MXPA06004996A - Methods and compositions using thalidomide for the treatment and management of cancers and other diseases - Google Patents

Abstract

Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass the administration of thalidomide alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associated with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of thalidomide. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

METHODS AND COMPOSITIONS USING TALIDOMIDE FOR THE TREATMENT AND MANAGEMENT OF CANCER AND OTHER DISEASES 1. FIELD OF THE INVENTION This invention relates to methods for treating, preventing and / or managing specific cancers and other diseases including, but not limited to, those associated with, or characterized by, unwanted angiogenesis, by the administration of thalidomide alone or in combination with other therapeutics. In particular, the invention encompasses the use of specific combinations or "cocktails" of drugs and other therapy, for example, radiation to treat these specific cancers, including those refractory to conventional therapy. The invention also relates to pharmaceutical compositions and dosage regimens. 2. BACKGROUND OF THE INVENTION 2.1 PATHOBIOLOGY OF CANCER AND OTHER DISEASES Cancer is characterized mainly by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or spread by lymphatic or blood-borne transmission. of malignant cells to regional lymph nodes and distant sites (metastasis). Clinical data and molecular biological studies indicate that cancer is a 'multistage process that begins with minor pre-neoplastic changes, which can under certain conditions progress to neoplasia. The neoplastic lesion can clonally evolve and develop an increasing capacity for invasion, growth, metastasis and heterogeneity, especially under conditions where the neoplastic cells evade the immune supervision of the host. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993). There is a huge variety of cancers which are described in detail in the medical literature. Examples include cancer of the lung, colon, rectum, prostate, breast, brain and intestine. The incidence of cancer continues to rise when the general population ages, as new cancers develop and when susceptible populations grow (for example, people infected with AIDS or exposed excessively to sunlight). A tremendous demand exists therefore for new methods and compositions that can be used to treat patients with cancer. Many types of cancers are associated with new formation of blood vessels, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been explained. The most direct of these mechanisms is the secretion by cytokine tumor cells with angiogenic properties. Examples of these cytokines include the acidic and basic fibroblast growth factor (a, b-FGF), angiogenin, vascular endothelial growth factor (VEGF) and TNF-a. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent decomposition of the extracellular matrix where some cytokines are stored (eg, b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-a, bFGF). A variety of other diseases and disorders are also associated with, or characterized by, unwanted angiogenesis. For example, improved or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, neovascular eye diseases, choroidal neovascular diseases, neovascular retinal diseases, rubeosis (neovascularization of the elbow), viral diseases , genetic diseases, inflammatory diseases, allergic diseases and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; premature retinopathy; rejection of corneal graft; neovascular glaucoma; fibroplasia behind the lens; and proliferative vitreoretinopathy. Accordingly, compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF-a, may be useful in the treatment and prevention of various diseases and conditions. 2. 2 METHODS FOR TREATING CANCER Current cancer therapy may involve surgery, chemotherapy, hormone therapy and / or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, Vol. 3, Rubenstein and Federman , eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All these methods have significant disadvantages for the patient. Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often cause serious side effects. Hormone therapy is rarely given as a unitary agent. Although hormone therapy may be effective, it is often used to prevent or delay the recurrence of cancer after other treatments have removed most of the cancer cells. Biological therapies and immunotherapies are limited in number and can produce side effects such as rash or swelling, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions. With respect to chemotherapy, there is a variety of chemotherapeutic agents available for the treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly or indirectly by inhibiting the biosynthesis of precursors - deoxyribonucleotide triphosphate, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman and Gilman '' s: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGra Hill, New York). Despite the availability of a variety of chemotherapeutic agents, chemotherapy has many disadvantages. Stockdale, Medicine, vol. 3 Rubenstein and Federman, eds., Chap. 12, sec. 10,1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant and often dangerous side effects including severe nausea, spinal cord depression and immunosuppression. Furthermore, even with the administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often turn out to be resistant to other drugs, even if the agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as resistance to pleiotropic or multidrug drug. Due to drug resistance, many cancers prove to be refractory to standard chemotherapeutic treatment protocols. Other diseases or conditions associated with, or characterized by, unwanted angiogenesis are also difficult to treat. However, some compounds such as protamine, hepaine and steroids have been proposed to be useful in the treatment of certain specific diseases. Taylor et al., Nature 297: 307 (1982); Folkman et al., Science 221: 719 (1983); and U.S. Patent Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives thereof have also been proposed for the treatment of such diseases and conditions. U.S. Patents Nos. 5,593,900, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 for D'Amato. Still, there is a significant need for safe and effective methods to treat, prevent and manage cancer and other diseases and conditions, particularly for diseases that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, although they are reduced or avoid the toxicities and / or side effects associated with conventional therapies. 2. 3 THALIDOMIDE Thalidomide is a racemic compound sold under the Thalomid® brand and chemically named a- (N-phthalimido) glutarimide or 2- (2,6-dioxo-3-piperidinyl) - 1H-isoindol-1,3 (2H) -Diona. The compound has structure I: I Thalidomide was originally developed in the 50 's to treat morning sickness, but due to its teratogenic effects it was withdrawn from use. Thalidomide has been approved in the United States for the acute treatment of cutaneous manifestations of erythema nodosum leprosum in leprosy.

Physician's Desk Reference, 1153-1157 (57th ed., 2003). o Because its administration in pregnant women can cause birth defects, the sale of thalidomide is strictly controlled. Id. Supposedly thalidomide has been studied in the treatment of other diseases such as host disease against chronic graft, rheumatoid arthritis, • sarcoidosis, various inflammatory skin diseases and inflammatory bowel disease. See, generally, Koch, H.P., Prog. Med. Chem. 22: 165-242 (1985). See, also, Moller, D.R., et al. , J. Immunol. 159: 5157-5161 (1997); Vasiliauskas, E.A., et al. , Gastroenterology 117: 1278-1287 (1999); Ehrenpreis, E.D., et al. , Gastroenterology 117: 1271-1277 (1999). It has also been claimed that thalidomide can be combined with other drugs to treat ischemia / reperfusion associated with coronary and cerebral occlusion. See, U.S. Patent No. 5,643,915, which is incorporated herein by reference. Supposedly thalidomide has been investigated clinically in the treatment of specific types of cancers, such as refractory multiple myeloma, brain, melanoma, breast, colon, mesothelioma and renal cell carcinoma. See, for example. , 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 also been reported that thalidomide can be used to prevent the development of chronic cardiopathy in rats caused by doxorubicin. Costa, P.T., et al. , Blood 92 (10: suppl.1): 235b (1998). Other reports that relate to the use of thalidomide in the treatment of specific cancers include its combination with carboplatin in the treatment of gioblastoma multiforme. McCann, J., Drug Topics 41-42 (June 21, 1999). Supposedly thalidomide has also been used as an antiemetic during the treatment of astrocytoma. Zwart, D., Arzneim. -Forsch. 16 (12): 1688-1689 (1966). If there is a general mechanism by which thalidomide helps in the treatment of some cancers, its nature remains unclear. See, for example, Morei-ra, A.L., et al. , J. Exp. 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 a (TNF-a) and the production of interleukin 12 (IL-12). See, for example, Moller, D.R., et al. , J. Immunol. 159: 5157-5161 (1997); Moreira, A.L., et al. , J. Exp. Med. 177: 1675-1680 (1993); U.S. Patent Nos. 5,593,990, 5,629,327 and 5,712,291 for D 'ato and U.S. Patent No. 5,385,901 for Kaplan. And in vi tro studies suggest that thalidomide affects the production of a variety of other proteins. See, for example, McHügh, S.M., et al. , Clin. Exp. Immunol. 99: 160-167 (1995). Thalidomide can also affect mechanisms related to epithelial or endothelial function or growth. D'Amato M., et al. , Proc. Na ti. Acad. Sci. 91: 4082-4085 (1994). 3. COMPENDIUM OF THE INVENTION This invention encompasses methods to treat and prevent certain types of cancer, including primary and metastatic cancer, as well as cancers that are refractory or resistant to conventional chemotherapy. The methods comprise administering to a patient in need of such treatment or prevention a therapeutic - or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention also encompasses methods for managing certain cancers (e.g., preventing or prolonging their recurrence, or lengthening the remission time) which comprise administering to a patient in need of such treatment a prophylactically effective amount of thalidomide, or a salt, solvate , hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof. In the particular methods of the invention, thalidomide is administered in combination with a therapy conventionally used to treat, prevent or manage cancer. Examples of such conventional therapies include, but are not limited to surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. This invention also encompasses methods for treating, managing or preventing diseases and disorders other than cancer, which are associated with, or characterized by, unwanted angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention of an amount Therapeutically or prophylactically effective thalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. In other methods of the invention, thalidomide is administered in combination with a therapy conventionally used to treat, prevent or manage diseases or disorders associated with, or characterized by, unwanted angiogenesis. Examples of such therapies include, but are not limited to surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. This invention encompasses pharmaceutical compositions, single unit dose forms, dosage regimens and kits which comprise thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second, or additional, active agent. The second of the active agents includes specific combinations, or "cocktails" of drugs. 4. DETAILED DESCRIPTION OF THE INVENTION A first embodiment of the invention encompasses methods of treating, managing or preventing cancer, which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of thalidomide, or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof. In particular methods encompassed by this modality, thalidomide is administered in combination with another drug ("second active agent") or method to treat, manage or prevent cancer. The second of the active agents includes small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. The methods or therapies that may be used in combination with the administration of thalidomide include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy and other therapies based on no drugs currently used to treat, prevent * or manage Cancer. Another embodiment of the invention encompasses methods for treating, managing or preventing diseases and disorders other than cancer, which are characterized by undesired angiogenesis. These methods comprise the administration of a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Examples of diseases and disorders associated with, or characterized by, unwanted angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, neovascular retinal diseases. and rubeosis (neovascularization of the elbow). Specific examples of diseases and disorders associated with, or characterized by, unwanted angiogenesis include, but are not limited to, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, attrition, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary, hypercalcemia associated with malignancy, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia and 5q syndrome. In particular methods encompassed by this embodiment, thalidomide is administered in combination with a second active agent or a method for treating, managing or preventing the disease or condition. The second of the active agents includes small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or therapies, which may be used in combination with the administration of thalidomide include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy and other therapies based without drugs currently used to treat, prevent or manage a disease and conditions associated with or characterized by unwanted angiogenesis. The invention also encompasses pharmaceutical compositions (e.g., unique unit dosage forms) that can be used in methods described in the preser-te. Particular pharmaceutical compositions comprise thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second active agent. 4. 1 COMPOUNDS OF THE INVENTION The compounds used in the invention include racemic thalidomide, stereomerically enriched or stereomerically pure thalidomide; and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs thereof. As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises a stereoisomer of a compound and is substantially free of another stereoisomer of that compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, more preferably greater than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, still more preferably greater than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, and more preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition comprising greater than about 60% by weight of a stereoisomer of a compound, preferably greater than about 70% by weight. , more preferably greater than about 80% by weight of a stereoisomer of the compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having a chiral center. Thalidomide can be purchased either commercially (from Celgene Corp. New Jersey) or prepared according to known methods. See, for example. , I.D. Fratta et al. , toxicol. Appl. Pharmacol. 7,268 (1965), and the references described herein. Enantiomerically pure thalidomide can be analyzed using known solution agents or chiral columns as well as other techniques of standard synthetic organic chemistry. See, for example, Blaschke, Arzneimittelforschung 29: 1640-1642(1979); Shealy et al. , Chem. Indus. 1030 (1965); and Casini et al. , Drug Ed. Sci. , 19: 563 (1964). As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt or salts" includes salts of acidic or basic portions of or compounds to which the term refers. The basic portions are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions. Suitable organic acids include, but are not limited to maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic acids , stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharide, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, or pamoic acids (i.e., 1,1 '-methylene-bis- (2-hydroxy-3-) naphthoate.) Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids Compounds that include a portion of amine can form pharmaceutically acceptable salts with several amino acids, in addition to the acids The compounds that are acidic by nature are capable of forming salts with several pharmaceutically acceptable bases. used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, ie, salts that contain pharmacologically acceptable cations such as, but are not limited to, alkali metal or alkaline earth metal salts and calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not mimicked, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, eglumaine (N-methylglucamine), lysine and procaine. As used herein to describe a compound or a chemical moiety, the term "derivative" means a compound or chemical portion 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 union) or where at least one hydrogen atom is replaced with a different atom or chemical portion. Examples of different atoms and chemical moieties include, but are not limited to, halogen, oxygen, nitrogen, sulfur, hydroxy, methoxy, alkyl, amine, amide, ketone and aldehyde. As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize or otherwise be reacted under biological conditions (in vi tro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, thalidomide derivatives including biohydrolyzable portions such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate analogues. Other examples of prodrugs include thalidomide derivatives which include portions of -NO, -N02, -0N0 or -ONO2. As used herein and unless otherwise indicated, the terms "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureido" and "biohydrolyzable phosphate" means a carbamate, a carbonate, a ureide or a phosphate, respectively , of a compound that either: 1) does not interfere with the biological activity of the compound, but can confer on that compound advantageous in vivo properties, such as absorption, duration of action, or the onset of action; 2) is biologically inactive, but is converted in vivo into the biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines and polyetheramines. As used herein and unless otherwise indicated, the term "biohydrolyzable ester" means an ester of a compound that either: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties on that compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo into the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylamino alkylesters and cholinesters. As used herein and unless otherwise indicated, the term "biohydrolyzable amide" means an amide of a compound that either: 1) does not interfere with the biological activity of the compound, but may confer on said compound advantageous in vivo, such as absorption, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo into the biologically active compound. Examples of biohydrolyzable amides include, but are not limited to lower alkylamides, α-amino acid amides, alkoxyacylamides and alkylaminoalkylcarbonylamides. 4. 2 THE SECOND OF THE ACTIVE AGENTS Thalidomide can be combined with other pharmacologically active compounds ("The second of the active agents") in methods and compositions of the invention. It is believed that certain combinations work synergistically in the treatment of particular types of cancer and certain diseases and conditions associated with, or characterized by, unwanted angiogenesis. Thalidomide can work to alleviate adverse effects associated with a certain second of the active agents, and some of the second of the active agents can be used to alleviate adverse effects associated with thalidomide. One or more second ingredients or active agents can be used in the methods and compositions of the invention together with thalidomide. The second of the active agents may be large molecules (eg, proteins) or small molecules (eg, inorganic, organometallic or synthetic organic molecules). Examples of active agents of large molecules include, but are not limited to, hematopoietic growth factors, cytokines and monoclonal and polyclonal antibodies. Specific examples of the active agents are anti-CD40 monoclonal antibodies (such as, for example, SGN-40); histone deacetylase inhibitors (such as, for example, SAHA and LAQ 824); inhibitors of heat shock protein 90 (such as, for example, 17-AAG); insulin-like growth factor-1 receptor kinase inhibitors; inhibitors of vascular endothelial growth factor receptor kinase (such as, for example, PTK787); inhibitors of the insulin growth factor receptor; inhibitors of acyltransferase of lysophosphatidic acid; . inhibitors of the IkB kinase; p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib and erlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab (Herceptin®) and pertuzumab (Omnitarg ™)); VEGFR antibodies (such as, for example, bevacizumab (Avastin ™)); VEGFR inhibitors (such as, for example, specific kinase inhibitors flk-1, SU5416 and ptk787 / zk222584); P13K inhibitors (such as, for example, wortmanin); C-Met inhibitors (such as, for example, PHA-665752); monoclonal antibodies (such as, for example, rituximab (Rituxan®), tositumomab (BexxarT), edrecolomab (Panorex®) and G250); and anti-TNF-a antibodies. The active agents of typical large molecules are biological molecules, such as proteins of natural origin or artificially made. Proteins that are particularly useful in this invention include proteins that stimulate the survival and / or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vi tro or in vivo. Others stimulate the division and differentiation of committed erythrocyte progenitors in cells in vi tro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-11 ("rIL2") and canaripox IL-2), IL-10, IL-12 and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-la and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

Particular proteins that can be used in the methods and compositions of the invention include, but are not limited to: filgrastim, which is sold in the United States under the trademark Neupogen® (Amgen, Thousand Oaks, CA); sargramostim, which is sold in the United States under the Leukine® brand (Immunex, Seattle, A); and recombinant EPO, which is sold in the United States under the trademark EpogenT (Amgen, Thousand Oaks, CA). Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein for reference. The recombinant and mutated forms of G-CSF can be prepared as described in U.S. Patent Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which are incorporated herein by reference. This invention encompasses the use of native, naturally occurring and recombinant proteins. The invention further encompasses mutants and derivatives (eg, modified forms) of naturally occurring proteins that exhibit, in vivo, at least some pharmacological activity of the proteins to which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term "mutants" are proteins that lack portions of carbohydrate normally present in their naturally occurring forms (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by combining IgG1 or IgG3 to the protein or active portion of the protein of interest. See, for example. , Penichet, M.L. and Morrison, S.L., J. Immunol. Methods 248: 91-101 (2001). The active agents of large molecules can be administered in the form of anti-cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, G-CSF and GM-CSF can be used in the methods, pharmaceutical compositions and kits of the invention. See, for example, Emens, L.A., et al. , Curr. Opinion Mol. Ther. 3 (l): 77-84 (2001). In one embodiment of the invention, the large molecule active agent reduces, eliminates or avoids an adverse effect associated with the administration of thalidomide. Depending on the disease or condition being treated, adverse effects may include, but are not limited to, numbness and drowsiness, dizziness and orthostatic hypotension, neutropenia, infections resulting from neutropenia, viral load increased by HIV, bradycardia, Stevens syndrome. -Johnson and toxic epidermal necrolysis and attacks (eg, major epilepsy). A specific adverse effect is neutropenia. The second of the active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of thalidomide. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with thalidomide (eg, before, after or simultaneously). Examples of the second of the active agents of small molecules, include, but are not limited to anti-cancer agents, antibiotics, immunosuppressive agents and stereos. Examples of anti-cancer agents include, but are not limited to: semaxanib; cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin; benzoyl hydrochloride; Acronine; adozelesina; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlina; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; sodium brequinar; biririmine; busulfan; cactinomycin; calusterona; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; Corylemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; decarbazine; Dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; Doxorubicin hydrochloride; droloxifene; Droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromato; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; sodium estramustine phosphate; etanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; sodium fostriecin; gemcitabine; cyclohex hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; iproplatin; Irinotecan; Irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansina; mechlorethamine hydrochloride; Megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitinomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; Peliomycin; pentaxin; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; pentamethane; porfimer of sodium; porphyromycin; Prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sodium esparfosate; Esparsomycin; Spirogermanium hydrochloride; spiromustine; Spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; Teroxirone; testolactone; tiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; Toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidin sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zipiplatine; zinostatin; and zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-l, 25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; - acilfulveno; adecipenol; adozelesina; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografol; inhibitors of angiogenesis; antagonist D; antagonist G, antarelix; morphogenetic protein 1 anti-dorsolization; antiandrogen, prosthetic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicolin glycinate; modulators of the apoptosis gene; apoptosis regulators; Apurinic acid; ara- CDP-DL-PTBA; arginine deaminase; asulacrine; atamestia; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathirosine; Baccatin III derivatives; balanol batimastat; BCR / ABL antagonists; benzoclorins; benzoylstaurosporine; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylpermine; bisnafida; bistratene A; bizelesin; breflato; biririmine; budotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; inhibitor derived from cartilage; carzelesin; inhibitors of casein kinase (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismicin TO; colismicin B; combretastatin A; combretastatin analogue; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacin A; cyclopentantraquinones; Cycloplatam; cipemycin; cytarabine ocfosfatc; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmicin SA; ebselen; ecomustine; edelfosin; Edrecolomab; eflornithine; elemena; emitefur; epirubicin; epristerida; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; Finasteride; flavopiridol; flezelastine; fluaster: na; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulina; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosin; ilomastat; imatinib (for example, Gleevec®), imiquimod; immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguan; iododoxorubicin; ipomeanol; 4-; iroplact; irsogladine; isobengazol; isohomohalicondrine B; itasetron; jasplaquinolide; kahalaluro F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; Leukemia inhibition factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarosol; linear polyamine analog; lipophilic dysharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecap; lutetium texaphyrin; lyophilin; lytic peptides; Maytansine; manosta ina A; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; they went meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; fibroblast growth factor of mitotoxin-saporin; mitoxantrone; ofarotene; molgramostim; Erbitux, human chorionic gonadotropin; cell wall sk of A + monophosphoryl lipid mycobacterium; mopidamol; mustard anticancer agent; micaperoxide B; p extract, mycobacterial cell network; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavina; nafterpina; nartograstim; nedaplatin; memorubicin; neridronic acid; nilutamide; nisamycin; Nitric oxide modulators; nitroxide antioxidant; nitrulin; oblimersen (Genasense®); 06-benzylguanine; octreotide; okicenona; oligonucleotides; onapristone; ondansetron; ondansetron; oracine; oral cytokine inducer; ormaplatin; osaterone; Oxaliplatin; oxaunomycin; paclitaxel; Paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxytriol; panomiphene; parabactin; pazeliptina; pegaspargase; peldesina; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilic alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetina A; placetina B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer of sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immune modulator based on protein A; inhibitor of protein kinase C; inhibitors of protein kinase C, microalgal; inhibitors of the protein tyrosine phosphatase; inhibitors of nucleoside purine phosphorylase; purpurins; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras rasnesyl transferase protein inhibitors; ras inhibitors; ras-GAP inhibitor; Demethylated reteliptine; rhenium etidronate Re 186; rhizoxin; ribozymes; retinan? da RII, roitukina; romurtida; roquinimex; Rubiginone Bl; ruboxyl; safingol; saintopine; SarCNU; sarcofitol A; sargramostim; Sdi imitators 1; semustine; inhibitor 1 derived from senescence; sense oligonucleotides; inhibitors of signal transduction; sizofiran; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; Somatomedin binding protein; sonermin; Esparfosic acid; Spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stihadid; stromelysin inhibitors; Sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista suramin; suainsonin; talimustine; tamoxifen etiodide; tauromustine; tazarotene; sodium tecogalan; tegafur; telurapyrilio; telomerase inhibitors; temoporfin; teniposicla; tetrachlorodecaoxide; tetrazomine; Taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimic; timalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulation hormone; ethyl etiopurpurine tin; tirapazamine; titanocene bichloride; topsentin; toremifene; Translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; Tyrphostins; UBC inhibitors; ubenimex; growth inhibitory factor derived from the urogenital sinus; Urokinase receptor antagonists; vapreotide; variolina B velaresol; veramina; verdins; verteporfin; vinorelbine vinxaltine; vitaxin; vorozole; zanoterone; zipiplatine zilascorb; and zinostatin estimalmer. Other second active agents include, but are not limited to, mTOR inhibitors (such as rapamycin), androgens, pamidronate, peptide D1 / 3-MAGE3 vaccine, NY-ES0-1 / ISC0MATRIX vaccine, PS-341 proteasome inhibitor, etanercept, mesna, bortezomib, azacytidine and glucocorticoids. The second of the specific active agents include, but are not limited to 2-methoxyestradiol, telomestatin, inducers of apoptosis in multiple myeloma cells (such as, for example, TRAIL), statins semaxanib, cyclosporine, etanercept, doxycycline bortezomib, oblimersen (Genasense®), remicade, docetaxel celecoxib, melphalan, dexamethasone (Decadron®), gemcitabine steroids, cisplatin, temozolomide, etoposide cyclophosphamide, temodar, carboplatin, procarbazine, gliadel tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere fluorouracil, leucovorin , irinotecan, xeloda, CPT-11 interferon alfa, pegylated interferon alfa (for example, PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM -CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclit axel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt ©), sulindac and etoposide. 4. 3 METHODS OF TREATMENT AND PREVENTION The methods of this invention encompass methods for treating, preventing and / or managing various types of cancer and diseases and disorders associated with, or characterized by, unwanted angiogenesis. As used herein, unless otherwise specified, the term "treating" refers to the administration of a compound of the invention or other additional active agent after the onset of the symptoms of the particular disease or disorder . As used herein, unless otherwise specified, the term "prevent" refers to administration prior to the onset of symptoms, particularly to patients at risk for cancer, and other diseases and disorders associated with, or characterized by, unwanted angiogenesis. The term "prevention" includes the inhibition of a symptom of the particular disease or disorder. Patients with a family history of cancer and diseases and disorders associated with, or characterized by, unwanted angiogenesis are preferred candidates for preventive regimens. As used herein and unless otherwise indicated, the term "manage" encompasses preventing the recurrence of the particular disease or disorder in a patient who has suffered from it, and / or prolonging a patient's time. who has suffered from the disease or disorder left in remission. As used herein, the term "cancer" includes, but is not limited to, solid tumors and blood borne tumors. The term "cancer" refers to the disease of skin, organ, blood and blood vessel tissues, including, but not limited to cancers of the bladder, bone or blood, brain, breast, cervix, breast, colon, endometrium, esophagus, eyes, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testicles, throat and uterus. Specific cancers include, but are not limited to spinal cord tumors, pheochromocytoma, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastasis, glioblastcma ultiforms, glioblastoma, brainstem glioma, malignant brain tumor of slow prognosis, glioma malignant, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, colo-rectal cancer Dukes C & amp;; D adenocarcinoma, non-operable colo-rectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acute myeloblastic leukemia of karotype, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma , low grade follicular lymphoma, localized or metastatic melanoma (or any kind, including, but not limited to, ocular), peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis , leimiosarcoma, progressive ossifying fibrodysplasia, hormone-refractory prostate cancer, soft tissue sarcoma at high risk of resection, non-operable hepatocellular carcinoma, Waldenstrom acroglobulinemia, burning myeloma, indolent myeloma, fallopian tube cancer, prostate cancer independent of androgen, stage IV non-metastatic prostate cancer dependent on an drógenos, prostate cancer insensible to hormones, prostate cancer insensitive to chemotherapy, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma and leiomyoma. In a specific modality, cancer is metastatic. In another modality, the cancer is refractory or resistant to chemotherapy or radiation. As used herein to refer to diseases and conditions other than cancer, the terms "diseases or disorders associated with, or characterized by, unwanted angiogenesis" "diseases or disorders associated with undesired angiogenesis" and "diseases or disorders characterized by undesired angiogenesis" "refers to diseases, disorders and conditions that are caused mediated or attended by unwanted, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, diseases Choroidal neovascular and retinal neovascular diseases. Examples of such diseases or disorders associated with undesired angiogenesis include, but are not limited to, diabetic retinopathy, premature retinopathy, corneal graft rejection, neovascular glaucoma, fibroplasia behind the lens, proliferative vitreoretinopathy, trachoma, myopia, optic cavities , epidemic keratoconjunctivitis, atopic keratitis, upper limbic keratitis, pterygium keratitis sicca, Sjoegren, acne rosacea, filectenulosis, syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, herpes simplex infection, herpes zoster infection, protozoan infection, Kaposi's sarcoma , Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, egeners sarcoidosis, scleritis, Steven Johnson's disease, perifigoideal radial keratotomy, sickle cell anemia, sarcoid, pseudoxanto to elasticum, disease of Pagets, occlusion d vein, artery occlusion, obstructive carotid disease, chronic uveitis, chronic vitritis, Lyme disease, Eales disease, Bechet's disease, retinitis, choroiditis, ocular histoplasmosis, Bests disease, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary sclerosing cholangitis, proctitis, primary biliary srosis, idiopathic pulmonary fibrosis, alcoholic hepatitis, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication , wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, hypercalcemia associated with malignancy, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, 5q syndrome and veterinary disorder caused by feline immunodeficiency virus, equine infectious anemia, goat arthritis virus, visna virus, maedi virus or lentivirus. In the specific embodiments of the invention, diseases or disorders associated with unwanted angiogenesis do not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, respiratory distress syndrome in adults, bone resorption disease, chronic obstructive pulmonary diseases, chronic pulmonary inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, disease fibrotic, cachexia, graft rejection, rheumatoid spondylitis, osteoporosis, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, erythema nodosum leprosum in leprosy, radiation damage, asthma, hyperoxic alveolar injury, malaria, mycobacterial infection and infections opportunists that result from HIV. This invention encompasses methods for treating patients who have been previously treated for cancer or diseases or disorders associated with, or characterized by, unwanted angiogenesis, but are not sensitive to standard therapies, as well as those who have not been previously treated. The invention also encompasses methods for treating patients regardless of the age of the patient, although some diseases or disorders are more common in certain age groups. The invention also encompasses methods for treating patients who have undergone surgery in an attempt to treat the disease or condition in question, as well as those who have not. Because patients with cancer and diseases and disorders characterized by undesired angiogenesis have heterogeneous clinical manifestations and variable clinical outcomes, the treatment given to a patient may vary, depending on their prognosis. The skilled practitioner may be able to easily determine without undue experimentation specific secondary agents, types of surgery and types of standard therapy based without drugs that can be effectively used to treat a particular patient with cancer and other diseases or disorders. The methods encompassed by this invention comprise administering one or more thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient (e.g., a human being) suffering or likely to suffer from cancer or a disease or disorder mediated by unwanted angiogenesis. In one embodiment of the invention, thalidomide is administered orally and daily in an amount of from about 50 to about 2,000 mg, preferably from about 50 to about 1,000 mg and -more preferably from about 50 to 800 mg. In a preferred embodiment, the recommended dose of thalidomide is from about 200 mg to about 800 mg. In a specific embodiment, thalidomide is administered in an amount from about 200 mq to about 800 mg per day to patients with relapsed multiple myeloma. In another specific embodiment, thalidomide is administered in an amount from about 200 mg to about 800 mg to patients with solid tumor. In a particular embodiment, thalidomide is administered to patients with glioma. In a specific embodiment, thalidomide is administered in an amount from about 200 mg to about 800 mg per day, or alternatively each alternate day, to patients with diseases or disorders associated with, or characterized by, unwanted angiogenesis including, but not limited to, , endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, attrition, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder, hypercalcemia associated with malignancy, apoplexy, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia and 5q syndrome. 4. 3.1 COMBINATION THERAPY Specific methods of the invention comprise administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with one or more of the second of the active agents, and / or in combination 'with radiation therapy, blood transfusions or surgery. Examples of second active agents are described herein (See, for example, section 4.2). The administration of thalidomide and the second of the active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (for example, if it can be administered orally without decomposing before entering the bloodstream) and the disease being treated. A preferred route of administration for thalidomide is oral. Preferred routes of administration for the second of the active agents or ingredients of the invention are known to those of ordinary skill in the art. See, for example. , Physician r s Desk Reference, 1755-1760 (56th ed., 2002). In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously and once or twice a day in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg , or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of the disease, and the amount (s) of thalidomide and any additional optional active agents currently administered to the patient. In a particular embodiment, the second active agent is oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX inhibitor -2, IL2, IL8, IL18, IFN, Ara-C, vinorelbine or a combination thereof. In certain embodiments, the second active agent is not a topoisomerase inhibitor (e.g., irinotecan). In certain embodiments, the second active agent is not temozolomide. In a particular embodiment, GM-CSF, G-CSF or EPO are administered subcutaneously for approximately five days in a four or six week cycle in an amount from about 1 to about 750 mg / mV, preferably in an amount from about 25. at about 500 mg / m2 / day, more preferably in an amount from about 50 to about 250 mg / m2 / day, and more preferably in an amount from about 50 to about 200 mg / day. In a certain embodiment, the GM-CSF can be administered in an amount from about 60 to about 500 mcg / m2 intravenously for 2 hours, or from about 5 to about 12 mcg / rrr / day subcutaneously. In a specific embodiment, the G-CSF can be administered subcutaneously in an amount of about 1 mcg / kg / day initially and can be adjusted depending on the elevation of the total granulocyte counts. The maintenance dose of G-CSF can be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In a certain modality, EPO can be administered subcutaneously in an amount of 10,000 units three times per week. In another embodiment, thalidomide in an amount from about 200 mg to about 800 mg per day and dacarbazine in an amount from about 200 to 1,000 mg / m2 / d are administered to patients with metastatic melanoma. In a specific modality, thalidomide is given to patients with metastatic melanoma whose disease has progressed in the treatment with dacarbazine, IL-2 or IFN. In a specific modality, thalidomide is administered to patients with relapsed or refractory multiple myeloma in combination with dexamethasone. In another modality, thalidomide is administered with melphalan and dexamethasone to patients with amyloidosis. In a specific modality, thalidomide and steroids can be administered to patients with amyloidosis. In another modality, thalidomide is administered with gemcitabine and cisplatin to patients with locally advanced or metastatic transitional cell bladder cancer. In another embodiment, thalidomide is administered in combination with a second active ingredient as follows: temoxolomide in pediatric patients with recurrent or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for recurrent or progressive CNS cancer: to treat patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastasis, recurrent brain tumors or newly diagnosed glioblastoma multiforme; Irinotecan to patients with recurrent glioblastoma; carboplatin in pediatric patients with brainstem glioma; procarbazine in pediatric patients with progressive malignant gliomas; cyclophosphamide in patients with slowly predicting malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforme; Gliadel © for recurrent malignant gliomas of high degree; temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic olidodendroglioma.

In another modality, thalidomide is administered - with methotrexate and cyclophosphamide - to patients with metastatic breast cancer. In another modality, thalidomide is administered with temoxolomide to patients with neuroendocrine tumors. In another modality, thalidomide is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer. In another modality, thalidomide is administered with gemcitabine to patients with pancreatic cancer. In another embodiment, thalidomide is administered to patients with colon cancer in combination with Arisa ©, taxol and / or taxotere. In another modality, thalidomide is administered with capecitabine to patients with refractory colorectal cancer or to patients who fail first-line therapy or have poor performance in colon or rectal adenocarcinoma. In another embodiment, thalidomide is administered in combination with fluorouracil, leucovorin. and irinotecan to patients with colorectal cancer of Dukes C & D o patients who have been previously treated for colorectal metastatic cancer. In another modality, thalidomide is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda and / or CPT-11.

In another modality, thalidomide is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with metastatic or non-operable colo-rectai carcinoma. In another modality, thalidomide is administered alone or in combination with interferon alfa or capecitabine to patients with non-operable or metastatic hepatocellular carcinoma; or with cisplatin or thiotepa in patients with primary or metastatic liver cancer. In another mode, thalidomide is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma. In another modality, thalidomide is administered in combination with fludarabine, carboplatin and / or topotecan to patients with refractory or recidivist acute myelogenous leukemia or at high risk. In another embodiment, thalidomide is administered in combination with liposomal daunorubicin, topotecan and / or cytarabine to patients with acute myeloblastic leukemia of unfavorable karotype. In another modality, thalidomide is administered in combination with gemcitabine and irinotecan to patients with non-small cell lung cancer. In one embodiment, thalidomide is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer. In one modality, thalidomide is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with Carbo / VP 16 and radiotherapy. In another embodiment, thalidomide is administered in combination with carboplatin and / or taxotere, or in combination with carboplatin, pacilitaxel and / or thoracic radiotherapy in patients with non-small cell lung cancer. In a specific modality, thalidomide is administered in combination with taxotere to patients with stage IIIB or IV non-small cell bronchopulmonary carcinomas. In another modality, thalidomide is administered in combination with oblimersen (Genasense®) in patients with non-small cell lung cancer. In another embodiment, thalidomide is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, large, diffuse B-cell lymphoma, or low-grade, relapsed, or refractory follicular lymphoma. In another embodiment, thalidomide is administered in combination with taxotere, IL-2, IFN, GM-CSF and / or dacarbazine to patients with various types or stages of melanoma. In another embodiment, thalidomide is administered alone or in combination with vinorelbine to patients with stage IIIB non-small cell bronchopulmonary carcinomas with pleural implants. In another modality, thalidomide is given to patients with several types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, trioxide arsenic, PEG INTRON-A, vincristine or a combination thereof. In another embodiment, thalidomide is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine "and / or dexamethasone (Decadron®). In another embodiment, thalidomide is administered to patients of various types or types. stages or ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone or a combination thereof. another modality, thalidomide is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU / LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciglovir , paclitaxel, adriamycin, docetaxel, estramustine, Emcyt or a combination thereof In another embodiment, thalidomide is administered to patients with types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, 'GM-CSF, Celebrex® or a combination thereof. In another modality, the. Thalidomide is administered to patients with various types or stages of cancer of gynecological, uterine or soft tissue sarcoma in combination with IFN, a COX-2 inhibitor such as Celebrex® and / or sulindac. In another embodiment, thalidomide is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof. In another embodiment, thalidomide is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF or a combination thereof. This invention also encompasses a method for increasing the dose of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to a patient (e.g., a human tserid) thalidomide, or a salt, solvate, pharmacologically acceptable clathrate, hydrate or prodrug thereof. Patients who can benefit from this method are those who are likely to suffer from an adverse effect associated with anti-cancer drugs to treat a cancer-specific skin, a 'subcutaneous tissue, lymph node, brain, lung, liver , bone, intestinal, colon, heart, pancreas, adrenal, renal, prostate, breast, colorectal or combinations thereof. The administration of thalidomide alleviates or reduces the adverse effects that are of such severity that they would otherwise limit the amount of the anti-cancer drug. In one embodiment, thalidomide can be administered orally and daily in an amount of from about 50 to about 2,000 mg, preferably from about 50 to about 1,000 mg, and more preferably from about 50 to about 800 mg before, during or after of the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In a particular embodiment, thalidomide is administered in combination with specific agents, such as heparin, aspirin, coumadin or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.

In one embodiment, thalidomide can be administered to patients with diseases and disorders associated with or characterized by unwanted angiogenesis in combination with additional active ingredients, including but not limited to anti-cancer, anti-inflammatory drugs. os, antihistamines, antibiotics and steroids. In another embodiment, this invention encompasses a method of treating, preventing and / or managing cancer, which comprises administering thalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, together with (e.g. , during or after) conventional therapy, including, but not limited to surgery, immunotherapy, biological therapy, radiation therapy or other therapy based on no drugs currently present to treat, prevent or manage cancer. The combined use of thalidomide and conventional therapy can provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that thalidomide can provide addictive or synergistic effects when given at the same time with conventional therapy. In another embodiment, this invention encompasses a method of treating, preventing and / or managing diseases and disorders associated with, or characterized by, unwanted angiogenesis, which comprises administering thalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug. of the same, together with (eg, before, during or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy or other drug-free therapy currently used to treat, prevent or manage diseases and disorders associated with or characterized by unwanted angiogenesis. The combined use of thalidomide and conventional therapy can provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that thalidomide can provide addictive or synergistic effects when given at the same time with conventional therapy. As discussed elsewhere herein, the invention encompasses a method for reducing, treating and / or preventing adverse or undesired effects associated with conventional therapy including, but not limited to surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. Thalidomide and another active ingredient can be administered to a patient before, during or after the occurrence of the adverse effect associated with conventional therapy. In one embodiment, thalidomide can be administered in an amount of from about 50 to about 2,000 mg, preferably from about 50 to about 1,000 mg, and more preferably from about 50 to about 800 mg orally and daily alone or in combination with a second active agent described herein (See, for example, section 4.2) before, during or after the use of conventional therapy. In a specific modality of this method, thalidomide and doxetaxol are administered to patients with non-small cell lung cancer who were previously treated with Carbo / VP 16 and radiotherapy. 4. 3.2 USE WITH TRANSPLANT THERAPY The compounds of the invention can be used to reduce the risk of Host Graft Disease (GVHD). Therefore, the invention encompasses a method for treating, preventing and / or managing cancer, which comprises administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, together with transplantation therapy. Since those experts in ordinary matter are aware, cancer treatment is often based on the stages and mechanism of the disease. For example, since the inevitable leukemic transformation develops in certain stages of cancer, the transplantation of peripheral blood stem cells, preparation of haematopoietic stem cells or bone marrow may be necessary. The combined use of thalidomide and transplant therapy provides a unique and unexpected synergism. In particular, thalidomide exhibits immunomodulatory activity that can provide addictive or synergistic effects when given at the same time with transplant therapy in patients with cancer. Thalidomide can work in combination with transplant therapy reducing complications associated with the invasive transplant procedure and the risk of GVHD. This invention encompasses a method of treating, preventing and / or managing cancer which comprises administering to a patient (e.g., a human) thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, haematopoietic stem cell preparation or bone marrow. Examples of suitable stem cells for use in the methods of the invention are described in U.S. Patent Application No. 10 / 411,655, filed April 11, 2003, by R. Hariri et al. , the entirety of which is incorporated herein by reference. In another embodiment, this invention encompasses a method for treating, preventing and / or managing diseases and disorders associated with, or characterized by, unwanted angiogenesis, which comprises administering to a patient (e.g., a human being) thalidomide, or a salt, pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate or prodrug thereof, before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, haematopoietic stem cell preparation or bone marrow. In one modality of this method, thalidomide is administered to patients with multiple myeloma before, durant. or after peripheral blood progenitor cell autotransplantation. In another modality, thalidomide is administered to patients with relapsing multiple myeloma after stem cell transplantation. In another modality, thalidomide and prednisone are administered as maintenance therapy to patients with multiple myeloma after autologous stem cell transplantation. In another modality, thalidomide and dexamethasone are administered as salvage therapy for low risk after transplantation in patients with multiple myeloma. In another modality, thalidomide and dexamethasone are administered as maintenance therapy to patients with multiple myeloma after bone marrow autotransplantation.

In another modality, thalidomide is administered after administration of high doses of melphalan and autologous stem cell transplantation to patients with multiple myeloma sensitive to chemotherapy. In another modality, thalidomide and PEG INTRO-A are administered as maintenance therapy to patients with multiple myeloma after autotransplantation of the peripheral stem cell selected from CD34. In another modality, thalidomide is administered with post-transplant consolidation chemotherapy to newly diagnosed patients with multiple myeloma to evaluate anti-angiogenesis. In another modality, thalidomide and dexamethasone are administered as maintenance therapy after consolidation of DCEP, after treatment with high doses of melphalan and peripheral blood stem cell transplantation to patients 65 years of age or older with myeloma. multiple. 4. 3.3 CYCLING THERAPY In certain embodiments, the prophylactic or therapeutic agents of the invention are administered cyclically to a patient. Cycle therapy involves the administration of an active agent over a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycle therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies and / or improve the effectiveness of the treatment. Accordingly, in a specific embodiment of the invention, thalidomide is administered daily in a single dose or divided into a cycle of four to six weeks with a rest period of about one week or two weeks. The invention also allows the frequency, number and duration of the dosing cycles to be increased. Thus, another specific embodiment of the invention encompasses the administration of thalidomide for more cycles that are typical when administered alone. In yet another specific embodiment of the invention, thalidomide is administered for a greater number of cycles that would normally cause dose-limiting toxicity in a patient to whom a second active ingredient is not being administered. In one embodiment, thalidomide is administered daily and continuously for three or four weeks after a break of one or two weeks. In a particular embodiment, thalidomide is administered in an amount of from about 200 mg to about 800 mg / day for three to four weeks, followed by a week or two weeks of rest in a cycle of four to six weeks. In one embodiment of the invention, thalidomide and a second active ingredient are administered orally, with the administration of thalidomide occurring 30 to 60 minutes before a second active ingredient, over a cycle of four to six weeks. In another embodiment of the invention, the combination of thalidomide and a second active ingredient is administered by intravenous infusion for approximately 90 minutes each cycle. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more typically from about two to about 16 cycles and even more typically from about four to about three cycles. 4. 4 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS Pharmaceutical compositions can be used in the preparation of individual single unit dosage forms. The pharmaceutical compositions and dosage forms of the invention comprise thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients. The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise the active ingredients described herein (e.g., thalidomide and a second active agent). Examples of additional or optional second active ingredients are described herein (see for example, section 4.2). The single unit dose forms of the invention are suitable for oral, muccosal (eg, nasal, sublingual, vaginal, buccal or rectal) or parenteral (eg, subcutaneous, intravenous, bolus, intramuscular or intra-arterial injection) administration , topical (for example, eye drops or other ophthalmic preparations), transdermal or transcutaneous to a patient. Examples of dosage forms include, but are not limited to: tablets; pills; capsules, such as soft elastic gelatin capsules; wafers; trociscos; pills; dispersions; suppositories; powder; aerosols (for example, sprays or nasal inhalers); gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or liquid water-in-oil emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The composition, form and type of dosage forms of the invention will normally vary depending on its use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients that it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients comprising an oral dosage form used to treat the same disease. These and other forms wherein the specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients comprising primary or secondary amines are particularly susceptible to such accelerated decomposition. Accordingly, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other than mono- or di-saccharides. As used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of an active ingredient. The lactose-free compositions of the invention may comprise excipients that are well known in the art and are listed, for example, in the American Pharmacopoeia (USP) 25-NF20 (2002). In general, the lactose-free compositions comprise active ingredients, a binder / filler, and a lubricant in pharmaceutically acceptable and pharmaceutically compatible amounts. Preferred free lactose dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate. This invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage in order to determine characteristics such as shelf life or the stability of formulations over time. . See for example, Jens T., Carstensen, Drug Stabili ty: Principies? Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Thus, the effect of water in a formulation can be of greater significance since moisture and / or steam are commonly encountered during manufacturing, handling, packing, storage, shipping and the use of formulations. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using low or anhydrous moisture containing ingredients and low humidity or low vapor conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or vapor during manufacture, packaging and / or storage is expected. An anhydrous pharmaceutical composition should be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using known materials to avoid exposure to water so that they can be included in suitable forms equnt. Examples of suitable packaging include, but are not limited to, hermetically sealed aluminum foil, plastics, dose unit containers (e.g., jars), blister packs and strip packaging. The invention further encompasses pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to antioxidants such as ascorbic acid, pH buffers or saline buffers. As the amounts and types of excipients, the specific amounts and types of dosage active agents may differ depending on factors such as, but not limited to, the route by which they will be administered to patients. However, typical dosage forms of the invention comprise thalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount from about 30 to about 2,000 mg. Typical dosage forms comprise a thalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in an amount of about 50, 100, 200, 300 or 400 mg. Typical dosage forms comprise the second active agent in an amount of from about 1 to about 3500 mg, from about 5 to about 2500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg. Of course, the specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or handled, and the amount (s) of thalidomide and any additional optional active agents administered to the patient at the same time. 4. 4.1 ORAL DOSAGE FORMS The pharmaceutical compositions of the invention which are suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets (eg, chewable tablets), pills, capsules and liquids (e.g. , flavored syrups). Such dosage forms contain predetermined amounts of active agents, and can be prepared by pharmacy methods well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Easton PA (1990). Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate mixture with at least one excipient according to conventional pharmaceutical combination techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of suitable excipients for use of solid oral dosage forms (e.g., powders, tablets, capsules and lozenges) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. . Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmacy methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then forming the product in the desired presentation if necessary. For example, a tablet can be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powders or granules, optionally mixed with an excipient. The molded tablets can be made by molding in a suitable machine a mixture of the wetted powdered compound with an inert liquid diluent. Examples of excipients that can be used in the oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropylmethylcellulose (eg, Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viseóse Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to,, talc, calcium carbonate (for example, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention is normally presented from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. Disintegrants are used in compositions of the invention that provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant can disintegrate in storage, while those that contain too little can not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of the disintegrant used varies based on the type of the formulation, and is easily discernible by those skilled in the ordinary art. Normal pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of the disintegrant, preferably from about 1 to about 5 weight percent of the disintegrant. Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium croscarmellose, crospovidone, potassium polacrilin, glycolate of sodium starch, potato starch or tapioca, other starches, pre-gelatinized starch, other starches, clays, other algin, other celluloses, gums and mixtures thereof. Lubricants that may be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate , ethyl oleate, ethyl laureate, agar and mixtures thereof. Additional lubricants include, for example, a siloid silica gel (AEROSIL200, manufactured by WR Grace Co., of Baltimore, MD), a synthetic silica coagulated aerosol (marketed by Degussa Co. of Plano, TX), CAB-O -SIL (a pyrogenic silica dioxide product sold by Cabot Co., of Boston, MA) and mixtures thereof. If used in all, the lubricants are normally used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms within which they are incorporated. A preferred solid oral dosage form of the invention comprises thalidomide, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin. See, for example, U.S. Patent Application No. 10 / 608,077 filed June 30, 2003, the entirety of which is incorporated herein by reference. 4. 4.2 DOSAGE FOR DELAYED DELAY DOSES Active ingredients of the invention may be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses unique unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel capsules, and lozenges that are adapted for controlled release. All controlled-release pharmaceutical products have a common goal to improve drug therapy over what was achieved by their uncontrolled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance that is used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations include the extended activity of the drug, a reduced frequency of dosage, and increased compliance of the patient. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects (eg, adverse). Most controlled release formulations are designed to initially release a quantity of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain this level of therapeutic or prophylactic effect for a period of time. extensive of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that it will replace. the amount of drug that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to pH, temperature, enzymes, water or other physiological or compound conditions. 4. 4.3 Parenteral Dosage Forms Parenteral dosage forms can be administered to patients by several routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intra-arterial. Because their administration normally deviates the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions. Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated in the parenteral dosage forms of the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of thalidomide and its derivatives. See for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference. 4. 4.4 Topical and Mucosal Dosage Forms The topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations known to one skilled in the art. . See for example, Remington's Pharmaceuti'cal Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 &1990); and Introductíon to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues within the oral cavity can be formulated as mouth rinses or as oral gels. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical art, and depend on the particular tissue to which a composition or pharmaceutical dosage form given. With that in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof. to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990). The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds, such as stearates can also be added to pharmaceutical dosage forms or compositions to advantageously alter the hydrophilic or lipophilic nature of one or more active ingredients so that delivery is improved. In this aspect, the stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or a surfactant, and as an agent that improves delivery or improves penetration. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. 4. 4.5 EQUIPMENT Normally, the active ingredients of the invention are not preferably administered to a patient at the same time or by the same route of administration. This invention therefore encompasses equipment which, when used by the medical practitioner, can simplify the administration of appropriate amounts of the active ingredients to a patient. A typical apparatus of the invention comprises a dosage form of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, pro-drug or clathrate thereof. The equipment encompassed by this invention may further comprise additional active ingredients such as oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin. , dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, cis-retenoic acid, or a mutant or pharmacologically active derivative thereof, or a combination thereof. Examples of additional active ingredients include, but are not limited to, those discussed herein (see for example, section 4.2). The kits of the invention may further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to syringes, perfusion bags, patches and inhalers.

The kits of the invention may further comprise cells or blood for transplantation as well as pharmaceutically acceptable carriers which may be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the equipment may comprise a sealed container of a suitable vehicle wherein the active ingredient may be dissolved to form a sterile, particle-free solution that is suitable for parenteral administration. . Examples of pharmaceutically acceptable carriers include, but are not limited to: Water for USP Injection; aqueous vehicles, such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

. EXAMPLE One of the biological effects exerted by thalidomide is the reduction of TNF-a synthesis. 'Thalidomide improves the degradation of TNF-a mRNA. The inhibition of TNF-a production after stimulation with LPS of human PBMC by thalidomide was investigated in vitro. The IC50 of thalidomide to inhibit the production of TNF-a after stimulation of F3MC LPS was -194 μM (50.1 μg / mL). The embodiments of the invention described above are intended to be merely exemplary, and those skilled in the art will recognize, or may be able to verify without using more than routine experimentation, numerous equivalents of specific compounds, materials and methods. All equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims (9)

1. CLAIMS 1. A method for treating, managing or preventing a specific cancer, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate or stereoisomer of the same.
2. 2. A method for treating, managing or preventing a specific cancer, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate or stereoisomer acceptable thereof, and a therapeutically or prophylactically effective amount of a second active ingredient, radiation therapy, hormonal therapy, biological therapy or immunotherapy.
3. 3. A method for treating, managing or preventing a disease associated with unwanted angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate or stereoisomer acceptable of it.
4. 4. A method for treating, managing or preventing a disease associated with unwanted angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate or stereoisomer acceptable thereof, and a therapeutically or prophylactically effective amount of a second active ingredient.
5. The method of claim 1, wherein the cancer is spinal cord tumor, pheochromocytoma, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastasis, gioblastoma multiforme, glioblastoma, brainstem glioma, brain tumor malignant of slow prognosis, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, colo-rectal cancer of Dukes C & D, non-operable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acute myeloblastic leukemia of karotype, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, localized or metastatic melanoma, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histocytosis, leiomyosarcoma, progressive ossifying fibrodysplasia, hormone refractory prostate cancer, sarcoma of soft tissue at high risk of resection, non-operable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, burning myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer , prostate cancer insensitive to hormones, prostate cancer in sensitive to chemotherapy, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma or leiomyoma.
6. The method of claim 2, wherein the cancer is spinal cord tumor, pheochromocytoma, advanced malignancy, amyloidosis, locally advanced bladder cancer, metastatic transitional cell bladder cancer, recurrent brain tumor, progressive brain tumor, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastasis, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumor of slow prognosis, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, metastatic breast cancer, neuroendocrine tumor, rectal adenocarcinoma, colo-rectal cancer Dukes C & D non-operable colo-rectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, acute myeloblastic leukemia of karotype, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, localized or metastatic melanoma, stage IIIB non-small cell lung cancer, multiple myeloma, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma , scleroderma, cutaneous vasculitis, Langerhans cell histocytosis, leimiosarcoma, progressive ossifying fibrodysplasia, hormone-refractory prostate cancer, soft tissue sarcoma at high risk of resection, non-operable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, fiery myeloma, indolent myeloma, cancer "fallopian tube, androgen-independent prostate cancer, stage IV non-metastatic prostate cancer dependent on androgens, prostate cancer insensitive to hormones, prostate cancer insensitive to chemotherapy, papillary thyroid carcinoma, follicular thyroid carcinoma, carcinoma of medullary thyroid or leiomi
7. 7. The method of claim 3 or 4, wherein the disease or disorder is diabetic retinopathy, retinopathy of a premature nature, rejection of cornea graft, neovascular glaucoma, fibroplasia behind the lens, proliferative vitreoretinopathy, trachoma, myopia. , optic cavities, epidemic keratoconjunctivitis, atopic keratitis, upper limbic keratitis, pterygium keratitis sicca, Sjogrens, acne rosacea, filectenulosis, syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, herpes simplex infection, herpes zoster infection, protozoan infection, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, keratolisis margii al, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis, Steven Johnson's disease, perifigoideal radial keratotomy, sickle cell anemia, sarcoid, pseudoxanthoma Elasticum, Pagets disease, vein occlusion, occlusion of artery, obstructive carotid disease, chronic uveitis, chronic vitritis, Lyme disease, Eales disease, Bechet's disease, retinitis, choroiditis, presumed ocular histoplasmosis, Bests disease, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, sclerosing cholangitis, rubeosis, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, attrition, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder, hypercalcemia associated with malignancy, stroke, circulatory shock , periodontitis, gingivitis, macrocytic anemia, refractory anemia, or 5q syndrome. The method of claim 2 or 4, wherein the second active ingredient is a hematopoietic growth factor, a cytokine, an anti-cancer agent, an antibiotic, a cox-2 inhibitor, an immunomodulatory agent, an immunosuppressive agent, a corticosteroid, or a mutant or pharmacologically active derivative thereof, or a combination thereof. The method of claim 8, wherein the second active ingredient is oblimersen, melphalan, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, taxotere, irinotecan, a COX-2 inhibitor, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL 2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin or a pharmaceutically acceptable salt, solvate or stereoisomer thereof or a mutant or pharmacologically active derivative thereof, or a combination thereof.