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`COVER SHEET FOR PRO VISIONAL APPLICA TI0N FOR PA TENT
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`fisfltant Comrmsswner for Patents
`'——-%XOPROVISIONAL PATENT APPLICATION
`Washington, DC 20231
`Sir:
`
`Thisis a request for filing a PROVISIONAL APPLICATION under 37 CFR 1.53(0)
`
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`METHODS OF USING SMALL AND LARGE
`
`
`MOLECULES FOR THE TREATMENT AND MANAGEMENT
`
`OF CANCER, AND COMPOSITIONS AND KITS USEFUL THEREIN
`
`PENNIE & EDMONDS LL17
`
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`PENNIE & EDMONDS in:
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`45,479
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`Date May 17, 2002
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`PR 0 VISIONAL APPLICA TI0N FILING ONL Y
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`METHODS OF USING SMALL AND LARGE
`
`MOLECULES FOR THE TREATMENT AND MANAGEMENT
`
`OF CANCER, AND COMPOSITIONS AND KITS USEFUL THEREIN
`
`1.
`
`FIELD OF THE INVENTION
`
`This invention relates to methods of treating and/or managing cancer using the
`
`combined administration of a small molecule-based active agent, such as a derivative or
`
`analogue of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
`
`or prodrug thereof and a large molecule—based active agent. Examples of large molecule—
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`10
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`based active agents include, but are not limited to, proteins such as IL—2, IL-10, IL-12, IL—
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`18, G—CSF, GM—CSF, and EPO. The invention further relates to pharmaceutical
`
`compositions, single unit dosage forms, and kits suitable for use in methods of treating
`
`and/or managing cancer.
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`15
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`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
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`tremendous demand therefore exists for new methods and compositions that can be used to
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`treat patients with cancer.
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`2.1.
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`PATHOBIOLOGY OF CANCER
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`Cancer is characterized primarily by an increase in the number of abnormal cells
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`derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or
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`lymphatic or blood-bome spread of malignant cells to regional lymph nodes and to distant
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`sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a
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`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).
`
`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.
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`Atypical metaplasia involves a somewhat disorderly metaplastic epithelium. Dysplasia is
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`frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most
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`disorderly form of non—neoplastic cell growth, involving a loss in individual cell uniformity
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`and in the architectural orientation of cells. Dysplastic cells often have abnormally large,
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`deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where
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`there exists chronic irritation or inflammation, and is often found in the cervix, respiratory
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`passages, oral cavity, and gall bladder.
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`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, 1., Brostoff, J and Kale, D.,
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`Immunology, l7.l—l7.12 (3rd ed., Mosby, St. Louis: 1993).
`
`10
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`2.2.
`
`TYPES OF CANCERS
`
`There is an enormous variety of cancers which are described in detail in the medical
`
`literature. Examples of some are discussed below.
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`2.2.1. AIDS-RELATED N ON-HODGKIN 'S LYMPHOMA
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`AIDS has been closely associated with a variety of cancers. Further, the types of
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`malignancies and their incidence rates are increasing as the development of effective
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`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.
`
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`2.2.2. PRIMARY AND METASTATIC CNS TUMORS
`
`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.
`
`Glioblastoma multifonn 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
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`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.
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`2.2.3. 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 (1 6th 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, S-fluorouracil, cisplatin, Vinblastine, taxol, taxotere, mitomycin
`
`C and occasionally other agents. Unfortunately, even with these agents, almost all women
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`10
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`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.
`
`Lung cancer is reportedly the leading cause of cancer death in men and women.
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`15
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`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.
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`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, combinations of cyclophosphamide plus
`
`doxorubicin plus cisplatin, and single agents alone or in combination, including ifosfamide,
`
`teniposide, vindesine, carboplatin, vincristine, taxol, nitrogen mustard, methotrexate,
`
`hexamethylmelarnine 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
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`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 (16‘h 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
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`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.
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`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 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).
`
`2.2.4. 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]. 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.
`
`2.2.5. 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
`
`humans are to a large extend unknown. The Merck Manual 1233 (16th 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
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`forms.
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`Acute leukemias are divided into lyrnphoblastic (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—
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`35
`
`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
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`and is the more common acute leukemia among adults; it is the form usually associated with
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`irradiation as a causative agent.
`
`Chronic leukemias are described as being lyrnphocytic (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/uL)
`
`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
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`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/uL, but may reach
`
`1,000,000/uL. CML is relatively easy to diagnose because of the presence of the
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`Philadelphia chromosome.
`
`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.
`
`2.2.6. 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 (16th 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. 1d.
`
`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 (SFU) and methyl-CCNU. Id.
`
`2.3.
`
`
`CANCER TREATMENTS
`
`In recent years, advances in medicine and pharmacology have produced an
`
`enormous number of cancer treatments using a wide variety of small and large molecule-
`
`based drugs.
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`2.3.1. THALIDOMIDE AND THALIDOMIDE ANALOGUES
`
`Thalidomide is a racemic compound sold under the tradename THALOMID® and
`
`chemically named (1-(N-phthalimido)glutarimide or 2—(2,6-dioxo—3-piperidinyl)~1H-
`
`isoindole-l,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, 1154-1158 (56th ed, 2002).
`
`Because its administration to pregnant women can cause birth defects, the sale of
`
`thalidomide is strictly controlled, Id. Thalidomide has reportedly been used to treat other
`
`diseases, such as 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. 15925157-
`
`5161 (1997); Vasiliauskas, EA, et al., Gastroenterology 117:1278-1287 (1999);
`
`Ehrenpreis, E.D., er al., Gastroenterology 117: 1271-127 7 (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 US. Patent No. 5,643,915, which is
`
`incorporated herein by reference.
`
`One of the most therapeutically significant uses of thalidomide is in the treatment of
`
`cancer. The compound has reportedly been investigated in the treatment of various types of
`
`cancer, such as refractory multiple myeloma, brain, breast, colon, and prostate cancer,
`
`melanoma, mesothelioma, and renal cell carcinoma. See, e. g., Singhal, S., et al., New
`
`England]. Med. 34l(21):1565—1571 (1999); and Marx, G.M., et al., Proc. Am. Soc. Clin.
`
`Oncology 18:454a (1999). Thalidomide reportedly can also be used to prevent the
`
`development of chronic cardiomyopathy in rats caused by doxorubicin. Costa, P.T., et al.,
`
`Blood 92(10zsuppl. 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 astrocytoma. Zwart,
`
`D., Arznez'm.—Forsch. 16(12): 1688—1689 (1966). The use ofthalidomide in combination
`
`with dexamethasone reportedly was effective in the treatment of patients suffering from
`
`multiple myeloma who also received, as supportive care, human granulocyte colony-
`
`stimulating factor (G—CSF), ciprofloxacin, and non—absorbable antifungal agents. Kropff,
`
`M.H., Blood 96(11 part l):168a (2000); see also, Munshi, N. et al., Blood 94(10 part
`
`1):578a (1999). Other chemotherapy combinations that comprise thalidomide are disclosed
`
`in International Application No. PCT/U801/ 15 326 to R. Govindarj an and A. Zeitlan, and in
`
`International Application No. PCT/USOl/15327 to J.B. Zeldis, et al.
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`While thalidomide may be used to treat some forms of cancer, reports concerning its
`
`ability to treat others, such as melanoma and breast, lung, and ovarian cancer have been
`
`disappointing. D'Amato, R.J., et al., Seminars in Oncology 28(6):597-601 (2001). The
`
`reasons Why thalidomide works well in the treatment of some cancer but not in the
`
`treatment of others are still unclear, as the mechanism by which thalidomide acts is still
`
`under investigation. See, e.g., Moreira, AL, 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., ei al., J.
`
`Immunol. 159:5157-5161 (1997). For example, thalidomide is known to be an
`
`antiangiogenic agent that can suppress tumor necrosis factor 0t (TNF—oc) and interleukin—12
`
`10
`
`(IL—12) production. See, e.g., Moller, D.R., et al., J. Immunol. 159:5157—5161 (1997);
`
`Moreira, AL, et al., J. Exp. Med. 17721675-1680 (1993); Zwingenberger, K. and Wnendt,
`
`S., J. Inflammation 46:177-211 (1996); US. Patent Nos. 5,593,990, 5,629,327, and
`
`5,712,291 to D'Amato and US. Patent No. 5,385,901 to Kaplan. However, in vitro studies
`
`of multiple myeloma cells suggest that the activity of thalidomide with respect to that form
`
`of cancer is not due to TNF-a inhibition. D'Amato, R.J., et al., Seminars in Oncology
`
`28(6):597-601 (2001).
`
`Reports are varied with regard to thalidomide's effect on the production of other
`
`proteins. See, e.g., McHugh, S.M., et al., Clin. Exp. Immunol. 99:160—167 (1995). For
`
`example, thalidomide reportedly decreases the production of human granulocytc-
`
`macrophage colony-stimulating factor (GM—CSF) in some in vitro tests. See, e.g., Joseph,
`
`I.B.J.K., lsaacs, J.T., J. Natl. Cancer Inst, 90(21):1648-1653 (1998); Kakimoto, T., et al.,
`
`Blood 96(11 part 2):289b (2000). However, studies have shown that thalidomide does not
`
`affect the production of GM-CSF in vivo. Moreira, A.L., et al., Brazilian J. Med. Biol. Res.
`
`30(10): 1 199— 1207 (1977). Still other studies have suggested that thalidomide may affect
`
`mechanisms related to epithelial or endothelial function or growth, and that thalidomide can
`
`increase the amount of in vitro cell differentiation induced by rhGM—CSF in human
`
`leukemia cells. D'Amato M., et al., Proc. Natl. Acad. Sci. 91 :4082-4085(1994); Ural, A.U.,
`
`et al., Blood 98(11 part 2):182(b) (2001). Citing in vitro studies using chronic lymphocytic
`
`leukemia (CLL) cells, other researchers have suggested that thalidomide influences antigen
`
`expression. Venugopal, V., et al., Blood 96(11 part 2): 232b (2000).
`
`Given the wide range of pharmacological effects attributed to thalidomide, perhaps
`
`it is not surprising that the administration of the compound to humans is attended by various
`
`adverse effects. Examples of adverse effects associated with thalidomide include, but are
`
`not limited to, drowsiness and somnolence, dizziness and orthostatic hypotension,
`
`neutropenia, increased HIV-viral load, bradycardia, Stevens—Johnson Sydrome and toxic
`
`epidermal necrolysis, and seizures (e. g., grand mal convulsions). Physicians’Des/c
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`Reference, 115 5—1 156 (56th ed., 2002). In some cases, such adverse effects can be dose
`
`limiting or, at the very least, reduce patient compliance.
`
`In an effort to provide compounds that have greater therapeutic safety and efficacy
`
`than thalidomide, researches have begun investigating a large number of other compounds,
`
`some of which are derivatives of thalidomide. See, e. g., Marriott, J .B., et (11., Expert Opin.
`
`Biol. Ther. l(4):l—8 (2001). Examples include, but are not limited to, the substituted 2-(2,6-
`
`dioxopiperidin-3-yl) phthalimies and substituted 2—(2,6—dioxopiperidin-3-yl)-l-
`
`oxoisoindoles described in United States Patent Nos. 6,281,230 and 6,316,471, both to
`
`G.W. Muller, et a]. While many such compounds have shown promise as therapeutic
`
`agents, their mechanisms of action and effectiveness, particularly when used in combination
`
`with other anti—cancer drugs, is still under investigation.
`
`2.3.2. LARGE MOLECULES
`
`Attempts to treat or manage various forms of cancer have also been made using
`
`large molecules, such as proteins. For example, growth factors and cytokines including
`
`interleukin—2 (IL—2), IL—12, G—CSF, and GM—CSF have been administered alone and in
`
`combination with various other drugs to cancer patients. In fact, recombinant forms of
`
`G—CSF and GM—CSF are currently sold in the United States for the treatment of symptoms
`
`associated with specific chemotherapies. A recombinant form of G—CSF known as
`
`filgrastim is sold in the United States under the trade name NEUPOGEN®, and is indicated to
`
`decrease the incidence of infection, as manifested by febrile neutropenia, in patients with
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`nonmyeloid malignancies receiving myelosuppressive anti—cancer drugs associated with a
`
`10
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`15
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`20
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`significant incidence of severe neutropenia with fever. PhysicianS’DeS/c Reference, 587—
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`592 (56th ed, 2002). A recombinant form of GM—CSF known as sargramostim is also sold
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`25
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`in the United States under the trade name LEUKINE®. LEUKINE® is indicated for use
`
`following induction chemotherapy in older adult patients with acute myelogenous leukemia
`
`(AML) to shorten time to neutrophil recovery. Physicz'ans’Desk Reference, 175 5-1760 (561h
`
`ed., 2002).
`
`Although both are colony stimulating factors, G-CSF and GM—CSF are distinct
`
`30
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`35
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`proteins with different physical, chemical, and biological properties. Metcalf, D., Blood
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`67(2):257—267 (1986). For example, GM-CSF stimulates granulocyte and macrophage
`
`colony formation and, at high concentrations, eosinophil, megakaryocyte, and erythroid
`
`colony formation. Id. at 258. On the other hand, G—CSF, at low concentrations, stimulates
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`exclusively the formation of granulocytic colonies that are characterized by their small
`
`average size, their maturity, and their relatively small total numbers. Id. at 259.
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`The administration of G—CSF and GM—CSF to specific patient populations is well
`
`documented. For example, it has been reported that the colony simulation factor G—CSF
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`reduced neutropenia and the severity of severe infections in elderly AML patients when it
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`was administered to them following chemotherapy using various combinations of drugs,
`
`such as CHOP (i.e., cyclophosphamide, doxorubicin, vincristinc, and prednisone) and
`
`cytarabine in combination with daunorubicin or idarubicin. Bokemeyer, C., et al.,
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`Onkologz'e 25:32-39 (2002). Children suffering from neutropenia reportedly have also been
`
`treated with G—CSF. Lehrnbecher, T., Brit. J. Haematol. 116:28-56 (2002). In addition,
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`patients suffering from locally advanced breast cancer were reportedly treated with
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`GM—CSF in combination with doxorubicin and cyclophosphamide, and both G-CSF and
`
`GM-CSF can reportedly accelerate the recovery of normal granulopoiesis after intensive
`
`initial cytotoxic chemotherapy for acute leukemia. Luykx—de Bakker, S.A., et al., Annals of
`
`Oncology 10:155—160 (1999); Bradsock, K.F., Current Pharm. Design 8:343-355 (2002).
`
`However, the final role these cytokines should play in the treatment of acute leukemia
`
`remains controversial. Bradsock, KHF, Current Pharm. Design 8:343—355 (2002).
`
`The controversy surrounding the use of growth—factors and cytokines such as G—CSF
`
`and GM-CSF is rooted not just in their expense, which can be significant. It is also based
`
`on reports that the proteins may be ineffective and even harmful when used in combination
`
`with other drugs. For example, an attempt to use GM—CSF to reduce the hematologic
`
`toxicity and morbidity induced by chemoradiotherapy in limited stage small—cell lung cancer
`
`(S CLC) actually increased the frequency and duration of life-threatening thrombocytopenia.
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`Bunn, P.A., et al., J Clin. Oncology 13(7): 1632-1641 (1995). Worse, patients who
`
`received GM-CSF had significantly more toxic deaths, more nonhematologic toxicities,
`
`more days in the hospital, a higher incidence of intravenous antibiotic usage, and more
`
`transfusions. Id. Indeed, contrary to predictions that G-CSF and GM—CSF would enable the
`
`administration of higher dosages of chemotherapteutics to patients suffering from SCLC,
`
`numerous investigations have demonstrated that they do not. Esterlind, K., Eur. Respir. J.
`
`18:1026—1043 (2001).
`
`Findings such as these emphasize what is already evident from the cancer literature,
`
`namely that while scientists' understanding of cancer and the pharmacological effects of
`
`various anti—cancer drugs is improving, it is still difficult—if not impossible—to predict ab
`
`initio the effect a particular combination of drugs may have on a given form of cancer.
`
`Consequently, continued research is necessary to provide new cancer therapies that are safe
`
`and effective.
`
`3.
`
`SUMMARY OF THE INVENTION
`
`This invention is based, in part, on the realization that certain small molecules,
`
`which are referred to herein as “small molecule-based active agents,” can be combined with
`
`large molecules (e. g, proteins) to treat and/or manage various forms of cancer. Particular
`
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`small molecule—based active agents include, but are not limited to, analogues and
`
`derivatives of thalidomide.
`
`Consequently, the invention encompasses a method of treating cancer which
`
`comprises administering to a patient in need of such treatment a therapeutically effective
`
`amount of a small molecule-based active agent, or a pharmaceutically acceptable salt,
`
`solvate, hydrate, clathrate, or prodrug thereof and a therapeutically effective amount of a
`
`growth-factor or cytokine, such as, but not limited to, IL-2, interleukin—10 (IL-10),
`
`interleukin-12 (IL-12), interleukin-18 (IL-l8), G—CSF, GM-CSF, and erythropoietin (EPO).
`
`The invention also encompasses a method of managing cancer (e.g., preventing or
`
`10
`
`prolonging its recurrence, or lengthening the time of remission) which comprises
`
`administering to a patient in need of such management a therapeutically effective amount of
`
`a small molecule—based active agent, or a pharmaceutically acceptable salt, solvate, hydrate,
`
`clathrate, or prodrug thereof and a therapeutically effective amount of a growth—factor or
`
`cytokine.
`
`15
`
`This invention further encompasses pharmaceutical compositions, single unit dosage
`
`forms, and kits which comprise a small molecule—based active agent, or a pharmaceutically
`
`acceptable salt, solvate, hydrate, clathrate, or prodrug thereof and a large molecule (e.g., a
`
`protein such as a growth-factor or cytokine).
`
`20
`
`4.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This invention is based, in part, on the understanding that various cancers can be
`
`effectively treated or managed by using a small molecule—based active agent in combination
`
`with certain large molecules, such as proteins (e.g., growth-factors, cytokines, and cytokine
`
`derivatives). Without being limited by theory, it is believed that certain small molecule-
`
`25
`
`based active agents and proteins can act in complementary or synergistic ways on tumor
`
`cells. It is also believed that certain proteins may reduce or eliminate particular adverse
`
`effects associated with some small molecule-based active agents, thereby allowing the
`
`30
`
`35
`
`administration of larger amounts of small molecule—based active agents to patients and/or
`
`increasing patient compliance.
`
`It is further believed that some small molecule-based active
`
`agents may reduce or eliminate particular adverse effects associated with some protein—
`
`based cancer therapies, thereby allowing the administration of larger amounts of protein to
`
`patients and/or increasing patient compliance.
`
`A first embodiment of the invention encompasses a method of treating cancer,
`
`which comprises administering to a patient in need of such treatment a therapeutically
`
`effective amount of a small molecule-based active agent, or a pharmaceutically acceptable
`
`salt, solvate, hydrate, clathrate, or prodrug thereof, and a therapeutically effective amount of
`
`a protein, a fusion protein thereof, or a vaccine that secretes the protein, wherein the protein
`
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`is IL—2, lL-lO, IL-12, IL—l 8, G-CSF, GM—CSF, EPO, or a pharmacologically active mutant
`
`or derivative thereof.
`
`Another embodiment of the invention encompasses a method of managing cancer,
`
`which comprises administering to a patient in need of such management a prophylactically
`
`effective amount of a small molecule—based active agent, or a pharrnaceutically acceptable
`
`salt, solvate, hydrate, clathrate, or prodrug thereof, and a therapeutically effective amount of
`
`a protein, a fusion protein thereof, or a vaccine that secretes the protein, wherein the protein
`
`is lL—2, lL-10, IL—12, IL—18, G—CSF, GM~CSF, EPO, or a pharrnacologically active mutant
`
`or derivative thereof.
`
`In specific methods of the invention, the cancer is of the bladder, bone or blood,
`
`brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph
`
`nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach