U.S. patent application number 11/074849 was filed with the patent office on 2005-07-07 for compositions and methods for the treatment of cancer.
This patent application is currently assigned to Celgene Corporation. Invention is credited to Barer, Sol, Zeitlin, Andrew L., Zeldis, Jerome B..
Application Number | 20050148524 11/074849 |
Document ID | / |
Family ID | 22756804 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050148524 |
Kind Code |
A1 |
Zeldis, Jerome B. ; et
al. |
July 7, 2005 |
Compositions and methods for the treatment of cancer
Abstract
This invention relates to compositions comprising thalidomide
and another anti-cancer drug which can be used in the treatment or
prevention of cancer. Preferred anti-cancer drugs are topoisomerase
inhibitors. A particular composition comprises thalidomide, or a
pharmaceutically acceptable salt, solvate, or clathrate thereof,
and irinotecan. The invention also relates to methods of treating
or preventing cancer which comprise the administration of a
thalidomide and another anti-cancer drug to a patient in need of
such treatment or prevention. The invention further relates to
methods of reducing or avoiding adverse side effects associated
with the administration of chemotherapy or radiation therapy which
comprise the administration of thalidomide to a patient in need of
such reduction or avoidance.
Inventors: |
Zeldis, Jerome B.;
(Princeton, NJ) ; Zeitlin, Andrew L.; (Basking
Ridge, NJ) ; Barer, Sol; (Westfield, NJ) |
Correspondence
Address: |
JONES DAY
51 Louisiana Aveue, N.W
WASHINGTON
DC
20001-2113
US
|
Assignee: |
Celgene Corporation
|
Family ID: |
22756804 |
Appl. No.: |
11/074849 |
Filed: |
March 9, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11074849 |
Mar 9, 2005 |
|
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09853617 |
May 14, 2001 |
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60204143 |
May 15, 2000 |
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Current U.S.
Class: |
514/43 ; 514/283;
514/323; 514/690 |
Current CPC
Class: |
A61K 31/724 20130101;
A61P 43/00 20180101; A61P 35/00 20180101; A61K 31/7056 20130101;
A61K 31/4745 20130101; A61K 31/47 20130101; A61K 31/454 20130101;
A61K 31/47 20130101; A61K 31/445 20130101; A61K 31/454 20130101;
A61K 2300/00 20130101; A61K 31/47 20130101; A61K 2300/00 20130101;
A61K 31/4745 20130101; A61K 2300/00 20130101; A61K 31/7056
20130101; A61K 2300/00 20130101; A61K 31/724 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/043 ;
514/283; 514/323; 514/690 |
International
Class: |
A61K 031/7052; A61K
031/454; A61K 031/4745 |
Claims
1-60. (canceled)
61. A method for treating multiple myeloma in a subject comprising
administering an amino analogue of thalidomide in combination with
irinotecan.
62. The method of claim 61, wherein the irinotecan is a
pharmaceutically acceptable salt.
63. The method of claim 62, wherein the pharmaceutically acceptable
salt of irinotecan is a hydrochloride salt.
64. The method of claim 63, wherein the irinotecan hydrochloride
salt is CPT- 11.
65. The method of claim 61, wherein the irinotecan is administered
as an oral dosage form.
66. The method of claim 61, wherein the amino analogue of
thalidomide is administered as an oral dosage form.
67. The method of claim 61, wherein the amino analogue of
thalidomide and irinotecan are administered sequentially.
68. The method of claim 67, wherein amino analogue of thalidomide
and irinotecan are administered sequentially in any order.
69. The method of claim 1, wherein the amino analogue of
thalidomide and irinotecan are administered simultaneously.
70. The method of claim 61, wherein the subject has had prior
chemotherapy.
71. The method of claim 70, wherein the prior chemotherapy
comprises treatment with MP, VAD, or treatment with one or more
alkylating agents.
72. The method of claim 70, wherein the prior chemotherapy
comprises treatment with cyclophosphamide and etoposide, or
treatment with etoposide, dexamethasone and doxorubicin.
73. The method of claim 70, wherein amino analogue of thalidomide
and irinotecan are administered sequentially, in any order.
74. The method of claim 70, wherein amino analogue of thalidomide
and irinotecan are administered simultaneously.
75. A pharmaceutical preparation for the treatment of multiple
myeloma comprising an amino analogue of thalidomide and
irinotecan.
76. The pharmaceutical preparation of claim 75 wherein the the
amino analogue of thalidomide and irinotecan are provided in a
single dosage device.
77. The pharmaceutical preparation of claim 75 wherein the amino
analogue of thalidomide and the irinotecan are provided in separate
dosage devices.
78. A method for treating multiple myeloma in a patient comprising
administering an oral amino analogue of thalidomide in combination
with oral irinotecan.
79. The method of claim 78, wherein the irinotecan is a
pharmaceutically acceptable salt form.
80. The method of claim 79, wherein the pharmaceutically acceptable
salt form of irinotecan is a hydrochloride salt.
81. The method of claim 80, wherein the irinotecan hydrochloride
salt is CPT-11.
82. The method of claim 78, wherein the amino analogue of
thalidomide and irinotecan are administered sequentially.
83. The method of claim 82, where the amino analogue of thalidomide
and irinotecan are administered sequentially in any order.
84. The method of claim 78, wherein the amino analogue of
thalidomide and irinotecan are administered simultaneously.
Description
1. FIELD OF THE INVENTION
[0001] This invention relates to pharmaceutical compositions
comprising thalidomide and an anti-cancer agent, particularly a
topoisomerase inhibitor, to methods of treating cancer, and to
methods of reducing or avoiding adverse effects associated with
anti-cancer agents such as topoisomerase inhibitors.
2. BACKGROUND OF THE INVENTION
[0002] The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible
populations (e.g., people infected with AIDS) grow. A tremendous
demand therefore exists for new methods and compositions that can
be used to treat patients with cancer.
2.1. Pathobiology of Cancer
[0003] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, or lymphatic
or blood-bome spread of malignant cells to regional lymph nodes and
to distant sites (metastasis). Clinical data and molecular biologic
studies indicate that cancer is a multistep process that begins
with minor preneoplastic changes, which may under certain
conditions progress to neoplasia.
[0004] Pre-malignant abnormal cell growth is exemplified by
hyperplasia, metaplasia, or most particularly, dysplasia (for
review of such abnormal growth conditions, see Robbins and Angell,
1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp.
68-79). Hyperplasia is a form of controlled cell proliferation
involving an increase in cell number in a tissue or organ, without
significant alteration in structure or function. As but one
example, endometrial hyperplasia often precedes endometrial cancer.
Metaplasia is a form of controlled cell growth in which one type of
adult or fully differentiated cell substitutes for another type of
adult cell. Metaplasia can occur in epithelial or connective tissue
cells. Atypical metaplasia involves a somewhat disorderly
metaplastic epithelium. Dysplasia is frequently a forerunner of
cancer, and is found mainly in the epithelia; it is the most
disorderly form of non-neoplastic cell growth, involving a loss in
individual cell uniformity and in the architectural orientation of
cells. Dysplastic cells often have abnormally large, deeply stained
nuclei, and exhibit pleomorphism. Dysplasia characteristically
occurs where there exists chronic irritation or inflammation, and
is often found in the cervix, respiratory passages, oral cavity,
and gall bladder.
[0005] The neoplastic lesion may evolve clonally and develop an
increasing capacity for invasion, growth, metastasis, and
heterogeneity, especially under conditions in which the neoplastic
cells escape the host's immune surveillance. Roitt, I., Brostoff, J
and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis:
1993).
[0006] Descriptions of only a few types of cancers are provided
below. Characteristics of other types of cancers are well known to
medical practitioners, and are described in the medical
literature.
2.2. AIDS-Related Non-Hodgkin's Lymphoma
[0007] AIDS has been closely associated with a variety of cancers.
Further, the types of malignancies and their incidence rates are
increasing as the development of effective antiretroviral therapies
and prophylaxis against opportunistic infections leads to prolonged
survival in the immunodeficient state for AIDS patients. Karp and
Broder, Cancer Res. 51:4747-4756 (1991). AIDS-related non-Hodgkin's
lymphoma is a very aggressive disease with a very high incidence of
central nervous system involvement. Since its discovery in 1981,
the incidence of AIDS-related non-Hodgkin's lymphoma has reportedly
increased. One reason for such an observation is that patients
infected with the AIDS virus now live longer than they used to.
2.3. Primary and Metastatic CNS Tumors
[0008] The incidence of primary and metastatic brain tumors is also
increasing in the United States. Unfortunately, the arsenal of
chemotherapeutics for these types of cancers is minimal, while the
need for such therapeutics is high.
[0009] Glioblastoma multiform and other primary and metastatic
central nervous system tumors are devastating malignancies. The
treatment of these tumors include surgery, radiation therapy and
treatment with agents such as the nitrosourea BCNU. Other
chemotherapeutic agents utilized include procarbazine, vincristine,
hydroxyurea and cisplatin. But even when all three modalities
(surgery, radiation therapy and chemotherapy) are utilized, the
average survival of patients with central nervous system
malignancies is only about 57 weeks. Clearly, new treatment
approaches are needed both for patients with newly diagnosed
primary and metastatic central nervous system tumors, as well as
for patients with such tumors which are refractory to the above
modalities.
2.4. Breast, Lung, Bladder and Prostate Cancers
[0010] In the United States, the cumulative risk of developing
breast cancer is reportedly about 10.2 percent. The Merck Manual
1815 (16.sup.th ed. 1992). The treatment for early breast cancer is
surgery, with or without radiation therapy, or surgery, with or
without radiation therapy, plus chemotherapy and/or hormonal
therapy. Current chemotherapy for patients with primary or
metastatic breast cancer includes treatment with cyclophosphamide,
methotrexate, doxorubicin, 5-fluorouracil, cisplatin, vinblastine,
taxol, taxotere, mitomycin C and occasionally other agents.
Unfortunately, even with these agents, almost all women who develop
metastatic breast cancer succumb to their disease. One particular
place that metastatic breast cancer does metastasize to is the
central nervous system. When central nervous system metastases do
occur, the usual treatment is surgery (for a solitary metastasis)
or radiation, or surgery plus radiation therapy.
[0011] Lung cancer is reportedly the leading cause of cancer death
in men and women. The Merck Manual 731 (16.sup.th ed. 1992). A
variety of causes exist, but cigarette smoking accounts for greater
than 90 percent of reported cases in men and greater than 70
percent of reported cases in women. Id.
[0012] Most patients with lung cancer present a tumor that has
already metastasized to a variety of organs, including lung, liver,
adrenal gland and other organs. Treatment of metastatic lung cancer
is not yet standardized. Ihde, D. C., The New England Journal of
Medicine 327:1434-1441 (1992). However, chemotherapy regimens that
are utilized include treatment with cisplatin plus etoposide,
combinations of cyclophosphamide plus doxorubicin plus cisplatin,
and single agents alone or in combination, including ifosfamide,
teniposide, vindesine, carboplatin, vincristine, taxol, nitrogen
mustard, methotrexate, hexamethylmelamine and others. Despite these
chemotherapeutic regimens the average patient with metastatic lung
cancer still only survives 7-12 months. One particular troublesome
place for metastases of lung cancer is the central nervous system.
The treatment for central nervous system metastases includes
surgery (to remove a solitary lesion), radiation therapy, or a
combination of both.
[0013] Each year about 50,000 new cases of bladder cancer are
reported in the United States. The Merck Manual 1749 (16.sup.th ed.
1992). Although at presentation the disease is usually localized,
most patients develop distant metastatic disease. The most recent
advances have been in the area of chemotherapy for patients with
such metastatic disease. One effective regimen is called the MVAC
regimen. It consists of treatment with methotrexate plus
vinblastine plus adriamycin (doxorubicin) plus cisplatin. Although
the response rate is high to this chemotherapeutic regimen, medical
oncologists are noting that one place the patients fail is with
metastases to the central nervous system.
[0014] It is estimated that more than 120,000 men will be diagnosed
with prostate cancer this year. The Merck Manual 1750 (16.sup.th
ed. 1992). The most common sites of metastases in patients with
prostate cancer are the bone and lymph nodes. The bone metastases
are particularly bothersome in that they can create intense pain
for the patient. The current treatment for metastatic prostate
cancer includes treatment with flutamide, leuprolide,
diethylstilbestrol, and other hormonal manipulations, as well as
chemotherapy (doxorubicin, estramustine phosphate, vinblastine,
suramin, cisplatin, and others). Unfortunately, none of these
agents are consistently helpful in the disease. In addition, as
patients with prostate cancer live longer with their malignancy,
they will most likely develop a higher incidence of metastases to
the central nervous system (including the spinal cord).
2.5. Esophageal Cancer
[0015] Several years ago, carcinoma of the esophagus reportedly
represented only about six percent of all cancers of the
gastrointestinal tract; however, it reportedly caused a
disproportionate number of cancer deaths. Boring, C. C., et al., CA
Cancer J. Clin. 43:7 (1993). These cancers usually arise from the
epithelial layer of the esophagus and are either squamous cell
carcinomas or adenocarcinomas. Overall, the 5 year survival is
about five percent.
2.6. Leukemia
[0016] Leukemia refers to malignant neoplasms of the blood-forming
tissues. Although viruses reportedly cause several forms of
leukemia in animals, causes of leukemia in humans are to a large
extend unknown. The Merck Manual 1233 (16.sup.th ed. 1992).
Transformation to malignancy typically occurs in a single cell
through two or more steps with subsequent proliferation and clonal
expansion. In some leukemias, specific chromosomal translocations
have been identified with consistent leukemic cell morphology and
special clinical features (e.g., translocations of 9 and 22 in
chronic myelocytic leukemia, and of 15 and 17 in acute
promyelocytic leukemia). Acute leukemias are predominantly
undifferentiated cell populations and chronic leukemias more mature
cell forms.
[0017] Acute leukemias are divided into lymphoblastic (ALL) and
non-lymphoblastic (ANLL) types. They may be further subdivided by
their morphologic and cytochemical appearance according to the
French-American-British (FAB) classification or according to their
type and degree of differentiation. The use of specific B- and
T-cell and myeloid-antigen monoclonal antibodies are most helpful
for classification. ALL is predominantly a childhood disease which
is established by laboratory findings and bone marrow examination.
ANLL, also known as acute myeloblastic leukemia (AML), occurs at
all ages and is the more common acute leukemia among adults; it is
the form usually associated with irradiation as a causative
agent.
[0018] Chronic leukemias are described as being lymphocytic (CLL)
or myelocytic (CML). CLL is characterized by the appearance of
mature lymphocytes in blood, bone marrow, and lymphoid organs. The
hallmark of CLL is sustained, absolute lymphocytosis
(>5,000/.mu.L) and an increase of lymphocytes in the bone
marrow. Most CLL patients also have clonal expansion of lymphocytes
with B-cell characteristics. CLL is a disease of older persons. In
CML, the characteristic feature is the predominance of granulocytic
cells of all stages of differentiation in blood, bone marrow,
liver, spleen, and other organs. In the symptomatic patient at
diagnosis the total WBC count is usually about 200,000/.mu.L, but
may reach 1,000,000/.mu.L. CML is relatively easy to diagnose
because of the presence of the Philadelphia chromosome.
[0019] The very nature of hematopoietic cancer necessitates using
systemic chemotherapy as the primary treatment modality, and
radiation therapy may be used as an adjunct to treat local
accumulations of leukemic cells. Surgery is rarely indicated as a
primary treatment modality, but may be used in managing some
complications. Bone marrow transplantation from an HLA-matched
sibling is sometimes indicated.
2.7. Colorectal Cancers
[0020] In 1999, the incidence of colorectal cancer in the United
States was 129,400 cases. In Western countries, cancers of the
colon and rectum account for more new cases of cancer than those of
any other anatomic site except the lung. The Merck Manual 852
(16.sup.th ed. 1992). Most colorectal cancers are
adenocarcinomas.
[0021] Despite the enormous number of deaths attributed to
colorectal cancers, their specific mechanism remains unknown. It is
known, however, that cancers of the colon and rectum spread in at
least five ways: directed extension through the bowel wall;
hematogenous metastases; regional lymph node metastases; perineural
spread; and intraluminal metastases. Id.
[0022] Primary treatment of colorectal cancers typically includes
surgery. Many patients, however, must also be treated with a
combination of radiation and chemotherapy. As of 1992, the most
effective chemotherapy regime consisted of the administration of
5-fluorouracil (5FU) and methyl-CCNU. Id.
2.8. Topoisomerase Inhibitors
[0023] Topoisomerases are enzymes that catalyze the relaxation of
negatively supercoiled deoxyribonucleic acid (DNA). The process
they catalyze is believed to comprise three steps: cleavage of one
or both strands of a supercoiled DNA; passage of a segment of DNA
through the break that is formed; and resealing of the break. Type
I topoisomerases cleave one strand of DNA; type II topoisomerases
cleave both strands. Stryer, L., Biochemistry 662-663 (3.sup.rd
ed., 1988).
[0024] Because supercoiled double-stranded DNA must be unwound
before processes such as replication, recombination, and
transcription can occur, inhibition of the unwinding process can
have dramatic consequences. For example, compounds that prevent or
slow topoisomerase activity can be used to prevent cell growth
and/or cause cell death. Such compounds, which are referred to as
"topoisomerase inhibitors," have thus shown promise in the
treatment of various types of cancer. Camptothecin and its
analogues are examples of topoisomerase inhibitors that exert their
effect by stabilizing DNA-topoisomerase I complexes, thereby
leaving an irreversible break in the double-stranded DNA with which
they are associated. Avgeropoulos, N. G., and Batchelor, T. T., The
Oncologist 4:209-224 (1999).
[0025] A specific camptothecin analogue is irinotecan (also
referred to as CPT-11), which is chemically named
(4S)-4,11-diethyl-4-hydroxy-9-[(4-pipe-
ridino-piperidino)carbonyl-oxy]1H-pyranol-[3',4':6,7]indolizinol[1,2-b]qui-
noline-3,14-(4H,12H)dione and is described in U.S. Pat. No.
4,604,463. The hydrochloride trihydrate of irinotecan is sold under
the tradename CAMPTOSAR.RTM., and is indicated in the United States
for the treatment of patients with metastatic carcinoma of the
colon or rectum that recurred or progressed following
5-fluorouracil based therapy. Physicians' Desk Reference, 2412-2418
(54.sup.th ed., 2000). It has also recently been approved in the
United States as a first-line therapy to treat patients with
metastic colorectal cancer in combination with 5-fluorouracil and
leucovorin. Irinotecan has also reportedly been used to treat other
cancers, such as malignant gliomas and NSCLC. See, e.g.,
Avgeropoulos, N. G., and Batchelor, T. T., The Oncologist 4:209-224
(1999).
[0026] Like other topoisomerase inhibitors, irinotecan and its
metabolites (e.g., SN-38) have numerous adverse effects. Examples
of such adverse effects include, but are not limited to, early and
late-forming diarrhea, nausea, vomiting, anorexia, constipation,
flatulence, leukopenia, anemia, neutropenia, asthenia, abdominal
cramping, fever, pain, loss of body weight, dehydration, alopecia,
dyspnea, insomnia, and dizziness. See, e.g., Physicians' Desk
Reference, 2415 (54.sup.th ed., 2000). The mechanisms by which
these undesired effects occur are not well understood, but are
believed to be different. In particular, the early and late-forms
of diarrhea typically experienced by patients are reportedly
mediated by different mechanisms. Id. But whatever their cause, the
severity of one or more of their adverse effects limits the amount
of topoisomerase inhibitors that can be administered to patients.
The effectiveness of topoisomerase inhibitors such as irinotecan is
consequently limited not only by their ability to inhibit
topoisomerase activity, but also by the severity and nature of
their adverse effects.
[0027] Attempts have been made to alleviate adverse effects
associated with irinotecan. For example, loperamide and the
combination of loperamide and acetorphan have reportedly been
administered to patients in an effort to reduce delayed-onset
diarrhea. Rothenberg, M. L., Annals of Oncology 8:837-855 (1997).
Unfortunately, these attempts met with limited success. Id.
2.9. Thalidomide
[0028] Thalidomide is a racemic compound sold under the tradename
THALOMID.RTM. and chemically named
.alpha.-(N-phthalimido)glutarimide or
2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione. Thalidomide
was originally developed in the 1950's to treat morning sickness,
but due to its tetragenic effects was withdrawn from use.
Thalidomide is now indicated in the United States for the acute
treatment of the cutaneous manifestations of erythema nodosum
leprosum. Physicians' Desk Reference, 911-916 (54.sup.th ed.,
2000). Because its administration to pregnant women can cause birth
defects, the sale of thalidomide is strictly controlled. Id.
[0029] In addition to treating symptoms of leprosy, thalidomide has
reportedly been used to treat chronic graft-vs-host disease,
rheumatoid arthritis, sarcoidosis, several inflammatory skin
diseases, and inflammatory bowel disease. See generally, Koch, H.
P., Prog. Med. Chem. 22:165-242 (1985). See also, Moller, D. R., et
al., J. Immunol. 159:5157-5161 (1997); Vasiliauskas, E. A., et al.,
Gastroenterology 117:1278-1287 (1999); and Ehrenpreis, E. D., et
al., Gastroenterology 117:1271-1277 (1999). It has further been
alleged that thalidomide can be combined with other drugs to treat
iscehemia/reperfusion associated with coronary and cerebral
occlusion. See U.S. Pat. No. 5,643,915, which is incorporated
herein by reference.
[0030] Thalidomide has also reportedly been clinically investigated
in the treatment of specific types of cancers. These include
refractory multiple myeloma, brain, melanoma, breast, colon,
mesothelioma, and renal cell carcinoma. See, e.g., Singhal, S., et
al., New England J. Med. 341(21):1565-1571 (1999); and Marx, G. M.,
et al., Proc. Am. Soc. Clin. Oncology 18:454a (1999). It has
further been reported that thalidomide can be used to prevent the
development of chronic cardiomyopathy in rats caused by
doxorubicin. Costa, P. T., et al., Blood 92(10:suppl. 1):235b
(1998). Other reports concerning the use of thalidomide in the
treatment of specific cancers include its combination with
carboplatin in the treatment of glioblastoma multiforme. McCann,
J., Drug Topics 41-42 (Jun. 21, 1999). Thalidomide has reportedly
also been used as an antiemetic during the treatment of
astrocytoma. Zwart, D., Arzneim.-Forsch. 16(12):1688-1689
(1966).
[0031] If there is a general mechanism by which thalidomide aids in
the treatment of some cancers, its nature remains unclear. See,
e.g., Moreira, A. L., et al., J. Expr. Med. 177:1675-1680 (1993);
McHugh, S. M., et al., Clin. Exper. Immunol. 99:160-167 (1995); and
Moller, D. R., et al., J. Immunol. 159:5157-5161 (1997). It has
been reported, however, that thalidomide is an antiangiogenic agent
that can suppress tumor necrosis factor .alpha. (TNF-.alpha.) and
interleukin 12 (IL-12) production. See, e.g., Moller, D. R., et
al., J. Immunol. 159:5157-5161 (1997); Moreira, A. L., et al., J.
Exp. Med. 177:1675-1680 (1993); U.S. Pat. Nos. 5,593,990,
5,629,327, and 5,712,291 to D'Amato and U.S. Pat. No. 5,385,901 to
Kaplan. And in vitro studies suggest that thalidomide affects the
production of a variety of other proteins. See, e.g., McHugh, S.
M., et al., Clin. Exp. Immunol. 99:160-167 (1995). Thalidomide may
also affect mechanisms related to epithelial or endothelial
function or growth. D'amato M., et al., Proc. Natl. Acad. Sci.
91:4082-4085(1994).
[0032] Given the great need for an effective and safe treatment of
cancer, there continues to be an extensive amount of research on
new drugs or ways of improving existing therapies. This invention
addresses the need for a safe and effective cancer treatment.
3. SUMMARY OF THE INVENTION
[0033] This invention is directed to pharmaceutical compositions,
pharmaceutical dosage forms, kits, methods of treating or
preventing cancer, methods of reducing or avoiding adverse effects
associated with chemotherapy and radiation therapy, and methods of
improving the tolerance of patients to chemotherapy and radiation
treatment.
[0034] A first embodiment of the invention encompasses a method of
treating primary and/or metastatic cancer, which comprises
administering to a patient in need of such treatment a
therapeutically effective amount of a topoisomerase inhibitor, or a
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, and a therapeutically effective amount of
thalidomide, or a pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof.
[0035] Specific examples of cancers that can be treated by this
method include, but are not limited to, cancer of the head, neck,
eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum,
stomach, prostate, breast, ovaries, kidney, liver, pancreas, and
brain. A specific cancer that can be treated by this method is
metastatic colorectal cancer.
[0036] A second embodiment of the invention encompasses a method of
increasing the dosage of a topoisomerase inhibitor that can be
safely and effectively administered to a patient, which comprises
administering to a patient in need of such an increased dosage an
amount of thalidomide, or a pharmaceutically acceptable prodrug,
salt, solvate, hydrate, or clathrate thereof, that is sufficient to
reduce a dose-limiting adverse effect associated with the
topoisomerase inhibitor. In a preferred method of this embodiment,
thalidomide is administered orally and daily in an amount of from
about 1 to about 2000 mg, preferably from about 50 to about 1000
mg, more preferably from about 100 to 750 mg, and most preferably
from about 200 to about 500 mg.
[0037] Examples of dose-limiting adverse effects associated with
topoisomerase inhibitors include, but are not limited to:
gastrointestinal toxicity such as, but not limited to, early and
late-forming diarrhea and flatulence; nausea; vomiting; anorexia;
leukopenia; anemia; neutropenia; asthenia; abdominal cramping;
fever; pain; loss of body weight; dehydration; alopecia; dyspnea;
insomnia; dizziness, mucositis, xerostomia, and kidney failure.
Specific dose-limiting adverse effects are early-forming diarrhea
and late-forming diarrhea.
[0038] A third embodiment of the invention encompasses a method of
reducing or preventing an adverse effect associated with
chemotherapy or radiation therapy, which comprises administering to
a patient in need of such treatment or prevention an amount of
thalidomide, or a pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof, that is sufficient to
reduce an adverse effect associated with the chemotherapy or
radiation therapy. This embodiment includes the use of thalidomide
to protect against or treat an adverse effect associated with the
use of chemotherapy or radiation therapy. The use of the
thalidomide in this embodiment encompasses raising a patient's
tolerance for chemotherapy or radiation therapy. In a preferred
method of this embodiment, thalidomide is administered orally and
daily in an amount of from about 1 to about 2000 mg, preferably
from about 50 to about 1000 mg, more preferably from about 100 to
750 mg, and most preferably from about 200 to about 500 mg.
[0039] Examples of adverse effects associated with chemotherapy and
radiation therapy include, but are not limited to: gastrointestinal
toxicity such as, but not limited to, early and late-forming
diarrhea and flatulence; nausea; vomiting; anorexia; leukopenia;
anemia; neutropenia; asthenia; abdominal cramping; fever; pain;
loss of body weight; dehydration; alopecia; dyspnea; insomnia;
dizziness, mucositis, xerostomia, and kidney failure.
[0040] A fourth embodiment of the invention encompasses a method of
increasing the therapeutic efficacy of a topoisomerase inhibitor
which comprises administering to a patient in need of such
increased therapeutic efficacy an amount of thalidomide, or a
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, that is sufficient to increase the therapeutic
efficacy of the topoisomerase inhibitor.
[0041] A fifth embodiment of the invention encompasses a
pharmaceutical composition comprising a topoisomerase inhibitor, or
a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, and thalidomide, or a pharmaceutically
acceptable prodrug, salt, solvate, hydrate, or clathrate
thereof.
[0042] A sixth embodiment of the invention encompasses a dosage
form comprising a topoisomerase inhibitor, or a pharmaceutically
acceptable prodrug, salt, solvate, hydrate, or clathrate thereof,
and thalidomide, or a pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof.
[0043] A seventh embodiment of the invention encompasses a kit for
use in the treatment or prevention of cancer which comprises a
parenteral dosage form of irinotecan, or a pharmaceutically
acceptable prodrug, salt, solvate, hydrate, or clathrate thereof,
and an oral dosage form of thalidomide, or a pharmaceutically
acceptable prodrug, salt, solvate, hydrate, or clathrate
thereof.
[0044] Examples of topoisomerase inhibitors that can be used in the
methods, compositions, and kits of the invention include, but are
not limited to, camptothecin, iriniotecan, SN-38, topotecan,
9-aminocamptothecin, GG-211, DX-8951f, saintopin, UCE6, UCE1022,
TAN-1518A, TAN-1518B, KT6006, KT6528, ED-110, NB-506, ED-110,
NB-506, rebeccamycin, bulgarein, Hoescht dye 33342, Hoechst dye
33258, nitidine, fagaronine, epiberberine, coralyne,
beta-lapachone, BC-4-1, IST-622, rubitecan, pyrazoloacridine,
XR-5000, and pharmaceutically acceptable prodrugs, salts, solvates,
clathrates, hydrates, and metabolites thereof. Preferred
topoisomerase inhibitors include, but are not limited to,
irinotecan, SN-38, and pharmaceutically acceptable prodrugs, salts,
solvates, hydrates, and clathrates thereof. In certain embodiments,
the topoisomerase inhibitor is other than irinotecan.
3.1. Definitions
[0045] As used herein, the term "cancer" includes but is not
limited to solid tumors and blood born tumors. The term cancer
refers to disease of skin tissues, organs, bone, cartilage, blood
and vessels. The invention encompasses the treatment of various
types of cancer including but not limited to cancer of the head,
neck, eye, mouth, throat, esophagus, chest, bone, lung, colon,
rectum, stomach, prostate, breast, ovaries, kidney, liver,
pancreas, and brain. The term "cancer" further encompasses primary
and metastatic cancers, unless otherwise indicated.
[0046] As used herein to describe a compound or chemical moiety,
the term "derivative" means a compound or chemical moiety wherein
the degree of saturation of at least one bond has been changed
(e.g., a single bond has been changed to a double or triple bond)
or wherein at least one hydrogen atom is replaced with a different
atom or a chemical moiety. Examples of different atoms and chemical
moieties include, but are not limited to, halogen, oxygen,
nitrogen, sulfur, hydroxy, methoxy, alkyl, amine, amide, ketone,
and aldehyde.
[0047] As used herein, the term "prodrug" means a derivative of a
compound that can hydrolyze, oxidize, or otherwise react under
biological conditions (in vitro or in vivo) to provide the
compound. Examples of prodrugs include, but are not limited to,
derivatives of topoisomerase inhibitors or thalidomide that
comprise biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, and biohydrolyzable ureides.
[0048] As used herein, the terms "biohydrolyzable carbamate,"
"biohydrolyzable carbonate," and "biohydrolyzable ureide" mean a
carbamate, carbonate, or ureide, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable
carbamates include, but are not limited to, lower alkylamines,
substituted ethylenediamines, aminoacids, hydroxyalkylamines,
heterocyclic and heteroaromatic amines, and polyether amines.
[0049] As used herein, the term "biohydrolyzable ester" means an
ester of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound. Examples
of biohydrolyzable esters include, but are not limited to, lower
alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters,
and choline esters.
[0050] As used herein, the term "biohydrolyzable amide" means an
amide of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound. Examples
of biohydrolyzable amides include, but are not limited to, lower
alkyl amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides.
[0051] As used herein, the term "pure diastereomer" means a
composition that comprises one diastereomer of a compound and is
substantially free of other diastereomers of the compound. A
typically pure diastereomer is a compound comprising greater than
about 80% by weight of one diastereomer of a compound and less than
about 20% by weight of other diastereomers of the compound, more
preferably greater than about 90% by weight of one diastereomer of
a compound and less than about 10% by weight of other diastereomers
of the compound, even more preferably greater than about 95% by
weight of one diastereomer of a compound and less than about 5% by
weight of other diastereomers of the compound, and most preferably
greater than about 99% by weight of one diastereomer of a compound
and less than about 1% by weight of other diastereomers of the
compound.
[0052] As used herein, the terms "optically pure," "pure
enantiomer," and "optically pure enantiomer" mean a composition
that comprises one enantiomer of a compound and is substantially
free of the opposite enantiomer of the compound. A typical
optically pure enantiomers is a composition comprising greater than
about 80% by weight of one enantiomer of a compound and less than
about 20% by weight of the opposite enantiomer of the compound,
more preferably greater than about 90% by weight of one enantiomer
of a compound and less than about 10% by weight of the opposite
enantiomer of the compound, even more preferably greater than about
95% by weight of one enantiomer of a compound and less than about
5% by weight of the opposite enantiomer of the compound, and most
preferably greater than about 99% by weight of one enantiomer of a
compound and less than about 1% by weight of the opposite
enantiomer of the compound.
4. DETAILED DESCRIPTION OF THE INVENTION
[0053] This invention encompasses pharmaceutical compositions,
pharmaceutical dosage forms, kits, methods of treating diseases or
conditions such as cancer, methods of preventing metastases,
methods of improving the therapeutic profile of anti-cancer drugs,
and methods of reducing or avoiding adverse effects associated with
chemotherapy and radiation therapy.
[0054] This invention is based, in part, on the ability of
thalidomide to: (1) treat cancer; (2) improve the efficacy or
tolerability of other chemotherapeutic or radiation therapies for
cancer, or; (3) lessen the severity of certain dose-limiting
toxicities of other anti-cancer drugs. Embodiments of the invention
include a method of treating or preventing cancer which comprises
the administration of thalidomide, or a derivative, analogue,
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, in combination with at least one other
anti-cancer drug to a patient. Another embodiment of the invention
encompasses a method of reducing or avoiding adverse effects
associated with an anti-cancer drug, which comprises administering
thalidomide, or a derivative, analogue, pharmaceutically acceptable
prodrug, salt, solvate, hydrate, or clathrate thereof to a patient.
Examples of other anti-cancer drugs that can be used in methods of
the invention include, but are not limited to, taxol (paclitaxel),
taxotere (docetaxel), doxorubicin, cisplatin, topoisomerase
inhibitors, and other drugs described herein (e.g., those described
below in Section 4.1.1.). In one embodiment, the most preferred
anti-cancer drugs are topoisomerase inhibitors. Other embodiments
of the invention encompass pharmaceutical compositions,
pharmaceutical dosage forms, and kits comprising thalidomide, or a
derivative, analogue, pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof, and at least one other
anti-cancer drug.
[0055] This invention further encompasses methods of: 1) allowing
the completion of chemotherapy in a greater percentage of patients;
2) avoiding deterioration of patients' nutritional status secondary
to gastrointestinal toxicity; and 3) improving the overall quality
of patients' life during chemotherapy.
[0056] Preferred embodiments of the invention are based on the
unique ability of thalidomide to improve the overall therapeutic
profile of topoisomerase inhibitors when used in the treatment or
prevention of various primary or metastatic cancers. For example,
thalidomide as used in this invention can improve the efficacy of
topoisomerase inhibitors at their common or approved doses.
Thalidomide can further be used in combination with lower doses of
topoisomerase inhibitors to reduce or avoid adverse affects
associated with them while maintaining their efficacy. Thalidomide
can also be used in methods of this invention to reduce or avoid
adverse effects that are associated with the administration of
topoisomerase inhibitors. Indeed, a preferred use of thalidomide is
to reduce or avoid intolerance of topoisomerase inhibitors so that
they can be used in greater amounts in the treatment of cancer. And
a specific embodiment of the invention encompasses the use of
thalidomide to reduce or avoid gastrointestinal toxicity caused by
topoisomerase inhibitors. In short, this invention encompasses
therapeutic effects that result from an unexpected and unique
synergy between thalidomide and topoisomerase inhibitors. One of
these therapeutic effects is an increased potency or efficacy of
topoisomerase inhibitor; another is a reduced toxicity or increased
safety of topoisomerase inhibitor.
[0057] Compositions of the invention include bulk drug compositions
useful in the manufacture of pharmaceutical compositions (e.g.,
impure or non-sterile compositions), pharmaceutical compositions
(i.e., compositions that are suitable for administration to a
patient), and individual dosage forms. Each of the compositions and
dosage forms of the invention comprise at least two of what are
referred to herein as "active ingredients." A first active
ingredient is a topoisomerase inhibitor, or a pharmaceutically
acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. A
second active ingredient is thalidomide, a derivative or analogue
of thalidomide, or a pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof.
[0058] Examples of topoisomerase inhibitors that can be used in the
methods and compositions of the invention include, but are not
limited to: camptothecin; irinotecan; SN-38; topotecan;
9-aminocamptothecin; GG-211 (GI 147211); DX-8951f; IST-622;
rubitecan; pyrazoloacridine; XR-5000; saintopin; UCE6; UCE1022;
TAN-1518A; TAN-1518B; KT6006; KT6528; ED-110; NB-506; ED-110;
NB-506; and rebeccamycin; bulgarein; DNA minor groove binders such
as, but limited to, Hoescht dye 33342 and Hoechst dye 33258;
nitidine; fagaronine; epiberberine; coralyne; beta-lapachone;
BC-4-1; and pharmaceutically acceptable salts, solvates,
clathrates, and prodrugs thereof. See, e.g., Rothenberg, M. L.,
Annals of Oncology 8:837-855(1997); and Moreau, P., et al., J. Med.
Chem. 41:1631 -1640(1998). Examples of camptothecin derivatives
that can be used in the methods and compositions of this invention
are disclosed by, for example, U.S. Pat. Nos.: 6,043,367;
6,040,313; 5,932,588; 5,916,896; 5,889,017; 5,801,167; 5,674,874;
5,658,920; 5,646,159; 5,633,260; 5,604,233; 5,597,829; 5,552,154;
5,541,327; 5,525,731; 5,468,754; 5,447,936; 5,446,047; 5,401,747;
5,391,745; 5,364,858; 5,340,817; 5,244,903; 5,227,380; 5,225,404;
5,180,722; 5,122,606; 5,122,526; 5,106,742; 5,061,800; 5,053,512;
5,049,668; 5,004,758; 4,981,968; 4,943,579; 4,939,255; 4,894,456;
and 4,604,463, each of which is incorporated herein by reference.
Preferred topoisomerase inhibitors include, but are not limited to,
irinotecan, SN-38, and pharmaceutically acceptable salts, solvates,
clathrates, and prodrugs thereof.
[0059] Many topoisomerase inhibitors comprise one or more chiral
centers. The methods and compositions of the invention encompass
the use of racemic mixtures of such topoisomerase inhibitors, as
well as enriched (i.e., uneven) mixtures of their diastereomers or
enantiomers, and pure diastereomers or enantiomers of such
inhibitors. Pure or substantially pure diastereomers or enantiomers
of topoisomerase inhibitors can be prepared by methods well known
in the art. These include, but are not limited to, resolution of
chiral salts, asymmetric synthesis, or chiral chromatography. See
generally, Beesley, T. E. and Scott, R. P. W., Chiral
Chromatography (John Wiley & Sons, New York: 1999); Principles
of Asymmetric Synthesis, Gawley, R. E. and Aube, J., eds.
(Elsevier, Amsterdam: 1996); Advanced Asymmetric Synthesis,
Stephenson, G. R., ed. (Chapman & Hall, London: 1996); and
Asymmetric Synthetic Methodology, Ager, D. R. and East, M. B., eds.
(CRC, Boca Raton: 1996). See also, Jacques, J., et al.,
Enanitiomers, Racemates and Resolutions (Wiley-Interscience, New
York: 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);
Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY:
1962); and Wilen, S. H., Tables of Resolving Agents and Optical
Resolutions, 268, Eliel, E.L., ed. (Univ. of Notre Dame Press,
Notre Dame: 1972). It is further contemplated that pharmaceutically
acceptable prodrugs of topoisomerase inhibitors be used in the
methods and compositions of the invention. Physiologically active
metabolites of topoisomerase inhibitors disclosed herein as well as
those known in the art can also be used in the methods and
compositions of the invention. An example of a physiologically
active metabolite of a topoisomerase inhibitor is SN-38, which is a
metabolite of irinotecan.
[0060] Thalidomide contains a chiral center, and is sold as a
racemate. The methods and compositions of the invention therefore
encompass the use of racemic thalidomide as well as optically pure
enantiomers of thalidomide. Optically pure enantiomers of
thalidomide can be prepared by methods well known in the art. These
include, but are not limited to, resolution of chiral salts,
asymmetric synthesis, or chiral chromatography. It is further
contemplated that pharmaceutically acceptable prodrugs, salts,
solvate, clathrates and derivatives of thalidomide be used in the
methods and compositions of the invention. Examples of derivatives
of thalidomide that can be used in the methods and compositions of
the invention include, but are not limited to, taglutimide,
supidimide, EM-12, and those disclosed by International Application
WO 94/20085, which is incorporated herein by reference. Other
derivatives of thalidomide encompassed by this invention include,
but are not limited to, 6-alkyl-2-[3'- or
4'-nitrophthalimido]-glutarimides and 6-alkyl-3-phenylglutarimides.
See, e.g., De, A. U., and Pal. D., J. Pharm. Sci. 64(2): 262-266
(1975). Preferred thalidomide derivatives are the amino analogues
of thalidomide such as amino-thalidomide.
4.1. Methods of Treatment and Prevention
[0061] This invention encompasses methods of treating and
preventing a wide variety of disease and conditions in mammals, and
in humans in particular. Although dosage forms of the invention can
be used in methods of the invention, the active ingredients
disclosed herein can be administered separately, in any appropriate
form, and by any suitable route.
[0062] Without being limited by theory, it is believed that the
combined use of a topoisomerase inhibitor and thalidomide to a
patient suffering from cancer provides a unique and unexpected
synergism. In particular, and without being limited by theory, it
is believed that thalidomide can work in combination with a
topoisomerase inhibitor to more rapidly kill cancer cells, while at
the same time reducing gastrointestinal (e.g., diarrhea) and other
side effects associated with chemotherapy (e.g., with topoisomerase
inhibitors) and radiation therapy.
[0063] Consequently, one embodiment of this invention encompasses
methods of treating and/or preventing of cancer. Examples of
cancers that can be treated are disclosed herein and include, but
are not limited to, primary and metastatic cancer of the head,
neck, eye, mouth, throat, esophagus, chest, bone, lung, colon,
rectum, stomach, prostate, breast, ovaries, kidney, liver,
pancreas, and brain. Specific examples of cancers that can be
treated include, but are not limited to: AIDS associated leukemia
and adult T-cell leukemia lymphoma; anal carcinoma; astrocytoma;
biliary tract cancer; cancer of the bladder, including bladder
carcinoma; brain cancer, including glioblastomas and
medulloblastomas; breast cancer, including breast carcinoma;
cervical cancer; choriocarcinoma; colon cancer including colorectal
carcinoma; endometrial cancer; esophageal cancer; Ewing's sarcoma;
gastric cancer; gestational trophoblastic carcinoma; glioma; hairy
cell leukemia; head and neck carcinoma; hematological neoplasms,
including acute and chronic lymphocytic and myelogeneous leukemia;
hepatocellular carcinoma; Kaposi's sarcoma; kidney cancer; multiple
myeloma; intraepithelial neoplasms, including Bowen's disease and
Paget's disease; liver cancer; lung cancer including small cell
carcinoma; lymphomas, including Hodgkin's disease, lymphocytic
lymphomas, non-Hodgkin's lymphoma, Burkitt's lymphoma, diffuse
large cell lymphoma, follicular mixed lymphoma, and lymphoblastic
lymphoma; lymphocytic leukemia; neuroblastomas; oral cancer,
including squamous cell carcinoma; ovarian cancer, including those
arising from epithelial cells, stromal cells, germ cells and
mesenchymal cells; pancreatic cancer; prostate cancer; rectal
cancer; sarcomas, including soft tissue sarcomas, leiomyosarcoma,
rhabdomyosarcoma, liposcarcoma, fibrosarcoma, and osteosarcoma;
skin cancer, including melanoma, Kaposi's sarcoma, basal cell
cancer and squamous cell cancer; testicular cancer, including
testicular carcinoma and germinal tumors (e.g., semicoma,
non-seminoma[teratomas, choriocarcinomas]), stromal tumors and germ
cell tumors; thyroid cancer, including thyroid adenocarcinoma and
medullar carcinoma; and renal cancer including adenocarcinoma and
Wilm's tumor.
[0064] The invention encompasses methods of treating of patients
with primary and metastatic cancers. It further encompasses methods
of treating patients who have been previously treated for cancer,
as well as those who have not previously been treated for cancer.
Indeed, the methods and compositions of this invention can be used
in first-line and second-line cancer treatments. In a specific
embodiment of the invention, the cancer is metastatic. In another
specific embodiment, the patient having a cancer is
immunosuppressed by reason of having previously undergone
anti-cancer therapy (e.g., chemotherapy radiation). In a preferred
embodiment, thalidomide is administered to a patient undergoing
topoisomerase treatment before any adverse effect or intolerance
occurs.
[0065] Other embodiments of the invention include methods of
increasing the dosage of a topoisomerase inhibitor that can be
safely and effectively administered to a patient, and methods of
varying the dosage cycle used to administer a topoisomerase
inhibitor to a patient while avoiding dose-limiting toxicities.
[0066] Another embodiment of the invention described in detail
encompasses a method of reducing, treating and/or preventing
adverse, or undesired, effects associated with chemotherapy and/or
radiation therapy.
4.1.1. Methods of Treating and/or Preventing Cancer
[0067] The methods of treating and/or preventing cancer encompassed
by this invention comprise administering at least two drugs (also
referred to herein as "active ingredients" or "active agents") to a
patient (e.g., a human) suffering, or likely to suffer, from
cancer: 1) an anti-cancer drug and; 2) thalidomide, a derivative or
analogue of thalidomide, or a pharmaceutically acceptable salt,
solvate, clathrate, hydrate, or prodrug thereof. Preferred
anti-cancer drugs are topoisomerase inhibitors, or pharmaceutically
acceptable salts, solvates, clathrates, hydrates, and prodrugs
thereof. The two active ingredients can be administered
concurrently, sequentially, and by the same or by different routes
of administration. For example, one active ingredient (e.g.,
thalidomide) can be administered to a patient prior to, during, or
after the administration of the other active ingredient.
[0068] A preferred method of the invention comprises the
administration of: 1) a topoisomerase inhibitor, or a
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof; 2) thalidomide, or a pharmaceutically acceptable
derivative, prodrug, salt, solvate, hydrate, or clathrate thereof;
and 3) radiation therapy. Administration of each of the drugs can
occur prior to, during, or after radiation therapy.
[0069] Another embodiment of the invention encompasses a method of
treating cancer which comprises the administration of at least
three active ingredients simultaneously or sequentially: 1) a
topoisomerase inhibitor, or a pharmaceutically acceptable prodrug,
salt, solvate, hydrate, or clathrate thereof; 2) thalidomide, or a
pharmaceutically acceptable derivative, prodrug, salt, solvate,
hydrate, or clathrate thereof; and 3) an additional anti- cancer
drug.
[0070] Examples of anti-cancer drugs that can be used in the
various embodiments of the invention, including pharmaceutical
compositions and dosage forms and kits of the invention, include,
but are not limited to: acivicin; aclarubicin; acodazole
hydrochloride; acronine; adozelesin; aldesleukin; altretamine;
ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine;
azetepa; azotomycin; batimastat; benzodepa; bicalutamide;
bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin sulfate; brequinar sodium; bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin;
carmustine; carubicin hydrochloride; carzelesin; cedefingol;
chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol
mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin;
daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine;
dezaguanine mesylate; diaziquone; docetaxel; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflomithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; interleukin II (including
recombinant interleukin II, or rIL2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1 ; interferon alfa-n3;
interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; rogletimide; safingol; safingol hydrochloride;
semustine; simtrazene; sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin;
streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone
acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
zinostatin; zorubicin hydrochloride. Other anti-cancer drugs
include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3;
5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;
adozelesin; aldesleukin; ALL-TK antagonists; altretamine;
ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin;
amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis
inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing
morphogenetic protein-1; antiandrogen, prostatic carcinoma;
antiestrogen; antineoplaston; antisense oligonucleotides;
aphidicolin glycinate, apoptosis gene modulators; apoptosis
regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2;
axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III
derivatives; balanol; batimastat; BCR/ABL antagonists;
benzochlorins; benzoylstaurosporine; beta lactam derivatives;
beta-alethine; betaclamnycin B; betulinic acid; bFGF inhibitor;
bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;
bistratene A; bizelesin; breflate; bropirimine; budotitane;
buthionine sulfoximine; calcipotriol; calphostin C; camptothecin
derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;
edelfosine; edrecolomab; eflomithine; elemene; emitefur;
epirubicin; epristeride; estramustine analogue; estrogen agonists;
estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
fadrozole; fazarabine; fenretinide; filgrastim; finasteride;
flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;
immunostimulant peptides; insulin-like growth factor-1 receptor
inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor; multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;
paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B 1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; signal transduction modulators; single chain antigen
binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor; stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
itanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Preferred additional anti-cancer drugs are 5-fluorouracil and
leucovorin. These two agents are particularly useful when used in
methods employing thalidomide and a topoisomerase inhibitor.
[0071] The magnitude of a prophylactic or therapeutic dose of each
active ingredient in the acute or chronic management of cancer will
typically vary with the specific active ingredients, the severity
and type of cancer, and the route of administration. The dose, and
perhaps the dose frequency, may also vary according to age, body
weight, response, and the past medical history of the patient.
Suitable dosing regimens can be readily selected by those skilled
in the art with due consideration of such factors by following, for
example, dosages reported in the literature and recommended in the
Physician's Desk Reference.RTM. (54.sup.th ed., 2000).
[0072] Unless otherwise indicated, the magnitude of a prophylactic
or therapeutic dose of each active ingredient used in an embodiment
of the invention will be that which is known to those in the art to
be safe and effective, or is regulatory approved.
[0073] In one embodiment of the invention, the topoisomerase
inhibitor irinotecan is administered parenterally about every three
weeks in an amount of from about 1 to about 1000 mg/m.sup.2,
preferably in an amount of from about 25 to about 750 mg/m.sup.2,
more preferably in an amount of from about 50 to about 500
mg/m.sup.2, and most preferably in an amount of from about 100 to
about 350 mg/m.sup.2. And in one embodiment of the invention,
thalidomide is administered orally and daily in an amount of from
about 1 to about 2000 mg, preferably from about 50 to about 1000
mg, more preferably from about 100 to 750 mg, and most preferably
from about 200 to about 500 mg.
[0074] As noted elsewhere herein, this invention encompasses a
method of reducing the time between therapeutically safe and
effective doses of anti-cancer drugs (e.g., topoisomerase
inhibitors). Consequently, in one specific embodiment of the
invention, irinotecan is administered in a cycle of less than about
three weeks (e.g., about once every two weeks, about once every ten
days, or about once every week). The invention further allows the
frequency, number, and length of anti-cancer drug dosing cycles to
be increased. Thus, another specific embodiment of the invention
encompasses the administration of irinotecan for more cycles than
are typical when it is administered alone. See, e.g., Physicians'
Desk Reference, 2412-2418 (54.sup.th ed., 2000). In yet another
specific embodiment of the invention, irinotecan is administered
for a greater number of cycles that would typically cause
dose-limiting toxicity in a patient to whom thalidomide is not also
being administered.
[0075] In a typical embodiment of the invention, a topoisomerase
inhibitor is administered by intravenous infusion over about 90
minutes every cycle. In a specific embodiment wherein the
topoisomerase inhibitor is irinotecan, one cycle comprises the
administration of about 125 mg/m.sup.2 irinotecan on days 1, 8, 15,
and 22, and then two weeks of rest. In another specific embodiment,
each cycles comprises the administration of about 350 mg/m.sup.2 of
irinotecan, followed by three weeks of rest. Typically, the number
of cycles during which a topoisomerase inhibitor such as irinotecan
is administered to a patient will be from about 1 to about 12
cycles, more typically from about 2 to about 10 cycles, and even
more typically from about 2 to about 8 cycles.
[0076] The dosage amounts and frequencies provided above are
encompassed by the terms "therapeutically effective,"
"prophylactically effective," and "therapeutically or
prophylactically effective" as used herein. When used in connection
with an amount of a thalidomide or thalidomide derivative, these
terms further encompass an amount of thalidomide or thalidomide
derivative that reduces, prevents, or eliminates an adverse effect
associated with the administration of radiation or an anti-cancer
drug such as a topoisomerase inhibitor, or an amount that otherwise
improves the efficacy of radiation therapy or of an anti-cancer
drug in the treatment or prevention of cancer.
[0077] The suitability of a particular route of administration
employed for a particular active ingredient will depend on the
active ingredient itself (e.g., whether it can be administered
orally without decomposing prior to entering the blood stream) and
the disease being treated. For example, treatment of tumors on the
skin or on exposed mucosal tissue may be more effective if one or
both active ingredients are administered topically, transdermally,
or mucosally (e.g., by nasal, sublingual, buccal, rectal, or
vaginal administration). Treatment of tumors within the body, or
prevention of cancers that may spread from one part of the body to
another, may be more effective if one or both of the active
ingredients are administered parenterally or orally. Similarly,
parenteral administration may be preferred for the acute treatment
of a disease, whereas transdermal or subcutaneous routes of
administration may be employed for chronic treatment or prevention
of a disease.
4.1.2. Methods of Increasing Anti-Cancer Drug Dosages
[0078] This invention encompasses a method of increasing the dosage
of an anti-cancer drug, such as a topoisomerase inhibitor, that can
be safely and effectively administered to a patient. This method
comprises administering to a patient (e.g., a human) thalidomide,
or a pharmaceutically acceptable derivative, salt, solvate,
clathrate, hydrate, or prodrug thereof. Patients that can benefit
by this method are those likely to suffer from an adverse effect
associated with an anti-cancer drug that is alleviated or reduced
by the administration of thalidomide, or a pharmaceutically
acceptable derivative, salt, solvate, clathrate, hydrate, or
prodrug thereof, and which is of such severity that it would
otherwise limit the amount of topoisomerase inhibitor that can be
safely and effectively administered to them. Such adverse effects
are referred to herein as "dose-limiting."
[0079] For example, adverse effects that are associated with
topoisomerase inhibitors and which can limit the amount of a
topoisomerase inhibitor that can safely and effectively be
administered to a patient include, but are not limited to:
gastrointestinal toxicity such as, but not limited to, early and
late-forming diarrhea and flatulence; nausea; vomiting; anorexia;
leukopenia; anemia; neutropenia; asthenia; abdominal cramping;
fever; pain; loss of body weight; dehydration; alopecia; dyspnea;
insomnia; dizziness, mucositis, xerostomia, and kidney failure.
[0080] According to a specific method of the invention,
thalidomide, or a pharmaceutically acceptable derivative, salt,
solvate, clathrate, hydrate, or prodrug thereof, is administered
prior to, during, or after a topoisomerase inhibitor. In one
embodiment, thalidomide is administered orally and daily in an
amount of from about 1 to about 2000 mg, preferably from about 50
to about 1000 mg, more preferably from about 100 to 750 mg, and
most preferably from about 200 to about 500 mg.
4.1.3. Methods of Treating and/or Preventing Adverse Effects
Associated with Chemotherapy and Radiation Therapy
[0081] As discussed elsewhere herein, this invention encompasses a
method of treating and/or preventing adverse effects associated
with chemotherapy and/or radiation therapy, such as that
administered to patients with cancer. This method comprises
administering to a patient (e.g., a human) thalidomide, or a
pharmaceutically acceptable derivative, salt, solvate, clathrate,
hydrate, or prodrug thereof before, during, or after the occurrence
of the adverse effect.
[0082] Examples of adverse effects associated with chemotherapy and
radiation therapy that can be treated or prevented by this method
include, but are not limited to: gastrointestinal toxicity such as,
but not limited to, early and late-forming diarrhea and flatulence;
nausea; vomiting; anorexia; leukopenia; anemia; neutropenia;
asthenia; abdominal cramping; fever; pain; loss of body weight;
dehydration; alopecia; dyspnea; insomnia; dizziness, mucositis,
xerostomia, and kidney failure.
[0083] According to this method, thalidomide, or a pharmaceutically
acceptable derivative, salt, solvate, clathrate, hydrate, or
prodrug thereof, is administered prior to, during, or after
chemotherapy or radiation therapy. In one embodiment of this
method, thalidomide is administered prior to the administration of
a topoisomerase inhibitor or radiation therapy. In another
embodiment, thalidomide is administered during or after the
administration of a topoisomerase inhibitor or radiation therapy.
In still another embodiment, thalidomide is administered at least
twice for each treatment with a topoisomerase inhibitor or
radiation therapy; e.g., once during the treatment and at least
once following the treatment, once prior to the treatment and once
during the treatment, once both prior to and at least once after
the treatment, or combinations thereof. Preferably, thalidomide is
administered before any adverse event or symptom occurs. Indeed,
thalidomide can be administered to a patient prior to the
administration of chemotherapy and/or radiation therapy, in which
case it can be considered as a protectant.
[0084] In a specific embodiment of this method, thalidomide is
administered in an amount of from about 1 to about 2000 mg,
preferably from about 50 to about 1000 mg, more preferably from
about 100 to 750 mg, and most preferably from about 200 to about
500 mg orally and daily following radiation therapy or the
administration of an anti-cancer drug such as, but not limited to,
a topoisomerase inhibitor.
4.2. Pharmaceutical Compositions and Dosage Forms
[0085] Pharmaceutical compositions can be used in the preparation
of individual dosage forms. Consequently, pharmaceutical
compositions and dosage forms of the invention comprise the active
ingredients disclosed herein (e.g., a topoisomerase inhibitor, or a
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, and thalidomide, a derivative or analogue of
thalidomide, or a pharmaceutically acceptable prodrug, salt,
solvate, hydrate, or clathrate thereof). Pharmaceutical
compositions and dosage forms of the invention can further comprise
one or more excipients.
[0086] Pharmaceutical compositions and dosage forms of the
invention can also comprise one or more additional active
ingredients. Examples of optional additional active ingredients
include, but are not limited to, leucovorin, 5-flurouracil, and
mixtures thereof.
[0087] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquid dosage forms suitable for
oral or mucosal administration to a patient, including suspensions
(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0088] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease.
These and other ways in which specific dosage forms encompassed by
this invention will vary from one another will be readily apparent
to those skilled in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18.sup.th ed., Mack Publishing, Easton Pa. (1990).
[0089] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form. For example, the decomposition of some active
ingredients may be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary
or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, this invention encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose other mono- or di-saccharides. As used herein, the
term "lactose-free" means that the amount of lactose present, if
any, is insufficient to substantially increase the degradation rate
of an active ingredient.
[0090] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In
general, lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0091] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0092] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0093] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0094] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0095] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise thalidomide, a derivative or
analogue of thalidomide, or a pharmaceutically acceptable salt,
solvate, clathrate, hydrate, or prodrug thereof in an amount of
from about 1 mg to about 2000 mg, more preferably from about 50 mg
to about 1000 mg, even more preferably from about 100 mg to about
750 mg, and most preferably from about 200 mg to about 500 mg.
Similarly, typical dosage forms of the invention comprise a
topoisomerase inhibitor or a pharmaceutically acceptable salt,
solvate, clathrate, hydrate, prodrug or derivative thereof in an
amount of from about 1 mg to about 1000 mg, more preferably from
about 25 mg to about 750 mg, even more preferably from about 50 mg
to about 500 mg, and most preferably from about 100 mg to about 350
mg.
4.2.1. Oral Dosage Forms
[0096] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18.sup.th ed., Mack Publishing, Easton Pa.
(1990).
[0097] Typical oral dosage forms of the invention are prepared by
combining the active ingredients in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0098] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0099] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0100] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0101] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM.and Starch 1500 LM.
[0102] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0103] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0104] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0105] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0106] A preferred solid oral dosage form of the invention
comprises thalidomide, anhydrous lactose, microcrystalline
cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous
silica, and gelatin.
4.2.2. Delayed Release Dosage Forms
[0107] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos.: 3,845,770;
3,916,899; 35 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein,, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0108] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0109] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
4.2.3. Parenteral Dosage Forms
[0110] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0111] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0112] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention. For example,
cyclodextrin and its derivatives can be used to increase the
solubility of thalidomide and its derivatives. See, e.g., U.S. Pat.
No. 5,134,127, which is incorporated herein by reference.
[0113] A preferred parenteral composition of the invention is
intended for dilution with 5% Dextrose Injection, USP, or 0.9%
Sodium Chloride Injection, USP, prior to administration to a
patient, and is an aqueous solution that comprises irinotecan,
sorbitol NF powder, and lactic acid, USP, and has a pH of from
about 3.0 to about 3.8.
4.2.4. Transdermal, Topical, and Mucosal Dosage Forms
[0114] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th
eds., Mack Publishing, Easton Pa. (1980 & 1990); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0115] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. With that fact in mind, typical
excipients include, but are not limited to, water, acetone,
ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or
ointments, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms if desired. Examples of such
additional ingredients are well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).
[0116] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
[0117] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
4.2.5. Kits
[0118] Typically, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0119] A typical kit of the invention comprises a dosage form of an
anti-cancer drug (e.g., a. topoisomerase inhibitor) or a
pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
clathrate thereof, and a dosage form of thalidomide, or a
pharmaceutically acceptable derivative, prodrug, salt, solvate,
hydrate, or clathrate thereof. Kits encompassed by this invention
can further comprise additional active ingredients. Examples of
optional additional active ingredients include, but are not limited
to, leucovorin, 5-flurouracil, and mixtures thereof.
[0120] Kits of the invention can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.
[0121] Kits of the invention can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
[0122] A specific kit of the invention comprises a solid dosage
form of thalidomide suitable for oral administration to a patient,
and a liquid dosage form of irinotecan suitable for dilution and
parenteral administration to a patient. A preferred oral dosage
form of thalidomide comprises 50 mg thalidomide, anhydrous lactose,
microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,
colloidal anhydrous silica, and gelatin. A preferred liquid dosage
form of irinotecan comprises 100 mg irinotecan hydrochloride,
sorbitol NF powder, and lactic acid, USP, and has a pH of from
about 3.0 to about 3.8.
[0123] Other kits encompassed by the invention will be readily
apparent to those skilled in the art, since thalidomide,
irinotecan, and other therapeutic and anti-cancer drugs or
radiation therapies are well known and/or commercially
available.
5. EXAMPLES
[0124] Certain embodiments of the invention, as well as certain
novel and unexpected advantages of the invention, are illustrated
by the following non-limiting examples.
5.1. Example 1: Treatment of Colorectal Cancer
[0125] A pilot clinical trial was conducted to investigate the
safety and efficacy of administering thalidomide (400 mg/day,
administered at bedtime) and irinotecan (325-350 mg/m.sup.2 every
21 days) to patients with metastatic colorectal cancer. An interim
analysis performed after enrollment of the first 9 patients on this
protocol (2-8 cycles of irinotecan) revealed a remarkable absence
of gastrointestinal toxicity typically associated with irinotecan.
See Table 1. All patients were able to complete the prescribed
chemotherapy regimen; only one patient required a 50% reduction of
the irinotecan dose due to asthenia, and only one patient required
a thalidomide dose reduction by 75% due to somnolence. Of the seven
patients that could be evaluated, one went into complete remission,
two attained partial remission, one had stable disease, and three
progressed.
1TABLE 1 Observed Toxicity Profile for Combination Therapy with
Thalidomide and Irinotecan in 9 Patients with Metastatic Colorectal
Cancer Compared with the Expected Toxicity Profile of Irinotecan
Monotherapy Expected (%) Observed (N) Symptom Grade 1-4 Grade 3-4
Grade 1-4 Grade 3-4 p Nausea 86.2 16.8 0 1 <0.00001 Vomiting
66.8 12.5 0 0 0.00005 Diarrhea 87.8 30.6 1 0 <0.00001 (Late)
Abdominal 23.7 2.3 0 0 n.s colic/pain Constipation 29.9 2.0 4 0
n.s. Asthenia 75.7 12.2 6 0 n.s.
[0126] The p-values shown in Table 1 refer to the probability of
observing the specified number of Grade 1-4 symptoms among 9
patients, given the expected frequencies of Grade 1-4 toxicity.
Expected frequencies of toxicity were obtained from Rothenberg, M.
L., et al., J. Clin. Oncology 14(4):1128-1135 (1996); Pitot, H. C.,
et al., J. Clin. Oncology 15(8):2910-2919 (1997); and Rothenberg,
M. L., et al., Cancer 85(4):786-795 (1999).
[0127] The complete absence of severe (grade 3-4) gastrointestinal
toxicity in the patients used in the study is striking,
statistically highly significant, and clinically very
important.
5.2. Example 2: Alternative Treatment of Colorectal Cancer
[0128] In this study, 5FU, leucovorin, irinotecan, and thalidomide
are used in combination to treat metastatic colorectal cancer.
Patients with histologically confirmed colon or rectal carcinoma
are treated using six week cycles, which comprise the intravenous
administration of 125 mg/m.sup.2 of irinotecan over 90 minutes,
followed by 20 mg/m.sup.2 bolus administration of leucovorin,
followed by 500 mg/m.sup.2 bolus administration of 5FU. Each drug
is administered weekly .times.4, followed by two weeks of rest.
Thalidomide is administered daily and orally at a dose of 400 mg at
bedtime. The response of each patient is assessed at the conclusion
of each cycle using methods and criteria described herein and known
to those skilled in the art.
5.3. Example 3: Treatment of Myelodysplastic Syndromes
[0129] The efficacy of using a combination of topotecan and
thalidomide in improving the ineffective hematopoiesis of poor
prognosis patients with myelodysplastic syndromes (MDS), patients
with refractory anemia with excess blasts (RAEB) who have greater
than about 15 percent blasts in the bone marrow (BM), RAEB in
transformation (RAEB-t), and patients with chronic myelomonocytic
leukemia (CMMoL) are determined as set forth below.
[0130] The treatment comprises administering topotecan
hydrochloride (Hycamtin) by intravenous infusion (1.25 mg/m.sup.2
over 30 minutes) to patients (RAEB>5%) for five days every 21
days, for three cycles (each cycle is 21 days). At the conclusion
of the cycles, each patient is evaluated. If the blasts have
decreased to less than about five percent or have decreased by
half, the administration of thalidomide is begun: it is first
administered orally at about 100 mg/day, and increased up to about
300 mg as tolerated for a maximum of about one year.
[0131] If, following the three initial cycles of topotecan therapy,
the blasts are still greater than five percent, two additional
cycles of topotecan are administered, after which thalidomide
therapy is begun. As above, thalidomide is first administered
orally at about 100 mg/day, and increased up to about 300 mg as
tolerated for a maximum of about one year.
[0132] Frequent monitoring of peripheral blood cell counts are
instituted during the treatment, since Hycamtin should only be
administered to patients with adequate bone marrow reserves,
including baseline neutrophil counts of at least 1,500
cells/mm.sup.3 and platelet count of at least 100,000/mm.sup.3.
Other precautions taken during the study are well known to those
skilled in the art.
[0133] During the therapy, apoptosis studies are performed on all
bone marrow samples using flow cytometry (TUNNEL technique) or DNA
laddering (gel electrophoresis or pulsed field electrophoresis)
techniques. Proliferation studies are also performed to determine
detailed cell cycle kinetics. Cytokine expression studies are also
performed. In particular, TNF-a is measured by standard ELISA
techniques on a weekly basis, while bone marrow aspirate is studied
by sorting and measuring mRNA levels using multiplex RT-PCR for a
variety of cytokines including ILI-.beta., TNF-.alpha., IL6, flt3
ligand, hSCF, and GM-CSF. An immunohistochemical detection of
TNF-.alpha. and IL1-.beta. is also performed on all biopsies.
5.4. Example 4: Treatment of Prostate Cancer
[0134] The efficacy of using a combination of docetaxel and
thalidomide in the treatment of prostate cancer is determined as
described below in patients with histologically confirmed prostate
or pancreatic cancer. The efficacy of the combination is also
determined with regard to progressive disease after therapy with
gemcitabine in patients with pancreatic cancer or after androgen
suppression therapy in patients with metastatic prostate
cancer.
[0135] Patients who meet criteria known to those skilled in the art
(e.g., those who are not pregnant, HIV-positive, or those with
active brain metastasis) are intravenously administered docetaxel
once weekly (Day 1) for a total of 24 weeks at a dose of 33
mg/M.sup.2. Premedication with dexamethasone 8 mg PO Q6H.times.3
doses, starting 12 hours before the administration of docetaxel is
given to decrease or prevent acute anaphylactoid reactions and to
decrease the severity or delay the onset of late-occurring fluid
retention problems.
[0136] Three days prior to starting treatment with thalidomide (Day
5), subjects are initiated on a bowel regimen to minimize the
occurrence of constipation. On week 2 (Day 8), patients first
receive thalidomide, which is administered daily at bedtime in four
schedules using a weekly dose-escalation design,. See, e.g.,
Gruber, M. L., et al., Cancer Investigation 2000; 18(suppl. 1):41
(abstract); Eisen T., Cancer Investigation 2000; 18 (suppl. 1):42
(abstract); and Figg. W., et al., Cancer Investigation 2000; 18
(suppl. 1):81 (abstract). Three patients are treated on the initial
schedule. If no dose-limiting toxicities are observed, three
patients are treated on the next schedule. If one of three patients
treated on a schedule develops a dose-limiting toxicity, three
additional patients are treated on that schedule. If two patients
treated on a schedule develop dose-limiting toxicity, the maximum
tolerated dose of thalidomide has been reached, and is defined to
be the previous schedule (or to be a does below the initial dose if
two patients develop dose-limiting toxicity on the first schedule).
If only three patients have been treated on the previous schedule,
then three additional patients are treated on the current one. If,
at any time, the data suggest a significant hazard to further dose
escalation, dose escalation is halted pending a review of the
data.
[0137] Thalidomide is given daily until progression, unacceptable
toxicity develops, or when the subject wishes to discontinue
treatment. For subjects who are stable and show no signs of
unacceptable toxicity, the maximum daily dose of thalidomide that
is given in this regime is 200 mg, 400 mg, 600 mg, or 800 mg for
each level shown in Table 2:
2TABLE 2 Dose of Thalidomide (mg/day) as a Function of Week and
Schedule WK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 I 50 100 150 200
200 2000 200 200 200 200 200 200 200 200 200 200 II 50 100 150 200
250 300 350 400 400 400 400 400 400 400 400 400 III 50 100 150 200
250 300 350 400 450 500 550 600 600 600 600 600 IV 50 100 150 200
250 300 350 400 450 500 550 600 650 700 750 800
[0138] Baseline radiographic studies are done for initial tumor
measurements. Chest X-ray is done to measure pulmonary metastases,
and a CT scan of the abdomen is done for those patients with liver
or other abdominal metastases that are measurable using that
modality. Baseline laboratory studies are also performed, such as
serum biochemistry, hematological, PSA (prostate patients only), CA
19-9 (pancreatic patients only), pregnancy, and binding protein
studies, as known to those skilled in the art. These studies are
continued during treatment to determine its effectiveness, and to
ensure the safety of each patient.
[0139] The embodiments of the invention described above are
intended to be merely exemplary, and those skilled in the art will
recognize, or will be able to ascertain using no more than routine
experimentation, numerous equivalents of specific compounds,
materials, and procedures. All such equivalents are considered to
be within the scope of the invention and are encompassed by the
appended claims.
* * * * *