(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2002/0035090 A1
`(43) Pub. Date:
`Mar. 21, 2002
`Zeldis et al.
`
`US 20020035090A1
`
`(54)
`
`COMPOSITIONS AND METHODS FOR THE
`TREATMENT OF CANCER
`
`Publication Classi?cation
`
`(76)
`
`Inventors: Jerome B. Zeldis, Princeton, NJ (US);
`Andrew L. Zeitlin, Basking Ridge, NJ
`(US); Sol Barer, West?eld, NJ (US)
`
`Correspondence Address:
`PENNIE & EDMONDS LLP
`1667 K STREET NW
`SUITE 1000
`WASHINGTON, DC 20006
`
`(21)
`(22)
`
`Appl. No.:
`
`09/853,617
`
`Filed:
`
`May 14, 2001
`
`Related US. Application Data
`
`(63)
`
`Non-provisional of provisional application No.
`60/204,143, ?led on May 15, 2000.
`
`(51) Int. C1.7 ................ .. A61K 31/724; A61K 31/7056;
`A61K 31/4745
`(52) us. Cl. ...................... .. 514/58; 514/43; 514/211.08;
`514/283; 514/291
`
`ABSTRACT
`(57)
`This invention relates to compositions comprising thalido
`mide and another anti-cancer drug Which can be used in the
`treatment or prevention of cancer. Preferred anti-cancer
`drugs are topoisomerase inhibitors. Aparticular composition
`comprises thalidomide, or a pharmaceutically acceptable
`salt, solvate, or clathrate thereof, and irinotecan. The inven
`tion 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 treat
`ment 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.
`
`DR. REDDY’S LABS., INC. EX. 1074 PAGE 1
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`US 2002/0035090 A1
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`Mar. 21, 2002
`
`COMPOSITIONS AND METHODS FOR THE
`TREATMENT OF CANCER
`
`2.2. AIDS-RELATED NON-HODGKIN’S
`LYMPHOMA
`
`1. FIELD OF THE INVENTION
`
`[0001] This invention relates to pharmaceutical composi
`tions 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 topoi
`somerase 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 meth
`ods 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-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 multistep process that begins With minor pre
`neoplastic changes, Which may under certain conditions
`progress to neoplasia.
`[0004] Pre-malignant abnormal cell groWth is exempli?ed
`by hyperplasia, metaplasia, or most particularly, dysplasia
`(for revieW of such abnormal groWth conditions, see Rob
`bins 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 signi?cant alter
`ation in structure or function. As but one example, endome
`trial hyperplasia often precedes endometrial cancer. Meta
`plasia 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 in?ammation, 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 sur
`veillance. 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.
`
`[0007] AIDS has been closely associated With a variety of
`cancers. Further, the types of malignancies and their inci
`dence rates are increasing as the development of effective
`antiretroviral therapies and prophylaxis against opportunis
`tic infections leads to prolonged survival in the immunode
`?cient state for AIDS patients. Karp and Broder, CancerRes.
`51:4747-4756 (1991). AIDS-related non-Hodgkin’s lym
`phoma is a very aggressive disease With a very high inci
`dence 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 sur
`gery, 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 CAN CERS
`
`[0010] In the United States, the cumulative risk of devel
`oping breast cancer is reportedly about 10.2 percent. The
`MerckManual 1815 (16th ed. 1992). The treatment for early
`breast cancer is surgery, With or Without radiation therapy, or
`surgery, With or Without radiation therapy, plus chemo
`therapy and/or hormonal therapy. Current chemotherapy for
`patients With primary or metastatic breast cancer includes
`treatment With cyclophosphamide, methotrexate, doxorubi
`cin, S-?uorouracil, 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 metasta
`siZe 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 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.
`
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`US 2002/0035090 A1
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`
`[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, DC,
`The New England Journal of Medicine 327:1434-1441
`(1992). HoWever, chemotherapy regimens that are utiliZed
`include treatment With cisplatin plus etoposide, combina
`tions of cyclophosphamide plus doXorubicin plus cisplatin,
`and single agents alone or in combination, including ifos
`famide, teniposide, vindesine, carboplatin, vincristine, taXol,
`nitrogen mustard, methotreXate, heXamethylmelamine and
`others. Despite these chemotherapeutic regimens the aver
`age 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 (16th 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 adriamy
`cin (doXorubicin) plus cisplatin. Although the response rate
`is high to this chemotherapeutic regimen, medical oncolo
`gists 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 (16th 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 ?utamide, leuprolide, diethylstilbestrol, and other hor
`monal manipulations, as Well as chemotherapy (doXorubi
`cin, estramustine phosphate, vinblastine, suramin, cisplatin,
`and others). Unfortunately, none of these agents are consis
`tently 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).
`
`cally occurs in a single cell through tWo or more steps With
`subsequent proliferation and clonal expansion. In some
`leukemias, speci?c chromosomal translocations have been
`identi?ed 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 predomi
`nantly undifferentiated cell populations and chronic leuke
`mias 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) classi?cation or according to their type and degree of
`differentiation. The use of speci?c B- and T-cell and
`myeloid-antigen monoclonal antibodies are most helpful for
`classi?cation. ALL is predominantly a childhood disease
`Which is established by laboratory ?ndings 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 associ
`ated With irradiation as a causative agent.
`
`[0018] Chronic leukemias are described as being lympho
`cytic (CLL) or myelocytic (CML). CLL is characteriZed by
`the appearance of mature lymphocytes in blood, bone mar
`roW, and lymphoid organs. The hallmark of CLL is sus
`tained, absolute lymphocytosis (>5,000/uL) and an increase
`of lymphocytes in the bone marroW. Most CLL patients also
`have clonal eXpansion of lymphocytes With B-cell charac
`teristics. 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/uL,
`but may reach 1,000,000/uL. CML is relatively easy to
`diagnose because of the presence of the Philadelphia chro
`mosome.
`
`[0019] The very nature of hematopoietic cancer necessi
`tates 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 transplan
`tation from an HLA-matched sibling is sometimes indicated.
`
`2.5. ESOPHAGEAL CANCER
`
`2.7. COLORECTAL CAN CERS
`
`[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 ?ve 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 (16th ed. 1992). Transformation to malignancy typi
`
`[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 MerckManual 852 (16th ed. 1992). Most colorec
`tal cancers are adenocarcinomas.
`
`[0021] Despite the enormous number of deaths attributed
`to colorectal cancers, their speci?c mechanism remains
`unknoWn. It is knoWn, hoWever, that cancers of the colon
`and rectum spread in at least ?ve 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
`
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`US 2002/0035090 A1
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`Mar. 21, 2002
`
`treated With a combination of radiation and chemotherapy.
`As of 1992, the most effective chemotherapy regime con
`sisted of the administration of 5-?uorouracil (5FU) and
`methyl-CCNU. Id.
`
`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.
`
`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 (3rd ed.,
`1988).
`[0024] Because supercoiled double-stranded DNA must
`be unWound before processes such as replication, recombi
`nation, and transcription can occur, inhibition of the unWind
`ing 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 inhibi
`tors,” 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 speci?c camptothecin analogue is irinotecan
`(also referred to as CPT-11), Which is chemically named
`(4S)-4,11
`-diethyl-4-hydroxy-9-[(4-piperidino-piperidi
`no)carbonyl-oxy]1H-pyranol-[3‘,4‘:6,7]indoliZinol[1,2-b]
`quinoline-3,14-(4H,12H)dione and is described in US. Pat.
`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 folloWing 5-?uorouracil based therapy. Physi
`cians’ Desk Reference, 2412-2418 (54th ed., 2000). It has
`also recently been approved in the United States as a
`?rst-line therapy to treat patients With metastic colorectal
`cancer in combination With 5-?uorouracil 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, anor
`exia, constipation, ?atulence, leukopenia, anemia, neutrope
`nia, asthenia, abdominal cramping, fever, pain, loss of body
`Weight, dehydration, alopecia, dyspnea, insomnia, and diZ
`Ziness. See, e. g., Physicians’ DeskReference, 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 one or more of their adverse effects limits the
`amount of topoisomerase inhibitors that can be administered
`
`[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® and chemically named ot-(N
`phthalimido)glutarimide or 2-(2,6-dioxo-3-piperidinyl)-1H
`isoindole-1,3(2H)-dione. Thalidomide Was originally devel
`oped 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 lepro
`sum. Physicians’ Desk Reference, 911-916 (54th 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, thali
`domide has reportedly been used to treat chronic graft-vs
`host disease, rheumatoid arthritis, sarcoidosis, several
`in?ammatory skin diseases, and in?ammatory boWel dis
`ease. 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., Gastro
`enterology 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 coro
`nary and cerebral occlusion. See US. Pat. No. 5,643,915,
`Which is incorporated herein by reference.
`[0030] Thalidomide has also reportedly been clinically
`investigated in the treatment of speci?c types of cancers.
`These include refractory multiple myeloma, brain, mela
`noma, breast, colon, mesothelioma, and renal cell carci
`noma. 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 devel
`opment of chronic cardiomyopathy in rats caused by doxo
`rubicin. Costa, P. T., et al., Blood 92(10:suppl. 1):235b
`(1998). Other reports concerning the use of thalidomide in
`the treatment of speci?c cancers include its combination
`With carboplatin in the treatment of glioblastoma multi
`forme. 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 thalido
`mide 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 0t (TNF-ot) and interleu
`
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`kin 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); US. Pat. Nos. 5,593,990,
`5,629,327, and 5,712,291 to D’Amato and Us. 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. Immu
`nol. 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 com
`positions, pharmaceutical dosage forms, kits, methods of
`treating or preventing cancer, methods of reducing or avoid
`ing adverse effects associated With chemotherapy and radia
`tion therapy, and methods of improving the tolerance of
`patients to chemotherapy and radiation treatment.
`
`[0034] A?rst embodiment of the invention encompasses a
`method of treating primary and/or metastatic cancer, Which
`comprises administering to a patient in need of such treat
`ment 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] Speci?c 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 speci?c cancer that can be
`treated by this method is metastatic colorectal cancer.
`
`[0036] A second embodiment of the invention encom
`passes 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 suf?cient to reduce a dose
`limiting adverse effect associated With the topoisomerase
`inhibitor. In a preferred method of this embodiment, thali
`domide 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 associ
`ated With topoisomerase inhibitors include, but are not
`limited to: gastrointestinal toxicity such as, but not limited
`to, early and late-forming diarrhea and ?atulence; nausea;
`vomiting; anorexia; leukopenia; anemia; neutropenia; asthe
`nia; abdominal cramping; fever; pain; loss of body Weight;
`dehydration; alopecia; dyspnea; insomnia; diZZiness,
`mucositis, xerostomia, and kidney failure. Speci?c 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 asso
`ciated With chemotherapy or radiation therapy, Which com
`prises 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 suf?cient to reduce an adverse effect associ
`ated 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 thalido
`mide in this embodiment encompasses raising a patient’s
`tolerance for chemotherapy or radiation therapy. In a pre
`ferred method of this embodiment, thalidomide is adminis
`tered 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 che
`motherapy and radiation therapy include, but are not limited
`to: gastrointestinal toxicity such as, but not limited to, early
`and late-forming diarrhea and ?atulence; 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 encom
`passes a method of increasing the therapeutic ef?cacy 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
`suf?cient to increase the therapeutic efficacy of the topoi
`somerase inhibitor.
`
`[0041] A ?fth 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 encom
`passes 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, cora
`
`DR. REDDY’S LABS., INC. EX. 1074 PAGE 5
`
`

`

`US 2002/0035090 A1
`
`Mar. 21, 2002
`
`lyne, beta-lapachone, BC-4-1, IST-622, rubitecan, pyraZolo
`acridine, XR-5000, and pharmaceutically acceptable pro
`drugs, 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, carti
`lage, 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, pros
`tate, 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 chemi
`cal 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 alde
`hyde.
`[0047] As used herein, the term “prodrug” means a deriva
`tive 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, biohydro
`lyZable carbamates, biohydrolyZable carbonates, and biohy
`drolyZable ureides.
`[0048] As used herein, the terms “biohydrolyZable car
`bamate,”“biohydrolyZable carbonate,” and “biohydrolyZ
`able ureide” mean a carbamate, carbonate, or ureide, respec
`tively, 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 biologi
`cally active compound. Examples of biohydrolyZable car
`bamates include, but are not limited to, loWer alkylamines,
`substituted ethylenediamines, aminoacids, hydroxyalky
`lamines, heterocyclic and heteroaromatic amines, and poly
`ether 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,
`a-amino acid amides, alkoxyacyl amides, and alkylami
`noalkylcarbonyl amides.
`
`[0051] As used herein, the term “pure diastereomer”
`means a composition th