(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`22 November 2001 (22.11.2001)
`
`PCT
`
`(10) International Publication Number
`WO 01/87307 A2
`
`(51) International Patent Classification7
`A61P 35/00 // (A61K 31/47, 31:445)
`
`A 6 1K 31/47,
`
`(21) International Application Number:
`
`PCT/US01/15327
`
`(22) International Filing Date:
`
`10 May 2001 (10.05.2001)
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EE, ES, Fl, GB, GD, GE, GH, GM,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
`LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX,
`MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW.
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/204,143
`
`15 May 2000 (15.05.2000)
`
`US
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, ER, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`(71) Applicant: CELGENE CORP. [US/US]; 7 Powder Horn
`Drive, Warren, N.T 07059 (US).
`
`Published:
`— without international search report and to be republished
`upon receipt of that report
`
`(72) Inventors: ZELDIS, Jerome, B.; 157 Christopher Drive,
`Princeton, NJ 08540 (US). ZEITLIN, Andrew; 1500
`Whitebridge Road, Millington, NJ 07946 (US). BARER,
`Sol; 625 Westfield Avenue, Westfield, NJ 07090 (US).
`
`tor two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(74) Agents: INSOGNA, Anthony, M. et al.; Pennie & Ed(cid:173)
`monds LLP, 1155 Avenue of the Americas, New York, NY
`10036 (US).
`
`<
`
`(54) Title: COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
`
`O
`m
`QQ (57) 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 arc topoisomcrasc 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
`1^^ such reduction or avoidance.
`
`^^
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`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2005, Page 1
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`COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER
`
`1. FIELD OF THE INVENTION
`This invention relates to pharmaceutical compositions comprising thalidomide and
`5 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.
`
`10
`
`2. BACKGROUND OF THE INVENTION
`, 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.
`
`15
`
`2.1. PATHOBIOLOGY OF CANCER
`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-borne spread of malignant cells to regional lymph nodes and to distant
`sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a
`20 multistep process that begins with minor preneoplastic changes, which may under certain
`conditions progress to neoplasia.
`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).
`25 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.
`30 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
`35 there exists chronic irritation or inflammation, and is often found in the cervix, respiratory
`passages, oral cavity, and gall bladder.
`The neoplastic lesion may evolve clonally and develop an increasing capacity for
`invasion, growth, metastasis, and heterogeneity, especially under conditions in which the
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`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).
`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
`5 medical literature.
`
`2.2. AIDS-RELATED NON-HODGKIN'S LYMPHOMA
`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
`10 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.
`15 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 MET ASTATIC CNS TUMORS
`The incidence of primary and metastatic brain tumors is also increasing in the
`20 United States. Unfortunately, the arsenal of chemotherapeutics for these types of cancers is
`minimal, while the need for such therapeutics is high.
`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
`25 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
`30 patients with such tumors which are refractory to the above modalities.
`
`2.4. BREAST. LUNG. BLADDER AND PROSTATE CANCERS
`In the United States, the cumulative risk of developing breast cancer is reportedly
`about 10.2 percent. The Merck Manual 1815 (16* ed. 1992). The treatment for early breast
`35 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
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`10
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`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
`5 metastasis) or radiation, or surgery plus radiation therapy.
`Lung cancer is reportedly the leading cause of cancer death in men and women.
`The Merck Manual 731 (16th 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.
`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
`15 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
`20 treatment for central nervous system metastases includes surgery (to remove a solitary
`lesion), radiation therapy, or a combination of both.
`Each year about 50,000 new cases of bladder cancer are reported in the United
`States. The Merck Manual 1749 (Id"1 ed. 1992). Although at presentation the disease is
`usually localized, most patients develop distant metastatic disease. The most recent
`25 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.
`It is estimated that more than 120,000 men will be diagnosed with prostate cancer
`this year. The Merck Manual 1750 (16lh 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,
`35 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
`
`30
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`3-
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`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).
`
`5
`
`2.5. ESOPHAGEAL CANCER
`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
`10 percent.
`
`2.6. LEUKEMIA
`Leukemia refers to malignant neoplasms of the blood-forming tissues. Although
`viruses reportedly cause several forms of leukemia in animals, causes of leukemia in
`15 humans are to a large extend unknown. The Merck Manual 1233 (16lh 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
`20 leukemia, and of 15 and 17 in acute promyelocytic leukemia). Acute leukemias are
`predominantly undifferentiated cell populations and chronic leukemias more mature cell
`forms.
`
`Acute leukemias are divided into lymphoblastic (ALL) and non-lymphoblastic
`(ANLL) types. They may be further subdivided by their morphologic and cytochemical
`25 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
`30 and is the more common acute leukemia among adults; it is the form usually associated with
`irradiation as a causative agent.
`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/|J.L)
`35 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
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`patient at diagnosis the total WBC count is usually about 200,000/|aL, but may reach
`1,000,000/nL. CML is relatively easy to diagnose because of the presence of the
`Philadelphia chromosome.
`The very nature of hematopoietic cancer necessitates using systemic chemotherapy
`5 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.
`
`10
`
`15
`
`20
`
`2.7. COLORECTAL CANCERS
`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' ed.
`1992). Most colorectal cancers are adenocarcinomas.
`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.
`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.
`
`25
`
`2.8. TOPOISOMERASE INHIBITORS
`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
`30 one strand of DNA; type II topoisomerases cleave both strands. Stryer, L., Biochemistry
`662-663 (3rd ed., 1988).
`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
`35 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
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`5
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`complexes, thereby leaving an irreversible break in the double-stranded DNA with winch
`they are associated. Avgeropoulos, N.G., and Batchelor, T.T., The Oncologist 4:209-224
`(1999).
`A specific camptothecin analogue is irinotecan (also referred to as CPT-11), which
`is chemically named (4S)-4,11 -diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyl-
`oxy]l//-pyranol-[3,,4,:6,7]mdolizinol[l,2-b]quinoline-3,14-(4/^,12/:/)dione and is described
`in U.S. Patent No. 4,604,463. The hydrochloride trihydrate of irinotecan is sold under the
`tradename CAMPTOSAR®, and is indicated in the United States for the treatment of
`patients with metastatic carcinoma of the colon or rectum that recurred or progressed
`10 following 5-fluorouracil based therapy. Physicians' Desk Reference, 2412-2418 (54lh 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
`15 (1999).
`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
`20 of body weight, dehydration, alopecia, dyspnea, insomnia, and dizziness. See, e.g..
`Physicians' Desk Reference, 2415 (54th 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
`25 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.
`Attempts have been made to alleviate adverse effects associated with irinotecan.
`30 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.
`
`35
`
`2.9. THALIDOMIDE
`Thalidomide is a racemic compound sold under the tradename THALOMID® and
`chemically named a-(Ar-phthalimido)glutarimide or 2-(2,6-dioxo-3-piperidinyl)-l//-
`isoindole-l,3(2i/)-dione. Thalidomide was originally developed in the 1950's to treat
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`morning sickness, but due to its tetragenic effects was withdrawn Irom 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 (54lh ed., 2000).
`Because its administration to pregnant women can cause birth defects, the sale of
`5 thalidomide is strictly controlled. Id.
`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
`10 (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. Patent No. 5,643,915, which is incorporated
`herein by reference.
`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! Med. 341(21):1565-1571 (1999); and Marx, G.M., etal,Proc. Am. Soc. Clin.
`Oncology 18:454a (1999). It has further been reported that thalidomide can be used to
`20 prevent the development of chronic cardiomyopathy in rats caused by doxorubicin. Costa,
`P.T., et al. Blood 92(10:suppl. l):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 (June 21, 1999).
`Thalidomide has reportedly also been used as an antiemetic during the treatment of
`25 astrocytoma. Zwart, D.,Arzneim.-Forsch. 16(12):1688-1689 (1966).
`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
`30 thalidomide is an antiangiogenic agent that can suppress tumor necrosis factor a (TNF-a)
`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. Patent Nos.
`5,593,990, 5,629,327, and 5,712,291 to D'Amato and U.S. Patent No. 5,385,901
`to Kaplan. And in vitro studies suggest that thalidomide affects the production of a variety
`35 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).
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`Given the great need for an effective and safe treatment" of cancer, there conlmneS tt>
`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.
`
`5
`
`10
`
`3. SUMMARY OF THE INVENTION
`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.
`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,
`15 salt, solvate, hydrate, or clathrate thereof.
`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.
`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
`25 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.
`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.
`• 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
`
`35
`
`20
`
`30
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`- 8-
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`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
`5 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.
`Examples of adverse effects associated with chemotherapy and radiation therapy
`10 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.
`A fourth embodiment of the invention encompasses a method of increasing the
`15 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.
`A fifth embodiment of the invention encompasses a pharmaceutical composition
`20 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.
`A sixth embodiment of the invention encompasses a dosage form comprising a
`topoisomerase inhibitor, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or
`25 clathrate thereof, and thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate,
`hydrate, or clathrate thereof.
`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
`30 dosage form of thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate,
`hydrate, or clathrate thereof.
`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,
`35 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
`
`Dr. Reddy’s Laboratories, Inc. v. Celgene Corp.
`IPR2018-01504
`Exhibit 2005, Page 10
`
`

`

`PCT/US01/15327
`WO 01/87307
`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.
`
`5
`
`20
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`3.1. DEFINITIONS
`As used herein, the term "cancer" includes but is not limited to solid tumors and
`blood bom 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
`10 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.
`As used herein to describe a compound or chemical moiety, the term "derivative"
`15 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.
`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,
`25 biohydrolyzable carbonates, and biohydrolyzable ureides.
`As used herein, the temis "biohydrolyzable carbamate," "biohydrolyzable
`carbonate," and "biohydrolyzable ureide" mean a carbamate, carbonat