COVER SHEET FOR PROVISIONAL APPLICATION FOR PATENT
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`GU/LLASU
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`==sistant Commissioner for Patents
`SSSPROVISIONAL PATENT APPLICATION
`Washington, DC 20231
`i
`Sir:
`This is a requestfor filmg a PROVISIONAL APPLICATIONunder 37 CFR 1.53(c).
`Docket Number
`9516-062-888
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`afe
`Express Mail No.:_N/A
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`Type a plus sign (+)
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`DCI - 322780.1
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`LAST NAME
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`FIRST NAME
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`MIDDLEINITIAL
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`RESIDENCE(CITY AND EITHER STATE OR FOREIGN COUNTRY)
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`INVENTOR(s) APPLICANT(s)
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`TITLE OF THE INVENTION (280 characters max)
`METHODS OF USING SMALL AND LARGE
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`MOLECULES FOR THE TREATMENT AND MANAGEMENT
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`OF CANCER, AND COMPOSITIONS AND KITS USEFUL THEREIN
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`PENNIE & EDMONDSur
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`Leb Wrdibllibfilbel
`20582
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`ORRESPONDENCE ADDRESS:
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`ENCLOSED APPLICATION PARTS (check all that apply)
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`© Applicant claims small entity status, see 37 CFR §1 27
`Specification,
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`slaims and Abstract
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` “) Drawing(s)s
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` A check or moncyorder 1s enclosed to cover the Provisional filing fees ESTIMATED
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`PROVISIONAL
`& $160
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`FILING FEE
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`AMOUNT
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`& The Commissioneris hereby authorized to charge the required filing fee to Deposit Account Number 16-1150
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`The invention was made by an agency of the United States Governmentor under a contract with an agency of the Untted States Government
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`& No.
`Yes, the name of the U.S Government agency and the Government contract numberare:
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`Respectfully submitted,
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`(ifappropriate)
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`For: Anthony M Insogna (Reg No 35,203)
`PENNIE & EDMONDS1:
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`Signature REGISTRATION NO.|45,479 Date May 17, 2002
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`Additional inventors are being named on separately numbered sheets attached hereto.
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`Tota] numberof cover sheet pages
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`PROVISIONAL APPLICATION FILING ONLY
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`ALVOGEN, Exh. 1052, p. 0001
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`METHODS OF USING SMALL AND LARGE
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`MOLECULES FOR THE TREATMENT AND MANAGEMENT
`OF CANCER, AND COMPOSITIONS AND KITS USEFUL THEREIN
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`1.
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`FIELD OF THE INVENTION
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`This invention relates to methods oftreating and/or managing cancer using the
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`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-
`based active agents include, but are not limited to, proteins such as IL-2, IL-10, IL-12, IL-
`18, G-CSF, GM-CSF, and EPO. The invention further relates to pharmaceutical
`compositions, single unit dosage forms, and kits suitable for use in methodsoftreating
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`and/or managing cancer.
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`2.
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`BACKGROUND OF THE INVENTION
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`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 demandtherefore 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 numberof abnormalcells
`derived from a given normaltissue, invasion of adjacent tissues by these abnormalcells, or
`lymphatic or blood-borne spread of malignantcells to regional lymph nodesandto distant
`sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a
`multistep process that begins with minor preneoplastic changes, which may undercertain
`conditions progress to neoplasia.
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`Pre-malignant abnormalcell growth is excmplificd by hyperplasia, metaplasia, or
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`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).
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`Hyperplasia is a form of controlled cell proliferation involving an increase in cell numberin
`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
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`of controlled cell growth in which one type of adult or fully differentiated cell substitutes
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`for another type of adult cell. Metaplasia can occur in epithelial or connective tissue cells.
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`Atypical metaplasia involves a somewhatdisorderly metaplastic epithelium. Dysplasia is
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`frequently a forerunnerof cancer, and is found mainlyin 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
`there exists chronic irritation or inflammation, and is often foundin the cervix, respiratory
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`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
`neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J and Kale, D.,
`Immunology, 17.1-17.12 (3% ed., Mosby, St. Louis: 1993).
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`2.2.
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`TYPES OF CANCERS
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`There is an enormous variety of cancers which are described in detail in the medical
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`literature. Examples of some are discussed below.
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`2.2.1. AIDS-RELATED NON-HODGKIN'S LYMPHOMA
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`AIDShas been closely associated with a variety of cancers. Further, the types of
`malignancies and their incidence rates are increasing as the developmentofeffective
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`antiretroviral therapies and prophylaxis against opportunistic infections leads to prolonged
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`survival in the immunodeficient state for AIDS patients. Karp and Broder, Cancer Res.
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`51:4747-4756 (1991). AIDS-related non-Hodgkin's lymphomais a very aggressive disease
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`with a very high incidence of central nervous system involvement. Since its discovery in
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`1981, the incidence of AIDS-related non-Hodgkin's lymphomahasreportedly increased.
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`One reason for such an observation is that patients infected with the AIDS virus now live
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`longer than they usedto.
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`2.2.2. PRIMARY AND METASTATIC CNS TUMORS
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`The incidence of primary and metastatic brain tumorsis also increasing in the
`United States. Unfortunately, the arsenal of chemotherapeutics for these types of cancersis
`minimal, while the need for such therapeutics is high.
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`Glioblastoma multiform and other primary and metastatic central nervous system
`tumors are devastating malignancies. The treatment of these tumors include surgery,
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`radiation therapy and treatment with agents such as the nitrosourea BCNU. Other
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`chemotherapeutic agents utilized include procarbazine, vincristine, hydroxyurea and
`cisplatin. But even whenall three modalities (surgery, radiation therapy and chemotherapy)
`are utilized, the average survival of patients with central nervous system malignanciesis
`only about 57 weeks. Clearly, new treatment approachesare 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
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`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 carly breast
`canceris surgery, with or withoutradiation therapy, or surgery, with or withoutradiation
`therapy, plus chemotherapy and/or hormonal therapy. Current chemotherapy for patients
`with primary or metastatic breast cancer includes treatment with cyclophosphamide,
`methotrexate, doxorubicin, 5-fluorouracil, cisplatin, vinblastine, taxol, taxotere, mitomycin
`C and occasionally other agents. Unfortunately, even with these agents, almost all women
`who develop metastatic breast cancer succumbto their disease. Oneparticular place that
`metastatic breast cancer does metastasize to is the central nervous system. When central
`nervous system metastases do occur, the usual treatmentis surgery (for a solitary
`metastasis) or radiation, or surgery plus radiation therapy.
`Lungcanceris 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. Jd.
`Mostpatients with lung cancer present a tumorthat has already metastasized to a
`variety of organs, including lung,liver, adrenal gland and other organs. Treatment of
`metastatic lung canceris not yet standardized. Ihde, D.C., The New England Journal of
`Medicine 327:1434-1441 (1992). However, chemotherapy regimensthat are utilized
`include treatment with cisplatin plus etoposide, combinations of cyclophosphamide plus
`doxorubicin plus cisplatin, and single agents alone or in combination, including ifosfamide,
`teniposide, vindesine, carboplatin, vincristine, taxol, nitrogen mustard, methotrexate,
`hexamethylmelamine and others. Despite these chemotherapeutic regimens the average
`patient with metastatic lung cancerstill only survives 7-12 months. Oneparticular
`troublesomeplace for metastases of lung cancer is the central nervous system. The
`treatment for central nervous system metastases includes surgery (to removea 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" ed. 1992). Althoughat presentation the disease is
`usually localized, most patients develop distant metastatic disease. The most recent
`advances havebeenin the area of chemotherapy for patients with such metastatic disease.
`Oneeffective regimen is called the MVACregimen. It consists of treatment with
`methotrexate plus vinblastine plus adriamycin (doxorubicin) plus cisplatin. Although the
`responserate 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 (16" ed. 1992). The most commonsites of metastases
`in patients with prostate cancer are the bone and lymph nodes. The bone metastases are
`particularly bothersomein 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
`cancerlive longer with their malignancy, they will most likely develop a higher incidence of
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`metastases to the central nervous system (including the spinal cord).
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`2.2.4. ESOPHAGEAL CANCER
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`Several years ago, carcinoma of the esophagus reportedly represented only about six
`percentof all cancers of the gastrointestinal tract; however, it reportedly caused a
`disproportionate numberof 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 andare either
`squamouscell carcinomas or adenocarcinomas. Overall, the 5 year survival is about five
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`percent.
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`2.2.5. LEUKEMIA
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`Leukemiarefers to malignant neoplasmsof the blood-formingtissues. Although
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`viruses reportedly cause several forms of leukemia in animals, causes of leukemia in
`humansare to a large extend unknown. The Merck Manual 1233 (16" ed. 1992).
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`Transformation to malignancy typically occurs in a single cell through two or moresteps
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`with subsequent proliferation and clonal expansion. In some leukemias, specific
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`chromosomaltranslocations have been identified with consistent leukemic cell morphology
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`and special clinical features (e.g., translocations of 9 and 22 in chronic myelocytic
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`leukemia, and of 15 and 17 in acute promyelocytic leukemia). Acute leukemias are
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`predominantly undifferentiated cell populations and chronic leukemias more maturecell
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`forms.
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`Acute leukemias are divided into lymphoblastic (ALL) and non-lymphoblastic
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`(ANLL) types. They may be further subdivided by their morphologic and cytochemical
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`appearance according to the French-American-British (FAB)classification or according to
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`their type and degree of differentiation. The use of specific B- and T-cell and myeloid-
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`antigen monoclonal antibodies are most helpful for classification. ALL is predominantly a
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`childhood disease whichis established by laboratory findings and bone marrow
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`examination. ANLL, also known as acute myeloblastic leukemia (AML), occursat all ages
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`and is the more commonacute leukemia amongadults; it is the form usually associated with
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`irradiation as a causative agent.
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`Chronic leukemias are described as being lymphocytic (CLL) or myelocytic (CML).
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`CLLis characterized by the appearance of mature lymphocytes in blood, bone marrow, and
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`lymphoid organs. The hallmark of CLL is sustained, absolute lymphocytosis (> 5,000/uL)
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`and an increase of lymphocytes in the bone marrow. Most CLL patients also have clonal
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`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
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`differentiation in blood, bone marrow,liver, spleen, and other organs. In the symptomatic
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`patient at diagnosis the total WBC countis usually about 200,000/nL, but may reach
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`1,000,000/uL. CMLis relatively easy to diagnose because of the presence of the
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`Philadelphia chromosome.
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`The very nature of hematopoietic cancer necessitates using systemic chemotherapy
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`as the primary treatment modality, and radiation therapy may be used as an adjunctto treat
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`local accumulations of leukemic cells. Surgery is rarely indicated as a primary treatment
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`modality, but may be used in managing some complications. Bone marrow transplantation
`from an HLA-matched sibling is sometimesindicated.
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`2.2.6. COLORECTAL CANCERS
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`In 1999, the incidence of colorectal cancer in the United States was 129,400 cases.
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`In Westem 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.
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`Despite the enormous numberof deathsattributed to colorectal cancers, their
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`specific mechanism remains unknown. It is known, however, that cancers of the colon and
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`rectum spread in at least five ways: directed extension through the bowelwall;
`hematogenous metastases; regional lymph node metastases; perineural spread; and
`intraluminal metastases.
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`Primary treatment of colorectal cancers typically includes surgery. Manypatients,
`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
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`5-fluorouracil (SFU) and methyl-CCNU. Jd.
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`2.3.
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`CANCER TREATMENTS
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`In recent years, advances in medicine and pharmacology have produced an
`enormous numberof cancer treatments using a wide variety of small and large molecule-
`based drugs.
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`2.3.1. THALIDOMIDE AND THALIDOMIDE ANALOGUES
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`Thalidomide is a racemic compound sold under the tradename THALOMID® and
`chemically named a-(N-phthalimido)glutarimide or 2-(2,6-dioxo-3-piperidinyl)-1/-
`isoindole-1,3(2//)-dione. Thalidomide wasoriginally developed in the 1950's to treat
`morning sickness, but due to its tetragenic effects was withdrawn from use. Thalidomide is
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`now indicated in the United States for the acute treatment of the cutaneous manifestations of
`erythema nodosum leprosum. Physicians’ Desk Reference, 1154-1158 (56" ed., 2002).
`Because its administration to pregnant women can cause birth defects, the sale of
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`thalidomideis strictly controlled. Jd. Thalidomide has reportedly been usedto 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. 159:5157-
`5161 (1997); Vasiliauskas, E.A., ef al., Gastroenterology 117:1278-1287 (1999);
`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
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`incorporated herein by reference.
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`Oneof the most therapeutically significant uses of thalidomideis in the treatment of
`cancer. The compoundhasreportedly 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 J. Med. 341(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 preventthe
`development of chronic cardiomyopathy in rats caused by doxorubicin. Costa, P.T., et al.,
`Blood 92(10:suppl. 1):235b (1998). Other reports concerning the use of thalidomide in the
`treatment of specific cancers include its combination with carboplatin in the treatment of
`globlastoma 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., Arzneim.-Forsch. 16(12):1688-1689 (1966). The use of thalidomide in combination
`with dexamethasonereportedly waseffective in the treatmentof patients suffering from
`multiple myeloma whoalso received, as supportive care, human granulocyte colony-
`stimulating factor (G-CSF), ciprofloxacin, and non-absorbable antifungal agents. Kropff,
`M.H., Blood 96(11 part 1):168a (2000); see also, Munshi, N. et al., Blood 94(10 part
`1):578a (1999). Other chemotherapy combinations that comprise thalidomideare disclosed
`in International Application No. PCT/US01/15326 to R. Govindarjan and A. Zeitlan, and in
`International Application No. PCT/US01/15327 to J.B. Zeldis,et al.
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`While thalidomide maybe used to treat some formsof cancer, reports concerningits
`ability to treat others, such as melanoma andbreast, lung, and ovarian cancer have been
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`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 notin the
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`treatment of othersarestill unclear, as the mechanism by which thalidomideactsisstill
`under investigation. 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.
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`Immunol. 159:5157-5161 (1997). For example, thalidomide is knownto be an
`antiangiogenic agent that can suppress tumornecrosis factor ao (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); Zwingenberger, K. and Wnendt,
`S., J. Inflammation 46:177-211 (1996); U.S. Patent Nos. 5,593,990, 5,629,327, and
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`5,712,291 to D'Amato and U.S. Patent No. 5,385,901 to Kaplan. However,in vitro studies
`of multiple myelomacells 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).
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`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 granulocyte-
`macrophage colony-stimulating factor (GM-CSF) in somein vitro tests. See, e.g., Joseph,
`I.B.J.K., Isaacs, J.T., J. Natl. Cancer Inst., 90(21):1648-1653 (1998); Kakimoto,T., ef al.,
`Blood 96(11 part 2):289b (2000). However, studies have shownthat thalidomide does not
`affect the production of GM-CSFin vivo. Moreira, A.L., et al., Brazilian J. Med. Biol. Res.
`30(10):1199-1207 (1977). Still other studies have suggested that thalidomide mayaffect
`mechanismsrelated to epithelial or endothelial function or growth, and that thalidomide can
`increase the amountofin vitro cell differentiation induced by rhGM-CSFin 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 pharmacologicaleffects attributed to thalidomide, perhaps
`it is not surprising that the administration of the compound to humansis 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 Sydromeand toxic
`epidermal necrolysis, and seizures (e.g., grand mal convulsions). Physicians’ Desk
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`Reference, 1155-1156 (56" ed., 2002). In some cases, such adverse effects can be dose
`limiting or, at the very least, reduce patient compliance.
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`In an effort to provide compoundsthat havegreater therapeutic safety and efficacy
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`than thalidomide, researches have begun investigating a large numberof other compounds,
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`some of which are derivatives of thalidomide. See, e.g., Marriott, J.B., et al., Expert Opin.
`Biol. Ther. 1(4):1-8 (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)-1-
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`oxoisoindoles described in United States Patent Nos. 6,281,230 and 6,316,471, both to
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`G.W. Muller, et a/. While many such compounds have shown promise as therapeutic
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`agents, their mechanismsofaction and effectiveness, particularly when used in combination
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`with other anti-cancer drugs,is still under investigation.
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`2.3.2. LARGE MOLECULES
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`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
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`interleukin-2 (IL-2), IL-12, G-CSF, and GM-CSF have been administered alone and in
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`combination with various other drugs to cancer patients. In fact, recombinant forms of
`G-CSF and GM-CSFare currently sold in the United States for the treatment of symptoms
`associated with specific chemotherapies. A recombinant form of G-CSF knownas
`filgrastim is sold in the United States under the trade name NEUPOGEN®,andis indicated to
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`decrease the incidenceof infection, as manifested by febrile neutropenia, in patients with
`nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a
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`significant incidence of severe neutropenia with fever. Physicians' Desk Reference, 587-
`592 (56" ed., 2002). A recombinant form of GM-CSF knownas sargramostim is also sold
`in the United States under the trade name LEUKINE®, LEUKINE®is indicated for use
`
`25
`
`following induction chemotherapy in older adult patients with acute myelogenous leukemia
`(AML)to shorten time to neutrophil recovery. Physicians' Desk Reference, 1755-1760 (56"
`ed., 2002).
`
`Although both are colony stimulating factors, G-CSF and GM-CSFaredistinct
`
`30
`
`35
`
`proteins with different physical, chemical, and biological properties. Metcalf, D., Blood
`67(2):257-267 (1986). For example, GM-CSFstimulates granulocyte and macrophage
`colony formation and, at high concentrations, eosinophil, megakaryocyte, and erythroid
`colony formation.
`/d. at 258. On the other hand, G-CSF, at low concentrations, stimulates
`exclusively the formation of granulocytic colonies that are characterized by their small
`average size, their maturity, and their relatively small total numbers.
`/d. at 259.
`The administration of G-CSF and GM-CSFto 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 whenit
`was administered to them following chemotherapy using various combinationsof drugs,
`such as CHOP(i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone) and
`cytarabine in combination with daunorubicin or idarubicin. Bokemeyer, C., et al.,
`5 Onkologie 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,
`patients suffering from locally advanced breast cancer were reportedly treated with
`GM-CSFin combination with doxorubicin and cyclophosphamide, and both G-CSF and
`
`GM-CSFcan reportedly accelerate the recovery of normal granulopoiesis after intensive
`10 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, K.F., Current Pharm. Design 8:343-355 (2002).
`
`The controversy surrounding the use of growth-factors and cytokines such as G-CSF
`
`15 and GM-CSFis 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-CSFto reduce the hematologic
`
`toxicity and morbidity induced by chemoradiotherapy in limited stage small-cell lung cancer
`(SCLC)actually increased the frequency and duration of life-threatening thrombocytopenia.
`
`20 Bunn, P.A., et al., J. Clin. Oncology 13(7):1632-1641 (1995). Worse, patients who
`
`received GM-CSFhad significantly more toxic deaths, more nonhematologic toxicities,
`
`more days in the hospital, a higher incidence of intravenousantibiotic usage, and more
`
`transfusions. Jd. Indeed, contrary to predictions that G-CSF and GM-CSF would enable the
`
`administration of higher dosages of chemotherapteutics to patients suffering from SCLC,
`
`25 numerous investigations have demonstrated that they do not. Osterlind, K., Eur. Respir. J.
`
`18:1026-1043 (2001).
`
`Findings such as these emphasize what is already evident from the cancerliterature,
`
`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
`
`30 initio the effect a particular combination of drugs may have on a given form ofcancer.
`
`Consequently, continued research is necessary to provide new cancer therapies that are safe
`
`andeffective.
`
`3.
`
`SUMMARYOF THE INVENTION
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`35
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`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, butare not limited to, analogues and
`derivatives of thalidomide.
`Consequently, the invention encompasses a method oftreating cancer which
`comprises administering to a patient in need of such treatmenta therapeutically effective
`amount of a small molecule-based active agent, or a pharmaceutically acceptablesalt,
`solvate, hydrate, clathrate, or prodrug thereof and a therapeutically effective amount ofa
`growth-factor or cytokine, such as, but not limited to, IL-2, interleukin-10 (IL-10),
`interleukin-12 (IL-12), interleukin-18 (IL-18), G-CSF, GM-CSF,and erythropoietin (EPO).
`The invention also encompasses a method of managing cancer(e.g., preventing or
`prolongingits recurrence, or lengtheningthe time of remission) which comprises
`administering to a patient in need of such management a therapeutically effective amount of
`a small molecule-basedactive agent, or a pharmaceutically acceptable salt, solvate, hydrate,
`clathrate, or prodrug thereof and a therapeutically effective amount of a growth-factor or
`
`cytokine.
`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 thereofand a large molecule(e.g., a
`protein such as a growth-factor or cytokine).
`
`10
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`15
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`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-
`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
`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 reduceoreliminate particular adverse effects associated with someprotein-
`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 methodoftreating 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
`
`25
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`30
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`35
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`is IL-2, IL-10, IL-12, IL-18, G-CSF, GM-CSF, EPO,or a pharmacologically active mutant
`
`or derivative thereof.
`
`Another embodimentof 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 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
`is IL-2, IL-10, IL-12, IL-18, G-CSF, GM-CSF, EPO,or a pharmacologically active mutant
`
`or derivative thereof.
`
`10
`
`In specific methods of the invention, the canceris 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,testis, throat, or
`
`uterus.
`
`Another embodiment of the invention encompasses a method of reducing or
`
`15
`
`avoiding an adverse effect associated with the administration of a small molecule-based
`active agent to a patient suffering from cancer, which comprises administering to a patient
`
`in need of such reduction or avoidance a therapeutically or prophylactically effective
`amount of a protein, a fusion protein thereof, or a vaccine that secretes the protein, wherein
`the protein is IL-2, IL-10, IL-12, IL-18, G-CSF, GM-CSF, EPO,or a pha