U.S. patent application number 14/317196 was filed with the patent office on 2015-10-01 for treatment of cancer with glufosfamide in patients not receiving insulin therapy.
The applicant listed for this patent is Threshold Pharmaceuticals, Inc.. Invention is credited to Jian-Xin Duan, Damian Handisides, Stewart Kroll, Harold E. Selick.
Application Number | 20150272973 14/317196 |
Document ID | / |
Family ID | 39831385 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150272973 |
Kind Code |
A1 |
Handisides; Damian ; et
al. |
October 1, 2015 |
Treatment of Cancer with Glufosfamide in Patients Not Receiving
Insulin Therapy
Abstract
The co-administration of glufosfamide and a glucose lowering
drug other than insulin is efficacious in cancer treatment.
Inventors: |
Handisides; Damian; (San
Carlos, CA) ; Kroll; Stewart; (Oakland, CA) ;
Duan; Jian-Xin; (South San Francisco, CA) ; Selick;
Harold E.; (Belmont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Threshold Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
39831385 |
Appl. No.: |
14/317196 |
Filed: |
June 27, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12594802 |
Jan 8, 2010 |
8765690 |
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PCT/US08/59578 |
Apr 7, 2008 |
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14317196 |
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60991660 |
Nov 30, 2007 |
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60952686 |
Jul 30, 2007 |
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60915882 |
May 3, 2007 |
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60910403 |
Apr 5, 2007 |
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Current U.S.
Class: |
424/94.61 ;
435/18; 435/7.4; 435/7.92; 436/501; 506/9; 514/25; 514/8.6 |
Current CPC
Class: |
A61K 31/70 20130101;
A61K 31/70 20130101; A61K 31/4035 20130101; A61K 31/4015 20130101;
C12Y 302/01 20130101; A61K 38/47 20130101; A61K 31/4439 20130101;
A61K 38/30 20130101; A61K 45/06 20130101; A61K 31/4965 20130101;
A61K 31/17 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/70 20060101
A61K031/70; A61K 38/47 20060101 A61K038/47; A61K 31/4035 20060101
A61K031/4035; A61K 31/17 20060101 A61K031/17; A61K 31/4439 20060101
A61K031/4439; A61K 31/4015 20060101 A61K031/4015; A61K 38/30
20060101 A61K038/30; A61K 31/4965 20060101 A61K031/4965 |
Claims
1. A method of treating cancer in a patient, comprising the steps
of: (i) determining whether a patient is receiving insulin therapy,
and, if so, then (ii) discontinuing the insulin therapy, before
(iii) administering a therapeutically effective amount of
glufosfamide to the patient.
2. The method of claim 1, wherein the cancer is primary pancreatic
cancer
3. The method of claim 1, wherein the cancer is chemotherapy
resistant pancreatic cancer.
4. The method of claim 1, wherein the cancer is pancreatic cancer
that has previously been treated unsuccessfully with a
chemotherapeutic agent other than glufosfamide.
5. The method of claim 1, wherein the patient has a normal glucose
level at the time administration of the blood glucose lowering drug
is initiated.
6. The method of claim 1, further comprising administering to the
patient a blood glucose lowering drug other than insulin.
7. A method of treating cancer in a patient, comprising (i)
determining if the patient is receiving a glucose lowering drug
other than insulin; (ii) initiating administration of a glucose
lowering drug other than insulin if the patient is not already
receiving such drug; and (iii) administering a therapeutically
effective amount of glufosfamide to the patient.
8. The method of claim 7, wherein the cancer is primary pancreatic
cancer
9. The method of claim 7, wherein the cancer is chemotherapy
resistant pancreatic cancer.
10. The method of claim 7, wherein the cancer is pancreatic cancer
that has previously been treated unsuccessfully with a
chemotherapeutic agent other than glufosfamide.
11. The method of claim 7, wherein the glucose lowering agent is a
sulfonylurea.
12. The method of claim 7, wherein the glucose lowering agent is a
thiazolidinedione.
13. The method of claim 7, wherein the glucose lowering drug is
selected from glipizide, glibenclamide, glimepiride, gliclazide,
and rosiglitazone.
14. The method of claim 7, wherein the glucose lowering drug is
selected from acetohexamide, chloropropamide, metformin,
nateglinide, pioglitazone, repaglinide, tolazamide, and
tolbutamide.
15. The method of claim 7, further comprising (iv) determining
whether a patient is receiving insulin therapy, and, if so, then
(v) discontinuing the insulin therapy before administering the
glufosfamide.
16. A method of determining whether a cancer in a cancer patient is
susceptible to treatment with glufosfamide, the method comprising:
(a) measuring the level of IGF-1 in the cancer patient, (b)
determining that if the level of the IGF-1 measured in step (a) is
larger than a predetermined level of IGF-1, the cancer is
susceptible to treatment with glufosfamide, optionally in
combination with a glucose lowering agent other than insulin.
17. A method of determining whether a cancer in a cancer patient is
susceptible to treatment with glufosfamide, the method comprising:
(a) measuring the level of a glucosidase in the cancer patient, (b)
determining that if the level of the glucosidase measured in step
(a) is larger than a predetermined level of the glucosidase, the
cancer is susceptible to treatment with glufosfamide, optionally in
combination with a glucose lowering agent other than insulin.
18. The method of claim 16, comprising measuring both the level of
IGF-1 and the level of glucosidase in the cancer patient.
19. The method of claim 16, further comprising administering to the
patient a therapeutically effective combination of glufosfamide and
IGF-1.
20. The method of claim 17, further comprising administering to the
patient a therapeutically effective combination of glufosfamide and
a glucosidase.
Description
CROSS-REFERENCE
[0001] This application claims priority to U.S. provisional
application Nos. 60/991,660, filed 30 Nov. 2007, 60/952,686, filed
30 Jul. 2007, 60/915,882, filed 3 May 2007 and 60/910,403, filed 5
Apr. 2007, each of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention provides methods for treating cancer with
glufosfamide administered in combination with glucose lowering
drugs other than insulin and, optionally, with other anti-cancer
therapies, such as surgery and radiation therapy. The invention
relates to the fields of biomedicine, pharmacology, and molecular
biology.
BACKGROUND OF THE INVENTION
[0003] Glufosfamide, also known as beta-D-glucosyl-ifosfamide
mustard or glc-IPM, is a prodrug of an alkylating agent that has
been used in the clinic as an investigational agent in the
treatment of cancer. See U.S. Pat. Nos. 5,622,936 and 6,489,302 and
PCT Publication Nos. WO 05/076888, WO 06/071955, WO 06/122227, and
WO 07/035961, each of which is incorporated herein by reference. In
contrast to the alkylating agent prodrug ifosfamide, metabolism of
glufosfamide does not release the toxic metabolite acrolein, and
also produces less of the toxic metabolite chloroacetaldehyde.
Glufosfamide was recently used in a Phase III clinical trial to
determine if was effective in the treatment of pancreatic cancer;
the trial did not meet its endpoints, although the data indicated
that the drug was having an anti-cancer effect. There accordingly
remains a need for new therapies for the treatment of cancer with
glufosfamide. The present invention meets this need by providing
novel combination therapies as summarized below and described in
detail herein.
SUMMARY OF THE INVENTION
[0004] In one aspect, the present invention provides a method of
treating cancer, said method comprising the steps of (i)
determining whether a patient is receiving a glucose lowering drug
other than insulin, and, if said patient is not receiving said
drug, then administering to said patient a glucose lowering drug
other than insulin, and then (ii) administering a therapeutically
effective amount of glufosfamide to said patients in need of such
treatment. In the course of treating patients, both those patients
determined to already be under treatment with a glucose lowering
drug other than insulin, and those newly receiving the glucose
lowering drug other than insulin may be treated with glufosfamide.
Accordingly, the glucose lowering drug can be administered prior to
or contemporaneously with the administration of glufosfamide, and
administration of the glucose lowering drug can continue after the
administration of glufosfamide. In certain embodiments, the glucose
lowering drug other than insulin is administered from at least 7
days to at least 1 day, at least 4 days to at least 2 days, and at
least 3 days prior to the glufosfamide administration. In one
embodiment, administration of the glucose lowering drug begins on
the day glufosfamide therapy is initiated. In certain other
embodiments, the glucose lowering drug other than insulin is
administered from 3 days to 1 day, and up to 2 days after the
glufosfamide administration. In certain other embodiments, the
glucose lowering agent other than insulin is administered within a
day of the glufosfamide administration.
[0005] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with a glucose
lowering drug other than insulin to a patient in need of such
treatment. In one embodiment, the patient is not suffering from
diabetes mellitus, i.e., the patient is not a diabetic patient. In
another embodiment, the patient is suffering from diabetes
mellitus, i.e., the patient is a diabetic patient. In one
embodiment, the patient does not have a glucose level that would
indicate that administration of a glucose lowering drug is
medically indicated. In one embodiment, the patient is receiving
insulin, and insulin administration is stopped, and administration
of a glucose lowering agent is initiated prior to the
administration of glufosfamide. In one aspect of the invention if a
patient identified as receiving insulin administration is stopped
and the patient is then treated with glufosfamide.
[0006] In one embodiment, the glucose lowering drug other than
insulin is selected from a sulfonylurea and a thiazolidinedione. In
various embodiments, the glucose lowering drug is selected from the
group consisting of glipizide, glibenclamide, glimepiride,
gliclazide, and rosiglitazone, acetohexamide, chloropropamide,
metformin, nateglinide, pioglitazone, repaglinide, tolazamide, and
tolbutamide. In one embodiment the glucose lowering drug is a
sulfonylurea.
[0007] A variety of cancers can be treated in accordance with the
present methods. In one embodiment, the cancer treated is a primary
pancreatic cancer. In another embodiment, the cancer is metastatic
pancreatic cancer. In another embodiment, the cancer is gemcitabine
resistant pancreatic cancer.
[0008] In one embodiment, the methods of the present invention are
practiced in combination with other methods for treating cancer,
including, for example, methods involving the administration of
other anti cancer drugs, radiation, and/or surgery. A variety of
anticancer drugs can be used in combination with the combination of
glufosfamide and a glucose lowering drug other than insulin for the
treatment of cancer as provided by the present invention.
Illustrative anticancer drugs useful in the methods of the
invention are described, for example, in the Physician's Desk
Reference, the Merck Index, U.S. Pat. No. 6,979,675; US Pat. Pub.
No. 2006/0276527; and PCT Pub. Nos. WO 06/057946 and WO 07/002931,
each of which is incorporated herein by reference.
[0009] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with an IGF to a
patient in need of such treatment. In one embodiment, the IGF is
IGF-1. In another embodiment, the method further comprises
administering another anti cancer drug and/or surgery and/or
radiation therapy.
[0010] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with an IGF raising
agent to a patient in need of such treatment; the IGF raising agent
being an agent that can raise IGF levels when administered to the
patient. In one embodiment, the method further comprises
administering another anti cancer drug and/or surgery and/or
radiation therapy. In one embodiment the IGF raising agent is a
sulfonylurea. In another embodiment the IGF raising agent excludes
a sulfonylurea. Illustrative anticancer drugs useful in certain
aspects of the invention are described, for example, in U.S. Pat.
No. 6,979,675; US Pat. Pub. No. 2006/0276527; PCT Pat. Pub. No. WO
06/57946; and PCT Pat. App. No. U.S. Ser. No. 06/015,881, each of
which is incorporated herein by reference.
[0011] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with a glycosidase
to a patient in need of such treatment. In one embodiment, the
glycosidase is a glucosidase. In another embodiment, the
glucosidase is a .beta.-glucosidase. In another embodiment, the
glucosidase is a glucuronidase. In another embodiment, the
glucosidase is a .beta.-glucocerebrosidase. In another embodiment,
the .beta.-glucocerebrosidase is Cerezyme.RTM. (Imiglucerase,
Genzyme).
[0012] In another aspect, the present invention provides a method
of determining whether a cancer in a cancer patient is susceptible
to treatment with glufosfamide, the method comprising the steps
of:
(a) measuring the level of an in IGF in the cancer patient, (b)
comparing the level of the IGF measured with a predetermined level
of the IGF, and (c) determining that, if the level of the IGF
measured is larger than the predetermined level of the IGF, the
cancer is susceptible to treatment with glufosfamide. In one
embodiment, the IGF is IGF-1.
[0013] In another aspect, the present invention provides a method
of determining whether a cancer in a cancer patient is susceptible
to treatment with glufosfamide, the method comprising the steps
of:
(a) measuring the level of a glycosidase in the cancer patient, (b)
comparing the level of the glycosidase measured with a
predetermined level of the glycosidase, and (c) determining that,
if the level of the glycosidase measured is larger than the
predetermined level of the glycosidase, the cancer is susceptible
to treatment with glufosfamide. In one embodiment, the glycosidase
is a glucosidase. In one embodiment, the glucosidase is a
disaccharidase. In another embodiment, the disaccharidase is
lactase phlorizin hydrolase.
[0014] These and other aspects and embodiments of the present
invention are described by the accompanying figures and the
detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 shows comparative plots of survival over time for
patients administered glufosfamide (Group 1) and patients
administered best supportive care (BSC, Group 2).
[0016] FIG. 2 shows comparative plots of survival over time for
patients in Groups 1 and 2 who had not received insulin prior to
initiation of glufosfamide therapy.
[0017] FIG. 3 shows comparative plots of patient survival over time
in months for patients in Groups 1 and 2 who received a glucose
lowering drug other than insulin during glufosfamide therapy.
[0018] FIG. 4 shows in vivo survival benefits of co-administration
of glufosfamide and the glucose lowering drug glimepiride in a
murine cancer model.
DETAILED DESCRIPTION OF THE INVENTION
[0019] This detailed description of the aspects and embodiments of
the present invention is organized as follows: Section I provides
definitions of terms used herein; Section II, in parts A and B,
describes a clinical trial of glufosfamide for the treatment of
gemcitabine resistant pancreatic cancer, including overall patient
survival (part A), and the results obtained for a subset of
diabetic patients receiving glucose lowering drugs other than
insulin (part B); Section III, in parts A through D, describes the
therapies provided by the present invention, including drug
administration cycles (part A), illustrative treatment combinations
(part B), cancers amenable to treatment (part C), and treatment of
hyperproliferative diseases other than cancer (part D); and Section
IV describes patient and in vivo treatment results that demonstrate
the efficacy of the present methods. This detailed description is
organized into sections only for the convenience of the reader, and
disclosure found in any section is applicable to disclosure
elsewhere in the specification.
I. DEFINITIONS
[0020] 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.
[0021] "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, such as the act of prescribing a drug. For example
and without limitation, a physician who instructs a patient to
self-administer a drug and/or provides a patient with a
prescription for a drug is, for purposes of the present invention,
"administering" the drug to the patient.
[0022] "Diabetes mellitus" refers to a group of metabolic diseases
characterized by high serum glucose levels, which can result, for
example, from defects in insulin secretion, action, or both.
[0023] A "diabetic patient" refers to a patient suffering from
diabetes mellitus.
[0024] "Glucose lowering drugs" refer to drugs that are capable of
reducing serum glucose levels in humans. Examples of glucose
lowering drugs include sulfonylureas and thiazolidinediones. Other
drugs useful as glucose lowering drugs include metformin,
nateglinide, glipizide, glibenclamide, glimepiride, gliclazide, and
rosiglitazone. Although one property of insulin is to lower glucose
levels, as used in the description of the methods of the invention,
"a glucose lowering drug" does not include insulin. Such drugs may
also be referred to herein as "glucose lowering drugs other than
insulin."
[0025] A "patient" refers to a mammal in need of treatment for
cancer or, in some embodiments, for a hyperproliferative disease
other than cancer. Generally, the patient is a human. In other
embodiments of the invention, however, the patient is a non-human
mammal, such as a non-human primate, a dog, cat, cow, horse,
rabbit, pig, or the like. In other embodiments of the invention,
the patient is an animal such as a mouse or rat, such as an animal
commonly used in screening, characterizing, and evaluating drugs
and therapies.
[0026] "Treatment" or "therapy" refers to a method for obtaining
beneficial or desired results, including clinical results. For
purposes of this invention, beneficial or desired clinical results
include, but are not limited to, alleviation or amelioration of one
or more symptoms, diminishment of extent of disease, stabilized
(i.e., not worsening) state of disease, preventing spread of
disease, delaying or slowing of disease progression, amelioration
or palliation of the disease state, and remission (whether partial
or total). "Treatment" can also mean prolonging survival as
compared to expected survival in the absence of receiving
treatment.
II. CLINICAL TRIAL INVESTIGATING THE TREATMENT OF GEMCITABINE
RESISTANT PANCREATIC CANCER BY ADMINISTRATION OF GLUFOSFAMIDE
[0027] Glufosfamide is a prodrug of an alkylating agent useful in
the treatment of cancer. A multi-center, randomized, open-label
phase 3 clinical trial was conducted to evaluate the safety and
efficacy of glufosfamide in treating gemcitabine resistant
metastatic pancreatic cancer as measured by overall survival
compared to BSC (best supportive care). Three hundred and three
patients were randomized to the trial: 148 patients were randomized
to the glufosfamide arm (n=148, Group 1) and 155 to BSC (n=155,
Group 2).
A. Overall Survival
[0028] Patients in Group 1 were administered glufosfamide for up to
42 weeks. Glufosfamide was administered intravenously over 6 hours
once every 3 weeks at 4500 mg/m.sup.2 for up to 14 doses. This
dosing schedule is shown in Table 1 below:
TABLE-US-00001 TABLE 1 Glufosfamide Week 1 2 3 Group 1 Administered
-- -- Group 2 -- -- --
[0029] One-quarter of the dose was infused over 30 minutes and the
remainder over the following five and one-half hours.
[0030] To assess the efficacy of glufosfamide treatment, patients
in Group 1 and Group 2 were not administered any medication known
to have antitumor effects other than glufosfamide, e.g., the
patients were not administered any other chemotherapy or systemic
cytotoxic/cytostatic agents. However, other appropriate supportive
measures and concomitant medications not known to have antitumor
effects, such as analgesics, antibiotics, transfusions,
hematopoietic colony-stimulating factors (as therapy but not as
prophylaxis), erythropoietin, and megestrol acetate for appetite
stimulation were administered when appropriate.
[0031] Tumor assessment was performed at baseline and once every 6
weeks for the first 24 weeks and then once every 9 weeks. The
primary efficacy indicator was the overall survival in Group 1
compared to that in Group 2.
[0032] The median overall survival was 105 days (95% confidence
interval (CI); 87-133 days) in Group 1 and 84 days (95% CI; 71-106
days) in Group 2 (see FIG. 1). The relative risk for overall
survival in Group 1 and Group 2 patients, determined from a
proportional hazards model with Karnofsky Performance Status (KPS)
as a stratification factor, was 0.848 (95% CI: 0.664-1.084), and
the two-sided stratified log-rank p-value was 0.187.
[0033] Patients (n=123) within Group 1 who were not administered
insulin prior to the first administration of glufosfamide
demonstrated a longer overall survival as compared to patients in
Group 2 that were not administered insulin prior to their
enrollment (n=123); the median overall survival within the Group 1
patients was 115 days (95% CI: 94-145 days) compared to 84 days
(95% CI; 70-102 days) for those within Group 2 (see FIG. 2). The
relative risk for overall survival in Group 1 and Group 2 patients,
determined as above, was 0.761 (95% CI: 0.581-0.998), and the
two-sided stratified log-rank p-value was 0.048.
[0034] While these results demonstrated that glufosfamide was
effective in delaying disease progression and death in some
patients, the trial did not meet its endpoints. The present
invention arose from the discovery that certain patients responded
to glufosfamide therapy much better than others and other patients
responded less well than others and that those responses correlated
with the co-administration of insulin or of a glucose-lowering drug
other than insulin the patient received while undergoing
glufosfamide therapy. Patients receiving insulin tended to
experience no benefit or less benefit from the administration of
glufosfamide and patients receiving a glucose lowering drug other
than insulin tended to experience more benefit from the
administration of glufosfamide than other patients not receiving
such drugs.
B. Glufosfamide Treatment in Combination with Glucose Lowering
Drugs
[0035] Seven diabetic patients (n=7) within Group 1 were treated
with a glucose lowering drug (glipizide, glibenclamide,
glimepiride, gliclazide, or rosiglitazone) but were not
administered insulin prior to the first administration of
glufosfamide. The median overall survival for these seven Group 1
patients was 418 days (95% CI; 85 days-643 days). In contrast,
diabetic patients within Group 2 (n=14) who received various
glucose lowering drugs other than insulin had a median overall
survival of 73 days (95% CI; 45-102 days). The relative risk for
overall survival in this subset of Group 1 and Group 2 patients,
determined as above, was 0.24 (95% CI: 0.07-0.87), and the
two-sided stratified log-rank p-value was 0.020. See FIG. 3. These
results indicated that the benefits of glufosfamide therapy are
greatly enhanced by the coadministration of a glucose lowering drug
other than insulin. Accordingly, the present invention provides
methods of treating cancer in patients by co-administering with
glufosfamide a glucose lowering drug other than insulin, such as a
sulfonylurea and a thiazolidinedione, to improve the effectiveness
of glufosfamide therapy in the treatment of cancer.
III. THERAPEUTIC METHODS OF THE INVENTION
[0036] In one aspect, the present invention provides a method of
treating a patient diagnosed with cancer, by [0037] 1) determining
whether the patient is receiving a glucose lowering drug other than
insulin, and, [0038] 2) if it is determined the patient is not
receiving a glucose lowering drug other than insulin, then
administering such a drug, and [0039] 3) administering a
therapeutically effective amount of glufosfamide to the
patient.
[0040] Thus a patient under prior treatment with a glucose lowering
drug other than insulin is treated by administering a
therapeutically effective amount of glufosfamide, and a patient not
under prior treatment with a glucose lowering drug other than
insulin is treated with such a glucose lowering drug and with a
therapeutically effective amount of glufosfamide. The glucose
lowering drug can be administered prior to and/or contemporaneously
with and/or after the initiation of the administration of
glufosfamide ("Glufos Day 1"). As used in this context,
"contemporaneously" can mean the two drugs are administered on the
same day, or on consecutive days, or within a week of one another.
It will be understood that use of the word "or" in this context
does not exclude combinations, such as administration the day
before and the same day as glufosfamide administration.
[0041] In one approach the glucose lowering drug is administered as
part of a treatment regimen contemporaneously with each of multiple
administrations of glufosfamide (e.g, at least 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13 or 14 rounds of administration). In one approach
the glucose lowering drug is administered as part of a treatment
regimen contemporaneously with each administrations of
glufosfamide.
[0042] In one approach the glucose lowering drug is administered at
least once during each round of glufosfamide administration. For
example, Table 1, above, shows a 3 week administration cycle. Thus
in one embodiment the glucose lowering drug is administered at
least once during each cycle of glufofamide treatment (whether on a
three-week cycle or a different cycle). More often the glufosfamide
is given more than once during each cycle, such as at least 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or at least 14 times.
[0043] In one approach the glucose lowering drug is administered as
part of a treatment regimen contemporaneously with each
administrations of glufosfamide. For example, the glucose lowering
drug may be given daily throughout the course of glufosfamide
treatment, or daily at least through several cycles.
[0044] Again, it will be understood that description of certain
administration schedules is not intended to be limiting, and that,
for example, combinations of administration schedules described
herein.
[0045] In one the glucose lowering drug is administered throughout
approach the glucose lowering drug is administered as part of a
treatment regimen contemporaneously with each of multiple
administrations of glufosfamide (e.g, at least 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13 or 14 rounds of administration). In one approach
the glucose lowering drug is administered as part of a treatment
regimen contemporaneously with each administrations of
glufosfamide.
[0046] When the glucose lowering drug ("GLD") is administered prior
to Glufos Day 1, the GLD administration can begin at least 7 (Day
-7), at least 6 (Day -6), at least 5 (Day -5), at least 4 (Day -4),
at least 3 (Day -3), at least 2 (Day -2) or at least 1 (Day -1)
day(s) prior to Glufos Day 1. Once initiated the GLD can be
administered daily (including multiple doses in one same day) or
less frequently. For illustration and not limitation, the GLD can
be administered prior to Glufos Day 1 on Days -7, -5, -3, and -1;
or Days -7, -6, -5, -4, and -3; or Days -4, -3, -2, and -1; or Days
-4, -3, and -2. In various embodiments the GLD is administered for
at least 1, at least 2, at least 3, at least 4, at least 5, at
least 6 or at least 7 days during the seven-day period preceding
initiation of glufosfamide treatment.
[0047] When the glucose lowering drug other than insulin is
administered contemporaneously with the initiation of glufosfamide
administration it is administered the same day glufosfamide is
administered.
[0048] When the GLD is administered after the initiation of
glufosfamide therapy it can be administered daily, on the same days
glufosfamide is administered (e.g., once every 21 days if a
three-week treatment cycle is used), one day before and/or one day
after glufosfamide treatment, or according to another schedule. The
GLD therapy can continue for the duration of glufosfamide treatment
(e.g., up to 42 weeks, using the treatment cycle described above)
or for a shorter period.
[0049] In one embodiment of the methods of the invention, the
cancer patient is administered a glucose-lowering drug other than
insulin at least during the period of time in which the patient is
being administered glufosfamide. Often, in accordance with the
methods of the invention, a glucose lowering drug other than
insulin is administered throughout the period of glufosfamide
administration and, usually, prior to initiation of glufosfamide
treatment.
[0050] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with a glucose
lowering drug other than insulin to a patient in need of such
treatment. In one embodiment, the patient is not suffering from
diabetes mellitus, i.e., the patient is not a diabetic patient, but
the patient is administered a glucose lowering drug other than
insulin, before, during, and/or after initiation of glufosfamide
therapy. In another embodiment, the patient is suffering from
diabetes mellitus, i.e., the patient is a diabetic patient, and, if
the patient is receiving insulin, the insulin administration is
stopped prior to administering glufosfamide.
[0051] In an aspect, the invention provides a method of treating
cancer in a patient, said method comprising (i) determining if said
patient is receiving a glucose lowering drug other than insulin;
(ii) initiating administration of a glucose lowering drug other
than insulin if said patient is not already receiving such drug;
and (iii) administering a therapeutically effective amount of
glufosfamide to said patient in need of cancer treatment.
[0052] In one embodiment, the patient has a normal glucose level at
the time administration of the glucose lowering drug other than
insulin is initiated.
[0053] In one embodiment, the glucose lowering drug is a
sulfonylurea. In one embodiment, the glucose lowering drug is a
thiazolidinedione. In other embodiments, the glucose lowering drug
is selected from the group consisting of glipizide, glibenclamide,
glimepiride, gliclazide, and rosiglitazone. Other glucose lowering
drugs other than insulin useful in the methods of the present
invention include, but are not limited to, acetohexamide,
chloropropamide, metformin, nateglinide, pioglitazone, repaglinide,
tolazamide, and tolbutamide.
[0054] In one aspect, the present invention provides a method of
treating a patient diagnosed with cancer, by [0055] 1) determining
whether the patient is receiving a glucose lowering drug other than
insulin, and, [0056] 2) if it is determined the patient is not
receiving a glucose lowering drug other than insulin, then
administering such a drug, and [0057] 3) administering a
therapeutically effective amount of glufosfamide to the patient. In
an embodiment the glucose lowering drug other than insulin is
administered prior to the initiation of glufosfamide therapy. In an
embodiment the glucose lowering drug other than insulin is
administered contemporaneously with administration of glufosfamide
therapy.
[0058] In one aspect, the present invention provides a method of
treating a patient diagnosed with cancer, by [0059] 1) determining
whether the patient is receiving a glucose lowering drug other than
insulin, and, [0060] 2) if it is determined the patient is
receiving a glucose lowering drug other than insulin, discontinuing
therapy with the glucose lowering drug and initiating therapy with
a different glucose lowering drug, and [0061] 3) administering a
therapeutically effective amount of glufosfamide to the patient. In
an embodiment the glucose lowering drug other than insulin is
administered prior to the initiation of glufosfamide therapy. In an
embodiment the glucose lowering drug other than insulin is
administered contemporaneously with administration of glufosfamide
therapy.
[0062] In one aspect, the present invention provides a method of
treating a patient diagnosed with cancer, by [0063] 1) determining
whether the patient is receiving a glucose lowering drug other than
insulin, and, [0064] 2) if it is determined the patient is
receiving a glucose lowering drug other than insulin, discontinuing
therapy with the glucose lowering drug and initiating therapy with
a different glucose lowering drug, and [0065] 3) if it is
determined the patient is receiving a glucose lowering drug other
than insulin, discontinuing therapy with the glucose lowering drug
and initiating therapy with a different glucose lowering drug, and
[0066] 4) administering a therapeutically effective amount of
glufosfamide to the patient. In an embodiment the glucose lowering
drug other than insulin is administered prior to the initiation of
glufosfamide therapy. In an embodiment the glucose lowering drug
other than insulin is administered contemporaneously with
administration of glufosfamide therapy.
[0067] In one embodiment, if it is determined that a patient
diagnosed with cancer is receiving insulin, then the insulin
therapy is discontinued, prior to administration of glufosfamide.
In one embodiment the glucose lowering drug other than insulin is
administered to the patient in combination with glufosfamide. In
one embodiment, the glucose lowering drug other than insulin is
administered prior to the administration of glufosfamide.
[0068] The reference Guney et al., Neuro. Endocrinol. Lett., 2002,
23(5-6):437-9, incorporated herein by reference, discloses that
certain sulfonylurea-based glucose lowering drugs stimulate IGF-1
production. IGF-1, in turn, can upregulate the production of
certain glucosidases. While the invention is not to be limited by
any theory of mechanism of action, upregulated glucosidase levels
in a cancer cell may lead to faster accumulation of and greater
levels of isophosphoramide in cancer cells following glufosfamide
administration.
[0069] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with an IGF raising
agent to a patient in need of such treatment; the IGF raising agent
being an agent that can raise IGF levels when administered to the
patient. In one embodiment, the method further comprises
administering another anti-cancer drug and/or surgery and/or
radiation therapy. In one embodiment the IGF raising agent is a
sulfonylurea. In another embodiment the IGF raising agent excludes
a sulfonylurea. Illustrative anticancer drugs useful in certain
aspects of the invention are described, for example, in U.S. Pat.
No. 6,979,675; US Pat. Pub. No. 2006/0276527; PCT Pat. Pub. No. WO
06/57946; and PCT Pat. App. No. U.S. Ser. No. 06/015,881, each of
which is incorporated herein by reference.
[0070] Thus, in another aspect, the present invention provides a
method of treating cancer comprising administering a
therapeutically effective amount of glufosfamide in combination
with a compound having IGF-1 activity (an "IGF") to a patient in
need of such treatment. In one embodiment, the IGF is IGF-1. IGF-1
is available commercially as INCRELEX.TM. (Tercica, Brisbane,
Calif.) and can be, for example and without limitation,
administered at 0.04 to 0.12 mg/kg (40 to 120 .mu.g/kg) twice daily
by subcutaneous injection. See also, Dagogo-Jack et al., Int. J.
Obes. Relat. Metab. Disord., 1998, 22(11):1110-15, incorporated
herein by reference. In another embodiment, the method further
comprises administering another anti-cancer drug and/or surgery
and/or radiation therapy. When additional anti-cancer agents are
employed in the methods of the invention, they are typically
administered at their approved doses and dosing frequency, or at
lower doses or reduced frequency.
[0071] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with a glycosidase
to a patient in need of such treatment. In one embodiment, the
glycosidase is a glucosidase. In another embodiment, the
glucosidase is a .beta.-glucosidase. In another embodiment, the
glucosidase is a glucuronidase. In another embodiment, the
glucosidase is a .beta.-glucocerebrosidase. In another embodiment,
the .beta.-glucocerebrosidase is Cerezyme.RTM. (Imiglucerase,
Genzyme).
[0072] In another aspect, the present invention provides a method
of treating cancer comprising administering a therapeutically
effective amount of glufosfamide in combination with an agent that
raises IGF-1 levels or activity ("an IGF raising agent") to a
patient in need of such treatment. In one embodiment, the method
further comprises administering another anti cancer drug and/or
surgery and/or radiation therapy. In one embodiment the IGF raising
agent is a sulfonylurea. In another embodiment the IGF raising
agent is an agent other than a sulfonylurea.
[0073] In accordance with the methods of the invention, an IGF, an
IGF raising agent, or a glycosidase administered in combination
with glufosfamide or another anti-cancer drug can be administered
in any amount that is therapeutically effective, and such amount
will typically be the same as or less than the amounts of that drug
that are routinely utilized clinically when the drug is not
co-administered with an anti-cancer agent. A therapeutically
effective amount of a glucosidase administered according to the
present methods can be determined from the enzymatic activity of
the glucosidase reported in literature and upon reading this
disclosure in its entirely. A method for determining glucosidase
activity is described for example in the reference Sun et al., J.
Chromatograpy B, 2006, 832:224-30, incorporated herein by
reference. The glucosidase Cerezyme.RTM. is administered by
intravenous infusion over 1-2 h in the dosage range from 2.5
unit/kg of body weight 3 times a week to 60 unit/kg once every 2
weeks, product information for Cerezyme.RTM. available from Genzyme
Corporation.
[0074] In another aspect, the present invention provides a method
of determining whether a cancer in a cancer patient is susceptible
to treatment with glufosfamide, the method comprising the steps
of:
(a) measuring the level of an in IGF in the cancer patient, (b)
comparing the level of the IGF measured with a predetermined level
of the IGF, and (c) determining that, if the level of the IGF
measured is larger than the predetermined level of the IGF, the
cancer is susceptible to treatment with glufosfamide. In one
embodiment, the IGF is IGF-1.
[0075] In another aspect, the present invention provides a method
of determining whether a cancer in a cancer patient is susceptible
to treatment with glufosfamide, the method comprising the steps
of:
(a) measuring the level of a glycosidase in the cancer patient, (b)
comparing the level of the glycosidase measured with a
predetermined level of the glycosidase, and (c) determining that,
if the level of the glycosidase measured is larger than the
predetermined level of the glycosidase, the cancer is susceptible
to treatment with glufosfamide. In one embodiment, the glycosidase
is a glucosidase. In one embodiment, the glucosidase is a
disaccharidase. In another embodiment, the disaccharidase is
lactase phlorizin hydrolase.
[0076] In another aspect, the present invention provides a method
of determining whether a cancer in a cancer patient is susceptible
to treatment with glufosfamide, the method comprising the steps of
(i) measuring the level of an IGF in the cancer patient, (ii)
comparing the level of the IGF measured with a predetermined level
of the IGF, and (iii) determining that, if the level of the IGF
measured is larger than the predetermined level of the IGF, the
cancer is susceptible to treatment with glufosfamide, and if the
level is lower, then determining that the level should be increased
prior to the administration of glufosfamide therapy. In one
embodiment, the IGF is IGF-1. In one embodiment, the predetermined
level of the IGF-1 is the level of IGF-1 found in normal humans. In
another embodiment, the predetermined level of the IGF-1 is 200-450
ng/mL. See http://www.usdoctor.com/hgh.htm and Ho et al., Clin.
Endocrinol., 1994, 41(1):75-83, incorporated herein by reference.
In another embodiment, the predetermined level of the IGF-1 is
about 300-400 ng/mL. In various embodiments a predetermined level
of about 200 ng/mL, about 300 ng/mL, about 400 ng/mL or about 450
ng/mL is used.
[0077] Various methods can be employed to determine the level of
IGF in a patient including, but not limited to, radioimmunoassay by
competitive protein binding, enzyme-linked immunoabsorbant assay,
immunochemiluminescence assay, immunofunctional assay, kinase
receptor activation assay, and free IGF-1 assay. See Clemmons et
al., Pituitary, 2007, DOI 10.1007/s11102-007-0032-z, incorporated
herein by reference.
A. Administration Cycles
[0078] Cancer chemotherapy treatment typically involves multiple
"rounds" or "cycles" of drug administration, where each cycle
comprises administration of the drug one or more times according to
a specified schedule (e.g., daily; once per week for two or more
weeks; multiple times a week either on consecutive days or
non-consecutive days; once every cycle, which may be a day, week,
or month, for example; multiple times every cycle [for example and
without limitation every three weeks for three consecutive days],
wherein each cycle ranges from 1 day to 1 week up to several weeks,
such as 2, 3, 4, 5, 6, 7, or 8 weeks). For example and without
limitation, chemotherapeutic drugs can be administered for from 1
to 8 cycles, or for more cycles (i.e., a longer time period).
[0079] As is understood in the art, treatment with anti-cancer
therapeutic drugs can be suspended temporarily if toxicity is
observed, or for the convenience of the patient, without departing
from the scope of the invention, and then resumed.
[0080] In one embodiment of the invention, glufosfamide is
administered for 1, 2, 3, 4, 5, 6, 7, 8, or more than 8 dosage
cycles, and each cycle involves the administration by infusion of
glufosfamide in the range of: [0081] a) about 1.0 to about 8.0
g/m.sup.2; about 1.0 to about 6.0 g/m.sup.2; about 1.5 to about 4.5
g/m.sup.2; about 4.5 to about 8.0 g/m.sup.2; about 4.5 to about 6.0
g/m.sup.2; or about 4.5 to about 5.0 g/m.sup.2 or over an infusion
period of 1-6 hours once every three weeks; [0082] b) about 1.0 to
about 3.0 g/m.sup.2, about 1.5 to about 3.0 g/m.sup.2 or about 1.5
to about 2.0 g/m.sup.2 over an infusion period of 1-6 hours for
three consecutive days (days 1, 2 and 3) every three weeks; [0083]
c) about 1.0 to about 2.0 g/m.sup.2 or about 1.5 to about 2.0
g/m.sup.2 over an infusion period of 1-6 hours once per week; or
[0084] d) about 1.0 to about 8.0 g/m.sup.2; about 1.0 to about 6.0
g/m.sup.2; or about 1.5 to about 4.5 g/m.sup.2 over an infusion
period of 1-6 hours once every four weeks.
[0085] In one embodiment, glufosfamide is administered for 1, 2, 3,
4 or more than 4 dosage cycles, wherein each cycle is a seven-week
cycle. In one embodiment, glufosfamide is administered for 1, 2, 3,
4, 5, 6, or more than 6 dosage cycles, wherein each cycle is a
three-week cycle. In one embodiment, glufosfamide is administered
for 1, 2, 3, 4, 5, 6, or more than 6 dosage cycles, wherein each
cycle is a four-week cycle. In one embodiment, glufosfamide is
administered weekly in the range of 1.0 to about 3.0 g/m.sup.2, for
example and without limitation on Days 1 and 8 of a 21 day cycle;
on Days 1, 8, and 15 of a 28 day cycle; or Days 1, 8, and 15 of a
21 day cycle.
[0086] As used in this context, an "infusion period of 1-6 hours"
includes without limitation, an infusion period of about 1, about
2, about 3, about 4, about 5, and about 6 hours.
[0087] In those embodiments of the invention in which an
anti-cancer drug in addition to glufosfamide is co-administered
with a glucose lowering drug other than insulin and glufosfamide,
the cycles chosen for administration of the additional anti-cancer
drug will typically be those commonly used for administering the
anti-cancer drug when used alone or in combination with other
agents.
B. Treatment Combinations
[0088] During chemotherapy treatment of cancer, two, three, or four
anti-cancer drugs can be administered to a patient "in combination"
by administering them as part of the same course of therapy. A
course of therapy refers to the administration of combinations of
drugs believed by the medical professional to work together
additively, complementarily, synergistically, or otherwise to
produce a more favorable outcome than that anticipated for
administration of a single drug for the total number of cycles
believed to provide efficacious treatment. A course of therapy can
be for one or a few days, but, as discussed in the context of
treatment cycles above, more often extends for several weeks or
months.
[0089] When more than one drug (e.g., two drugs) is administered to
a patient, as in the methods of the present invention, each drug
can be administered according to its own schedule. It will be clear
that administration of drugs, even those administered with
different periodicity, can be coordinated so that both drugs are
administered on the same day at least some of the time or,
alternatively, so the drugs are administered on consecutive days at
least some of the time.
[0090] When two or more anti-cancer drugs are administered in
combination, as in certain embodiments of the methods of the
present invention, a variety of schedules can be used. In one case,
for example and without limitation, Drug 1 is first administered
prior to administration of Drug 2, and treatment with Drug 1 is
continued throughout the course of administration of Drug 2;
alternatively, Drug 1 is administered after the initiation or
completion of Drug 2 therapy; alternatively, Drug 1 is first
administered contemporaneously with the initiation of the other
cancer therapy. As used in this context, "contemporaneously" means
the two drugs are administered on the same day or on consecutive
days or within a week of one another.
[0091] The present invention contemplates that the drugs used in
combination in the methods of the invention can be co-formulated
for administration in combination or can be administered as
separate compositions Similarly, the present invention contemplates
that certain drugs combinations will be administered simultaneously
(for drugs administered by infusion), other drug combinations will
be co-administered in separate compositions, other drug
combinations will be administered at different times on the same
day, or on consecutive days, or according to other schedules. As
clear from this context, "co-administration" means administration
in the same course of therapy.
[0092] In accordance with the methods of the invention, a glucose
lowering drug administered in combination with glufosfamide can be
administered in any amount that is therapeutically effective, and
such amount will typically be the same as, but could be less or
more than, the amount of that drug that is routinely utilized
clinically when the drug is administered for its previously
approved indications. In similar fashion, the anti-cancer agent
other than glufosfamide administered according to the present
methods is likewise typically administered in the amounts used for
its previously approved anti-cancer therapeutic indications
(although lower amounts, reduced frequency may be employed in some
instances). Thus, the therapeutically effective amount of a drug
that can be administered is known to physicians and provided, for
example and without limitation, in the product descriptions found
in the most recent editions of the PHYSICIANS' DESKREFERENCE,
Medical Economics Company, Inc., Oradell, N.J.; and Goodman &
Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS", McGraw-Hill,
New York; and/or are available from the Federal Drug Administration
and/or are discussed in the medical literature.
[0093] For illustration and not limitation, the administration of
glufosfamide and various other anti-cancer drugs for treatment of
cancer is found in US Patent Application Nos. 61/027,768, filed 11
Feb. 2008; 60/991,660, filed 30 Nov. 2007; 60/952,686, filed 30
Jul. 2007; 60/915,882, filed 3 May 2007; and 60/910,403, filed 5
Apr. 2007, and PCT Pub. Nos. WO 05/076888, WO 06/071955, WO
06/122227, and WO 07/035961, each of which is incorporated herein
by reference. The administration and dosing schedules described in
these publications and applications are suitable for use in the
methods of the present invention.
C. Cancers Treatable in Accordance with the Methods of the
Invention
[0094] In one embodiment, the present invention provides methods
for treating pancreatic cancer. In another embodiment, the cancer
treated is selected from a primary pancreatic cancer, metastatic
pancreatic cancer, and gemcitabine resistant pancreatic cancer
(primary and metastatic). Chemotherapy-resistant pancreatic cancers
(see, e.g., Araneo et al., 2003, Cancer Invest. 21:489-96; Kozuch
et al., 2001, The Oncologist 6:488-95; Noble and Goa, 1997, Drugs
54: 447-72N; Stephens et al., 1998, Oncol. Nurs. Forum 25:87-93;
Burris and Storniolo, 1997, Eur. J. Cancer 33: Suppl 1:S18-22;
Rothenberg et al., 1996, Ann. Oncol. 7:347-53, each of which is
incorporated herein by reference) can be treated using the methods
disclosed herein. In one embodiment of the invention, serum
carbohydrate 19-9 is used as a marker for evaluating the response
to such glufosfamide therapy in pancreatic cancer (Ziske et al.,
2003, Br. J. Cancer, 89:1413-17, incorporated herein by
reference).
[0095] In various embodiments, the methods of the present invention
are employed to treat a cancer selected from the group consisting
of breast cancer, colorectal cancer, gall bladder cancer,
non-Hodgkin's lymphoma, kidney cancer, liver cancer, lung cancer,
ovarian cancer, pancreatic cancer, sarcoma, and stomach cancer.
[0096] In one embodiment of the present invention, glufosfamide and
a glucose lowering drug other than insulin are co-administered to a
subject in need of treatment for breast cancer. Breast cancer is
commonly treated by various combinations of surgery, radiation
therapy, chemotherapy, and hormone therapy. In accordance with the
methods of the invention, glufosfamide is administered alone, or in
combination with gemcitabine, or in combination with another
anti-cancer drug for the treatment of breast cancer, and a glucose
lowering drug other than insulin is co-administered with
glufosfamide.
[0097] In one embodiment of the present invention, glufosfamide and
a glucose lowering drug other than insulin are co-administered to a
subject in need of treatment for colorectal cancer or metastatic
colorectal cancer. Colorectal cancer or metastatic colorectal
cancer is currently treated by radiation therapy, surgery, and/or
chemotherapy (e.g., administration of fluorouracil). In one
embodiment, glufosfamide is the only anti-cancer agent administered
to treat colorectal cancer; in another embodiment, glufosfamide is
co-administered with another anti-cancer agent, such as
gemcitabine, to treat colorectal cancer. In another embodiment,
glufosfamide and bevacizumab are administered in combination with a
glucose lowering drug other than insulin to a subject in need of
treatment for colorectal cancer; optionally, gemcitabine or
fluorouracil is also co-administered.
[0098] In one embodiment of the present invention, glufosfamide and
a glucose lowering drug are co-administered as a second-line
therapy for non-Hodgkins lymphoma after CHOP (cyclophosphamide,
adriamycin, vincristine, and prednisone) therapy has failed.
[0099] In one embodiment of the present invention, glufosfamide and
a glucose lowering drug are co-administered to a subject in need of
treatment for ovarian cancer. Optionally, gemcitabine is also
co-administered. In one embodiment, glufosfamide and a glucose
lowering drug are co-administered, and again, gemcitabine can be
optionally co-administered, as a second line therapy in the
treatment of ovarian cancer, optionally in combination with an
approved second line therapy after failure on cis/carboplatin
and/or a taxane or other first line therapy. In another aspect,
glufosfamide and a glucose lowering drug are co-administered as a
first line therapy in the treatment of ovarian cancer, optionally
in combination with gemcitabine and/or cis/carboplatin and/or a
taxane and/or another first line therapy.
[0100] In one embodiment of the invention, glufosfamide and a
glucose lowering drug are co-administered as a first- or
second-line therapy to treat a PET-positive sarcoma. A
"PET-positive" sarcoma is a sarcoma detectable by positron emission
tomography. In one embodiment, glufosfamide and a glucose lowering
drug are co-administered as a second line therapy in the treatment
of a sarcoma either alone or in combination with another approved
second line therapy after treatment failure on doxorubicin or
failure on another first line therapy. In another embodiment,
glufosfamide and a glucose lowering drug are co-administered as a
first line therapy in the treatment of a sarcoma in combination
with doxorubicin or in combination with another approved first line
therapy.
[0101] In one embodiment of the present invention, glufosfamide and
a glucose lowering drug are co-administered as a second line
therapy in small-cell lung cancer (SCLC) optionally in combination
with gemcitabine and optionally with another approved second line
therapy after first line failure on carboplatin or cisplatin, VP16,
and/or a taxane. In another aspect, glufosfamide and a glucose
lowering drug are co-administered alone or in combination with
gemcitabine as a first line therapy in the treatment of SCLC,
optionally in combination with carboplatin or cisplatin, VP16,
and/or a taxane or other approved first line therapy.
[0102] In general, the methods of the present invention can be used
for treatment of any cancer. In various embodiments, the cancer
treated is selected from the group consisting of 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. In other embodiments, the cancer treated is selected from
the group consisting of 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,
small cell lung cancer, topical skin lesion, veticulum cell
sarcoma, and Wilm's tumor.
D. Treatment of Hyperproliferative Diseases Other than Cancer
[0103] In another aspect, the methods of the present invention are
practiced to treat a disease other than cancer that is
characterized by cellular hyperproliferation (e.g., an abnormally
increased rate or amount of cellular proliferation). In various
embodiments, the hyperproliferative disease is selected from the
group consisting of allergic angiitis 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-S
chonlein 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.
[0104] In one embodiment, the hyperproliferative disease treated is
psoriasis, a disease characterized by the cellular
hyperproliferation of keratinocytes which builds up on the skin to
form elevated, scaly lesions. In another embodiment, the
hyperproliferative disease treated is multiple sclerosis, a disease
characterized by progressive demyelination in the brain. In another
embodiment, the hyperproliferative diseases treated is rheumatoid
arthritis, a multi-system, chronic, relapsing, inflammatory disease
that can lead to destruction and ankylosis of the joints affected
by the disease.
[0105] The invention, having been described in summary and in
detail, is illustrated but not limited by the Examples below, which
demonstrates the efficacy of the administration of glufosfamide in
combination with a glucose lowering drug other than insulin to
treat cancer.
IV. EXAMPLES
Example 1
Glufosfamide Treatment of Patients Receiving Glucose Lowering Drugs
Other than Insulin
[0106] Seven diabetic patients (Group 1A) having gemcitabine
resistant pancreatic cancer were treated with glufosfamide for 2-11
cycles in combination with various glucose lowering drugs (GLDs)
other than insulin (see Table 2 below). Glufosfamide was
administered intravenously over 6 hours, once every 3 weeks, at
4500 mg/m.sup.2. The GLD was administered orally, once every day or
qd, 738-139 days prior to the first glufosfamide administration;
except that, the GLD was administered to patient no. 6 three times
daily or tid. Fourteen diabetic patients (Group 2A) who did not
receive GLDs and glufosfamide, received BSC. Tumor assessment was
performed at baseline and once every 6 weeks for the first 24 weeks
and then once every 9 weeks. Efficacy outcomes were evaluated based
on comparing the overall median survival in Group 1A with that in
Group 2A. The median overall survival in the Group 1A patients was
418 days (95% CI; 85 days-643 days) compared to 84 days (95% CI; 45
days-102 days) for those in group 2A (FIG. 3). The results
demonstrate that glufosfamide administered in combination with a
glucose lowering drug other than insulin is effective in treatment
of gemcitabine resistant pancreatic cancer in diabetic
patients.
TABLE-US-00002 TABLE 2 GLD Glufosfamide admin- Amount
administration Ac- istered of cycles (4500 tual Pa- for days GLD
mg/m.sup.2 over a over- tient GLD prior to first admin- period of 6
all I.D. admin- Glufosfamide istered hours once sur- No. istered
administration (mg) every 3 weeks) vival 1 Glipizide 738 5 11 418 2
Glibenclam- 462 5 2 85 ide 3 Rosiglit- 453 8 2 479 azone maleate 4
Glimepiride 154 2 2 54 5 Gliclazide 139 40 2 145 6 Glibenclam- 308
1 tablet 14 643 ide 7 Gliclazide 657 90 4 476+
Example 2
Co-Administration of Glufosfamide and Glimepiride
[0107] This example demonstrates the efficacy of glufosfamide
administered in combination with a glucose lowering drug,
glimepiride, for the treatment of cancer. A total of sixty male NCr
nu/nu mice, 5-6 weeks old, were used in the study. Original
breeding pairs were purchased from Taconic, Germantown, N.Y. Test
animals were bred and maintained in a HEPA filtered environment for
the experiment. Cages, food and bedding were autoclaved. The animal
diets were obtained from PMI Nutrition International Inc.
(Brentwood, Mo.).
[0108] RFP expression vector: The pDsRed-2 vector was purchased
from Clontech (Palo Alto, Calif.). The vector expresses enhanced
RFP and the neomycin resistance gene on the same bicistronic
message that contains an internal ribosome entry site.
[0109] RFP vector production: PT67, an NIH3T3-derived packaging
cell line, expressing the 10 Al viral envelope, was purchased from
Clontech. PT67 cells were cultured in DMEM supplemented with 10%
fetal bovine serum. For vector production, packaging cells (PT67),
at 70% confluence, were incubated with a precipitated mixture of
N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl
sulfate reagent and saturating amounts of pDsRed-2 plasmid for 18
h. Fresh medium was replenished at this time. The cells were
examined by fluorescence microscopy 48 h post-transfection. For
selection, the cells were cultured in the presence of 200-1000
.mu.g/ml G418 for 7 days.
[0110] RFP gene transduction of MiaPaCa-2 cells: For RFP gene
transduction, 20% confluent MiaPaCa-2 cells (ATCC, Rockville, Md.)
were incubated with a 1:1 precipitated mixture of retroviral
supernatants of PT67 cells and RPMI 1640 for 72 h. Fresh medium was
replenished at this time. MiaPaCa-2 cells were harvested by
trypsin-EDTA 72 h posttransduction and subcultured at a ratio of
1:15 into selective medium that contained 200 .mu.g/ml G418. The
level of G418 was increased to 1000 .mu.g/ml stepwise. The
brightest MiaPaCa-2 cell clones expressing RFP were selected,
combined, and then amplified and transferred by conventional
culture methods.
[0111] Subcutaneous Xenografts: Tumor stocks were made by
subcutaneously injecting MiaPaCa-2-RFP cells at a concentration of
5.times.10.sup.6 cells/200 W into the flank of nude mice. see e.g.,
Bouvet et al. Cancer Res., 2002, 62, 1534-40 incorporated herein by
reference. The strong RFP expression of tumors grown in the
subcutis of mice was confirmed before harvest. The tumor tissues
harvested from s.c growth in nude mice were inspected, and any
grossly necrotic or suspected necrotic or non-RFP tumor tissues
were removed. Tumor tissues were subsequently cut into small
fragments of approximately 2 mm.sup.3.
[0112] Surgical Orthotopic Implantation (SOD: The animals were
transplanted by surgical orthotopic implantation (SOI) using the
MiaPaCa-2-RFP tumor fragments harvested from the stock animals. The
animals were anesthetized with isoflurane and the surgical area was
sterilized using iodine and alcohol. An incision approximately 1.5
cm long was made in the left upper abdomen of the nude mouse using
a pair of surgical scissors. The pancreas was exposed, and then two
pieces of the MiaPaCa-2-RFP tumor fragments of 2 mm.sup.3 were
transplanted to the mouse pancreas with 8-0 surgical sutures
(nylon) after the capsule of the transplantation site had been
stripped. The abdomen was closed with 6-0 surgical sutures (silk).
All procedures of the operation described above were performed with
a 7.times. magnification microscope (Olympus) under HEPA filtered
laminar flow hoods.
[0113] Study animals: The orthotopically-transplanted animals used
for the study were divided into 6 groups 1 day after SOI. Groups
for each of the cohort conditions were randomly chosen. Treatment:
Treatments were started on day 1 after SOL Table 3 shows the
treatment schedule.
TABLE-US-00003 TABLE 3 Num- Dose Dosing ber of Group Agents (mg/kg)
Schedule Route Mice 1 Untreated -- -- -- 10 Control 2 Glufosfamide
50 qd .times. 7 i.v. 10 3 Glemiperide + 0.2 + 50 qd .times. 14 +
p.o. + i.v. 10 Glufosfamide qd .times. 7 4 Glemiperide + 1.0 + 50
qd .times. 14 + p.o. + i.v. 10 Glufosfamide qd .times. 7 5
Glemiperide + 12 + 50 qd .times. 14 + p.o. + i.v. 10 Glufosfamide
qd .times. 7 6 Glemiperide 12 qd .times. 14 p.o 10
[0114] Primary tumor size and body weight measurement: Primary
tumor sizes and body weights were measured weekly using an
electronic caliper and an electronic scale. Primary tumor sizes
were estimated by measuring the perpendicular minor dimension (W)
and major dimension (L). Approximate tumor volume was calculated by
the formula (W.sup.2.times.L).times.1/2.
[0115] Fluorescence optical tumor imaging (FOTI): The FluorVivo
imaging system (INDEC Biosystems, Santa Clara, Calif.) was used for
whole body and open imaging. Whole body optical imaging of
GFP-expressing tumors was performed once a week after GFP-visible
tumors were established. At necropsy, open imaging was acquired for
each animal.
[0116] Study endpoint: The study was ended when the last animal
died on Aug. 15, 2007. Test animals were opened and imaged to
visualize metastasis. The primary tumor was excised and weighed
using an electronic balance.
[0117] Statistical methods used in efficacy evaluation: Tumor
volumes and tumor weights were compared using the Student's t-test
with an .alpha.=0.05. Metastatic frequency of all groups were
analyzed with Fisher's exact test with an .alpha.=0.05. Comparison
of animal survival time between each treatment group and untreated
control was analyzed using the Log-rank analysis with an
.alpha.=0.05.
[0118] The survival improvement is graphically shown in FIG. 4 and
demonstrates that when administered in combination with glimepiride
(12 mg/kg), glufosfamide (50 mg/kg) was more effective in extending
survival compared to glufosfamide administered alone. Median
overall survival was 35 days (log rank p-value <0.01) for
glufosfamide administered in combination with glimepiride (12
mg/kg), compared to 26 days for treatment with glufosfamide
alone.
[0119] 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.
[0120] 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.
* * * * *
References