitions are provided to assist the reader.
Unless otherwise defined, all terms of art, notations, and other
scientific or medical terms or terminology used herein are intended
to have the meanings commonly understood by those of skill in the
chemical and medical arts. In some cases, terms with commonly
understood meanings are defined herein for clarity and/or for ready
reference, and the inclusion of such definitions herein should not
be construed as representing a substantial difference over the
definition of the term as generally understood in the art.
[0020] "A," "an," and, "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
a compound refers to one or more compounds or at least one
compound. As such, the terms "a" (or "an"), "one or more", and "at
least one" are used interchangeably herein.
[0021] "About" as used herein is used to provide flexibility to a
numerical range endpoint by providing that a given value may be "a
little above" or "a little below" the endpoint accounting for
variations one might see in measurements taken among different
instruments, samples, and sample preparations. In one aspect,
"about" refers to .+-.20% of a quantity and includes, but is not
limited to, .+-.15%, .+-.10%, and .+-.5% of the quantity.
[0022] "Active agent" refers to a compound with a desired
pharmacological effect and includes all pharmaceutically acceptable
forms of the active agent described. For example, the active agent
can be in an isomeric mixture, a solid complex bound to an ion
exchange resin, or the like. In addition, the active agent can be
in a solvated form. Active agent also includes all pharmaceutically
acceptable salts, derivatives, and analogs of the active agent
being described, as well as combinations thereof. For example, the
pharmaceutically acceptable salts of the active agent may include,
without limitation, the sodium, potassium, calcium, magnesium,
ammonium, tromethamine, L-lysine, L-arginine, N-ethylglucamine,
N-methylglucamine and salt forms thereof, as well as combinations
thereof and the like. Any form of the active agent may be suitable
for use in the compositions of the present invention, e.g., a
pharmaceutically acceptable salt of the active agent, a free acid
or free base of the active agent, or a mixture thereof.
[0023] "Administering" or "administration of" a drug to a patient
(and grammatical equivalents of this phrase) refers to direct
administration, which may be administration to a patient by a
medical professional or may be self-administration, and/or indirect
administration, which may be the act of prescribing a drug. For
example, a physician who instructs a patient to self-administer a
drug and/or provides a patient with a prescription for a drug is
administering the drug to the patient.
[0024] "Advanced solid tumor" refers to a solid tumor that has
relapsed, progressed, metastasized after, and/or is refractory to,
the initial or first line treatment. Advanced solid tumors include,
but are not limited to, metastatic tumors in bone, brain, liver,
lungs, lymph node, pancreas, prostate, and soft tissue
(sarcoma).
[0025] "Cancer" refers to leukemias, lymphomas, carcinomas, and
other malignant tumors of potentially unlimited growth that can
expand locally by invasion and systemically by metastasis. Examples
of cancers include, but are not limited to, cancer of the adrenal
gland, bone, brain, breast, bronchi, colon and/or rectum,
gallbladder, head and neck, kidneys, larynx, liver, lung, neural
tissue, pancreas, prostate, parathyroid, skin, stomach, and
thyroid. Certain other examples of cancers include, acute and
chronic lymphocytic and granulocytic tumors, adenocarcinoma,
adenoma, basal cell carcinoma, cervical dysplasia and in situ
carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell
tumor, glioblastoma multiforma, hairy-cell tumor, intestinal
ganglioneuroma, hyperplastic corneal nerve tumor, islet cell
carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas,
malignant carcinoid, malignant melanomas, malignant hypercalcemia,
marfanoid habitus tumor, medullary carcinoma, metastatic skin
carcinoma, mucosal neuroma, myeloma, mycosis fungoides,
neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian
tumor, pheochromocytoma, polycythermia vera, primary brain tumor,
small-cell lung tumor, squamous cell carcinoma of both ulcerating
and papillary type, hyperplasia, seminoma, soft tissue sarcoma,
retinoblastoma, rhabdomyosarcoma, renal cell tumor, topical skin
lesion, veticulum cell sarcoma, and Wilm's tumor.
[0026] "Dose" and "dosage" refer to a specific amount of active or
therapeutic agents for administration.
[0027] "Dosage form" refers to physically discrete units suitable
as unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active agent calculated to
produce the desired onset, tolerability, and therapeutic effects,
in association with one or more suitable pharmaceutical excipients
such as carriers.
[0028] "Excipient" includes any inert substance combined with an
active agent such as TH-302 to prepare a convenient dosage form and
vehicle for delivering the active agent.
[0029] "Formulation" and "composition" are used interchangeably and
refer to a mixture of two or more compounds, elements, or
molecules. In some aspects the terms "formulation" and
"composition" may be used to refer to a mixture of one or more
active agents with a carrier or other excipients. A pharmaceutical
formulation is suitable for administration to a human or
mammal.
[0030] "Hyperproliferative disease" refers to a disease
characterized by cellular hyperproliferation (e.g., an abnormally
increased rate or amount of cellular proliferation), including
cancer as well as other diseases, such as those where the
hyperproliferation is part of an immune reaction, as occurs in
autoimmune disorders. Examples of hyperproliferative diseases other
than cancer include, but are not limited to, allergic angitis and
granulomatosis (Churg-Strauss disease), asbestosis, asthma,
atrophic gastritis, benign prostatic hyperplasia, bullous
pemphigoid, coeliac disease, chronic bronchitis and chronic
obstructive airway disease, chronic sinusitis, Crohn's disease,
demyelinating neuropathies, dermatomyositis, eczema including
atopic dermatitis, eustachean tube diseases, giant cell arteritis,
graft rejection, hypersensitivity pneumonitis, hypersensitivity
vasculitis (Henoch-Schonlein purpura), irritant dermatitis,
inflammatory hemolytic anemia, inflammatory neutropenia,
inflammatory bowel disease, Kawasaki's disease, multiple sclerosis,
myocarditis, myositis, nasal polyps, nasolacrimal duct diseases,
neoplastic vasculitis, pancreatitis, pemphigus vulgaris, primary
glomerulonephritis, psoriasis, periodontal disease, polycystic
kidney disease, polyarteritis nodosa, polyangitis overlap syndrome,
primary sclerosing cholangitis, rheumatoid arthritis, serum
sickness, surgical adhesions, stenosis or restenosis, scleritis,
scleroderma, strictures of bile ducts, strictures (of duodenum,
small bowel, and colon), silicosis and other forms of
pneumoconiosis, type I diabetes, ulcerative colitis, ulcerative
proctitis, vasculitis associated with connective tissue disorders,
vasculitis associated with congenital deficiencies of the
complement system, vasculitis of the central nervous system, and
Wegener's granulomatosis.
[0031] "Hypoxia activated prodrug" or "HAP" refers to a prodrug
wherein the prodrug is less active or inactive, relative to the
corresponding drug, and comprises the drug and one or more
bioreducible groups. HAPs include prodrugs that are activated by a
variety of reducing agents and reducing enzymes, including without
limitation single electron transferring enzymes (such as cytochrome
P450 reductases) and two electron transferring (or hydride
transferring) enzymes. In some embodiments, HAPs are
2-nitroimidazole triggered hypoxia-activated prodrugs. Examples of
HAPs include, without limitation, TH-302, TH-281, PR104 and AQ4N.
Methods of synthesizing TH-302 are described in PCT Pat. App. Pub.
Nos. WO 07/002,931 and WO 08/083,101, incorporated herein by
reference. Methods of synthesizing PR104 are described in US Pat.
App. No. 2007/0032455, incorporated herein by reference. Other
examples of HAPs are described, for example, in US Pat. App. Nos.
2005/0256191, 2007/0032455 and 2009/0136521 (each of which is
incorporated herein by reference) and PCT Pat. App. Pub. Nos. WO
00/064864, WO 04/087075, and WO 07/002931 (incorporated herein by
reference).
[0032] "Patient" and "subject" are used interchangeably to refer to
a mammal in need of treatment for cancer or other
hyperproliferative disease. Generally, the patient is a human.
Generally, the patient is a human diagnosed with cancer. In certain
embodiments a "patient" or "subject" may refer to a non-human
mammal such as a non-human primate, a dog, cat, rabbit, pig, mouse
or rat such as animals used in screening, characterizing, and
evaluating drugs and therapies.
[0033] "Pharmaceutically acceptable carrier, excipient, or diluent"
refers to a carrier, excipient, or diluent that is useful in
preparing a pharmaceutical formulation that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable, and
includes a carrier, excipient, or diluent that is acceptable for
human pharmaceutical use and/or veterinary use. A "pharmaceutically
acceptable carrier, excipient, or diluent" can refer to one or more
than one such carrier, excipient, or diluent.
[0034] "Pharmaceutically acceptable salt" refers to salts of active
agents that are prepared with relatively nontoxic acids. The
compound of the present invention contains relatively basic
functionalities, and acid addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient
amount of the desired acid, either neat or in a suitable inert
solvent. Examples of pharmaceutically acceptable acid addition
salts include those derived from inorganic acids like hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogen-phosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, e.g., Berge, S. M. et al., "Pharmaceutical
Salts," Journal of Pharmaceutical Science, 66:1 19, 1977). Certain
specific compounds of the present invention contain both basic and
acidic functionalities that allow the compounds to be converted
into either base or acid addition salts. The neutral forms of the
compounds may be regenerated by contacting the salt with a base and
isolating the parent compound in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar solvents,
but otherwise the salts are equivalent to the parent form of the
compound for the purposes of the present invention.
[0035] "Prodrug" refers to a compound that, after administration,
is metabolized or otherwise converted to a biologically active or
more active compound (or drug) with respect to at least one
property. A prodrug, relative to the drug, is modified chemically
in a manner that renders it, relative to the drug, less active or
inactive, but the chemical modification is such that the
corresponding drug is generated by metabolic or other biological
processes after the prodrug is administered. A prodrug may have,
relative to the active drug, altered metabolic stability or
transport characteristics, fewer side effects or lower toxicity, or
improved flavor (for example, see the reference Nogrady, 1985,
Medicinal Chemistry A Biochemical Approach, Oxford University
Press, New York, pages 388-392, incorporated herein by reference).
A prodrug may be synthesized using reactants other than the
corresponding drug.
[0036] "QnD" or "qnd" refers to drug administration once every n
days. For example QD (or qd) refers to once every day or once daily
dosing, Q2D (or q2d) refers to a dosing once every two days, Q7D
refers to a dosing once every 7 days or once a week, Q5D refers to
dosing once every 5 days.
[0037] "Reduction" of a symptom or symptoms (and grammatical
equivalents of this phrase) refers to decreasing the severity or
frequency of the symptom(s), or elimination of the symptom(s).
[0038] "Solid tumor" refers to a cancer other than leukemia.
[0039] "T.sub.1/2" refers to the "half-life" of a drug; i.e., the
amount of time required for the concentration of a drug in, e.g.,
plasma, serum, or blood, to be halved. The t.sub.1/2 of anticancer
drugs that are not hypoxically activated are provided for example,
in most recent editions of the PHYSICIANS' DESK REFERENCE, Medical
Economics Company, Inc., Oradell, N.J.; and Goodman & Gilman's
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS", McGraw-Hill, New York
and/or are discussed in the medical literature. The t.sub.1/2 of
hypoxically activated prodrugs can be found in the literature or
determined using routine pharmacokinetic analysis methods.
[0040] "Therapeutically effective amount" of a drug refers to an
amount of a drug that, when administered to a patient with cancer
or other hyperproliferative disease, will have the intended
therapeutic effect, e.g., alleviation, amelioration, palliation or
elimination of one or more manifestations of cancer or another
hyperproliferative disease in the patient. A therapeutic effect
does not necessarily occur by administration of one dose, and may
occur only after administration of a series of doses. Thus, a
therapeutically effective amount may be administered in one or more
administrations.
[0041] "Treating" or "treatment of" a condition or patient refers
to taking steps to obtain beneficial or desired results, including
clinical results. For purposes of this invention, beneficial or
desired clinical results include, but are not limited to,
alleviation or amelioration of one or more symptoms of cancer or
other hyperproliferative disease; diminishment of extent of
disease; delay or slowing of disease progression; amelioration,
palliation, or stabilization of the disease state; or other
beneficial results. Treatment of cancer may, in some cases, result
in partial response or stable disease.
[0042] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0043] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 1 to about 5" should be interpreted to
include not only the explicitly recited values of about 1 to about
5, but also include individual values and sub-ranges within the
indicated range. Thus, included in this numerical range are
individual values such as 2, 3, and 4 and sub-ranges such as from
1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5,
individually. This same principle applies to ranges reciting only
one numerical value as a minimum or a maximum. Furthermore, such an
interpretation should apply regardless of the breadth of the range
or the characteristics being described.
[0044] Abbreviations used in the description include:
[0045] CT--Computed tomography (CT)
[0046] D5W--5% dextrose in water
[0047] DLT--Dose limiting toxicity
[0048] HAP(s)--Hypoxia Activated Prodrug(s)
[0049] NSCLC--Non-Small Cell Lung Cancer
[0050] PD--Progressive disease
[0051] PR--Partial response
[0052] RECIST--Response Evaluation Criteria In Solid Tumors
[0053] SCLC--Small Cell Lung Cancer
[0054] SD--Stable disease
[0055] SLD--Sum of the longest diameters
[0056] TGD--Tumor growth delay
[0057] TGI--Tumor growth inhibition
II. PHARMACEUTICAL FORMULATIONS OF TH-302 AND OTHER COMPOUNDS OF
FORMULA I
[0058] TH-302, and other compounds of Formula I including TH-281,
can be administered to patients in accord with the invention in any
pharmaceutically acceptable formulation. For example, PCT
Publications WO 08/083101 and WO 07/002931, both incorporated
herein by reference, disclose methods for preparing liquid
pharmaceutical formulations of TH-302 and other compounds of
Formula I. WO 07/002931 discloses that TH-302 can be provided as a
lyophilized powder in a vial and reconstituted in saline or 5%
dextrose in water (D5W) immediately prior to administration. After
reconstitution in D5W, the TH-302 formulation must be used within 8
hours. The shelf life for this lyophilized TH-302 formulation is
about 1 year at 2-8.degree. C. WO 08/083101 discloses that TH-302
can be administered as a liquid formulation in ethanol (containing
up to 50 mg of TH-302 per ml). However, these prior art
formulations have limitations in that they are not suitable for
high concentrations of drug, and the stability (particularly with
respect to keeping the active agent from precipitating) during long
term storage and/or dilution of TH-302 is suboptimal.
[0059] The present inventors discovered that the poor aqueous
solubility of the nitro-heteroaryl phosphoramide class of
hypoxia-activated cancer drugs, such as TH-302, and other compounds
of Formula I, can be improved by providing a nonionic surfactant
for prolonged storage in an alcohol environment. This section
describes certain preferred formulations containing ethanol and a
nonionic surfactant such as TWEEN 80.RTM.. TWEEN 80 is sorbitan
mono-oleate polyoxyethylene, CAS number 9005-65-6. Advantageously
these preferred parenterally administrable pharmaceutical
compositions provide improved stability and reduced degradation and
precipitation for TH-302, as well as for other nitro-heteroaryl
phosphoramide class hypoxia-activated cancer drugs with poor
solubility, including TH-281, and other compounds of Formula I. In
addition, these preferred formulations provide for a higher
concentration of the active drug, e.g., TH-302, relative to other
formulations that have been previously described. Because these
liquid formulations are stable over the long term, no
lyophilization of the drug is required, which eliminates the need
to reconstitute a lyophilisate before use. Preferably, the
pharmaceutically acceptable formulation is suitable for parenteral
administration.
[0060] The present inventors have developed a concentrated, stable
pharmaceutical composition and methods which can improve the
stability of a poorly soluble nitro-heteroaryl phosphoramide class
of hypoxia-activated cancer drug, such as TH-302 and other
compounds of Formula I, by solubilizing and dispersing the drug
within the solution for prolonged storage. In addition, including a
nonionic surfactant in these formulations is useful for preventing
precipitation and degradation of hypoxia-activated cancer drugs,
particularly, TH-302 and TH-281, that may occur upon dilution with
an aqueous media before administration.
[0061] Thus, according to the present invention, a stable TH-302
liquid formulation is provided as a mixture of a nonionic
surfactant and a pharmaceutically acceptable alcohol. Preferably
the alcohol is ethanol. Preferably the nonionic surfactant is TWEEN
80.
[0062] Ethanol is preferably included in an amount at least 70% of
the mixture by volume. More preferably, the amount of alcohol used
is at least about 70% to about 95% by volume, e.g., at least 70%,
at least 80%, at least 90%, or at least about 95%.
[0063] In one embodiment, the TWEEN 80 or other nonionic surfactant
is included in an amount of at least about 5% v/v of the mixture.
For example, the nonionic surfactant can be included in an amount
of about 5 to 10% of the formulation by volume. The nonionic
surfactant helps inhibit precipitation of TH-302 out of the
solution in the carrier. In addition, the nonionic surfactant may
provide various other functions and advantages, such as acting as
an antimicrobial or antibacterial agent.
[0064] Other exemplary nontoxic, nonionic surfactants suitable for
use in the present invention include, but are not limited to,
polysorbates (e.g., polyoxyethylene (20) sorbitan monolaurate,
polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)
sorbitan monostearate and polyoxyethylene (20) sorbitan
monooleate); alkylated aryl polyether alcohols known as
TRITON.RTM.; polyethylene glycol tertdodecyl throether available as
NONIC.RTM.; fatty and amide condensate or ALROSOL.RTM.; aromatic
polyglycol ether condensate or NEUTRONYX.RTM.; fatty acid
alkanolamine or NINOL.RTM. sorbitan monolaurate or SPAN.RTM.;
polyoxyethylene sorbitan esters or TWEENs.RTM.; sorbitan
monolaurate polyoxyethylene or TWEEN 20.RTM.;
polyoxypropylene-polyoxyethylene or PLURONIC.RTM.; polyglycolyzed
glycerides such as LABRASOL, and polyoxyethylated castor oil such
as CREMOPHOR.
[0065] Typically, the liquid compositions of the present invention
comprise from about 10 mg/ml to about 300 mg/ml of the active
agent. One skilled in the art understands that the foregoing
concentrations can be adjusted depending upon the particular active
agent utilized and the amount of active agent desired in the final
formulation. The amount of TH-302 included in the present liquid
formulation is dictated by the intended use. Generally, the
concentration of TH-302 will be in the range of 10 mg/ml to about
300 mg/ml or 30 mg/ml to about 300 mg/ml, more typically 50 mg/ml
to 200 mg/ml, more usually 50 mg/ml to about 150 mg/ml, and even
more usually 50 mg/ml to 125 mg/ml, and most usually greater than
50 mg/ml, such as about 60 mg/ml, 60 mg/ml to 100 mg/ml, 100 mg/ml
to 150 mg/ml, 100 mg/ml to 200 mg/ml, or 100 mg/ml to about 300
mg/ml. These concentrations refer to the free base form of TH-302
or other agent; if TH-302 or other active agent is formulated or
administered as a pharmaceutically acceptable salt or other form,
the concentrations are adjusted so that an amount equivalent to the
free base is used.
[0066] According to one embodiment, the carrier is ethanol, and the
pharmaceutical formulation includes at least 5% v/v TWEEN 80. In
one embodiment, the formulation comprises about 5 to 10% (v/v)
TWEEN 80, 90-95% (v/v) ethanol, and about 50 mg/ml to 125 mg/ml
TH-302, such as about 60 mg/ml TH-302. In one preferred embodiment,
the formulation comprises about 5% TWEEN 80, about 95% ethanol, and
about 60 mg/ml TH-302.
[0067] Thus, in an embodiment, the active agent in the formulation
is TH-302, including all pharmacologically acceptable forms. In one
aspect, the invention provides a liquid composition, wherein the
active agent is TH-302 in its non-salt form. In other embodiments,
the active agent is TH-281, optionally in its non-salt form, or
another compound of Formula I. In the embodiments of the invention,
the active agent can be provided for dissolution into the
formulation of the invention in any suitable form. For example, it
can be in the form of a powder, pellet, or a granule (i.e., an
aggregate of smaller units of active agent). Any pharmaceutical
grade of TH-302 or other compound of Formula I may be used.
[0068] Advantageously, chemical degradation is minimized in the
formulations of the present invention. Thus it has been
unexpectedly found that the present formulation comprising a
nonionic surfactant provides a long-term stability characterized by
TH-302 degradation of 15% or less over a period of 31 days or less
at about -20.degree. C. to about 25.degree. C. See Example 1,
infra. Typically a formulation comprising a nonionic surfactant
(e.g., TWEEN 80) provides a long-term stability characterized by
TH-302 degradation of 5% or less over a period of 31 days or less
at about -20.degree. C.
[0069] Furthermore, advantageously the TH-302 liquid formulation
produced according to the present invention exhibits superior
stability, where stability, in this instance, is characterized by
TH-302 remaining in solution, e.g., not precipitating during
storage or upon thawing.
[0070] In some embodiments, the formulation may optionally further
comprise other components described herein. Thus, in various
embodiments of the pharmaceutical formulations of the invention,
mixtures of carriers are used. When a second carrier (in addition
to ethanol) is used, it is generally N,N-dimethylacetamide (DMA).
When used, the amide carrier is preferably included in an amount up
to about 20% of the formulation by volume. Preferably the amount of
amide carrier used is about 10% to about 20% by volume. In some
embodiments the formulation consists of ethanol and TH-302. In some
embodiments the formulation consists of ethanol, DMA and
TH-302.
[0071] The compositions of the present invention can additionally
include an antioxidant, preserving agents such as methyl-, ethyl-,
and propyl-hydroxy-benzoates, butylated hydroxytoluene, and
butylated hydroxyanisole; opacifying agents and chelating agents.
Suitable antioxidants and chelating agents, include for example,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
propyl gallate (PG), ascorbyl palmitate, disodium EDTA
(ethylenediamine tetraacetic acid; also known as disodium
edentate), EDTA, tartaric acid, citric acid, citric acid
monohydrate, and sodium sulfite. In one embodiment, the foregoing
compounds are included in the pharmaceutical formulations in
amounts in the range of about 0.01% to about 5% w/w. In one
specific embodiment, the pharmaceutical formulation includes BHA,
BHT, or PG used at a range of about 0.02% to about 1% and disodium
EDTA, citric acid, or citric acid monohydrate used at a range of
about 2% to about 5%. In one embodiment, the pharmaceutical
formulation includes BHA used at about 0.05% w/w.
[0072] Any suitable method can be used to mix the formulation
comprising the active agent, alcohol carrier, and non-ionic
surfactant. In one embodiment, the active agent, alcohol carrier,
and non-ionic surfactant are combined, and the mixture is
administered directly to the patient, optionally after
dilution.
[0073] The liquid pharmaceutical formulations of the invention can
be conveniently provided in dosage forms. Methods for preparing
dosage forms of other liquid formulations are known, and it will be
apparent to those skilled in the art upon consideration of the
instant disclosure how to prepare suitable dosage forms of the
pharmaceutical formulations of the invention. For example, a liquid
dosage form of the present invention can be prepared according to
the procedures set forth, for example, in Remington: The Science
and Practice of Pharmacy, 20th Ed., Lippincott, Williams &
Wilkins (2003), and similar publications. The dosage form to be
administered will, in any event, contain a quantity of the active
agent in a therapeutically effective amount for relief of the
condition being treated when administered in accordance with the
teachings of this invention.
[0074] The pharmaceutical formulations of the invention can be
packaged in any packaging that facilitates stability of the drug
formulation. The pharmaceutical formulations provided by this
invention may be contained in a sterilized vessel such as syringes,
vials, or ampoules of various sizes and capacities. The sterilized
vessel may optionally contain between 1-50 ml, 1-25 ml, 1-20 ml,
1-10 ml or 1-5 ml of the formulations. Sterilized vessels maintain
sterility of the pharmaceutical formulations, facilitate
transportation and storage, and allow administration of the
pharmaceutical formulations without prior sterilization step.
[0075] The present invention also provides a kit for administering
the liquid formulation comprising the active agent to a host in
need thereof. In one embodiment, the kit comprises the active agent
(e.g., TH-302) and a carrier (e.g., ethanol), comprising the
nonionic surfactant (e.g., TWEEN 80). Mixing the active agent into
a solution comprising the carrier and the surfactant preferably
results in the formation of a pharmaceutical formulation according
to the present invention. For example, the kit may comprise a first
vessel comprising a hypoxia-activated cancer drug in a solid form;
and a vessel comprising a carrier that contains a nonionic
surfactant; wherein adding the carrier to the solid drug results in
the formation of a pharmaceutical formulation for administering the
drug. Mixing the solid drug and carrier may optionally form a
pharmaceutical formulation that comprises TH-302 in a concentration
described above, e.g., about 60 mg/ml. For illustration, between 30
and 300 mg TH-302 per ml of the carrier, optionally between 50 and
200 mg, and between 100 mg and 150 mg per ml of the carrier and
nonionic surfactant may be used.
[0076] The pharmaceutical formulations provided in vessels or kits
may be in a form that is suitable for direct administration or may
be in a concentrated form that requires dilution relative to what
is administered to the patient. For example, pharmaceutical
formulations, described in this invention, may be in a form that is
suitable for direct administration via intravenous administration
or may be in a concentrated form that is diluted prior to
administration. In one embodiment, about 500 to 1200 mg of TH-302
in a formulation of the invention is administered to a patient over
30-60 minutes after dilution in D5W to about 500 ml total
volume.
[0077] The compositions of the present invention are useful in
therapeutic applications, e.g., for treating cancer. While the
formulations of this invention may be delivered via various routes
of administration, they are typically administered intravenously
(e.g., by infusion) but any acceptable method may be used (e.g.,
intraarterially, via local delivery by catheter or stent, and the
like).
[0078] In one embodiment, a hypoxia-activated cancer drug
formulation is infused through a connector, such as a Y site
connector, that has three arms, each connected to a tube. As an
example, BAXTER.RTM. Y-connectors of various sizes can be used. A
vessel containing hypoxia-activated cancer drug formulation is
attached to a tube further attached to one arm of the connector.
Infusion fluids, such as 0.9% sodium chloride, or 5% dextrose, or
5% glucose, or Lactated Ringer's, are infused through a tube
attached to the other arm of the Y-site connector. The infusion
fluids and hypoxia-activated cancer drug formulations are mixed
inside the Y site connector. The resulting mixture is infused into
the patient through a tube connected to the third arm of the Y site
connector. The advantage of this administration approach over the
prior art is that the hypoxia-activated cancer drug is mixed with
infusion fluids before it enters the patient's body, thus reducing
the time when decomposition of therapeutic formulations may occur
due to contact with water. In some embodiments, the
hypoxia-activated cancer drug is mixed less than 10, 5, 2 or 1
minutes before entering the patient's body. In some embodiments the
hypoxia-activated cancer drug is mixed less than 8, 6, 4, 2 or 1
hours before entering the patient's body.
[0079] As noted above, pharmaceutical formulations according to the
present invention provide the further advantage because the
nonionic surfactant/alcohol solution can be readily mixed with
water, D5W or saline, the formulations can be easily and readily
further diluted just prior to administration. For example, the
pharmaceutical formulations can be diluted with water, saline or
D5W within the 8 hour period preceding administration to a
patient.
[0080] In one embodiment, the infusion administration is performed
after determining the mg dose for a patient by multiplying the
patient's body surface area by the prescribed TH-302 dose. The
appropriate number of vials (for example, 100 mg/vial) of TH-302
are removed from a -20.degree. C. freezer and left in an ambient
room condition for 30-60 minutes to allow vials to warm to room
temperature. Each 100 mg vial is reconstituted with 25 ml sterile
D5W and shaken well. The number of ml of reconstituted TH-302
required is calculated by multiplying the desired mg dose by 0.25
(e.g., a 1000 mg dose requires 250 ml). Prior to adding
reconstituted TH-302 to a 500/1000 ml sterile D5W IV bag, the
equivalent volume of TH-302 to be added to the bag is removed, so
that when the reconstituted drug is added to the bag the total
volume is 500/1000 ml.
[0081] Patients may be infused with hypoxia-activated cancer drug
formulations for any therapeutically suitable time, e.g., about 15,
30, or 45 minutes or for 1, 2, 3, 4, 5 or more hours. The speed and
volume of the infusion can be regulated according to the patient's
needs. The regulation of the infusion of hypoxia-activated cancer
drug formulations can be performed according to existing protocols.
For illustration, Table 1 outlines exemplary dilution volumes and
infusion times based on total dose administered for TH-302 (longer
infusion times are permitted based on physician judgment of the
time required to administer the infusion volume).
TABLE-US-00001 TABLE 1 Total TH-302 Infusion Volume Infusion
Duration* Dose (mg) (ml) (minutes) <1000 500 30 1000 or higher
1000 60 *Longer infusions are permitted based on investigator
judgment on the length of time required to administer the infusion
volume.
[0082] An individual patient's surface area can be determined using
routine methods known to oncologists and other medical providers.
For an adult human, a dose of 1 mg/m.sup.2 of an active agent
(drug)=about 1.7 mg of that agent or drug per patient (i.e., the
prototypical adult human has 1.7 m.sup.2 of surface area).
Therefore, for example, 100 mg/m.sup.2 of a drug=about 170 mg of
that drug per patient.
[0083] As described in more detail below, the pharmaceutical
formulations of the invention may be co-administered with other
agents. Co-administration in the context of this invention is
defined to mean the administration of more than one therapeutic
agent in the course of a coordinated treatment to achieve an
improved clinical outcome. Such co-administration may also be
coextensive, that is, occurring during overlapping periods of time.
The additional agent administered may be in any conventional form
and may include infusion fluids, therapeutic compounds, nutritious
fluids, anti-microbial fluids, buffering and stabilizing agents.
Therapeutic compounds, in this context, include, but are not
limited to, anti-neoplastic agents, alkylating agents, agents that
are members of the retinoids superfamily, antibiotic agents,
hormonal agents, plant-derived agents, biologic agents,
interleukins, interferons, cytokines, immuno-modulating agents, and
monoclonal antibodies. As discussed in detail in Section IV, when
the additional agent is an anti-neoplastic drug in preferred
embodiments administration of the two agents is
non-contemporaneous.
[0084] Optionally, the TH-302 formulations of the present invention
may be administered, or co-administered with a non-hypoxia
activated anticancer agent, via local delivery. See Sections III-V,
infra, and Examples. The formulation, dose, administration route,
frequency, and such other modes of administration of various
anticancer agents other than TH-302, such as docetaxel,
doxorubicin, gemcitabine, and pemetrexed, administered in
accordance with the present methods, are disclosed herein,
available in medical literature, and/or known to one of skill in
the art. Local delivery of the pharmaceutical formulations of this
invention can be by a variety of techniques and structures that
administer the pharmaceutical formulation at or near a desired
site. Examples of local delivery techniques and structures are not
intended to be limiting but rather as illustrative of the
techniques and structures available. Examples include local
delivery catheters, site-specific carriers, implants, direct
injection, or direct applications.
[0085] Local delivery by a catheter allows the administration of a
sequential combination of therapeutic agents and/or compositions
directly to the desired site according to the methods of the
invention. Examples of local delivery using a balloon catheter are
described in EP 383 492 A2 and U.S. Pat. No. 4,636,195. Additional
examples of local, catheter-based techniques and structures are
disclosed in U.S. Pat. No. 5,049,132 and U.S. Pat. No. 5,286,254.
Generally, the catheter is placed such that the therapeutic agents
can be delivered at or near the desired site. Dosages delivered
through the catheter can vary, according to determinations made by
one of skill, but often are in amounts effective to create a
cytotoxic or cytostatic effect at the desired site. Preferably,
these total amounts are less than the total amounts for systemic
administration of the pharmaceuticals of this invention, and are
less than the maximum tolerated dose. Delivery of the
pharmaceutical formulations of this invention through catheters
preferably should be formulated to a viscosity that enables
delivery through a small treatment catheter, and may be formulated
with pharmaceutically acceptable additional ingredients (active and
inactive).
[0086] Local delivery by an implant describes the placement of a
matrix that contains the pharmaceutical formulations of this
invention into the desired site. The implant may be deposited by
surgery or other means. The implanted matrix releases the inventive
combination of therapeutic agents and/or compositions by diffusion,
chemical reaction, solvent activators, or other equivalent
mechanisms. Examples are set forth in Langer, 1990, Science
249:1527-33. Often the implants may be in a form that releases the
inventive combination of therapeutic agents and/or compositions
over time; these implants are termed time-release implants. The
material of construction for the implants will vary according to
the nature of the implant and the specific use to which it will be
put. For example, bio-stable implants may have a rigid or
semi-rigid support structure, with inventive combination of
therapeutic agents and/or composition delivery taking place through
a coating or a porous support structure. Other implants may be made
of a liquid that stiffens after being implanted or may be made of a
gel. The amounts of inventive combination of therapeutic agents
and/or composition present in or on the implant may be in an amount
effective to treat cell proliferation generally, or a specific
proliferation indication, such as the indications discussed
herein.
[0087] The formulations of the present invention can be used to
treat any type of cancer in a subject, particularly cancers
containing substantial areas of hypoxic tissue. Such cancers
include but are not limited to lung cancer (including small cell
lung cancer and non-small cell lung cancer), breast cancer, colon
cancer, head and neck cancer, ovarian cancer, pancreatic cancer,
soft tissue sarcomas, and prostate cancer. The formulations of the
invention can also be used to treat non-cancer hyperproliferative
diseases.
[0088] TH-302 formulated as discussed above may be administered as
monotherapy or in combination with administration of another
anticancer agent(s). The formulation may be administered in
conjunction with a therapeutic cancer treatment, including but not
limited to surgery (e.g., in an adjuvant or neoadjuvant setting) or
radiation.
III. ADMINISTRATION OF TH-302 IN CANCER MONOTHERAPY
[0089] TH-302 can be administered as monotherapy, i.e., alone, not
in combination with any other anticancer agent, to treat cancer. In
preferred embodiments, TH-302 is administered as a monotherapy for
the treatment of melanoma (including metastatic melanoma) or SCLC
(including refractory SCLC). As discussed infra and in Example 2,
TH-302 has exhibited remarkable anticancer activity when
administered to patients diagnosed with melanoma or with SCLC.
[0090] TH-302 is usually administered intravenously (e.g., by
infusion) for monotherapy. In some embodiments, a
TH-302/ethanol/TWEEN 80 formulation discussed supra is diluted into
D5W or saline for infusion. Although a variety of dosage schedules
are possible, typically TH-302 is administered for one or more
cycles of (a) once weekly for 3 consecutive weeks followed by a
week of no TH-302 administration (e.g., administered on days 1, 8,
and 15 of a 28 day cycle) referred to as a "4 week cycle"; (b) once
per week; (c) once every three weeks; or (d) twice every three
weeks (e.g., administered on days 1 and 8 of a 21-day cycle). For a
dosing regimen comprising a "4 week cycle," TH-302 can be
administered, for example, at a dose of 480 mg/m.sup.2 to 670
mg/m.sup.2, most preferably 480 mg/m.sup.2 to 575 mg/m.sup.2,
preferably about 575 mg/m.sup.2. For weekly administration, TH-302
can be administered once weekly at doses up to 575 mg/m.sup.2. For
once every three week administration, the dose can be up to 670
mg/m.sup.2. For some patients, doses up to 940 mg/m.sup.2 or higher
can be administered once every 3 weeks. Other doses may be selected
based on the patient's age, health and other factors.
[0091] In various embodiments of the present invention, the amount
of TH-302 administered is about 670 mg/m.sup.2, 575 mg/m.sup.2, 560
mg/m.sup.2, 480 mg/m.sup.2, 360 mg/m.sup.2, 240 mg/m.sup.2, and 120
mg/m.sup.2, when the TH-302 is administered intravenously (e.g., by
infusion).
[0092] Like other anticancer agents, TH-302 is usually administered
in multiple cycles. For example and not for limitation, TH-302 may
be administered using a "4 week cycle" for from 1 to 13 cycles,
from 1 to 7 cycles, or from 1 to 4 cycles. As a second example,
TH-302 may be administered at a frequency of once every week for 3
to 52, 3 to 28, 3 to 6, or 3 to 8 cycles (weeks). As a third
example, TH-302 may be administered at a frequency of once every
three weeks for 3 to 52, 3 to 28, 3 to 6, or 3 to 8 weeks. It will
be recognized by medical professionals that certain of these
periods of TH-302 administration include one or more weeks of drug
holidays during which no TH-302 is administered.
[0093] As noted, TH-302 has shown benefit in patients with
metastatic melanoma. The historical response rate in first-line
metastatic melanoma is about 10%, so the results of treatment with
TH-302 are quite remarkable. Eleven subjects with metastatic
melanoma have been treated with TH-302 monotherapy at initial doses
of 575 mg/m.sup.2 to 670 mg/m.sup.2 as part of a 3 consecutive week
dosing regimen repeated every 4 weeks. RECIST tumor assessments
have been performed for eight subjects. Three of the eight subjects
assessed have had partial responses and three of eight subjects
have had stable disease. Four of the eight subjects continued
on-study for additional dosing cycles. Two of the three subjects
with a partial response continued on-study through at least Cycle 3
and Cycle 7. The other subject discontinued with clinical
deterioration associated with neurological decline from brain
metastases.
[0094] Eight subjects with SCLC have been treated with TH-302
monotherapy at initial doses of 480 mg/m.sup.2 to 670 mg/m.sup.2 as
part of a 3 consecutive week dosing regimen repeated every 4 weeks
(this excludes one subject dosed at 60 mg/m.sup.2 during the
initial dose escalation). RECIST tumor assessments were performed
initially for seven subjects. Two of seven subjects had partial
responses and another three of these same seven subjects had stable
disease. The historical response rate in refractory SCLC is less
than 10%, so, again, these results are quite remarkable. One of the
seven subjects continued on-study for additional cycles of
treatment.
[0095] After the MTD was established at 575 mg/m.sup.2 for TH-302
monotherapy administered once per week for three weeks of a four
week cycle, a once every three week TH-302 dosing regimen was
initiated. Six subjects have been dosed at 940 mg/m.sup.2 and two
of six subjects have had a dose limiting toxicity. The MTD for the
once every three week dosing is 670 m g/m.sup.2 unless a dose
between 670 mg/m.sup.2 and 940 mg/m.sup.2 is explored.
[0096] Other therapeutically effective doses of TH-302 for
monotherapy are provided by the invention. In various embodiments,
the therapeutically effective dose of TH-302 in the methods of
treating cancer is in an amount in the range of about 100
mg/m.sup.2-about 700 mg/m.sup.2, 200 mg/m.sup.2-about 700
mg/m.sup.2, about 300 mg/m.sup.2-about 600 mg/m.sup.2, about 350
mg/m.sup.2-about 550 mg/m.sup.2, about 400 mg/m.sup.2-about 500
mg/m.sup.2, about 400 mg/m.sup.2-about 600 mg/m.sup.2, about 450
mg/m.sup.2-about 550 mg/m.sup.2, about 450 mg/m.sup.2-about 575
mg/m.sup.2, about 480 mg/m.sup.2-about 670 mg/m.sup.2, and about
670 mg/m.sup.2-<940 mg/m.sup.2. In another aspect, the present
invention provides methods of treating cancer comprising
administering TH-302 in an amount in the range of about 700
mg/m.sup.2-about 1200 m g/m.sup.2 or about 800 mg/m.sup.2-about
1000 mg/m.sup.2, particularly when prophylaxis against toxicity is
provided, for example as discussed below. In some embodiments the
therapeutically effective dose of TH-302 for monotherapy is about
200 mg/m.sup.2-about 500 mg/m.sup.2.
[0097] In one aspect, the invention provides administering TH-302
monotherapy to a patient with small cell lung cancer. In some
embodiments the TH-302 is administered once per week for 3 weeks
followed by one week with no administration (e.g., days 1, 8 and 15
of a 28-day cycle). In some embodiments the TH-302 is administered
to a patient with small cell lung cancer once per week for 3 weeks
followed by one week with no administration at a dose in the range
of about 480 mg/m.sup.2-about 670 mg/m.sup.2. In some embodiments
the TH-302 is administered for at least 2, at least 3, at least 4,
at least 5, or at least 6 28-day cycles. In some embodiments the
TH-302 is administered once every three weeks (e.g., day 1 of a
21-day cycle). In some embodiments the TH-302 is administered to a
patient with small cell lung cancer once every 3 weeks at a dose in
the range of about 670 mg/m.sup.2-less than 940 mg/m.sup.2. In some
embodiments the TH-302 is administered for at least 2, at least 3,
at least 4, at least 5, or at least 6 21-day cycles.
[0098] In one aspect, the invention provides administering TH-302
monotherapy to a patient with metastatic melanoma. In some
embodiments the TH-302 is administered once per week for 3 weeks
followed by one week with no administration (e.g., days 1, 8 and 15
of a 28-day cycle). In some embodiments the TH-302 is administered
at a dose in the range of about 480 mg/m.sup.2-about 670
mg/m.sup.2, sometimes about 575 mg/m.sup.2-about 670 mg/m.sup.2. In
some embodiments the TH-302 is administered for at least 2, at
least 3, at least 4, at least 5, or at least 6, 28-day cycles.
[0099] TH-302 has an attractive safety profile as monotherapy. It
is well tolerated at relatively high doses and does not induce
significant dose limiting myelosuppression. The dose limiting
toxicities in a dose escalation study were mucositis with one grade
3 event involving the oral mucosa and one grade 3 event involving
the gastrointestinal mucosa. TH-302 also produces a predictable
skin rash that is dose proportional and reversible. The rash is
typically grade 1 or grade 2 depending on the dose and increased in
incidence starting at a weekly monotherapy dose of 480 mg/m.sup.2.
The skin rashes and mucosal toxicities observed in clinical trials
are consistent with the underlying pharmacology of a
hypoxia-activated prodrug, because both the normal skin and the
superficial mucosa contain regions of significant hypoxia. In a
clinical trial of patients receiving TH-302 (575 mg/m.sup.2) the
rash has been managed proactively with subject education stressing
the importance of personal hygiene including skin hygiene, keeping
the skin dry and avoiding prolonged high pressure on skin regions,
topical agents containing zinc oxide, anti-fungal agents, and
anti-bacterial agents. Anecdotal reports from clinical sites show
an apparent decrease in severity and duration of the skin toxicity.
Similarly, prophylactic use of "Miracle Mouth Wash" (contains
dexamethasone, diphenhydramine, nystatin, and tetracycline) seems
to reduce the incidence and severity of the oral lesions. Thus, in
one embodiment, the present invention provides methods for treating
cancer in which the patient is administered TH-302 (or another
compound of Formula I) in combination with an oral and/or topical
formulation of a drug or other agent to prevent mucosal and/or skin
damage. Preferably the drug or agent is administered
prophylactically (prior to development of significant mucosal or
skin damage). For example, and not for limitation, suitable topical
agents include one or a combination of the following: topical
agents containing zinc oxide, anti-fungal agents, anti-oxidants
and/or anti-bacterial agents. Topical anti-oxidants available for
use in humans include topical vitamin C, topical vitamin E, topical
melatonin and combinations thereof (see Dreher and Maiback, 2001,
"Protective Effects of Topical Antioxidants in Humans" Oxidants and
Antioxidants in Cutaneous Biology. Current Problems in Dermatology.
Basel, Karger 29:157-164). Topical DMSO may be used (see U.S. Pat.
No. 6,060,083, incorporated herein by reference). Other agents
include, for example, vitamin K analogs (see Pat. Pub. US
2009/0239952, incorporated herein by reference), topical Vitamin C,
topical Vitamin E topical corticosteroids, menthol cream, topical
minocycline; lotions such as clindamycin 2%/hydrocortisone 1%,
glutamine solutions and melatonin. Systemic agents including
anti-fungal agents (e.g., nystatin) and anti-bacterial agents
(e.g., tetracycline) may be used.
[0100] In addition to administration of TH-302 for treatment of
cancer, other compounds of Formula I, such as TH-281, and can be
administered in monotherapy, in accord with the methods, doses,
schedules and prophylaxis described herein in relation to
TH-302.
IV. ADMINISTERING HAP AND NON-HAP ANTICANCER AGENTS IN COMBINATION
THERAPY
[0101] The present invention also provides methods for treating
cancer by administering hypoxia activated prodrugs, including
TH-302, to cancer patients, in combination with another anticancer
drug, wherein the therapeutic efficacy of the combination treatment
is maximized and the toxicity of the combination treatment
minimized by administering the hypoxia activated prodrug ("HAP")
and the other anticancer drug non-contemporaneously. See Example 3,
infra. Administering two drugs a certain time period apart in
accordance with the present invention is referred to as
"non-contemporaneous administration" of the two drugs.
Administering two drugs together or one immediately after the other
(with no or less than a 30 minute delay between ceasing the
administration of the first and initiating the administration of
the second drug) is referred to as "contemporaneous administration"
of the two drugs.
[0102] Thus, in one aspect, the present invention provides a method
of treating cancer by administering two anticancer drugs, a hypoxia
activated prodrug and an anticancer drug that is not hypoxically
activated, to a patient in need of such treatment, wherein the
non-HAP anticancer drug is administered at least about 30 minutes
after the immediate prior administration of the hypoxia activated
prodrug is stopped. In an embodiment, the second drug is
administered 30 minutes to 8 hours after administration of the HAP
drug has stopped. In another embodiments, the second drug is
administered 1 to 6 hours after administration of the HAP drug has
stopped (e.g., about 2 hours, about 3 hours or about 4 hours after
administration of the HAP drug). In some embodiments, the duration
of the time between administration of TH-302 and the non-HAP drug
(e.g., docetaxel) is from 1 to 10 hours, from 2 to 6 hours, or from
3 to 5 hours. In exemplary embodiments, the non-HAP anticancer drug
is administered 1 hour or longer (e.g., 1, 2, 4, or 6 hours) after
administration of the HAP has stopped. Typically, at least a 2 hour
delay is employed. Thus, generally, the time of administration of
the non-HAP drug is at least 30 minutes to one hour, typically at
least 2 hours, sometimes at least 4 hours, and in any event no more
than 24 hours after administration of the HAP. In various
embodiments, the delay between completion of the administration of
the HAP and administration of the second agent is shorter than 8
hours; for example, the delay may be less than 6, less than 6, or
less than 4, hours.
[0103] In another aspect, the present invention provides a method
for treating cancer in a patient comprising administering a hypoxia
activated prodrug in combination with another anticancer drug in
which the HAP is administered first, and the delay between
completing the administration of the HAP and beginning
administration of the other anticancer drug is equal to about the
t.sub.1/2 of the HAP, or equal to at least the t.sub.1/2 of the
HAP, or equal to about twice the t.sub.1/2 of the HAP, or equal to
at least twice the t.sub.1/2 of the HAP. In one embodiment the
delay is in the range bounded by the t.sub.1/2 of the HAP and twice
the t.sub.1/2 of the HAP.
[0104] In one embodiment, the HAP is TH-302, TH-281, or another
compound of Formula I. In another embodiment the hypoxia activated
prodrug is AQ4N. In one embodiment, the HAP is PR104 having a
structure of formula shown below:
##STR00004##
[0105] Pharmaceutically active salts of PR104 are also useful in
accordance with the methods of the present invention. PR104 is a
HAP for which the maximum tolerated dose (MTD) and recommended dose
was determined, after a Phase I study, to be 1,100 mg/m.sup.2. See,
Jameson et al., J. Clin. Oncol., 26: 2008 (May 20 suppl; abstr
2562; incorporated herein by reference). Phase II studies with
PR104 were initiated by administering PR104 at 200-275 mg/m.sup.2.
See, Tchekmedyian et al., J Clin Oncol 26: 2008 (May 20 suppl.;
abstr. 3575; incorporated herein by reference). However, when
administered in combination with gemcitabine or docetaxel, the MTD
of PR104 plus gemcitabine or docetaxel was 140 mg/m.sup.2 for PR104
plus gemcitabine and <200 mg/m.sup.2 for PR104 plus docetaxel.
The methods of the present invention allow higher doses of HAPs to
be administered in such combination therapies, including HAPs such
as TH-302, TH-281, PR104, and AQ4N (see for example, PCT Pat. Pub.
Nos. WO 00/064864, WO 04/087075, WO 07/002931, and WO 08/083101,
and US Pat. App. Pub. No. 2007/0032455, each of which is
incorporated herein by reference).
[0106] In another embodiment, the hypoxia activated prodrug is
selected from the group consisting of the N-oxides of the vinca
alkaloids. Certain N-oxides of the vinca alkaloids useful in the
methods of the present invention are provided in the PCT patent
publication No. WO 07/098091, incorporated herein by reference. In
one embodiment, the HAP is a compound described in any of PCT
publication Nos. WO 2000/064864; 2004/087075; 2005/086951;
2005/087075; 2006/057946; 2007/002931; 2008/083101; 2008/151253;
2009/018163; and 2009/033165; PCT application No. U.S. Ser. No.
09/044,038; US patent application publication Nos. 20050256191 and
20070032455; and U.S. provisional patent application No.
61/218,043, each of which is incorporated herein by reference.
Routes, frequency, and such other parameters of administering
therapeutically effective amounts of HAPs are described in these
publications as well (see also Jameson et al., J. Clin. Oncol., 26:
2008 (May 20 suppl.; abstr. 2562) and Tchekmedyian et al., J. Clin.
Oncol. 26: 2008 (May 20 suppl.; abstr. 3575)). Other exemplary
hypoxia activated prodrugs include benzotriazines, such as
Tirapazamine (TPZ; SR4233; 1,2,4-benzotriazin-3-amine 1,4-dioxide),
nitroaromatic compounds (e.g. misonidazole;
1-methyl-3-(2-nitro-1-imidazolyl)-2-propanol and RB 6145;
2-nitroimidazole) (see, e.g., Adams et al., 1994, Int. J. Radiat.
Oncol. Biol. Phys. 29:231-38), anthraquinones (e.g. AQ4N;
1,4-Bis-[[2-(dimethylamino-N-oxide)ethyl]amino]5,8-dihydroxyanthracene-9,-
-10-dione) (see, e.g., Patterson, 1993, Cancer Metastasis Rev.
12:119-34; Patterson, 2002, Drug Metab. Rev. 34:581-92; Patterson
et al., 2000, Br. J. Cancer 82:1984-90), the chloroquinoline
DNA-targeting unit to 2-nitroimidazole (e.g. NLCQ-1;
4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline
hydrochloride) (see, e.g., Papadopoulou et al.. 2003, Clin. Cancer
Res. 9:5714-20), dinitrobenzamide mustards (e.g. SN 23862;
5-(N,N-bis(2-chloroethyl)amino)-2,4-dinitrobenzamide and SN 28343)
(see, e.g., Siim et al., 1997, Oncol. Res. 9:357-69; Helsby, et
al., 2003, Chem. Res. Toxicol. 16:469-78), nitrobenzyl
phosphoramidate mustards (Nitroheterocyclic Phosphoramidates) (see,
e.g., Borch et al., 2000, J. Med. Chem. 43:2258-65),
nitrobeterocyclic methylquaternary salts (Nitroarylmethyl
Quaternary Salts) (see, e.g., Tercel et al., 2001, J. Med. Chem.
44:3511-22), cobalt(III) complexes (see, e.g., Wilson et al., 1994,
Int. J. Radiat. Oncol. Biol. Phys. 29:323-27) and indoloquinones
(see, e.g., Everett et al., 2002, Biochem. Pharmacol. 63:1629-39),
each incorporated by reference herein. In one embodiment, the HAP
is not Tirapazamine or a Tirapazamine analog.
[0107] Cancer therapy typically involves multiple cycles of drug
administration, and for many cancers, multiple drugs are
administered. For illustration, and not for limitation, two
anticancer drugs, A and B, may be administered in various
administration sequences, as illustrated below:
[0108] i. ABAAABAAABAA (repeats or "cycles" of ABAA);
[0109] ii. ABAABAABAABA (cycles of ABA);
[0110] iii. ABABABABABABABAB (cycles of AB);
[0111] iv. ABBABBABBABBABB (cycles of ABB); and
[0112] v. ABBBABBBABBBABBB (cycles of ABBB).
Any of these (and other) cycles of administration can be employed
in accordance with the present methods. For example, the sequence
ABAAABAAABAA can represent 3 cycles in which "A" is TH-302
administered on Days 1, 8 and 15 of a 28 day cycle, and "B" is
gemcitabine administered non-contemporaneously with A on Day 1 of
the cycle. It will be understood that where there are multiple
cycles and/or multiple administrations a drug(s) within a cycle,
the delay between completing administration of HAP and initiation
of administration of the non-HAP drug refers to the period between
sequential administrations of HAP and non-HAP. For example, in a
cycle AB.sub.1B.sub.2B.sub.3 the period between completing
administration of A and beginning administration of B.sub.1 is
measured (rather than, for example, the period between completing
administration of A and beginning administration of B.sub.3).
[0113] Hyperproliferative diseases other than cancer may also be
treated using the methods of the invention.
[0114] In some embodiments, the anticancer drug that is not
hypoxically activated is selected from the group consisting of
platinum alkylators (cisplatin, carboplatin, oxaliplatin, and
satraplatin), docetaxel, doxorubicin, gemcitabine, paclitaxel,
5-fluorouracil, and pemetrexed.
[0115] The anticancer drugs administered in accordance with the
present invention can be administered via a variety of routes,
including, without limitation IV and oral routes. Routes,
frequency, and therapeutically effective amounts of administering
anticancer drugs that are not hypoxia activated are provided, for
example, in most recent editions of the PHYSICIANS' DESK REFERENCE,
Medical Economics Company, Inc., Oradell, N.J.; and Goodman &
Gilman's "THE PHARMACOLOGICAL BASIS OF THERAPEUTICS", McGraw-Hill,
New York, Brown et al., Cancer Lett., 1978, 5:291-97 (incorporated
herein by reference), Yamada et al., Cancer Lett., 2001, 172:17-25
(incorporated herein by reference), and/or are available from the
Federal Drug Administration and/or are discussed in the medical
literature.
[0116] In another aspect, the present invention provides a method
of treating cancer and other hyperproliferative diseases, said
method comprising administering a hypoxia activated prodrug and
radiation therapy, to a patient in need of such treatment, wherein
the HAP (e.g., TH-302) is administered from about 1 hour to about
48 hours, more typically about 1 to 24 hours before the radiation
therapy is started. In one embodiment HAP treatment and radiation
treatment both are administered within a 24 hour period, the HAP is
administered first, and the radiation is administered at least
about 30 minutes and no more than 24 hours after administration of
the HAP is stopped. In one embodiment the lag between
administration of the HAP and radiation treatment is 2-4 hours,
such as about 2 hours or about 4 hours.
V. COMBINATION THERAPIES WITH TH-302 IN COMBINATION WITH OTHER
ANTICANCER AGENTS
[0117] The present invention provides methods of treating cancer by
administering TH-302 in combination with a second anticancer agent
(other than a HAP) to a patient in need of such treatment.
[0118] As is discussed below, a wide variety of solid tumors and
advanced solid tumors can be treated using such combination
therapy, and a wide variety of anticancer agents can be
administered in combination with TH-302 for therapeutic benefit.
For example, clinical data show that the combination of TH-302 with
gemcitabine has remarkable activity in first-line pancreatic cancer
and the combinations of TH-302 with docetaxel or pemetrexed have
remarkable activity in refractory non-small cell lung cancer
(NSCLC). The combination of TH-302 with doxorubicin is very
promising in soft tissue sarcoma.
[0119] Anticancer agents, which may be used in combination with
TH-302, are well know. In certain embodiments the anticancer agent
other than TH-302 is selected from the group consisting of
docetaxel, doxorubicin, gemcitabine, and pemetrexed. See Tables 2
and 3, infra. In certain embodiments the anticancer agent other
than TH-302 is selected from the group consisting of platinum
alkylators (cisplatin, carboplatin, oxaliplatin, and satraplatin),
docetaxel, doxorubicin, gemcitabine, paclitaxel, 5-fluorouracil,
and pemetrexed.
[0120] Clinical observations to date support the following
conclusions. In accordance with the methods of the invention,
TH-302 can be broadly combined with commonly used standard
chemotherapies particularly including gemcitabine, docetaxel,
pemetrexed, and doxorubicin. The MTD of TH-302 in each of the
combinations will likely be greater than 50% of the MTD of weekly
TH-302 monotherapy. Broad activity has been observed with RECIST
responses in all four of the combinations of TH-302 with
gemcitabine, docetaxel, pemetrexed, and doxorubicin. Partial
responses were observed at all TH-302 dose levels including at the
lowest dose of TH-302 (240 mg/m.sup.2) studied in the combinations.
The response rates are considerably higher than one would expect
based on prior studies in similar trials or in similar trials of
specific tumors such as pancreatic cancer, recurrent NSCLC, and
soft-tissue sarcoma. In addition, many of the responses are
durable, thus providing well-defined clinical benefit for the
subjects. The proportion of subjects with stable disease on
treatment is also notable and the measure of clinical benefit
described by the sum of partial responses (28%) and stable disease
(51%) is nearly 80%.
TH-302 Administration for Combination Therapy
[0121] The formulation, dose, administration route, frequency, and
such other modes of administration of TH-302 include those
described herein below and those described in Section II, supra
(discussing administration of TH-302 for monotherapy). One of
ordinary skill in the art, upon reading this disclosure, will
appreciate that in certain embodiments of the present invention,
when administered as part of a combination treatment for cancer,
TH-302 is typically administered in amounts lesser than those
administered in TH-302 monotherapy. In preferred embodiments,
administration of TH-302 and a second chemotherapeutic agent is
conducted in accord with the methods described in Section IV,
supra. That is, the drugs are administered non-contemporaneously,
with the administration of the non-HAP beginning after
administration of the TH-302. Typically administration of the
non-HAP commences 30 min to 6 hours after completion of TH-302
administration (e.g., a delay of about 1, about 2, about 3, about
4, about 5, or about 6 hours). In some embodiments administration
of the non-HAP commences about 2 hours after completion of TH-302
administration.
[0122] In preferred embodiments of the combination therapies of the
invention, TH-302 is usually administered by IV infusion at a dose
of 200 mg/m.sup.2-500 mg/m.sup.2. For example, in certain
embodiments, when administered in combination with another
anticancer agent, TH-302 is administered in an amount of about 120
mg/m.sup.2, 240 mg/m.sup.2, 340 mg/m.sup.2, 400 mg/m.sup.2, 480
mg/m.sup.2, and 560 mg/m.sup.2. The dose will depend, in part, on
what chemotherapeutic agent other than TH-302 is used, as well as
the patient's condition and cancer being treated. The MTD of TH-302
plus gemcitabine is anticipated to be 340-400 mg/m.sup.2; the MTD
of TH-302 plus docetaxel is 340 mg/m.sup.2, and the MTD of TH-302
plus pemetrexed is 480 mg/m.sup.2; and the MTD of TH-302 plus
doxorubicin is anticipated to be 300 mg/m.sup.2; in each case when
the non-HAP drug is non-contemporaneously administered at
conventional doses, e.g., as described below.
[0123] In various embodiments, TH-302 may be administered in
combination with another agent in an amount in the range of about
100 mg/m.sup.2-about 700 mg/m.sup.2, about 300 mg/m.sup.2-about 600
mg/m.sup.2, about 350 mg/m.sup.2-about 550 mg/m.sup.2, about 400
mg/m.sup.2-about 500 mg/m.sup.2, about 400 mg/m.sup.2-about 600
mg/m.sup.2, about 450 mg/m.sup.2-about 550 mg/m.sup.2, about 200
mg/m.sup.2-about 500 mg/m.sup.2, or about 200 mg/m.sup.2-575
mg/m.sup.2.
[0124] In combination treatment of cancer, TH-302 may be
administered according to a variety of schedules, including those
described is administered for one or more 4 week cycles, as
described above for TH-302 monotherapy (i.e., once per week for
three weeks followed by one week without administering TH-302). In
other embodiments of the present invention, for combination
treatment of cancer, TH-302 is administered for one or more 3 week
cycles. In a 3 week administration cycle, TH-302 can be
administered once weekly for 2 consecutive weeks followed by a week
of no TH-302 or, alternatively, can be administered once every 3
weeks. In certain embodiments of the present invention, for
combination treatment of cancer, TH-302 is administered weekly.
TH-302 may be administered once weekly for seven weeks followed by
one week of no administration, followed by one or more 28-day
cycles.
[0125] TH-302 is usually administered intravenously, typically by
infusion. In some embodiments TH-302 is formulated with ethanol and
TWEEN 80 as discussed in Section II, supra (discussing
administration of TH-302 for monotherapy). In preferred embodiments
TH-302 is administered prior to administration of the second,
non-HAP anticancer agent, and administration of TH-302 is stopped
at least 30 minutes to one hour (or at least 2-6 hours) before
administration of the second, non-HAP anticancer agent is
initiated, i.e., as described in Section III, supra. In one
embodiment, the present invention provides methods of treating
cancer comprising administering TH-302 intravenously, in
combination with another anticancer agent to a patient in need of
such treatment, where the TH-302 is administered in an amount of up
to about 1000 mg/m.sup.2. In some embodiments the dose of TH-302
used in a particular combination therapy and administration
schedule is in the range bounded by the MTD for the particular
schedule and combination and a dose equal to the MTD minus 100
mg/m.sup.2 (i.e., in some embodiments the dose of TH-302 used in a
particular combination therapy and administration schedule is dosed
up to 100 mg/m.sup.2 less than the MTD).
Treatable Cancers
[0126] A variety of solid tumors and advanced solid tumors can be
treated in accordance with the present methods for combination
therapy with TH-302. TH-302 may be administered in combination with
one (or more) additional chemotherapeutic agents as an initial or
first line treatment, for treatment of refractory or metastatic
cancer, and as adjuvant or neoadjuvant therapy.
[0127] Thus, in one embodiment of the present invention, the cancer
is treated, following diagnosis, in the neoadjuvant setting
(chemotherapy is administered to the patient before surgery to
shrink the primary tumor and facilitate removal of the primary
tumor). In another embodiment, the combination therapy is
administered, following diagnosis, as adjuvant treatment
(chemotherapy is given after the tumor is removed and the patient
is staged; if there is a high likelihood of recurrent then
prophylactic chemotherapy is given to delay recurrence and improve
survival). In another embodiment, the combination therapy is
administered for treatment of refractory or metastatic cancer
(chemotherapy is given for recurrence(s) or spread of the
cancer).
[0128] Treatable cancers in accordance with the methods herein
include, therefore, previously untreated cancers, a refractory
cancer, and a metastatic cancer. In another embodiment of the
present invention, the relapsed cancer, refractory cancer, or
metastatic cancer treated is selected from the group consisting of
lung cancer, liver cancer, prostate cancer and skin cancer.
[0129] The data across indications and dose groups for human
patients treated to date are provided in Tables 2 and 3, below.
Tumor responses reported across all dose groups and across all
combinations suggest that TH-302 has activity in a broad range of
tumor subtypes and in combination with a range of standard
chemotherapies. Importantly, substantial doses of TH-302 can be
combined with the approved full doses and full schedules of all
standard chemotherapies in accordance with the methods of the
invention.
TABLE-US-00002 TABLE 2 TH-302 Combination Therapy: Overall Efficacy
by Tumor Type TH-302 + gemcitabine TH-302 + docetaxel TH-302 +
pemetrexed TH-302 + doxorubicin Cancer mg/m.sup.2 mg/m.sup.2
mg/m.sup.2 mg/m.sup.2 Type 240 340 480 575 240 340 480 240 340 480
575 240** 340 Bile Duct SD SD Ovarian PD PR Esophageal PR PD
Pancreatic PR SD SD SD PR NSCLC PR SD PR PR -2 SD PD SD SD Prostate
SD-2 Ampullary SD Neuro- SD SD SD endocrine Soft Tissue SD PD PR-2
PR Sarcoma SD-2 PD SD Colorectal SD SD PD Anal PR Urachal SD
Urethral PD Breast SD Melanoma SD SD PD HCC SD Renal PD PR PR
Thyroid PR Parotid SD Unknown PD-2 1.degree.
TABLE-US-00003 TABLE 3 TH-302 as Combination Therapy: Overall
Efficacy TH-302 Number Weekly with Dose Number of Tumor Partial
Stable Progressive (mg/m.sup.2) Subjects Assessment Response
Disease Disease Gemcitabine 240 7 5 2 2 1 340 6 3 1 2 0 480 6 3 1 2
0 575 7 3 2 1 0 Docetaxel 240 8 6 1 4 1 340 5 3 1 1 1 480 7 4 0 3 1
Pemetrexed 240 5 5 2 2 1 340 6 2 0 2 0 480 9 8 1 3 4 575 7 4 1 2 1
Doxorubicin 240 6 4 2 2 0 340 4 3 1 1 1 Total 83 53 15 (28%) 27
(51%) 11 (21%)
[0130] The data shown in Tables 2 and 3 demonstrate that the
combination therapies of the invention are effective in treating a
wide variety of cancers. Thus, methods of the invention include
treatment of:
[0131] (a) NSCLC, prostate cancer, neuroendocrine cancer, anal
cancer, urachal cancer, urethral cancer, breast cancer, melanoma,
and renal cell carcinoma with TH-302 and docetaxel;
[0132] (b) bile duct cancer, ovarian cancer, esophageal cancer,
pancreatic cancer, NSCLC, ampullary cancer, neuroendocrine cancer,
soft tissue sarcoma, and thyroid cancer with TH-302 and
gemcitabine; and
[0133] (c) esophageal cancer, pancreatic cancer, NSCLC,
neuroendocrine cancer, soft tissue sarcoma, colorectal cancer,
hepatocellular carcinoma (HCC), renal cancer, and parotid cancer
with TH-302 and pemetrexed.
[0134] In one embodiment of the present invention, TH-302 is
administered in combination with docetaxel, the cancer treated is
prostate cancer, and TH-302 is administered in an amount in the
range of about 200 mg/m.sup.2-500 mg/m.sup.2, usually about 340
mg/m.sup.2. In another embodiment of the present invention, TH-302
is administered in combination with doxorubicin, the cancer treated
is soft tissue sarcoma, and TH-302 is administered in an amount in
the range of about 200 mg/m.sup.2-500 mg/m.sup.2, e.g., 240
mg/m.sup.2-340 mg/m.sup.2. In another embodiment of the present
invention, TH-302 is administered in combination with pemetrexed,
the cancer treated is non small cell lung cancer (NSCLC), and
TH-302 is administered in an amount in the range of about 200
mg/m.sup.2-500 m g/m.sup.2, usually about 400 mg/m.sup.2. In
another embodiment of the present invention, TH-302 is administered
in combination with gemcitabine, the cancer treated is pancreatic
cancer, and TH-302 is administered in an amount in the range of
about 200 mg/m.sup.2-500 mg/m.sup.2, usually about 340-400
mg/m.sup.2.
[0135] For combination therapy, TH-302 (or other compound of
Formula I) can be administered at frequencies and durations
described for TH-302 monotherapy above. Thus, in one embodiment of
the present invention, the TH-302 is administered at a frequency of
once every week. In another embodiment of the present invention, TH
302 is administered in multiple cycles, each cycle of
administration being a 4 week cycle wherein, TH-302 is administered
once weekly for 3 consecutive weeks. In this embodiment, for each
administration cycle, TH-302 administered once weekly for 3
consecutive weeks is administered on days 1, 8, and 15, followed by
a week of no drug administration, followed by a week of no TH-302
administration. In one embodiment of the present invention, the
TH-302 is administered for a period in the range of 3 weeks-52
weeks, 3 weeks-28 weeks, 3 weeks-16 weeks, and 3 weeks-8 weeks.
Thus, in accordance with the present methods, TH-302 can be
administered, for example and without limitation, for 1-13, 1-7, or
1-4 cycles. Certain of these periods of TH-302 administration
include one or more weeks of drug holidays during which no TH-302
is administered.
Administration of Anticancer Agents Other than TH-302
[0136] The formulation and dose, route, frequency, and such other
modes of administration of various anticancer agents, other than
TH-302, administered in accordance with the present methods, are
disclosed herein, are available in medical literature, and/or are
known to one of skill in the art. Thus, the doses of the non-TH-302
chemotherapeutic agent (e.g., gemcitabine, docetaxel, pemetrexed,
doxorubicin, and others anticancer agents) are approved doses
listed in their respective product labeling. The therapeutically
effective amount of an anticancer agent other than TH-302
administered in accordance with the present methods, at least for
known and approved anticancer agents, are known to physicians and
are provided, for example and without limitation, in the product
descriptions found in the PHYSICIANS' DESK REFERENCE, 2003, 57th
Ed., Medical Economics Company, Inc., Oradell, N.J; Goodman &
Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS" 2001, 10.sup.th
Edition, McGraw-Hill, New York; and/or are available from the
Federal Drug Administration and/or are discussed in the medical
literature. Illustrative dosing amounts and schedules for various
cancers in accordance with the methods of the invention are
described herein.
[0137] For illustration and not for limitation, the following
dosages and schedules may be used: [0138] Gemcitabine may be
administered IV at 1,000 mg/m.sup.2 IV over 30 minutes. For
example, gemcitabine may be administered IV at 1,000 mg/m.sup.2 IV
over 30 minutes on Days 1, 8, and 15 of each 28-day cycle and
TH-302 may be administered on Days 1, 8, and 15 of each 28-day
cycle. In an other example, gemcitabine and TH-302 are administered
once weekly for seven weeks followed by one week of no
administration, followed by one or more 28-day cycles in which
TH-302 and gemcitabine are administered on Days 1, 8, and 15 of
each 28-day cycle. [0139] Docetaxel may be administered IV at 75
mg/m.sup.2 over 60 minutes. For example, docetaxel may be
administered IV at 75 mg/m.sup.2 over 60 minutes on Day 1 of each
21-day cycle and TH-302 may be administered on Days 1 and 8 of each
21-day cycle. [0140] Pemetrexed may be administered IV at 500
mg/m.sup.2 over 10 minutes. For example, pemetrexed may be
administered IV at 500 mg/m.sup.2 over 10 minutes on Day 1 of each
21-day cycle and TH-302 may be administered on Days 1 and 8 of each
21-day cycle. [0141] Doxorubicin may administered as bolus
injection at 75 mg/m.sup.2 on Day 1 of a 21-day cycle and TH-302
may be administered on Days 1 and 8 of each 21-day cycle.
[0142] The following sections (A)-(E) provide additional discussion
of treatment of cancers using TH-302 in combination with other
anticancer agents. Although illustrative dosages and schedules are
described below, it will be appreciated that for treatment of
cancer, e.g., lung, prostate, pancreatic, colon, and soft tissue
sarcomas, the dose and schedule of administration of TH-302 and
other agents may include the doses and schedules described
elsewhere in this description.
A. Treatment of Lung Cancer Using TH-302 in Combination Therapy
with Docetaxel, Pemetrexed, a Platinum-Containing Drug,
Doxorubicin, or Gemcitabine
[0143] The present invention provides methods for treating subjects
with NSCLC of squamous cell histology by administering TH-302 in
combination with pemetrexed, docetaxel, gemcitabine, a
platinum-containing drug, or doxorubicin.
[0144] As discussed in, e.g., Examples 4 and 5, infra, TH-302 may
be administered to patients with lung cancer, including SCLC,
NSCLC, and NSCLC of squamous cell histology in combination with
other anticancer agents.
[0145] In clinical trials, analysis was carried out on ten human
subjects with relapsed or refractory NSCLC who had been treated
with the combination of TH-302 plus pemetrexed or TH-302 plus
docetaxel. RECIST tumor assessments were performed for eight
subjects. Three of eight subjects had partial responses while four
of these same eight subjects had stable disease. The historical
response rate in second-line NSCLC is less than 10% in several
large pivotal studies. These eight subjects have received a median
of 2.5 prior systemic chemotherapies. Two of the eight subjects
continued on the study (e.g., receiving Cycle 5 to Cycle 16). Two
of the three subjects with partial responses discontinued after
completing the study in the absence of progression; one had
completed 10 cycles and the other had received 16 cycles.
[0146] Two subjects with recurrent/refractory NSCLC were treated
with gemcitabine and TH-302. One of the two subjects had a RECIST
partial response and continued on-study (receiving Cycle 5).
[0147] Two of the partial responses described above, one in
combination with docetaxel and one in combination with gemcitabine,
were seen in subjects with NSCLC of squamous cell histology. NSCLC
of squamous cell histology is particularly refractory to
chemotherapy. The pemetrexed-approved indications in NSCLC exclude
subjects with NSCLC of squamous cell histology. The one patient
with NSCLC of squamous cell histology treated with pemetrexed in
combination with TH-302 continued on-study at Cycle 5 with stable
disease.
[0148] i) Docetaxel
[0149] The present invention provides a method of treating a
patient diagnosed with lung cancer (e.g., NSCLC) comprising
administering a therapeutically effective dose of TH-302 in
combination with a therapeutically effective dose of docetaxel. As
discussed in Example 4, infra, administration of TH-302 and
docetaxel showed antitumor activity in human patients. As shown in
Example 6, infra, administration of a single dose of TH-302 and a
single dose of docetaxel inhibited tumor growth in an H460 ectopic
lung cancer model. Also, in a series of ectopic lung cancer models,
some using H460 cells and some using Calu-6 cells, administration
of a series of doses of TH-302 and a variety of chemotherapeutic
agents inhibited tumor growth. The tumor growth inhibition was
greater than that with either TH-302 or other chemotherapy
alone.
[0150] Therapeutically effective doses of docetaxel (e.g.,
Taxotere; Sanofi-Aventis) may be determined by medical
professionals by reference to materials available from the FDA
and/or the medical literature. An exemplary dose, for illustration
and not limitation, is 75 mg/m.sup.2 administered as a one-hour
intravenous infusion. Illustrative therapeutically effective doses
of TH-302 are described above. Other doses may be used as deemed
appropriate by medical professionals and/or approved by the
FDA.
[0151] In some embodiments, administration of docetaxel is preceded
by administration of TH-302, with the gap between the end of TH-302
administration and the beginning of docetaxel administration being
at least 30 minutes to one hour, typically at least 2 hours, and in
any event no more than 24 hours. In some embodiments, the duration
of the time between TH-302 and docetaxel administrations is from 1
to 10 hours, from 2 to 6 hours, or from 3 to 5 hours. In some
embodiments the gap between the end of TH-302 administration and
the beginning of docetaxel administration is about 2 hours.
[0152] ii) Pemetrexed
[0153] The present invention also provides a method for treating a
patient diagnosed with lung cancer, including NSCLC, comprising
administering a therapeutically effective dose of TH-302 in
combination with administering a therapeutically effective dose of
pemetrexed. As discussed in Example 4, infra, administration of
TH-302 and pemetrexed showed antitumor activity in human patients.
As discussed in Example 6, infra, administration of TH-302 and
pemetrexed dramatically inhibited tumor growth in a NSCLC
model.
[0154] Therapeutically effective doses of pemetrexed may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose, for illustration and not limitation, is 500 mg/m.sup.2
administered IV over 10 minutes once every three weeks.
Illustrative therapeutically effective doses of TH-302 are
described above. Other doses may be used as deemed appropriate by
medical professionals and/or approved by the FDA.
[0155] In some embodiments, administration of pemetrexed is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of pemetrexed
administration being at least one hour and not more than 24 hours.
In some embodiments, the duration of the time between TH-302 and
pemetrexed administrations is from 1 to 10 hours, from 2 to 6
hours, or from 3 to 5 hours. In some embodiments the gap between
the end of TH-302 administration and the beginning of pemetrexed
administration is about 2 hours.
[0156] iii) Platinum-Containing Drugs
[0157] The present invention also provides a method for treating a
patient diagnosed with lung cancer (including NSCLC) comprising
administering a therapeutically effective dose of TH-302 in
combination with administering a therapeutically effective dose of
a platin (e.g., such as cisplatin or carboplatin). As discussed in
Example 6, infra, administration of TH-302 and cisplatin inhibited
tumor growth in two lung cancer models, one using H460 cells and
one using Calu-6 cells. As discussed in Example 6, infra,
administration of TH-302 and carboplatin inhibited tumor growth in
an H460 lung cancer model.
[0158] Therapeutically effective doses of cisplatin and carboplatin
may be determined by medical professionals by reference to
materials available from the FDA and/or the medical literature. An
exemplary dose of cisplatin, for illustration and not limitation,
is 100 mg/m.sup.2 once every four weeks. Therapeutically effective
doses of carboplatin may be determined by medical professionals
using the Calvert formula (Calvert et al., 1989, J. Clin. Oncol.
7:1748-56). Illustrative therapeutically effective doses of TH-302
are described above for illustration. Other doses may be used as
deemed appropriate by medical professionals and/or approved by the
FDA.
[0159] In some embodiments, administration of the
platinum-containing drug is preceded by administration of TH-302,
with the gap between the end of TH-302 administration and the
beginning of platinum-containing drug administration being at least
30 minutes to one hour, typically at least 2 hours, and in any
event no more than 24 hours. In some embodiments the duration of
the time between TH-302 and platinum-containing drug
administrations is from 1 to 10 hours, from 2 to 6 hours, or from 3
to 5 hours. In some embodiments the gap between the end of TH-302
administration and the beginning of administration of a
platinum-containing drug is about 2 hours.
[0160] iv) Doxorubicin
[0161] The present invention also provides a method for treating a
patient diagnosed with lung cancer comprising administering a
therapeutically effective dose of TH-302 in combination with
administering a therapeutically effective dose of doxorubicin. As
discussed in Example 5, infra, administration of TH-302 and
doxorubicin showed antitumor activity in human patients. As
discussed in Example 6, infra, administration of TH-302 and
doxorubicin inhibited tumor growth in a Calu-6 lung cancer
model.
[0162] Therapeutically effective doses of doxorubicin may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose is 40 to 75 mg/m.sup.2 given as a single intravenous injection
every 21 to 28 days. Therapeutically effective doses of TH-302 are
described above. Other doses may be used as deemed appropriate by
medical professionals and/or approved by the FDA.
[0163] In some embodiments, administration of doxorubicin is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of doxorubicin
administration being at least 30 minutes to one hour, typically at
least 2 hours, and in any event no more than 24 hours. In some
embodiments the duration of the time between TH-302 and doxorubicin
administration is from 1 to 10 hours, from 2 to 6 hours, or from 3
to 5 hours. In some embodiments the gap between the end of TH-302
administration and the beginning of doxorubicin administration is
about 2 hours.
[0164] v. Gemcitabine
[0165] The present invention also provides a method for treating a
patient diagnosed with lung cancer comprising administering a
therapeutically effective dose of TH-302 in combination with
administering a therapeutically effective dose of gemcitabine. As
discussed in Example 4, infra, administration of TH-302 and
gemcitabine had beneficial effect in patients with, e.g.,
pancreatic cancer.
[0166] Therapeutically effective doses of gemcitabine may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose is 1000 mg/m.sup.2 given i.v. over 30 minutes on days 1, 8 and
15 of a 28 day cycle. Therapeutically effective doses of TH-302 are
described above. Other doses may be used as deemed appropriate by
medical professionals and/or approved by the FDA.
[0167] In some embodiments, administration of doxorubicin is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of gemcitabine
administration being at least 30 minutes to one hour, typically at
least 2 hours, and in any event no more than 24 hours. In some
embodiments the duration of the time between TH-302 and gemcitabine
administrations is from 1 to 10 hours, from 2 to 6 hours, or from 3
to 5 hours. In some embodiments the gap between the end of TH-302
administration and the beginning of gemcitabine administration is
about 2 hours.
B. Treatment of Prostate Cancer Using TH-302 in Combination Therapy
with a Taxane
[0168] The present invention provides a method for treating a
patient diagnosed with prostate cancer comprising administering a
therapeutically effective dose of TH-302 in combination with
administering a therapeutically effective dose of a taxane such as
docetaxel or paclitaxel. As discussed in Example 6, infra,
administration of TH-302 and docetaxel or paclitaxel dramatically
inhibited tumor growth in a prostate cancer model.
[0169] Therapeutically effective doses of taxanes may be determined
by medical professionals by reference to materials available from
the FDA and/or the medical literature. For illustration and not
limitation, an exemplary dose is 75-100 mg/m.sup.2 given as an
intravenous infusion once every 21 days for docetaxel and 175
mg/m.sup.2 given as an intravenous infusion every 21 days for
paclitaxel. Illustrative therapeutically effective doses of TH-302
are described above. Other doses may be used as deemed appropriate
by medical professionals and/or approved by the FDA.
[0170] Two human subjects with castrate resistant prostate cancer
have been treated with the combination of TH-302 plus docetaxel.
RECIST tumor assessments have been performed for both subjects and
both subjects had stable disease. Both subjects had a decrease in
PSA of over 50% from their baseline value. One of the two had
severe pain involving the lumbar spine and this resolved on
treatment. After 5 cycles, one of the two subjects had a >90%
decrease in PSA dropping from 861 ng/ml to 45 ng/ml; the other
subject has had a >50% decrease in PSA from the baseline PSA of
28 ng/ml.
[0171] In some embodiments, administration of paclitaxel or
docetaxel is preceded by administration of TH-302, with the gap
between the end of TH-302 administration and the beginning of
paclitaxel or docetaxel administration being at least 30 minutes to
one hour, typically at least 2 hours, and in any event no more than
24 hours. In some embodiments, the duration of the time between
TH-302 and paclitaxel or docetaxel administrations is from 1 to 10
hours, from 2 to 6 hours, or from 3 to 5 hours. In some embodiments
the gap between the end of TH-302 administration and the beginning
of paclitaxel or docetaxel administration is about 2 hours.
C. Treatment of Pancreatic Cancer Using TH-302 in Combination
Therapy with Gemcitabine
[0172] The present invention provides a method for treating a
patient diagnosed with pancreatic cancer comprising administering a
therapeutically effective dose of TH-302 in combination with
administering a therapeutically effective dose of gemcitabine.
Administration of TH-302 and gemcitabine provided benefit to
patients with first-line pancreatic cancer (see Example 4, infra).
Moreover, administration of TH-302 and gemcitabine dramatically
inhibited tumor growth in a pancreatic cancer model (see Example 6,
infra). While the maximum tolerated dose for TH-302 in combination
with gemcitabine has not been established, it is anticipated to be
at least 340 mg/m2. This dose is effective for treating subjects
with first-line pancreatic cancer.
[0173] Therapeutically effective doses of gemcitabine may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose, for illustration and not limitation, is 1,000 mg/m.sup.2
administered IV over 30 minutes once per week. Illustrative
therapeutically effective doses of TH-302 are described above.
Other doses may be used as deemed appropriate by medical
professionals and/or approved by the FDA.
[0174] In some embodiments, administration of gemcitabine is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of gemcitabine
administration being at least 30 minutes to one hour, typically at
least 2 hours, and in any event no more than 24 hours. In some
embodiments, the duration of the time between TH-302 and
gemcitabine administrations is from 1 to 10 hours, from 2 to 6
hours, or from 3 to 5 hours. In some embodiments the gap between
the end of TH-302 administration and the beginning of gemcitabine
administration is about 2 hours.
D. Treatment of Soft Tissue Sarcomas Using TH-302 in Combination
Therapy with Doxorubicin
[0175] The present invention provides a method for treating a
patient diagnosed with a soft tissue sarcoma comprising
administering a therapeutically effective dose of TH-302 in
combination with administering a therapeutically effective dose of
doxorubicin. Administration of TH-302 and doxorubicin provided
benefit to patients with soft tissue sarcomas (see Example 5,
infra). Moreover, administration of TH-302 and doxorubicin
inhibited tumor growth in a sarcoma model (see Example 6,
infra).
[0176] Therapeutically effective doses of doxorubicin may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose, for illustration and not limitation, is 40 to 60 mg/m.sup.2
given as a single intravenous injection every 21 to 28 days.
Illustrative therapeutically effective doses of TH-302 are
described above. The maximum tolerated dose for the TH-302 in
combination with a doxorubicin regimen has not been established,
but subjects can be treated, in accordance with the methods of the
invention at a TH-302 dose of at least 240 mg/m.sup.2 in
combination with the approved doxorubicin dose of 75 mg/m.sup.2.
Other doses may be used as deemed appropriate by medical
professionals and/or approved by the FDA.
[0177] In some embodiments, administration of doxorubicin is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of doxorubicin
administration being at least 30 minutes to one hour, typically at
least 2 hours, and in any event no more than 24 hours. In some
embodiments, the duration of the time between TH-302 and
doxorubicin administration is from 1 to 10 hours, from 2 to 6
hours, or from 3 to 5 hours. In some embodiments the gap between
the end of TH-302 administration and the beginning of doxorubicin
administration is about 2 hours.
E. Treatment of Colon Cancer Using TH-302 in Combination Therapy
with Cisplatin (CDDP) or 5-Fluorouracil (5FU)
[0178] The present invention provides a method for treating a
patient diagnosed with colon cancer comprising administering a
therapeutically effective dose of TH-302 in combination with
administering a therapeutically effective dose of cisplatin. As
discussed in Example 6, infra, administration of TH-302 and
cisplatin inhibited tumor growth in a HT-29 colon cancer model.
[0179] In one aspect, the invention provides a patient diagnosed
with colon cancer comprising administering a therapeutically
effective dose of TH-302 and administering a therapeutically
effective dose of 5-fluorouracil (5FU). As discussed in Example 6,
infra, administration of TH-302 and 5FU inhibited tumor growth in
an HT-29 colon cancer model.
[0180] Therapeutically effective doses of cisplatin may be
determined by medical professionals by reference to materials
available from the FDA and/or the medical literature. An exemplary
dose, for illustration and not limitation, is 100 mg/m.sup.2 once
every 3 to 4 weeks.
[0181] Therapeutically effective doses of 5FU may be determined by
medical professionals by reference to materials available from the
FDA and/or the medical literature. An exemplary dose, for
illustration and not limitation, is 150 mg/m.sup.2 daily.
[0182] Illustrative therapeutically effective doses of TH-302 are
described above. Other doses may be used as deemed appropriate by
medical professionals and/or approved by the FDA.
[0183] In some embodiments, administration of 5FU or CDDP is
preceded by administration of TH-302, with the gap between the end
of TH-302 administration and the beginning of 5FU or CDDP
administration being at least 30 minutes to one hour, typically at
least 2 hours, and in any event no more than 24 hours. In some
embodiments, the duration of the time between TH-302 administration
and administration of 5FU or CDDP is from 1 to 10 hours, from 2 to
6 hours, or from 3 to 5 hours. In some embodiments the gap between
the end of TH-302 administration and the beginning of 5FU or CDDP
administration is about 2 hours.
F. Combination Therapy with Other Compounds of Formula I
[0184] While the combination therapies described above have been
described with respect to TH-302, the methods of the invention also
include combination therapies with other compounds of Formula I,
including, without limitation, TH-281. While the therapeutically
effective dose may vary depending on which compound of Formula I is
selected, the dose will typically be an amount in the range of
about 200 mg/m.sup.2-about 700 mg/m.sup.2, about 300
mg/m.sup.2-about 600 mg/m.sup.2, about 350 mg/m.sup.2-about 550
mg/m.sup.2, about 400 mg/m.sup.2-about 500 mg/m.sup.2, about 400
mg/m.sup.2-about 600 mg/m.sup.2, and about 450 mg/m.sup.2-about 550
mg/m.sup.2. In various embodiments of the present invention, the
dose administered is about 560 mg/m.sup.2, 480 mg/m.sup.2, 400
mg/m.sup.2, 340 mg/m.sup.2, 240 mg/m.sup.2, or 120 mg/m.sup.2. In
other embodiments, the dose administered is in an amount in the
range of about 700 mg/m.sup.2-about 1200 mg/m.sup.2 or about 800
mg/m.sup.2-about 1000 mg/m.sup.2.
EXAMPLES
[0185] The following examples are intended for illustration only
and should not be construed to limit the scope of the invention.
Example 1 describes formulations of the invention. Example 2
describes TH-302 monotherapy. Example 3 demonstrates the advantages
of administering a HAP prior to administering another anti-cancer
agent and incorporating a delay period between administrations.
Examples 4 and 5 demonstrate the efficacy of TH-302 combination
therapies in treating human cancers in human patients. In human
trials lyophilized TH-302 was resuspended in D5W for administration
to patients. Example 6 demonstrates the efficacy of TH-302
combination therapies in treating human cancers in animal
models.
Example 1
Pharmaceutical Formulations of TH-302
[0186] This example describes pharmaceutical formulations of TH-302
as well as the results of experimentation demonstrating the
advantages of certain formulations. As discussed below, a
formulation containing TH-302, ethanol and TWEEN 80 provided
advantages over other formulations including higher solubility of
TH-302, allowing for a more concentrated solution, greater
stability on storage, and the absence of precipitation when the
concentrated formulation is diluted into D5W or saline.
[0187] The experimentation was performed on the following systems
(or equivalents): HP 1090 Series II, with Alltech, Alltima C18,
50.times.4.6, 3 .mu.M or 5 .mu.m HPLC column; HP1090 pump;
Diode-Array Detector; and Chemstation version A.08.01 data
acquisition system. The following reversed phase HPLC conditions
were used for the experimental studies: column temperature was room
temperature; there was no sample thermostat; the detector
wavelength was 325 nm, 254 nm; the pump configuration was gradient;
the flow rate was 0.8 ml/min.; the injection volume was 10 .mu.L;
the run time was 11 min.; the needle wash was with ethyl alcohol;
the diluent and blank were water. The Gradient Table was as
follows:
TABLE-US-00004 TABLE 4 Time Mobile phase A (%) Mobile phase B (%)
(mins) (water) (acetonitrile) 0.01 95 5 4.5 5 95 7 5 95 8 95 5 11
95 5
The materials and reagents were TH-302, prepared under GMP by
Syngene; anhydrous 200 proof Sigma-Aldrich Cat. No. 459836-2L ethyl
alcohol; HPLC grade or equivalent acetonitrile and water; benzyl
alcohol Sigma-Aldrich Cat. No. 108006-100 ml; N,N-dimethylacetamide
(DMA) Sigma-Aldrich Cat. No. 185884-500 ml; and 2 ml Vial Labfile
AMB Wheaton Cat. No. W224681.
[0188] TH-302 formulations were subjected to different conditions
to produce partial degradation. The test solutions and standards
were individually stressed under the same conditions. Test
solutions for evaluation were prepared according to the procedures
described below.
[0189] A following series of comparative formulations (1, 2A and
2B) were prepared to evaluate the stability of TH-302 using various
combinations of the indicated solvents (ethanol (EtOH) and in
DMA/EtOH/Benzyl alcohol) without a nonionic surfactant. These
formulations were studied in accelerated stability conditions at
various temperatures (4.degree. C., 20.degree. C., and 37.degree.
C.) for up to 154 days.
[0190] Formulation 1 was prepared as follows. A 50 mg/ml solution
of TH-302 in EtOH was prepared. 2.5 g of TH-302 were weighed out
and transferred into a volumetric flask (50 ml). 46 ml of EtOH were
added and the mixture was stirred at room temperature for 1.5
hours. After all the solid disappeared completely, the solution was
diluted to 50 ml by the addition of ethanol. The solution was
transferred into 2-ml vials with 1 ml of solution in each vial. The
concentration was 50 mg/ml. The vials were stored at different
temperatures (4.degree. C. (refrigerator); 20.degree. C. (bench);
37.degree. C. (water bath)) for the various times shown below.
Samples were taken on days 28, 65, 106 and 154 for LC analysis. 50
.mu.L was aliquoted from the 50 mg/ml TH 302 solutions, added to
volumetric flasks (50 ml), and diluted with water to the 50 ml
volume and mixed well. The concentration was 50 .mu.g/ml.
[0191] The stability of Formulation 1 at the various temperatures
and times is shown in the following Tables 5-7.
TABLE-US-00005 TABLE 5 Stability of TH-302 (50 mg/ml) in EtOH at
37.degree. C. Relative retention time to TH-302 Days TH-302 0.98*
0.96** 0 97.64% 2.36% N/D 28 95.66% 2.34% 2.00% 65 92.54% 2.37%
5.09%
TABLE-US-00006 TABLE 6 Stability of TH-302 (50 mg/ml) in EtOH at
20.degree. C. Relative retention time to TH-302 Days TH-302 0.98*
0.96 0 97.64% 2.36% N/D 28 97.65% 2.35% N/D 65 97.61% 2.39% N/D 106
97.66% 2.34% --** 154 97.0% 2.44% 0.56%
TABLE-US-00007 TABLE 7 Stability of TH-302 (50 mg/ml) in EtOH at
4.degree. C. Relative retention time to TH-302 Days TH-302 0.98*
0.96** 0 97.64% 2.36% N/D 154 97.51% 2.49% N/D *Mono chloro
impurity **Unidentified degradation product was observed, Product
couldn't be integrated. N/D not detected
[0192] HPLC chromatograms of TH-302 (50 mg/ml) in EtOH at
37.degree. C. for 65 days and of TH-302 in EtOH (50 mg/ml) at
4.degree. C. for 154 days showed that TH-302 in ethanol (50 mg/ml)
is stable at 4.degree. C., and shows no degradation out to day 154.
However, TH-302 in this formulation shows degradation when stored
at higher temperatures, e.g. 37.degree. C. While TH-302 in pure
ethanol is relatively stable at low temperatures, the highest
solubility of TH-302 in ethanol is about 80 mg/ml even at higher
temperatures.
[0193] A degradation product having the structure below
[(2-chloroethyl)({[(2-bromoethyl)amino][(2-nitro-3-methylimidazol-4-yl)me-
thoxy]phosphoryl})amine] ("monochloro impurity") (2.4%) was noted
at study start and did not notably increase over time at any of the
stability condition temperatures tested.
##STR00005##
[0194] Formulation 2A was prepared as follows. 1.2 g of TH-302 was
weighed out and transferred into a solution of benzyl alcohol (600
mg) and DMA (1200 mg) in a volumetric flask (10 ml). The mixture
became a clear solution after agitating for 5 min. The solution was
diluted to 10 ml by the addition of ethanol. The solution was
transferred into 2 ml vials with 0.2 ml solution in each vial. The
TH-302 concentration was 120 mg/ml. The vials were stored at
different temperatures (4.degree. C. (refrigerator); 20.degree. C.
(bench); 37.degree. C. (water bath)) for the various times shown
below.
[0195] Formulation 2A that was at 4.degree. C. was warmed to room
temperature (RT) and kept at this temperature for 30 min.
Formulation 2A at 37.degree. C. was cooled down to RT kept at this
temperature for 30 min. 20 .mu.L of the 120 mg/ml TH 302 solutions
from each vial stored at different temperatures (4.degree. C.;
20.degree. C.; 37.degree. C.) was transferred into a corresponding
volumetric flask (50 ml). The solutions were then diluted with
water to the 50 ml volume and mixed well. The final concentration
of TH-302 was 48 .mu.g/ml. Formulation 2B was prepared using the
same procedure as for preparing solution 2A, except the amount of
DMA was reduced to 1000 mg.
[0196] The stability of Formulations 2A and 2B at various
temperatures and times is shown in the following tables.
TABLE-US-00008 TABLE 8 Stability of TH-302 in DMA/EtOH/Benzyl
alcohol (120 mg/ml) at 37.degree. C. Formulation 2A Relative
retention time to TH-302 Days TH-302 0.98* 0.96** 0.95** 0 97.36%
2.64% 0 0 28 94.12% 2.60% 2.30% 0.98%
TABLE-US-00009 TABLE 9 Stability of TH-302 in DMA/EtOH/Benzyl
alcohol (120 mg/ml) at 37.degree. C. Formulation 2B Relative
retention time to TH-302 Days TH-302 0.98* 0.96** 0.95** 0 97.70%
2.29% 0 0 28 94.41% 2.56% 2.20% 0.83% *Mono chloride impurity;
**Other Degradation product
TABLE-US-00010 TABLE 10 Stability of TH-302 in DMA/EtOH/Benzyl
alcohol (120 mg/ml) at 20.degree. C. Formulation 2A Relative
retention time to TH-302 Days TH-302 0.98* 0.96** 31 97.45% 2.55% 0
67 97.27% 2.48% 0.28%
TABLE-US-00011 TABLE 11 Stability of TH-302 in DMA/EtOH/Benzyl
alcohol (120 mg/ml) at 20.degree. C. Formulation 2B Relative
retention time to TH-302 Days TH-302 0.98* 0.96** 31 97.65% 2.35% 0
67 97.24% 2.52% 0.25% *Mono chloride impurity; **New impurity
TABLE-US-00012 TABLE 12 Stability of TH-302 (120 mg/ml) in
DMA/EtOH/Benzyl alcohol at 4.degree. C. Formulation 2A Relative
retention time to TH-302 Days TH-302 0.98* 0.96 31 97.57% 2.43% 0
67 97.57% 2.43% 0
TABLE-US-00013 TABLE 13 Stability of TH-302 (120 mg/ml) in
DMA/EtOH/Benzyl alcohol at 4.degree. C. Formulation 2B Relative
retention time to TH-302 Days TH-302 0.98* 0.96 31 97.54% 2.46% 0
67 97.60% 2.40% 0 *Mono chloride impurity
[0197] HPLC analysis of the samples showed that TH-302 is stable in
DMA/EtOH/Benzyl alcohol (120 mg/ml) at 4.degree. C. and room
temperature (RT) for at least 10 weeks (67 days). Crystals of
TH-302 were observed in 4.degree. C. samples and dissolved upon
warming to RT for 30 min. Two impurities (for a total of about 3%)
were observed after TH-302 was incubated at 37.degree. C. for 4
weeks in DMA/EtOH/Benzyl alcohol. One of the impurities (0.25%) was
observed at RT after 10 weeks. The other impurity was the
monochloro compound, which was present at time zero and did not
notably increase. No difference between formulations 2A and 2B was
observed. The comparison of Formulations 1, 2a and 2b showed that
TH-302 is has similar stability in EtOH and in DMA/EtOH/Benzyl
alcohol.
[0198] This study evaluated the stability of a 200 mg/ml TH-302
solution in PEG 400 without a nonionic surfactant (Formulation 3)
for 4 weeks at 37.degree. C. Formulation 3 was made with 2 g of
TH-302, which was transferred into PEG-400 (10 ml). The mixture
became a clear solution after agitating at 40.degree. C. for 15
min. The solution was transferred into 2 ml vials with 0.2 ml
solution in each vial. The concentration of TH-302 was 200 mg/ml.
The vials were stored at different temperatures (2-8.degree. C.
(refrigerator, i.e., 4.degree. C.); 37.degree. C. (water bath)) for
the various times shown below. This stock solution was cooled down
to RT and kept at this temperature for 30 min. 20 of the 200 mg/ml
TH 302 solutions were transferred into a volumetric flask (50 ml).
The solutions were then diluted with water to the 50 ml volume and
mixed well. The final concentration of TH-302 was 80 .mu.g/ml. 19
ml of water was injected into this solution in a 100 ml vial and a
dark brown clear solution was obtained. 50 .mu.L of the resulting
solution was transferred into a volumetric flask (5 ml) and diluted
with water to 5 ml. The final concentration of TH-302 was 50
.mu.g/ml. HPLC analysis showed that Formulation 3 was less stable
than Formulations 1, 2A and 2B. The concentration of TH-302 in this
formulation decreased over one month at room temperature,
demonstrating this formulation did not keep TH-302 in solution
(i.e., precipitation occurred).
[0199] Another comparative of Formulation 4, an aqueous solution of
lyophilized TH-302 without a nonionic surfactant was conducted. The
following procedure was used to prepare Formulation 4. 19 ml of
water were injected into the TH-302 in a 100 ml vial and a dark
brown clear solution was obtained. 50 .mu.L of the resulting
solution was transferred into a volumetric flask (5 ml) and diluted
with water to 5 ml. The final concentration of TH-302 was 50
.mu.g/ml. One formulation of TH-302 that has been used in human
clinical trials is a lyophilized powder that is stored at
-20.degree. C. and reconstituted just prior to patient
administration (reconstituted lyophilized product).
[0200] HPLC analysis was used to analyze the relative stability of
Formulations 1-4 at 37.degree. C. after 28 days. The results are
shown in the following table.
TABLE-US-00014 TABLE 14 Stability of TH-302 in different
formulations at 37.degree. C. on Day 28 Lyophilized TH-302
reconstituted Formulation EtOH EtOH/DMA PEG-400 in D5W TH-302% 95.6
94.4 84.2 <1%
[0201] Based on the stability data at 37.degree. C. on day 28,
TH-302 has the following stability order in the various
formulations: Ethanol>Ethanol/Benzyl
alcohol/DMA>PEG-400>>reconstituted lyophilized
product.
[0202] Formulations of TH-302 in pure DMA proved to be problematic
when the drug solution was reconstituted in saline or D5W. TH-302
precipitated out when the TH-302/DMA solution was reconstituted in
saline or D5W bags at the final concentration of 5 mg/ml.
[0203] Formulations of TH-302 in DMA/PEG-400 proved to be
problematic when the drug solution was reconstituted in saline or
D5W. TH-302 precipitated out when the TH-302/DMA/PEG-400 solution
was reconstituted in saline or D5W bags at the final concentration
of 5 mg/ml.
[0204] A comparative study of Formulations 7A-L (TH-302 in
EtOH/DMA/TWEEN 80 or EtOH/DMA) after reconstitution in saline was
conducted as follows. First, the following vehicles were prepared.
[0205] Vehicle A was prepared as follows: Into a 20 ml vial was
added a mixture of EtOH (4 ml), DMA (0.75 ml) and TWEEN 80 (0.25
ml). The mixture was then well mixed by stirring for 5 min. [0206]
Vehicle B was prepared as follows: Into a 20 ml vial was added a
mixture of EtOH (3.75 ml), DMA (1.0 ml) and TWEEN 80 (0.25 ml). The
mixture was then well mixed by stirring for 5 min. [0207] Vehicle C
was prepared as follows: Into a 20 ml vial was added a mixture of
EtOH (3.5 ml), DMA (1.25 ml) and TWEEN 80 (0.25 ml). The mixture
was then well mixed by stirring for 5 min. [0208] Vehicle D was
prepared as follows: Into a 20 ml vial was added a mixture of EtOH
(4.25 ml), DMA (0.25 ml). The mixture was then well mixed by
stirring for 5 min.
[0209] The following stock solutions of TH-302 were prepared from
the above vehicles: [0210] 100 mg/ml solutions were prepared as
follows: 50 mg of TH-302 was allowed to dissolve in 0.5 ml of
vehicle A, B, C, D in a corresponding 2 ml vial. The mixture in
each vial was stirred for 5 min and a clear solution was obtained
from all the vehicles. [0211] 150 mg/ml solutions were prepared as
follows: 75 mg of TH-302 was allowed to dissolve in 0.5 ml of
vehicle A, B, C, D in a corresponding 2 ml vial. The mixture in
each vial was stirred for 5 min and a clear solution was obtained
from all the vehicles. [0212] 200 mg/ml solutions were prepared as
follows: 100 mg of TH-302 was allowed to dissolve in 0.5 ml of
vehicle A, B, C, D in a corresponding 2 ml vial. The mixture in
each vial was stirred for 10 min and a clear solution was obtained
from all the vehicles.
[0213] The stability of the various formulations of TH-302 stored
at -20.degree. C. was analyzed. 0.1 ml of each solution prepared by
the method described above was transferred into the corresponding 2
ml vial, the solutions were stored at -20.degree. C. for 24 hr, and
precipitation of TH-302 from the solution was observed in some
vehicle. The vials with TH-302 precipitation were moved to room
temperature and allowed to stay at room temperature for 30 min to
determine if TH-302 can redissolve into the solutions under these
conditions. The results are shown in the following table.
TABLE-US-00015 TABLE 15 Stability of the solutions at -20.degree.
C. and redissolution of TH-302 into vehicle at room temperature
Formulation Vehicle Concentration Precipitation Re-dissolution 7A A
100 mg/ml No 7B A 150 mg/ml Yes Yes 7C A 200 mg/ml Yes No 7D B 100
mg/ml No 7E B 150 mg/ml No 7F B 200 mg/ml Yes Yes 7G C 100 mg/ml No
7H C 150 mg/ml No 7I C 200 mg/ml No 7J D 100 mg/ml No 7K D 150
mg/ml Yes Yes 7L D 200 mg/ml Yes No
[0214] The 150 mg/ml solutions from each vehicle were chosen to
test the reconstitution in saline. 0.1 ml of the solution was
re-dissolved in 3 ml of saline in the corresponding 20 ml flask.
After the solutions were mixed completely, precipitation of TH-302
was observed in some tests. The test was repeated 4 times.
Precipitation was not observed with vehicles A, B, and C
(containing TWEEN 80), but was observed in one of the four tests of
vehicle D (not containing TWEEN 80). Reconstitution of the
formulated TH-302 solution in saline at 5 mg/ml showed that the
addition of TWEEN 80 prevents the precipitation of TH-302. In
addition, ethanol/DMA was a better solvent than ethanol or PEG-400
at higher concentrations of TH-302.
[0215] A comparative study of Formulations 8A-F (TH-302 in
EtOH/DMA/TWEEN 80) after reconstitution of the solutions in saline
was conducted. The stability of each TH-302 solution at -20.degree.
C. and 2-8.degree. C. was tested. Three vials from each formulation
were stored at 2-8.degree. C. in the dark to test the stability of
the solution. Analysis was performed on Days 0, 7, 18 and 31.
TH-302 did not precipitate out from any of the six formulations at
2-8.degree. C. over 31 days. When the solutions were stored at
-20.degree. C., half of the formulations gave TH-302 crystals over
24 hrs, but the crystals re-dissolved in less than 1 hr after the
solutions were warmed to room temperature. The results are
summarized in the following table (measured at Day 7).
TABLE-US-00016 TABLE 16 Stability of TH-302 solution at -20.degree.
C. and 2-8.degree. C. % Precip- Redis- Precip- Formu- TH-302 TWEEN
% itation solve itation lation (mg/ml) 80 DMA at -20.degree. C. at
RT at 2-8.degree. C. 8A 100 5 15 Yes Yes No 8B 100 10 15 No No 8C
150 5 15 Yes Yes No 8D 150 10 15 Yes Yes No 8E 150 5 20 No No 8F
150 10 20 No No
[0216] The chemical stability of TH-302 in different formulations
was also tested at different temperatures, and the results are
summarized in the following tables.
TABLE-US-00017 TABLE 17 Chemical stability of TH-302 at 40.degree.
C. Day 7 Day 18 Day 31 Formulation Day 0 40.degree. C. 40.degree.
C. 40.degree. C. 8A 86.0 .+-. 0.7 76.3 .+-. 6.5 65.1 .+-. 5.5 8B
84.0 .+-. 1.2 71.2 .+-. 8.1 63.9 .+-. 1.1 8C 88.1 .+-. 4.5 72.9
.+-. 6.4 70.3 .+-. 8.7 8D 91.3 .+-. 2.6 66.0 .+-. 3.4 63.6 .+-. 1.1
8E 86.6 .+-. 1.6 68.5 .+-. 7.1 73.6 .+-. 7.1 8F 88.5 .+-. 1.7 74.6
.+-. 7.7 67.8 .+-. 0.5 DP 88.2 .+-. 1.9 64.4 .+-. 3.1 52.9 .+-. 2.5
33.2 .+-. 0.4
TABLE-US-00018 TABLE 18 Chemical stability of TH-302 at 25.degree.
C. Day 18 Day 31 Formulation Day 0 25.degree. C. 25.degree. C. 8A
86.0 .+-. 0.7 81.8 .+-. 9.3 84.8 .+-. 8.5 8B 84.0 .+-. 1.2 84.9
.+-. 3.7 86.4 .+-. 4.6 8C 88.1 .+-. 4.5 84.6 .+-. 4.2 86.6 .+-. 2.0
8D 91.3 .+-. 2.6 85.6 .+-. 5.1 79.7 .+-. 1.9 8E 86.6 .+-. 1.6 83.8
.+-. 3.9 79.0 .+-. 2.9 8F 88.5 .+-. 1.7 86.7 .+-. 3.6 74.3 .+-. 4.9
DP 88.2 .+-. 1.9 77.5 .+-. 6.7 70.2 .+-. 4.8
[0217] The above data show that TH-302 in the six formulations is
significantly more stable than in the reconstituted lyophilized
drug product formulation (DP; lyophilized TH-302 reconstituted in
D5W), when the solutions were stored at 25.degree. C. Three out of
the 6 formulations showed only minimum degradation of TH-302 over
31 days when compared with TH-302 in the DP formulation under the
similar conditions, which showed over 18% degradation. As the data
above demonstrates, the use of TWEEN 80 allowed for a more
concentrated formulation of TH-302 and was shown to stabilize
TH-302 better than the other formulations at similar
concentrations.
[0218] Accordingly, the combinations of ethanol, and TWEEN 80, or
ethanol, TWEEN 80, and DMA are excellent formulations for TH-302.
TH-302 has good solubility in these formulations (up to 300 mg/ml)
depending on the ratio of DMA/Ethanol/TWEEN 80. While increasing
the concentration of DMA in the vehicle enhances the solubility of
TH-302 in the liquid formulation, may affect the chemical stability
of TH-302 in the formulation. TWEEN 80 prevented TH-302
precipitation when the drug solution was reconstituted in saline or
D5W. Based on these results, a combination of nonionic surfactant,
ethanol, and optionally DMA provides a concentrated formulation of
TH-302 with suitable stability for long-term storage.
Example 2
Treatment of Lung Cancer and Melanoma in Human Patients Using
TH-302 Monotherapy
[0219] A Phase 1 clinical trial was conducted with TH-302. The
starting dose was 7.5 mg/m.sup.2 IV over 30-60 min administered
once weekly for 3 weeks of a 4 week cycle. A modified accelerated
titration design was used. Two of five patients dosed at 670
mg/m.sup.2 exhibited dose limiting toxicity (DLT): herpes simplex
perianal/rectal ulcers and dehydration due to mucositis. Six
patients were enrolled at an intermediate dose of 575 mg/m.sup.2,
and this dose was established as the MTD for this administration
schedule, as five of the six patients did not exhibit a DLT at this
dose.
[0220] There was evidence of anticancer activity even at the lowest
dose, with one NSCLC patient exhibiting stable disease (SD) for 7.3
months. Two patients, one with SCLC treated at 480 mg/m.sup.2 and
another with melanoma treated at 670 mg/m.sup.2, had unconfirmed
partial responses, as described in more detail below; 16 patients
had stable disease.
[0221] Mucosal toxicity was dose-limiting, and skin and mucosal
toxicity was common at doses above 240 mg/m.sup.2, but these were
reversible. In one embodiment of the invention, TH-302 is
co-administered with an agent that prevents or ameliorates skin
and/or mucosal toxicity. The most common TH-302-related adverse
events (AEs) were nausea, skin toxicity, vomiting and fatigue.
Hematologic toxicity was mild and limited.
Treatment of Lung Cancer
[0222] In this study, a 39 year old male suffering from a lung
cancer (a refractory small cell lung cancer) that had metastasized
to liver was treated as follows. Lyophilized TH-302 was diluted
with D5W and administered to the patient at an amount of 480
mg/m.sup.2, according to the following 4 week dosing cycle: TH-302
was administered once every week for 3 weeks, on days 1, 8, and 15,
followed by a week of no TH-302 administration. The patient was
administered 2 cycles (i.e. 6 doses) of TH-302, and the lung and
liver cancers assessed by a computed tomography (or CT) scan. The
CT scan demonstrated that the cancer in lung and liver had reduced
in area by over 50% (44% decrease in sum of the longest diameters
[SLD] of target lesions). LDH had decreased 72%, and liver function
tests had normalized. The Cycle 2 tumor assessment also showed a
large empyema that required surgical intervention, and a 22-day
delay of Cycle 3 dosing. Confirmation CT scan one month after the
Cycle 2 scan showed progressive disease.
[0223] Three other patients with lung cancer (one with NSCLC and 2
with SCLC) in the study responded to TH-302 monotherapy with stable
disease.
[0224] These results demonstrate that the methods of the invention
are efficacious in the treatment of lung cancer, including NSCLC
and SCLC.
Treatment of Melanoma
[0225] This study also demonstrated that the methods of the
invention are useful in the treatment of melanoma. A 74 year old
male patient suffering from a primary melanoma (a skin cancer) that
had metastasized to liver and lung was treated as follows. TH-302
was administered to the patient at an amount of 670 mg/m.sup.2
using a 4 week (28 day) dosing cycle: TH-302 was administered once
every week for 3 weeks, on days 1, 8, and 15, followed by a week of
no TH-302 administration. The patient was administered 2 cycles of
TH-302 and assessed by a CT scan. The CT scan demonstrated that the
cancer in lung and liver had reduced in area by over 50% (53%
decrease in SLD of target lesions).
[0226] Enrollment in the study was expanded at the MTD in patients
with metastatic melanoma. TH-302 was administered intravenously
over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Eligible
patients had ECOG.ltoreq.1, at least one target lesion by RECIST,
and acceptable hematologic, liver, and renal function. Patients
with symptomatic brain metastases were excluded unless previously
treated and well controlled for at least 3 months. Nine patients
with metastatic melanoma have been treated in the study. The median
age was 70 (range 23-78) with 5 females and 4 males and ECOG 0/1 in
4/5 patients. Four patients had an elevated baseline LDH.
Metastatic sites included liver in 7 patients and lung in 6
patients. All patients had received at least one prior systemic
chemotherapeutic regimen. Two serious adverse events, seizures and
ascites, were reported; neither was considered related to study
drug. Skin adverse events were reported in 8 patients and mucosal
adverse events were reported in 4 patients including one grade 3
event. Myelosuppression was not significant, with one event of
grade 3/4 neutropenia and anemia and no events of grade 3/4
thrombocytopenia. Eight patients have had RECIST tumor assessments.
Three of 8 (37%) patients had RECIST partial responses (one
confirmed, one unconfirmed, one unconfirmed continuing on study), 3
of 8 (38%) patients had ongoing stable disease after 2 months of
therapy, and 2 of 8 (25%) patients had progressive disease.
Example 3
Effect of Administration Schedule for HAP and Non-HAP
Chemotherapeutic Agents in Combination Therapy
[0227] As demonstrated herein (also see Examples 4 and 5 below),
combination therapy of cancer with HAP and non-HAP anticancer
agents provide more efficacious treatment with fewer side effects.
For this demonstration, ectopic models were employed in nude mice.
Anti-tumor activity was evaluated by tumor growth delay (TGD) and
tumor growth inhibition (TGI). Body weight change, gross and
microscopic assessment of tissue changes, and hematologic assays
served for toxicity assessment. Testing in these models was
conducted generally as follows. 1.times.10.sup.6 (H460 human
non-small cell lung cancer or HT1080 human fibrosarcoma cells) or
3.times.10.sup.6 (PC-3 human prostate cancer cells) were implanted
in the subcutaneous space of the right flank to obtain ectopic
xenograft models. Randomization and dosing was initiated when
tumors reached a certain size (100-150 mm.sup.3). API grade of
TH-302 was used in all experiments while docetaxel, gemcitabine,
cisplatin, pemetrexed, and doxorubicin were purchased from
commercial sources.
[0228] In one study, the effect of different TH-302/docetaxel
dosing regimens in the H460 tumor growth (NSCLC) model was
examined. The H460 cells were prepared in 30% Matrigel and 70%
RPMI1640. Mice were anesthetized by isoflurane and were implanted
subcutaneously with 1.times.10.sup.6 cells (in 200 .mu.l) at the
flank position. We selected 110 mice bearing similar size tumors
(.about.100 mm.sup.3) for the study. Mice bearing similar tumor
size were randomly assigned into different groups. Treatment
started on day 1 (7 days after tumor implantation) except as noted.
TH-302 was administered intraperitoneally (IP) at 150 mg/kg, and
docetaxel was administered intravenously (IV) at 10 mg/kg. Animals
were observed daily and tumor measurements and body weights
recorded twice weekly. The tumor growth delay (TGD) to reach 500
mm.sup.3 and 1000 mm.sup.3 of drug treated tumors as compared to
vehicle treated tumors and the tumor growth inhibition (TGI)
(1-T/C) where T/C=(Tn-Ti)/(Cn-Ci) where Tn is tumor volume in the
treatment group on Day n and Ti is the initial tumor volume in the
treatment group, and Cn is the tumor volume in the vehicle control
group on Day n and Ci is the initial tumor volume in the vehicle
control group and Day n is the last measurement when the animals in
the control group are all still alive are presented in Table 19.
Different antitumor effects were observed with different dose
sequencing. Results showed that, in general, TH-302 given before
docetaxel produced a superior antitumor response, and
administration of TH-302 4 hours before the chemotherapeutic was
better than the other time intervals tested, e.g. 24 or 48 hours
before, or simultaneously.
[0229] In a study conducted substantially as described above except
the cells implanted were PC-3 human prostate cancer cells and
3.times.10.sup.6 cells were implanted and mice were randomized into
separate groups when their tumors reached .about.150 mm.sup.3
TH-302 first provided the best results. Administering the non-HAP
drug (docetaxel) 4 hours after stopping the administration of the
HAP drug (TH-302) demonstrated the best treatment efficacy. The
results for the 2, 4, and 24 hour delay tests are included in Table
19, below.
[0230] In a study conducted substantially as described above except
the cells implanted were H460 NSCLC cells and 1.times.10.sup.6
cells were implanted and mice were randomized into separate groups
when their tumors reached .about.100 mm.sup.3 and the
chemotherapeutic employed was pemetrexed at a dose of 150 mg/kg
given once a week (Q7D) for two weeks IP and the TH-302 was given
at 100 mg/kg given once a week (Q7D) for two weeks IP.
Administering the non-HAP drug (pemetrexed) 2 hours after the
administration of the HAP drug (TH-302) demonstrated the best
treatment efficacy, when compared to simultaneous administration or
when a 4, 8, or 24 hour delay was employed. The results for the
tests are included in Table 19.
[0231] In a study conducted substantially as described above except
the cells implanted were HT1080 human fibrosarcoma cells and
1.times.10.sup.6 cells were implanted and mice were randomized into
separate groups when their tumors reached .about.100 mm.sup.3 and
the chemotherapeutic employed was doxorubicin at a dose of 4 mg/k
given once IV and the TH-302 was given at a dose of 100 mg/kg once.
Administering the non-HAP drug (doxorubicin) drug 2 hours or 4
hours after the administration of the HAP drug (TH-302)
demonstrated the best treatment efficacy, when compared to
simultaneous administration or when an 8 or 24 hour delay was
employed or when the doxorubicin was administered before the HAP
drug with a 2 hour delay. The results for the tests are included in
the Table below.
[0232] Simultaneous administration of the HAP and non-HAP
anticancer agents exhibited the greatest toxicity. For example,
co-incident administration of TH-302 and the chemotherapeutic often
exhibited the most severe body weight (BW) loss when compared to
the other schedules. This was observed in the PC-3 (prostate
carcinoma) model in which TH-302 and docetaxel were administered
and in the PC-3 prostate cancer model in which TH-302 and cisplatin
were administered.
[0233] In a study conducted substantially as described above except
the cells implanted were PC-3 human prostate cancer cells and
5.times.10.sup.6 cells were implanted and mice were randomized into
separate groups when their tumors reached .about.100 mm.sup.3 and
the chemotherapeutic employed was cisplatin at a dose of 6 mg/k
given once a week for 2 weeks (Q7D.times.2) IV and the TH-302 was
given at a dose of 50 mg/kg once daily for 5 days a week for 2
weeks, and on the day both agents were given TH-302 was given 2
hours before, simultaneously, or 2 hours after the cisplatin.
Administering the non-HAP drug (cisplatin) drug 2 hours after the
administration of the HAP drug (TH-302) demonstrated the best
treatment efficacy, when compared to contemporaneous administration
or when the cisplatin was administered before the HAP drug with a 2
hour. TH-302 administered contemporaneously with docetaxol in the
PC-3 prostate cancer model showed toxic side effects in the mice,
and 6 out of 10 mice tested with this administration schedule were
sacrificed due to >20% body weight loss.
[0234] Another test was conducted to demonstrate how combination
treatment in accordance with present methods provides reduced
toxicity, particularly with respect to suppression of blood cell
counts. In this test, TH-302 was administered to CD1 mice, and
gemcitabine was then administered 0, 2, 4, 8, 16, or 24 h after
stopping the administration of TH-302. The safety of the
combination administration was measured by its effect on in blood
cell counts (white blood cells or WBC, neutrophil, lymphocytes,
monocyte, red blood cells or RBC, and hemoglobin or Hb) 2 days
after the administration of TH-302 (the higher the blood cell
count, the safer being the administration of the drugs in
combination). Both drugs were administered intraperitoneally;
TH-302 was administered at a dose of 75 mg/kg, and gemcitabine was
administered at 300 mg/kg. The results demonstrated that
non-contemporaneous administration of TH-302 and gemcitabine, for
example, when gemcitabine was administered 2 h or 4 h after the
administration of TH-302, was less toxic than administering them
together.
[0235] In summary, these experiments demonstrated that (i) the
greatest antitumor efficacy was observed by a regiment in which the
HAP anticancer agent was administered first, and there was some
delay between administration of the HAP and administration of the
non-HAP anticancer agent; and (ii) simultaneous administration of
the HAP and non-HAP anticancer agents exhibited the greatest
toxicity.
TABLE-US-00019 TABLE 19 TGD500, TGD1000, Days to Days to Days (vs.
Days (vs. Group 500 mm.sup.3 1000 mm.sup.3 vehicle) vehicle) Ti Tn
T/C TGI TH-302 + Group 1: Vehicle 13 20 97.35 1113.92 Docetaxel
Group 2: TH-302 100 mg/kg ip once 21 31 8 11 99.34 531.74 42.5%
57.5% H460 Group 3: Docetaxol 10 mg/kg iv once 18 27 5 7 96.08
681.36 57.6% 42.4% NSCLC Group 4: TH-302 + Docetaxol (1 hr delay)
21 32 8 12 96.49 525.00 42.2% 57.8% Group 5: TH-302 + Docetaxol (4
hr delay) 32 >40 19 >20 96.58 223.20 12.5% 87.5% Group 6:
TH-302 + Docetaxol (24 hr delay) 25 34 12 14 97.32 373.24 27.1%
72.9% Group 7: TH-302 + Docetaxol (48 hr delay) 25 33 12 13 96.45
345.02 24.5% 75.5% Group 8: Docetaxol + TH-302 (4 hr delay) 25 35
12 15 97.37 400.38 29.8% 70.2% Group 9: Docetaxol + TH-302 (24 hr
delay) 25 35 12 15 96.70 367.45 26.6% 73.4% Group 10: Docetaxol +
TH-302 (48 hr delay) 22 31 9 11 97.79 506.61 40.2% 59.8% Group 11:
day 2 TH-302 + Docetaxol (1 hr 23 31 10 11 98.35 447.84 34.4% 65.6%
delay) TH-302 + Group 1: Vehicle 16 nd 137.86 1005.44 Docetaxel
Group 2: TH-302 150 mg/kg, ip, once 25 nd 9 nd 137.63 559.95 48.7%
51.3% PC-3 Group 3: Docetaxol 10 mg/kg, iv, once 26 nd 10 nd 137.55
563.22 49.1% 50.9% prostate Group 4: TH-302 + Docetaxol 31 nd 15 nd
137.21 433.40 34.1% 65.9% cancer (coincidently) Group 5: TH-302 +
Docetaxol (2 hr delay) 32 nd 16 nd 137.22 389.14 29.0% 71.0% Group
6: TH-302 + Docetaxol (4 hr delay) 40 nd 24 nd 137.56 240.49 11.9%
88.1% Group 7: TH-302 + Docetaxol (24 hr delay) 38 nd 22 nd 137.41
262.84 14.5% 85.5% Group 8: Docetaxol + TH-302 (2 hr delay) 31 nd
15 nd 136.91 401.78 30.5% 69.5% Group 9: Docetaxol + TH-302 (4 hr
delay) 37 nd 21 nd 137.10 312.62 20.2% 79.8% Group 10: Docetaxol +
TH-302 (24 hr delay) 35 nd 19 nd 137.52 341.89 23.6% 76.4% TH-302 +
Group 1: Vehicle 12 21 117.01 1086.98 Pemetrexed Group 2: TH-302
100 mg/kg ipQ7Dx2 19 30 7 9 115.80 598.34 49.7% 50.3% H460 Group 3:
PMX 150 mg/kg ip Q7Dx2 14 24 2 3 115.31 817.45 72.4% 27.6% NSCLC
Group 4: TH-302 + PMX (0 hr delay) 19 30 7 9 115.65 619.70 52.0%
48.0% Group 5: TH-302 + PMX (2 hr delay) 22 31 10 10 115.41 481.15
37.7% 62.3% Group 6: TH-302 + PMX (4 hr delay) 21 28 9 7 115.19
557.19 45.6% 54.4% Group 7: TH-302 + PMX (8 hr delay) 22 31 10 10
115.44 481.56 37.7% 62.3% Group 8: TH-302 + PMX (24 hr delay) 22 30
10 9 114.68 504.77 40.2% 59.8% TH-302 + Group 1: Vehicle 12 nd
109.20 998.94 Doxorubicin Group 2: TH-302 100 mg/kg ip 1/wkx2wks 22
nd 10 nd 109.43 334.66 25.3% 74.7% HT1080 Group 3: Dox 4 mg/kg iv
1/wkx2wks 24 nd 12 nd 109.61 154.79 5.1% 94.9% sarcoma Group 4:
TH-302 + Dox (0 hr delay) 29 nd 17 nd 109.96 95.76 -1.6% 101.6%
Group 5: TH-302 + Dox (2 hr delay) 33 nd 21 nd 109.49 52.36 -6.4%
106.4% Group 6: TH-302 + Dox (4 hr delay) 33 nd 21 nd 109.63 58.27
-5.8% 105.8% Group 7: TH-302 + Dox (8 hr delay) 26 nd 14 nd 109.40
114.27 0.5% 99.5% Group 8: TH-302 + Dox (24 hr delay) 24 nd 12 nd
109.42 195.24 9.6% 90.4% Group 9: Dox + TH-302 (2 hr delay) 27 nd
15 nd 109.05 87.31 -2.4% 102.4% TH-302 + Group 1: Vehicle 14 nd nd
90.72 1061.83 Cisplatin Group 2: CisPt Q7Dx2wk + TH-302 27 nd 13 nd
91.47 338.67 25.50% 74.50% PC-3 50 mg/kg QDx5/wkx2wk (2 hr delay)
prostate Group 3: TH-302 50 mg/kg QDx5/wkx2wk + 30 nd 16 nd 93.12
250.73 16.20% 83.80% cancer CisPt Q7Dx2wk (0 hr delay) Group 4:
TH-302 50 mg/kg QDx5/wkx2wk + 30 nd 16 nd 89.33 216.11 13.10%
86.90% CisPt Q7Dx2wk (2 hr delay)
Example 4
Combination Therapy with TH-302 and Gemcitabine, Docetaxel, or
Pemetrexed
[0236] This Example demonstrates the non-contemporaneous
administration of an anticancer agent other than TH-302 in
combination with TH-302 for the treatment of cancer. A Phase 1/2,
3-arm, multicenter, dose-escalation study was conducted using a
classic dose escalation design to demonstrate the efficacy and
determine the safety of TH-302 when administered in combination
with gemcitabine, docetaxel, or pemetrexed. The initial dose of
TH-302 was 240 mg/m.sup.2. TH-302 was administered by intravenous
(IV) infusion over 30 minutes on Days 1, 8, and 15 of a 28-day (4
week) cycle (Arm A) or Days 1 and 8 of a 21-day (3 week) cycle
(Arms B & C) as noted below. Gemcitabine, docetaxel or
pemetrexed was administered 2 h after the TH-302 infusion was
completed. The starting doses of gemcitabine, docetaxel or
pemetrexed remained fixed according to approved doses listed in
their respective product labeling. The treatment regimen, dose,
schedule and cycle length of these drugs were as follows
[0237] Treatment Arm A: Gemcitabine was administered IV at 1,000
mg/m.sup.2 IV over 30 minutes on Days 1, 8, and 15 of each 28-day
cycle. TH-302 was administered as above on Days 1, 8, and 15 of
each 28-day cycle.
[0238] Treatment Arm B: Docetaxel was administered IV at 75
mg/m.sup.2 over 60 minutes on Day 1 of each 21-day cycle. TH-302
was administered as above on Days 1 and 8 of each 21-day cycle.
[0239] Treatment Arm C: Pemetrexed was administered IV at 500
mg/m.sup.2 over 10 minutes on Day 1 of each 21-day cycle. TH-302
was administered as above on Days 1 and 8 of each 21-day cycle.
[0240] A. Study Drug Exposure and Determination of Dose Limiting
Toxicity
[0241] The dose was initiated at 240 mg/m.sup.2 and dose escalation
was then continued with 40% increases from the previous dose level;
however lower dose increases of 20-40% were also applicable based
on treatment outcome. The dose of TH-302 was escalated in cohorts
of 3-6 patients. If a subject experienced a dose limiting toxicity
(DLT), 3 additional patients were enrolled at that dose level for a
total of 6 patients in that cohort. If no additional DLTs were
observed, dose escalation was resumed. However, if 2 or more of 6
patients within a cohort experience a DLT, that dose was considered
to exceed the maximum tolerated dose (MTD). The MTD was then
defined at the next lower dose level in which 6 patients were
treated and less than 1 subject experienced a DLT. The maximum dose
of TH-302 used was the single agent (TH-302 monotherapy) MTD or the
highest dose tested in that study if the MTD was not reached.
[0242] CT scans were done every 2 cycles. The objectives of the
study were to determine the MTD and DLT of TH-302 and to evaluate
the safety, pharmacokinetics (PK) and preliminary efficacy of
TH-302 in combination with gemcitabine (G), docetaxel (D), or
pemetrexed (P) in advanced solid tumors. Seventy-two patients have
been enrolled and have sufficient follow-up to be included in the
dose escalation summary. Fifty patients were enrolled with
sufficient tumor assessment follow-up. Patients were enrolled at 7
US sites from August 2008 to August 2009 and received study drug.
Study drug exposure and DLTs are summarized below.
TABLE-US-00020 TABLE 20 TH-302 plus Gemcitabine Median Dose No. of
No. DLT DLTs Cycles (mg/m.sup.2) Patients Evaluable (description)
(Range) Ongoing 240 7 6 1 (grade 3 ALT 4 (1-11+) 3 elevation) 340 6
3 0 3 (2-7) 3 480 6 5 2 (grade 4 4 (2-6+) 5 thrombo- cytopenia;
grade 3 pain/fatigue) 575 7 6 2 (grade 4 2 (1-3+) 6 thrombo-
cytopenia; grade 3 esophagitis)
TABLE-US-00021 TABLE 21 TH-302 plus Docetaxel Median Dose No. of
No. DLT DLTs Cycles (mg/m.sup.2) Patients Evaluable (description)
(Range) Ongoing 240 7 7 1 (febrile 4 (1-10+) 1 neutropenia) 340 6 5
0 2 (1-8+) 4 480 7 6 2 (grade 4 3 (2-6+) 6 neutropenia)
TABLE-US-00022 TABLE 22 TH-302 plus Pemetrexed Median Dose No. of
No. DLT DLTs Cycles (mg/m.sup.2) Patients Evaluable (description)
(Range) Ongoing 240 5 3 0 10 (2-16) 1 340 5 5 0 2 (2-8+) 3 480 9 6
1 (grade 3 oral 2 (1-6+) 3 candidiasis) 575 7 5 1 (grade 3 oral 3
(1-4+) 3 mucositis/Gr 4 thromo- cytopenia)
[0243] The results to date demonstrate that TH-302 can be
administered safely in combination with full dose gemcitabine,
docetaxel or pemetrexed but may increase the hematologic toxicity
of these agents.
[0244] The MTD of TH-302 plus gemcitabine is anticipated to be
340-400 mg/m.sup.2; the MTD of TH-302 plus docetaxel is 340
mg/m.sup.2 and the MTD of TH-302 plus pemetrexed is 480 mg/m.sup.2.
The primary dose limiting toxicities have been hematologic. While
the contribution of TH-302 to the hematologic toxicity is hard to
determine when TH-302 is combined with a myelosuppressive
chemotherapy, greater hematologic toxicity than would be expected
with single agent chemotherapy is evident in the gemcitabine and
pemetrexed arms. Skin and mucosal toxicity are common at doses
above 240 mg/m.sup.2. The mechanism is unknown but may be due to
activation of TH-302 in areas of epithelium that are normally
hypoxic. The addition of TH-302 to standard chemotherapies does not
appear to enhance the toxicity in other body systems. Higher
response rates than would be expected with single agent
chemotherapy are evident.
[0245] B. Anti-Tumor Activity
[0246] Anti-tumor activity was observed in the majority of
patients. Multiple responses in pancreatic cancer, NSCLC and
transitional cell cancers have been reported (see Tables 2 and 3 in
the Detailed Description of the Invention, above).
[0247] To date, 45 patients have been assessed for response. Of
these 12 patients (27%) had a RECIST criteria partial response
(PR), 22 patients (49%) achieved stable disease (SD) and 11
patients (24%) had progressive disease. The partial response
included both confirmed and unconfirmed partial responses. In a
confirmed partial response, partial response was maintained through
a subsequent response assessment at least 28 days later, and in an
unconfirmed partial response, the partial response was reported at
one assessment but was not maintained in a subsequent response
assessment.
[0248] i) Gemcitabine Arm
[0249] In the TH-302 plus gemcitabine arm, TH-302 was administered
intravenously for 30 to 60 minutes on days 1, 8 and 15 of a 28 day
cycle. Gemcitabine is dosed according to its package insert on days
1, 8 and 15 of a 28 day cycle. The TH-302 maximum tolerated dose
(MTD) has not been established with the dose cohort currently being
expanded at 340 mg/m.sup.2. Two dose limiting toxicities were
reported at each of two higher TH-302 doses levels. Fifteen
patients have had tumor assessments, 6 of whom had a PR in the
following cancers: pancreatic (2), ovarian, esophageal, squamous
non-small cell lung cancer (NSCLC) and thyroid and 7 patients with
SD.
[0250] Eight human subjects with pancreatic cancer have been
treated with TH-302 in combination with gemcitabine. RECIST tumor
assessments have been performed for four subjects. At their initial
tumor assessment, two of four subjects had partial responses and
the other two of the same four subjects had stable disease. The
historical response rate for first-line pancreatic cancer is less
than 10% in multiple large studies. Two of these four subjects
continue on-study and are receiving Cycle 4 or Cycle 6. One of the
subjects with a partial response discontinued with an infection;
the other discontinued after a new lesion was detected. CA19-9 is a
protein that has been identified as a tumor marker for a number of
gastrointestinal cancers including pancreatic cancer. Generally,
values of CA19-9 (IU/ml) are associated with the extent of tumor
burden. Higher levels of CA19-9 are associated with poorer
survival. In addition, CA 19-9 responses, defined as a greater than
50% decrease from the baseline CA19-9, have been shown to predict
for a better prognosis. Two of the four subjects had an elevated
CA19-9 prior to the combination therapy. Both of these subjects had
CA19-9 responses with CA19-9 decreases of 78% and 98%.
[0251] ii) Docetaxel Arm
[0252] In the TH-302 plus docetaxel arm, TH-302 was administered
intravenously on days 1 and 8 of a 21 day cycle. Docetaxel was
dosed according to its package insert on day 1 of the 21 day cycle.
The TH-302 MTD has been established at 340 mg/m.sup.2 and the dose
expansion has been initiated at this dose in patients with castrate
resistant prostate cancer and in patients with second-line NSCLC.
Eleven patients have had tumor assessments, 2 of whom achieved PRs
in NSCLC and anal cancer and 6 patients with SD.
[0253] iii) Pemetrexed Arm
[0254] In the TH-302 plus pemetrexed arm, TH-302 was administered
intravenously on days 1 and 8 of a 21 day cycle. Pemetrexed was
dosed according to its package insert on Day 1 of the 21 day cycle.
The TH-302 MTD has been established at 480 mg/m.sup.2 and the dose
expansion has been initiated at a TH-302 dose of 400 mg/m.sup.2 in
patients with second-line non-squamous NSCLC. Nineteen patients
have had tumor assessments, 4 of whom achieved PRs in NSCLC (2) and
transitional cell carcinoma (2) and 9 patients with SD.
[0255] Overall, 8 patients with relapsed or refractory NSCLC have
been treated with TH-302 in combination with either docetaxel or
pemetrexed and have been assessed for response. Of the 8 patients
assessed, 3 patients achieved PRs, 4 patients achieved SD and 1
patient had PD. The median time on treatment for the 8 patients has
been 5.3 months.
Example 5
Combination Therapy with TH-302 and Doxorubicin
[0256] A Phase 1/2, multicenter, dose-escalation study of patients
with soft tissue sarcoma using a classic dose escalation design was
conducted to demonstrate the efficacy and safety of TH-302 when
administered in combination with doxorubicin in accordance with the
present invention. The dose of TH-302 was escalated in cohorts of
3-6 subjects. The initial dose of TH-302 was 240 mg/m.sup.2, a dose
with no Cycle 1 grade 2 or greater toxicity (excluding fatigue,
nausea, vomiting, alopecia, and diarrhea) in the single agent Phase
1 study. A Dose Level minus 1 was built into the study. Dose
escalation continued with 40% increases from the previous dose
level; however, lower dose increases of 20-39% could also be
administered.
[0257] If a subject experienced a DLT, 3 additional subjects were
enrolled at that dose level for a total of 6 subjects in that
cohort. If no additional DLTs were observed, dose escalation
resumed. However, if 2 or more of 6 subjects within a cohort
experience a DLT, that dose will be considered to exceed the MTD.
The MTD will then be defined at the next lower dose level whereby 6
subjects are treated and <1 subject experiences a DLT. The
maximum dose of TH-302 is the single agent MTD or the highest dose
tested in that study if the MTD was not reached. MTD is based on
toxicities occurring during the first cycle. An additional 12
subjects will be enrolled at the MTD for the dose expansion portion
of the study.
[0258] TH-302 was administered by IV infusion over 30-60 minutes on
Days 1 and 8 of a 21 day cycle. The dose of doxorubicin remained
fixed: 75 mg/m.sup.2 administered by bolus injection starting on
Day 1 of a 21-day cycle (if serum bilirubin is above the ULN but
.ltoreq.1.5.times.ULN, the dose was reduced to 56 mg/m.sup.2).
Doxorubicin was administered starting two hours after completion of
TH-302 infusion on Day 1 of each cycle.
[0259] Ten patients have been treated in this study with TH-302, 6
patients at 240 mg/m.sup.2 and 4 patients at 340 mg/m.sup.2. The
patient age range was 19-85. The sarcomas treated included
liposarcoma (3), leiomyosarcoma (3), synovial sarcoma (2) and
pleomorphic (2). The first 3 patients at 240 mg/m.sup.2 had G4
neutropenia at Day 15. Subsequent patients are receiving
granulocyte-stimulating factor (GCSF) on Day 8 in accordance with
the methods of the invention. A DLT of Grade 4 thrombocytopenia at
Day 15 and a DLT of grade 3 infection occurred in two patients
treated at 340 mg/m.sup.2. Myelosuppression appears to be the DLT,
with the effects partially obviated by use of GCSF. Thus, in one
embodiment of the invention GCSF is co-administered with TH-302 to
treat cancer.
[0260] RECIST tumor assessments have been performed for seven
subjects. Three of seven subjects had partial responses and another
three of these same seven subjects have had stable disease. The
historical response rate in first-line soft tissue sarcoma is
between 15% and 25%. Two of the seven subjects continue on-study
and are receiving Cycle 4 or Cycle 11. All three subjects with
partial responses continued on-study to receive TH-302 alone after
completing the doxorubicin component of the study.
Example 6
Combination Therapies With TH-302 in Cancer Models
[0261] This example demonstrates that the methods of the invention
for combination therapy of cancer with HAP and non-HAP anticancer
agents have anticancer activity superior to either agent by itself.
For this demonstration, ectopic, orthotopic and metastatic models
were employed in nude mice. Anti-tumor activity was evaluated by
tumor growth inhibition (TGI) and tumor growth delay (TGD). Body
weight change, gross and microscopic assessment of tissue changes,
and hematologic assays served for toxicity assessment.
a) Methods
[0262] Testing in these models was conducted generally as follows.
1.times.10.sup.6 H460 human non-small cell lung cancer or HT1080
human fibrosarcoma cells were implanted in the subcutaneous space
of the right flank to obtain ectopic xenograft models. For the
orthotopic pancreatic model, red-fluorescent protein (RFP)
expressing MIA PaCa2 tumors were surgically implanted on the
surface of the pancreas. The prostate metastatic model was created
by the intraventricular injection of 3.times.10.sup.6
luciferase-expressing PC-3 cells. Randomization and dosing was
initiated when tumors reached a certain size (100-150 mm.sup.3) in
ectopic models, or imaging showed certain disease progression in
the orthotopic and metastatic models. API grade of TH-302 was used
in all experiments while docetaxel, gemcitabine, doxorubicin and
pemetrexed were purchased from commercial sources.
b) TH-302 with Pemetrexed in a Lung Cancer Model
[0263] Inhibition of tumor growth after administration of the
combination of TH-302 and pemetrexed was greater than for either
drug individually in an ectopic lung cancer model using H460 cells.
See Table 23.
c) TH-302 with Doxorubicin in a Lung Cancer Model
[0264] Inhibition of tumor growth after administration of TH-302
and doxorubicin drugs was greater than for either drug individually
in an ectopic tumor model using Calu-6 cells. See Table 23.
d) TH-302 with Carboplatin in a Lung Cancer Model
[0265] Inhibition of tumor growth after administration of TH-302
and carboplatin was greater than for either drug individually in an
ectopic tumor model using H460 cells. See Table 23.
e) TH-302 with 5FU in a Colon Cancer Model
[0266] Inhibition of tumor growth after administration of TH-302
and 5FU was greater than for either drug individually in an ectopic
tumor model using HT-29 cells. See Table 23.
f) TH-302 with Doxorubicin in a Soft Tissue Sarcoma Model
[0267] Inhibition of tumor growth after administration of the
combination TH-302 and doxorubicin of drugs was greater than for
either drug individually in an ectopic tumor model using HT1080
cells. See Table 19.
g) TH-302 with Paclitaxel (Taxol) in a Prostate Cancer Model
[0268] TH-302 was tested as monotherapy and in combination with
Taxol (paclitaxel) in animals bearing highly invasive and
metastatic orthotopic prostate cancer PC-3 cells. Animals were
randomized into 6 groups of 8 mice each and then treated either
with vehicle; Taxol (12 mg/kg, IV, twice a week for 4 consecutive
weeks); TH-302 (30 or 50 mg/kg, IP, once a day for 5 days a week
for 2 consecutive weeks); or Taxol in combination with TH-302
(using the same single agent regimens). The study demonstrated
significant response rates with the combination therapy, at either
dose of TH-302, in which disease progression is tracked by tumor
volume. Taxol alone and TH-302 alone at either the 30 or 50 mg/kg
dose significantly inhibited primary tumor growth during the
treatment period. The greatest inhibition of primary tumor growth
occurred in the Taxol plus TH-302 combination therapy groups
regardless of TH-302 dose, with 4/8 mice (Taxol plus TH-302 at 30
mg/kg) or 3/8 mice (Taxol plus TH-302 at 50 mg/kg) demonstrating a
complete response after stringent post-mortem open body
fluorescence imaging. Inhibition of tumor growth after
administration of the combination of drugs was greater than for
either drug individually.
TABLE-US-00023 TABLE 23 TGD500, TGD1000, Days to Days to Days (vs.
Days (vs. Group 500 mm.sup.3 1000 mm.sup.3 vehicle) vehicle) Ti Tn
T/C TGI TH-302 + Group 1: Vehicle 14 24 94.13 1171.02 Pemetrexed
Group 2: PMX, 150 mg/kg 19 29 5 5 93.89 850.21 70.2% 29.8% H460
1/wkx2wks, IP NSCLC Group 3: TH-302, 50 mg/kg 26 34 12 10 93.07
507.13 38.4% 61.6% 5/wkx2wks, IP Group 4: TH-302, 50 mg/kg 29 40 15
16 92.47 401.35 28.7% 71.3% 5/wkx2wks, IP + PMX TH-302 + Group 1:
Vehicle 18 31 149.87 1069.73 Doxorubicin Group 2: Dox, 4 mg/kg. IV,
Q7Dx2 27 35 9 4 150.86 773.97 67.7% 32.3% Calu6 Group 3: TH-302, 50
mg/kg, IP, 29 39 11 8 150.90 695.67 59.2% 40.8% NSCLC QDx5/wkx2wks
Group 4: Dox + TH-302 32 44 14 13 151.00 482.72 36.1% 63.9% TH-302
+ Group 1: Vehicle 9.5 14 95.8 1180.8 Carboplatin Group 2:
Carboplatin 20 mg/kg, IV, 11.5 18.5 2 4.5 99.0 855.6 69.7% 30.3%
H460 Q7Dx2 NSCLC Group 3: TH-302, 100 mg/kg, IP, 13.5 nd 4 nd 97.3
706.0 56.1% 43.9% Q7Dx2 Group 4: TH-302, 150 mg/kg, IP, 14.5 nd 5
nd 95.8 641.6 50.3% 49.7% Q7Dx2 Group 5: TH-302, 150 mg/kg + 18.5
nd 9 nd 97.3 268.8 15.8% 84.2% Carboplatin Group 6: TH-302, 100
mg/kg + 19.5 nd 10 nd 105.7 367.3 24.1% 75.9% Carboplatin TH-302 +
Group 1: Vehicle 22 32 137.21 1007.72 5-FU Group 2: 5-FU, 50 mg/kg,
IV, Q3Dx4 31 43 9 11 139.11 514.11 43.1% 56.9% HT29 Group 3:
TH-302, 150 mg/kg, IP, 28 46 6 14 144.69 565.70 48.4% 51.6% colon
Q7Dx3 cancer Group 4: TH-302, 100 mg/kg, IP, 29 41 7 9 127.82
580.55 52.0% 48.0% Q3Dx5 Group 5: TH-302, 150 mg/kg (Q7Dx3) + 42 57
20 25 136.48 289.64 17.6% 82.4% 5-FU Group 6: TH-302, 100 mg/kg
(Q3Dx5) + 39 52 17 20 134.08 361.60 26.1% 73.9% 5FU
[0269] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes can be
made and equivalents can be substituted without departing from the
scope of the invention. In addition, many modifications can be made
to adapt a particular situation, material, composition of matter,
process, process step or steps, to achieve the benefits provided by
the present invention without departing from the scope of the
present invention. All such modifications are intended to be within
the scope of the claims appended hereto.
[0270] All publications and patent documents cited herein are
incorporated herein by reference as if each such publication or
document was specifically and individually indicated to be
incorporated herein by reference. Citation of publications and
patent documents is not intended as an indication that any such
document is pertinent prior art, nor does it constitute any
admission as to the contents or date of the same.
* * * * *