HK1088537A - Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases - Google Patents

Description

Methods and compositions for treatment and management of cancer and other diseases using immunomodulatory compounds

This application claims benefit from united states provisional patent application 60/424,600 (filed 11/6/2002) and united states patent application 10/438,213 (filed 5/13/2003), and united states patent application 10/438,213 claims priority to united states provisional patent application 60/380,842 (filed 5/17/2002) and 60/424,600 (filed 11/6/2002), which are all incorporated herein by reference.

1. Technical Field

The present invention relates to methods of treating, preventing and/or managing certain cancers and other diseases, including but not limited to those associated with or characterized by undesirable angiogenesis, by administering one or more immunomodulatory compounds alone or in combination with other therapeutic agents. In particular, the invention encompasses the use of specific combinations of drugs and other therapies such as radiation or "cocktail" to treat these specific cancers, including cancers that are refractory to conventional treatments. The invention also relates to pharmaceutical compositions and methods of administration.

2. Background of the invention

2.1 Pathology of cancer and other diseases

Cancer is mainly characterized by an increase in the number of abnormal cells derived from a specific normal tissue, invasion of adjacent tissues by these abnormal cells, or spread (metastasis) of malignant cells to regional lymph nodes and distant sites through lymph or blood. Clinical data and molecular biological studies indicate that cancer is a multi-stage process that begins with subtle preneoplastic changes that may in some cases progress to tumors. Tumor lesions may evolve asexually and develop an increased ability to invade, grow, metastasize, and heterogeneity, especially if the tumor cells are taken out of host immune surveillance. Roitt, i., Brostoff, J and Kale, d., Immunology, 17.1-17.12 (3 rd edition Mosby, st. louis, mo., 1993).

A wide variety of cancers are well described in the medical literature. Examples include lung, colon, rectal, prostate, breast, brain and intestinal cancers. With the aging of the general population, the incidence of cancer continues to climb, with the emergence of new cancers, and with the growth of susceptible populations (e.g., people infected with AIDS or people overexposed to sunlight). There is therefore a great need for new methods and compositions that can be used to treat patients suffering from cancer.

Many types of cancer are associated with the formation of new blood vessels, a process known as angiogenesis. Several mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of such cytokines include acidic and basic fibroblast growth factor (a, b-FGF), angiogenin, vascular endothelial growth factor (VBGF), and TNF- α. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and subsequent breakdown of the extracellular matrix, which is where certain cytokines (such as b-FGF) are stored. Angiogenesis can be induced indirectly by the recruitment of inflammatory cells, particularly macrophages, followed by the release of angiogenic cytokines (e.g., TNF- α, b-FGF).

Other types of diseases and disorders are also associated with or characterized by undesirable angiogenesis. For example, enhanced or unregulated angiogenesis means a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases (oculerovascular diseases), choroidal neovascular diseases (chorodalovascular diseases), retinal neovascular diseases (retina neovascular diseases), rubeosis (angular neovascular disease), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and disorders include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, and proliferative vitreoretinopathy.

Thus, compounds that are capable of controlling angiogenesis or inhibiting the production of certain cytokines, including TNF- α, may be useful in the treatment and prevention of various diseases and disorders.

2.2 Methods of treating cancer

Current treatments for cancer may include surgery, chemotherapy, hormone therapy and/or radiation therapy to eradicate tumor cells in a patient (see, e.g., Stockdale, 1998, "Medicine," Vol. 3, Rubenstein and Federman, ed., Chapter 12, section IV). More recently, treatment of cancer may also include biological or immunological therapy. All of these methods pose a number of obstacles to the patient. For example, surgery may be inappropriate or unacceptable to the patient due to the patient's health. In addition, surgery may not completely remove the tumor tissue. Radiation therapy is effective only when tumor tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy may also often cause serious side effects. Hormone therapy is rarely administered as a single therapeutic agent. Although hormone therapy may be effective, it is often used to prevent or delay recurrence of tumors after other therapies remove a large fraction of the tumor cells. Biotherapy and immunotherapy are limited in number and may produce side effects such as rashes or swelling, influenza-like symptoms including fever, chills and fatigue, digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a number of chemotherapeutic agents available for the treatment of cancer. Most cancer chemotherapies inhibit DNA synthesis, either directly or indirectly, by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors to prevent DNA replication and subsequent cell division. Gilman et al, Goodman and Gilman's: the pharmaceutical basic of therapeutics, 10 th edition (McGraw Hill, New York).

Despite the availability of many chemotherapeutic agents, chemotherapy has a number of drawbacks. Stockdale, Medicine, Vol.3, edited by Rubenstein and Federman, Chapter 12, section 10, 1998. Almost all chemotherapeutic agents are toxic and chemotherapy causes significant, often dangerous, side effects, including severe nausea, bone marrow suppression, and immunosuppression. In addition, even with the combination of chemotherapeutic agents, many tumors are resistant or develop resistance to the chemotherapeutic agents. Indeed, those cells that are resistant to the particular chemotherapeutic agents used in the treatment regimen often prove to be resistant to other drugs as well, even if those agents act by a different mechanism than those used in the particular treatment. This phenomenon is known as pleiotropic drug resistance or multidrug resistance. Many cancers prove difficult to cure for standard chemotherapeutic regimens due to drug tolerance.

Other diseases or conditions associated with or characterized by undesired angiogenesis are also difficult to treat. However, certain compounds such as protamine, hepain and steroids have been suggested to be beneficial for the treatment of certain specific diseases. Taylor et al, Nature 297: 307 (1982); folkman et al, Science 221: 719 (1983); and us patents 5,001,116 and 4,994,443. Thalidomide and certain derivatives thereof have also been proposed for use in the treatment of such diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355, all to D' Amato.

There remains a great need for safe and effective methods of treating, preventing and managing cancer and other diseases and conditions, particularly diseases that are refractory to standard therapies such as surgery, radiation therapy, chemotherapy and hormone therapy, while reducing or avoiding the toxicity and/or side effects associated with conventional therapies.

2.3 IMIDS ^TM

Many studies have been conducted with the object of providing compounds that can be safely and effectively used for the treatment of diseases associated with abnormal production of TNF- α. See, e.g., Marriott, j.b., et al, "Expert opin, biol. the." 1 (4): 1-8 (2001); muller, et al, Journal of Medicinal Chemistry 39 (17): 3238-3240 (1996); and G.W.Muller et al Bioorganic&Medicinal Chemistry Letters 8: 2669-2674(1998). Some studies have focused on selecting compounds that effectively inhibit TNF-. alpha.production by LPS-stimulated PBMCs. L.g. corral et al, "an.rheum.dis 58: (supplI) 1107-. These compounds are known as IMiDS^TM(Celgene Corporation) or immunomodulatory drugs, have been shown to be effective in inhibiting not only TNF- α but also LPS-induced production of monocytes IL1 β and IL 12. LPS-induced IL6 may also be partially inhibited by immunomodulatory compounds. These compounds are potent stimulators of LPS-induced IL 10. As above (Id.), IMiDS^TMSpecific examples of (a) include, but are not limited to: substituted 2- (2, 6-dioxopiperidin-3-yl)) Phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles are described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G.W. Muller et al.

3. Summary of the invention

The present invention includes methods of treating and preventing certain types of cancer, including primary and metastatic cancers, as well as cancers that are refractory to conventional chemotherapy or resistant to conventional chemotherapy. The method comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of managing certain cancers (e.g., preventing or prolonging their recurrence, or prolonging their remission) comprising administering to a patient in need of such management a prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular methods of the invention, immunomodulatory compounds are administered in combination with therapies 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.

The invention also encompasses methods of treating, managing or preventing diseases and disorders associated with or characterized by angiogenesis other than cancer, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In other methods of the invention, immunomodulatory compounds are routinely administered in combination with therapies for the treatment, prevention, or management of diseases and conditions associated with or characterized by angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy

The invention encompasses pharmaceutical compositions, single unit dosage forms, methods of administration, and kits comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second, or additional, active agent. The second active agent comprises a combination of specific drugs, or "cocktail" therapy.

4. Brief description of the drawings

FIG. 1 shows an in vitro study of 3- (4 amino-1-oxo-1, 3-dihydro-isoindol-2-yl) piperidine-2, 6-dione (Revimid)^TM) And the effect of thalidomide on inhibition of Multiple Myeloma (MM) cell line proliferation. As a marker for cell proliferation, [3H ] uptake by different MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226) was determined]-thymine.

5. Detailed description of the invention

A first embodiment of the present invention encompasses methods of treating, managing or preventing cancer, which comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In the particular methods encompassed by this protocol, the selective cytokine inhibitory drug is administered in combination with another drug ("second active agent") or method of treating, managing and preventing cancer. Second agents include small and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or treatments that may be used in combination with administration of immunomodulatory compounds include, but are not limited to, surgery, blood transfusion, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies currently used to treat, prevent, or manage cancer.

Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders characterized by undesired angiogenesis other than cancer, which comprise administering a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Examples of diseases and conditions associated with or characterized by undesired 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, retinal neovascular diseases, and rubeosis (neovascularization of the angle). Specific examples of diseases and conditions associated with or characterized by undesired angiogenesis include, but are not limited to, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting (wasting), cerebral (spinal) meningitis, silicon-induced fibrosis, asbestos-induced fibrosis, veterinary disease (veterinary disorder), malignancy-associated hypercalcemia, stroke, circulatory shock (circulatory shock), periodontitis, gingivitis, large cell anemia, refractory anemia, and 5 q-syndrome.

In particular methods encompassed by this embodiment, the selective cytokine inhibitory drug is administered in combination with a second active agent or method of treating, managing or preventing a disease or condition. Second agents include small and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or treatments for use in combination administration with an immunomodulatory compound include, but are not limited to: surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug-based therapies currently used to treat, prevent or manage diseases and conditions associated with or characterized by undesirable angiogenesis.

The invention also includes pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods disclosed herein. Particular pharmaceutical compositions include an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.

5.1 Immunomodulatory compounds

Compounds for use in the present invention include immunological compounds that are racemic, stereomerically enriched, or stereomerically pure, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof. Preferred compounds for use in the present invention are small organic molecules having a molecular weight of less than about 1,000g/mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.

As used herein and unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDs^TM"(Celgene Corporation) included small organic molecules that significantly inhibited TNF- α, LPS-induced monocyte IL1 β and IL12, and partially inhibited IL6 production. Specific immunomodulatory compounds are discussed below.

TNF- α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-alpha is responsible for different kinds of signaling (signalengents) within the cell. TNF- α may play a pathological role in cancer. Without wishing to be bound by theory, one of the biological effects produced by the immunomodulatory compounds of the invention is the reduction of TNF- α synthesis. Immunomodulatory compounds of the invention enhance the degradation of TNF- α mRNA.

Further, without wishing to be bound by theory, the immunomodulatory compounds used in the invention may also be potent T cell co-stimulators and can significantly increase cell proliferation in a dose-dependent manner. Immunomodulatory compounds of the invention have greater stimulatory effects on the CD8+ T cell subpopulation as compared to the CD4+ T cell subpopulation. In addition, the compounds of the present invention preferably have anti-inflammatory properties and are effective in assisting in the stimulation of T cells.

Specific examples of immunomodulatory compounds include, but are not limited to: cyano and carboxyl derivatives of substituted styrenes such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxy-2- (2, 6-dioxy-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxy-2- (2, 6-dioxy-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. Nos. 5,874,448 and 5,955,476; tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines, described in U.S. Pat. No. 5,798,368; 1-oxo and 1, 3-dioxy-2- (2, 6-dioxopiperidin-3-yl) isoindolines (e.g., thalidomide and 4-methyl derivatives of EM-12), including, but not limited to, those disclosed in U.S. Pat. Nos. 5,635,517 and 6,403,613; 1-oxo and 1, 3-dioxyisoindolines substituted at the 4-or 5-position of the indole ring (e.g., 4- (4-amino-1, 3-dioxyisoindolin-2-yl) -4-carbamoylbutyric acid), described in U.S. Pat. No. 6,380,239; isoindolin-1-one and isoindoline-1, 3-dione substituted at the 2-position with 2, 6-dioxo-3-hydroxypiperidin-5-yl (e.g., 2- (2, 6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl) -4-aminoisoindolin-1-one), described in U.S. Pat. No. 6,458,810; a class of non-polypeptide cyclic amides disclosed in U.S. Pat. nos. 5,698,579 and 5,877,200; analogs and derivatives of thalidomide include hydrolysates, metabolites, derivatives and precursors of thalidomide, such as those described in U.S. Pat. nos. 5,593,990, 5,629,327, and 6,071,948, all of which are D' Amato; amino thalidomide and analogs, hydrolysates, metabolites, derivatives and precursors of amino thalidomide, as well as substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindolines such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; and isoindole-imide compounds such as those described in U.S. patent application 09/972,487 (filed on 5/10/2001), U.S. patent application 10/032,286 (filed on 21/11/2001), and international application PCT/US01/50401 (international publication No. WO 02/059106). Each of the patents and patent applications listed (identified) herein are incorporated by reference in their entirety. Immunomodulatory compounds do not include thalidomide.

Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1, 3-dioxy-2- (2, 6-dioxopiperidin-3-yl) isoindolines substituted with amino groups on the phenyl ring, as described in U.S. Pat. No. 5,635,517, which is incorporated herein by reference. These compounds have the formula I:

wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂，R²Is hydrogen or lower alkyl, especially methyl. Specific immunomodulatory compounds include, but are not limited to:

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -4-aminoisoindoline;

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -5-aminoisoindoline;

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -6-aminoisoindoline;

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -7-aminoisoindoline;

1, 3-dioxy-2- (2, 6-dioxopiperidin-3-yl) -4-aminoisoindoline; and

1, 3-dioxy-2- (2, 6-dioxopiperidin-3-yl) -5-aminoisoindoline.

Other specific immunomodulatory compounds of the invention belong to the class of substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles, for example, those described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349, respectively; and 6,476,052, and International patent application PCT/US97/13375 (International publication No. WO98/03502), each of which is incorporated herein by reference. Representative compounds have the formula:

wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂

(i)R¹、R²、R³、R⁴Each of which is independently of the others halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms or (ii) R¹、R²、R³、R⁴One is-NHR⁵，R¹、R²、R³、R⁴The remainder of (1) is hydrogen;

R⁵is hydrogen or alkyl of 1 to 8 carbon atoms;

R⁶is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl or halogen;

provided that if X and Y are C ═ O and (i) R¹、R²、R³、R⁴Each of (i) is fluorine or (ii) R¹、R²、R³、R⁴One is amino, then R⁶Is not hydrogen.

Representative compounds of this class have the formula:

wherein R is¹Is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of these compounds in enantiomerically pure form (e.g., optically pure (R) or (S) enantiomer).

Other specific immunomodulatory compounds of the invention belong to the class of isoindole-imides and are disclosed in U.S. patent applications 10/032,286 and 09/972,487 and international patent application PCT/US01/50401 (international publication No. WO02/059106), each of which is incorporated herein by reference. Representative compounds have formula II:

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates and mixtures of stereoisomers thereof, wherein

One of X and Y is C ═ O, and the other is CH₂Or C ═ O

R¹Is H, (C)₁-C₈) Alkyl radical (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³，C(S)R³，C(O)OR⁴，(C₁-C₈) alkyl-N (R)⁶)₂，(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，C(O)NHR³，C(S)NHR³，C(O)NR³R^3′，C(S)NR³R^3′Or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H, F, benzyl, (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl, or (C)₂-C₈) An alkynyl group;

R³and R^3′Independently is (C)₁-C₈) Alkyl radical (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl group, (C)₀-C₈) alkyl-N (R)⁶)₂，(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵；

R⁴Is (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl (C)₁-C₄) alkyl-OR⁵Benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl, or (C)₀-C₄) Alkyl radical- (C)₂-C₅) A heteroaryl group;

R⁵is (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, or (C)₂-C₅) A heteroaryl group;

R⁶each occurrence is independently H, (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₂-C₅) Heteroaryl, or (C)₀-C₈) alkyl-C (O) O-R⁵Or R⁶Groups may be linked to form a heterocycloalkyl group;

n is 0 or 1; and is

Represents a chiral carbon center.

In specific compounds of formula II, when n is 0, R¹Is (C)₃-C₇) Cycloalkyl, (C2-C8) alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³，C(O)OR⁴，(C₁-C₈) alkyl-N (R)⁶)₂，(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，C(S)NHR³Or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H or (C)₁-C₈) An alkyl group; and

R³is (C)₁-C₅) Alkyl radical (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl group, (C)₅-C₈) alkyl-N (R)⁶)₂；(C₀-C₈) alkyl-NH-C (O) O-R⁵；(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵(ii) a And the other variables have the same definitions.

In other specific compounds of formula II, R²Is H or (C)₁-C₄) An alkyl group.

In other specific compounds of formula II, R¹Is (C)₁-C₈) Alkyl or benzyl.

In other specific compounds of formula II, R¹Is H, (C)₁-C₈) Alkyl, benzyl, CH₂OCH₃，CH₂CH₂OCH₃Or is or

In another embodiment of the compounds of formula II, R¹Is that

Or

Wherein Q is O or S, and R⁷Each occurrence independently is H, (C1-C8) alkyl, benzyl, CH₂OCH₃Or CH₂CH₂OCH₃。

In other specific compounds of formula II, R¹Is C (O) R³。

In other specific compounds of formula II, R³Is (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl group, (C)₁-C₈) Alkyl, aryl, or (C)₀-C₄) alkyl-OR⁵。

In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.

In other specific compounds of formula II, R¹Is C (O) OR⁴。

In other embodiments of formula II, H of C (O) NHC (O) can be replaced by (C)₁-C₄) Alkyl, aryl, or benzyl.

Other specific immunomodulatory compounds of the invention belong to the isoindole-imides and are disclosed in U.S. patent application 09/781,179, international publication No. WO 98/54170, and U.S. patent No. 6,395,754, each of which is incorporated herein by reference. Representative compounds have formula III:

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates and mixtures of stereoisomers thereof, wherein

One of X and Y is C ═ O, and the other is C ═ O or CH₂；

R is H or CH₂OCOR’；

(i)R¹、R²、R³、R⁴Each of which is independently of the others halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms or (ii) R¹、R²、R³、R⁴One of which is nitro or-NHR⁵，R¹、R²、R³、R⁴The remainder of (1) is hydrogen;

R⁵is hydrogen or alkyl of 1 to 8 carbon atoms;

R⁶is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro;

r' is R⁷-CHR¹⁰-N(R⁸R⁹)；

R⁷Is m-phenylene or p-phenylene or- (C)_nH2_n) -, where n is 0 to 4;

R⁸and R⁹Each of which is independently of the other hydrogen or alkyl of 1 to 8 carbon atoms, or R⁸And R⁹Linked together being a tetramethylene group, pentamethylene group, hexamethylene group, or-CH₂CH₂[X]X₁CH₂CH₂-, wherein [ X]X¹is-O-, -S-, or-NH-;

R¹⁰is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and

represents a chiral carbon center.

Other representative compounds have the formula

Wherein

One of X and Y is C ═ O, and the other is C ═ O or CH₂；

(i)R¹、R²、R³、R⁴Each independently of the others being halogen, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) R¹、R²、R³、R⁴One is-NHR⁵，R¹、R²、R³、R⁴The remainder of (1) is hydrogen;

R⁵is hydrogen or alkyl of 1 to 8 carbon atoms;

R⁶is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro;

R⁷is m-phenylene or p-phenylene or- (C)_nH_2n) -, where n is 0 to 4;

R⁸and R⁹Each of which is independently of the other hydrogen or alkyl of 1 to 8 carbon atoms, or R⁸And R⁹Linked together being a tetramethylene group, pentamethylene group, hexamethylene group, or-CH₂CH₂[X]X¹CH₂CH₂-, wherein [ X]X¹is-O-, -S-, or-NH-;

R¹⁰is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl.

Other representative compounds have the formula

Wherein

X and Y are as defined above;

R¹、R²、R³、R⁴each of which is independently of the others halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms or (ii) R¹、R²、R³、R⁴One being nitro or protected amino, R¹、R²、R³、R⁴The remainder of (1) is hydrogen; and

R⁶is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro.

Other representative compounds have the formula

Wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

(i)R¹、R²、R³、R⁴Each of which is independently of the others halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms or (ii) R¹、R²、R³、R⁴One is-NHR⁵，R¹、R²、R³、R⁴The remainder of (1) is hydrogen;

R⁵is hydrogen, or alkyl of 1 to 8 carbon atoms, or CO-R⁷-CH(R¹⁰)NR⁸R⁹Wherein R is⁷，R⁸，R⁹And R¹⁰Each as defined above; and

R⁶is alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro;

specific examples of the compounds have the formula

Wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

R⁶Is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, chlorine or fluorine;

R⁷is m-phenylene or p-phenylene or- (C)_nH_2n) -, where n is 0 to 4;

R⁸and R⁹Each of which is independently of the other hydrogen or alkyl of 1 to 8 carbon atoms, or R⁸And R⁹Linked together being a tetramethylene group, pentamethylene group, hexamethylene group, or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-, or-NH-; and

R¹⁰is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl.

The most preferred immunomodulatory compounds of the invention are 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione and 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Such compounds can be obtained by standard synthetic methods (see, e.g., U.S. Pat. No. 5,635,517, incorporated herein by reference). The compound is available from Celgene Corporation, Warren, NJ.. 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (ACTIMIDD)^TM) Has the following chemical structure:

the compound 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (REVIMID)^TM) Has the following chemical structure:

other specific immunomodulatory compounds of the invention include, but are not limited to: 1-oxy-2- (2, 6-dioxy-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. Nos. 5,874,448 and 5,955,476, each of which is incorporated herein by reference. Representative compounds have the formula:

wherein Y is oxygen or H²And

R¹、R²、R³、R⁴each of which is independently from the others hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or amino.

Other specific immunomodulatory compounds of the invention include, but are not limited to: tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines, described in U.S. Pat. No. 5,798,368, incorporated herein by reference. Representative compounds have the formula:

wherein R is¹、R²、R³、R⁴Each of which is independently of the others halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.

Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxyl and 1, 3-dioxy-2- (2, 6-dioxopiperidin-3-yl) isoindolines, disclosed in U.S. Pat. No. 6,403,613, which is incorporated herein by reference. Representative compounds have the formula

Wherein

Y is oxygen or H₂，

R¹And R²The first of (A) is halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, R is¹And R²The second of (a) is, independently of the first, hydrogen, halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, and

R³is hydrogen, alkyl or benzyl.

Specific examples of compounds of the invention have the formula:

wherein R is¹And R²The first of which is halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano or carbamoyl,

R¹and R²The second, independent of the first, is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino wherein the alkyl has 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano or carbamoyl, and

R³is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl. Other representative compounds have the formula:

R¹and R²The first of which is halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano, or carbamoyl,

R¹and R²The second, independent of the first, is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino wherein the alkyl has 1 to 4 carbon atoms, dialkylamino wherein each alkyl has 1 to 4 carbon atoms, cyano, or carbamoyl, and

R³is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl.

Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1, 3-dioxyisoindolines substituted at the 4-or 5-position of the indoline ring, described in U.S. patent 6,380,329, incorporated herein by reference. Representative compounds have the formula:

wherein the reference number is C^*The carbon atom(s) constituting the chiral centre (when n is other than 0 and R¹And R²When not identical); x¹And X²One of which is amino, nitro, alkyl of 1 to 6 carbon atoms or NH-Z, X¹Or X²Is hydrogen; r¹And R²Each of which is independently of the other hydroxy or NH-Z; r³Is hydrogen, alkyl of 1 to 6 carbon atoms, halogen or haloalkyl; z is hydrogen, aryl, alkyl of 1 to 6 carbon atoms, formyl or acyl of 1 to 6 carbon atoms; and n has a value of 0, 1 or 2; provided that if X is¹Is amino and n is 1 or 2, then R¹And R²Are not hydroxyl; and salts thereof. Other representative compounds have the formula:

wherein the reference number is C^*When n is not 0 and R¹Is different from R²When the current is over; x¹And X²One of which is amino, nitro, alkyl of 1 to 6 carbon atoms or NH-Z, X¹Or X²Is hydrogen; r¹And R²Independently of one another, is hydroxy or NH-Z; r³Is alkyl of 1 to 6 carbon atoms, halogen or hydrogen; z is hydrogen, aryl, or alkyl or acyl of 1 to 6 carbon atoms; and n has a value of 0, 1 or 2; and salts thereof. Specific examples of the compound have the formula

Wherein X¹And X²One of which is nitro or NH-Z, X¹Or X²Is hydrogen;

R¹and R²Independently of one another, is hydroxy or NH-Z;

R³is alkyl of 1 to 6 carbon atoms, halogen or hydrogen;

z is hydrogen, phenyl, acyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; and

n has a value of 0, 1 or 2;

provided that if X is¹And X²One is nitro and n is 1 or 2, then R¹And R²Are not hydroxyl; and

if-COR¹And- (CH)₂)_nCOR²Are different and are marked with C^*The carbon atom(s) constituting the chiral center. Other representative compounds have the formula:

wherein X¹And X²One is alkyl of 1 to 6 carbon atoms;

R¹and R²Independently of one another, is hydroxy or NH-Z;

R³is alkyl of 1 to 6 carbon atoms, halogen or hydrogen;

z is hydrogen, phenyl, acyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; and

n has a value of 0, 1 or 2; and

if-COR¹And- (CH)₂)_nCOR²Are different and are marked with C^*The carbon atom(s) constituting the chiral center.

Other specific immunomodulatory compounds of the invention include, but are not limited to: isoindolin-1-one and isoindoline-1, 3-dione substituted at the 2-position with 2, 6-dioxo-3-hydroxypiperidin-5-yl, described in U.S. Pat. No. 6,458,810, incorporated herein by reference. Representative compounds have the formula:

wherein

Reference number C^*The carbon atom of (a) constitutes a chiral center;

x is-C (O) -or-CH₂-；

R¹Is alkyl of 1 to 8 carbon atoms or-NHR³；

R²Is hydrogen, alkyl of 1 to 8 carbon atoms, or halogen;

and

R³is a hydrogen atom, and is,

alkyl of 1 to 8 carbon atoms unsubstituted or substituted with alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms,

a cycloalkyl group of 3 to 18 carbon atoms,

phenyl which is unsubstituted or substituted by alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms,

unsubstituted or substituted by alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms, or-COR⁴Substituted benzyl, in which

R⁴Is a hydrogen atom, and is,

alkyl of 1 to 8 carbon atoms unsubstituted or substituted with alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms,

a cycloalkyl group of 3 to 18 carbon atoms,

phenyl which is unsubstituted or substituted by alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms, or

Unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halogen, amino, or alkylamino of 1 to 4 carbon atoms or benzyl.

The compounds of the present invention are commercially available or can be prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salts" includes non-toxic acid and base addition salts of the compounds to which this term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, succinic, citric, malic, maleic, sorbic, aconitic, salicylic, phthalic, embonic, heptanoic, and the like.

Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. The bases which can be used for the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, i.e. salts containing pharmacologically acceptable cations, such as, but not limited to, alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-benzhydrylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.

As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that is capable of hydrolyzing, oxidizing or otherwise reacting under physiological conditions (in vivo or in vitro) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Examples of other prodrugs include those containing-NO, -NO₂-ONO, or-ONO₂Derivatives of some of the immunomodulatory compounds of the invention. Prodrugs can typically be prepared using well known methods, such as those described in 1 Burger's Medicinal Chemistry and drug discovery, 172-178, 949-982 (edited E.Wolff, 5 th edition, 1995) and Design of Prodrugs (H.Bundgaard, Ed., Elselvier, New York 1985).

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide," and "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate ester of a compound, respectively, which either: 1) does not interfere with the biological activity of the compound, but can impart beneficial properties to the compound in vivo, such as absorption, duration of action, or onset of action; or 2) is biologically inert but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl (e.g., phthalidyl and thiophthalidyl) esters, lower alkoxyacyloxyalkyl esters (e.g., methyloxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino esters (e.g., acetylaminomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, alkylaminoalkylcarbonyl amides. Biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylene diamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amides, and polyetheramines.

The various immunomodulatory compounds of the invention contain one or more chiral centers and may exist as racemic or diastereomeric mixtures of enantiomers. The invention includes the use of stereomerically pure forms of such compounds as well as the use of mixtures of those forms. For example, enantiomers containing equal or unequal amounts of particular immunomodulatory compounds of the invention may be used in methods and compositions of the invention. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example: jacques, J et al, Enantiomers, Racemates and solutions (Wiley-Interscience, New York, 1981); wilen, S.H et al, Tetrahedron 33: 2725 (1977); eliel, E.L., "Stereochemistry of Carbon Compounds" (McGraw-Hill, NY, 1962); and Wilen, S.H., pages 268 (E.L.Eliel. eds., Univ.of Notre Dame Press, Notre Dame, IN, 1972).

As used herein, unless otherwise indicated, the term "stereomerically pure" refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers is substantially free of other diastereomers of the compound. Typical stereomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. As used herein, unless otherwise indicated, the term "stereomerically enriched" refers to compositions containing greater than about 60% by weight of one stereoisomer of a compound, preferably including greater than about 70% by weight, more preferably greater than about 80% by weight, of one stereoisomer of a compound. As used herein, unless otherwise indicated, the term "enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a composition enriched in stereoisomers of a compound having one chiral center.

It should be noted that the described structures should be given higher weight if there is a difference between the structure described and the name given to the structure. In addition, if the stereochemistry of a structure or a portion of a structure is not used, e.g., indicated by a bold line (bold) or dashed line (dashed line), then the structure or portion of a structure is to be interpreted as encompassing all stereoisomers of it.

5.2 A second active agent

Immunomodulatory compounds can be used in combination with other pharmacologically active compounds ("second active agents") in the methods and compositions of the invention. It is believed that certain combinations may play a synergistic role in the treatment of certain types of cancer and certain diseases and conditions associated with or characterized by undesirable angiogenesis. Immunomodulatory compounds can also reduce adverse effects associated with certain second active agents that can be used to reduce adverse effects associated with immunomodulatory compounds.

One or more second active ingredients or agents may be used with the immunomodulatory compounds in the methods and compositions of the invention. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

Examples of macromolecular active agents include, but are not limited to: hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical macromolecular active agents are biomolecules such as naturally occurring or artificially prepared proteins. Proteins particularly useful in the present invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunocompetent producing (poetic) cells in vivo or in vitro. Other proteins stimulate the division and differentiation of committed erythroid progenitors in cells in vivo or in vitro. Specific proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL 2") and canarypox (canarypox) IL-2), IL-10, IL-12 and IL-18; interferons such as interferon alpha-2 a, interferon alpha-2 b, interferon alpha-n 1, interferon alpha-n 3, interferon beta-Ia, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

Specific proteins that may be used in the methods and compositions of the invention include, but are not limited to: filgrastim (filgrastim), in the United states under the trade name Neupogen^*(Amgen，Thousand Oaks, CA); sargramostin (sargramostim), tradename Leukine in the United states^*(Immunex, Seattle, WA); and recombinant EPO, available in the United states under the Epogent trade name^*(Amgen, Thousand Oaks, Calif.).

Recombinant and mutant forms of GM-CSF can be prepared according to the methods described in U.S. Pat. Nos. 5,391,485; 5,393,870 and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be prepared according to us patent 4,810,643; 4,999,291, respectively; 5,528,823 and 5,580,755; all of which are incorporated herein by reference.

The present invention encompasses the use of natural, naturally occurring, and recombinant proteins. The invention further includes mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit at least some of the pharmacological activity of the protein on which they are based in vivo. Examples of mutants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residue in the native form of the protein. The term "mutant" also includes proteins lacking the carbohydrate moiety that is normally present in its native form (e.g., a non-glycosylated form). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to an active portion of the protein or related proteins. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001).

Antibodies that can be used in combination with the compounds of the present invention include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to: trastuzumab (Herceptin)^*) Armilla-methyl (Rituxan)^*) Bevacizumab (Avastin)^TM)，pertuzum ab(Omnitarg^TM) Tositumomab (Bexxar)^*) Edokumab (Panorex)^*) And G250. The compounds of the invention may also be used in combination with anti-TNF-. alpha.antibodies or in combination with anti-TNF-. alpha.antibodies.

The macromolecular active agent may be administered in the form of an anti-cancer vaccine. Vaccines that secrete or cause secretion of cytokines such as IL-2, G-CSF, and GM-CSF can be used, for example, in the methods, pharmaceutical compositions, kits of the invention. See, e.g., emers, l.a., et al, current, opinionmol, the., l.3 (1): 77-84(2001).

In one embodiment of the invention, the macromolecular active agent reduces, eliminates or prevents adverse effects associated with administration of an immunomodulatory compound. Depending on the particular immunomodulatory compound and the disease or condition being treated, adverse effects include, but are not limited to, drowsiness and lethargy, dizziness and orthostatic hypotension, neutropenia, infection due to neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson syndrome and toxic epidermal necrolysis, and seizures (e.g., grand mal seizure). A particular adverse effect is neutropenia.

A second small molecule active agent may also be used to mitigate adverse effects associated with administration of an immunomodulatory compound. However, like some macromolecules, many small molecules are thought to provide a synergistic effect when administered with (e.g., before, after, or simultaneously with) an immunomodulatory compound. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of anti-cancer agents include, but are not limited to: acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; hexamethylmelamine; an apramycin; acetic acid dihydroamine anthraquinone; amsacrine; anastrozole; anthranilic acid; asparaginase enzyme; a triptyline; azacitidine; azatepa; azido mycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib; 2, jukening; a sirolimus; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicin hydrochloride; a dicentrine; (ii) dexomaplatin; 2, dizagutanin; dezaguinemesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; methyl androsterone propionate; azomycin; edatrexae; eflornithine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; hydrochloric acid fazoline; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; hydroxy (yl) urea; idarubicin hydrochloride; an ifosfamide; ilofovir dipivoxil; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; -Marpropico; maytansine; a nitrogen mustard; megestrol acetate; melengestrol acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; meltupipide; mitodomide; mitocarcin; mitorubin; mitogen; mitosin; mitomycin; mitosporin; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noggin; ormaplatin; oshuzuren; paclitaxel; a pemetrexed; a calicheamicin; neostigmine bromide; pelamicin sulfate; hyperphosphamide; a hematopoits; piposulfan; piroxantrone hydrochloride; mithramycin; pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium phosphono-aspartate; a sparamycin; helical germanium hydrochloride; spiromustine; cis-spiroplatinum; streptonigrin; streptozotocin; a sulfochlorophenylurea; talimox; sodium tegafur; taxotere; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; a tiroxiron; a testosterone ester; (ii) a thiopurine; thioguanine; thiotepa; thiazolfurin; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tobramzole hydrochloride; uracil mustard; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinblastine sulfate; vinorelbine tartrate; isovincamine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; and zorubicin hydrochloride.

Other anticancer drugs include, but are not limited to: 20-epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil (ethyluracil); abiraterone; aclarubicin; acylfulvenes (acylfulvenes); adecyenol; (ii) Alexanox; aldesleukin; ALL-TK antagonist; hexamethylmelamine; amifostine; sulfisoxazole (amidox); amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; an antagonist D; an antagonist G; anrlex; anti-dorsal morphogenetic protein-1; anti-androgens, prostate cancer; anti-estrogen agents; an antineoplastic ketone; an antisense oligonucleotide; aphidicolin glycinate (aphiticolinglinide); an apoptosis gene regulator; a modulator of apoptosis; depurination nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; amoxicillin; axinatatin 1; axinatatin 2; axinatatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; benzochlor; benzoylstaurosporine; beta lactam derivatives; beta-alethine; beta-clamycin B; betulinic (brain) acid; a bFGF inhibitor; bicalutamide; a bisantrene group; bisaziridinylsphermine; (ii) bisnefarde; bistetralene A; bizelesin; brefflate; briprimine; butootitanium; buthionine esulfoximine; calcipotriol; calpain C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; a carboxyamidotriazole; CaRest M3; CARN 700; a cartilage derived inhibitor; folding to get new; casein kinase Inhibitors (ICOS); castanospermine(ii) a Cecropin B; cetrorelix; (ii) chlorolins; a chloroquinoxaline sulfonamide; (ii) cicaprost; a cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin a 4; combretastatin analogs; a concanagen; crambescidin 816; clinatot; cryptophycin 8; cryptophycin a derivatives; curve A; cyclopentanthraquinones; cycloplatam; cypemycin; Ara-C ester (cytarabine ocfosfate); a cytolytic factor; a cytostatin; daclizumab; a dicentrine; dehydrogenatedmin B; deslorelin; dexamethasone; dexfosfamide; dexrazoxane; (ii) verapamil; diazaquinone; dynastine B; didox; diethylnorpermine; dihydro-5-azacytidine; 9-dihydropaclitaxel; a dioxamycin; diphenyl spiromustine; docetaxel; behenyl (alkane) alcohol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; bismycin sa (duocarmycin sa); ebselen; etokomustine; edifulin; epirubicin; eflornithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analog; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flutemastine; a flashterone; fludarabine; fluoroaurourigenin hydrochloride; fowler; 2, fulvestrant; fostrexed; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisamide; hypericin; ibandronic acid; idarubicin; ioxifene; iloperidone; ilofovir dipivoxil; ilomastat; imatinib (e.g., Gleevec *), imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iomycin; 4-sweet potato picrol; iprop; isoxagliadine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lancet; leinamycin; lenolatiri; sulfuric acid lentinan; leptin statin;letrozole; leukemia inhibitory factor; leukocyte interferon-alpha; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liazole; linear polyamine analogs; a lipophilic glycopeptide; a lipophilic platinum compound; lissoclinamide 7; lobaplatin; guanidinoethyl phosphoserine; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; cytolytic peptides (lytic peptides); maytansine; manostatin A; marimastat; (ii) maxolone; maspin; a matrix dissolution factor inhibitor; a matrix metalloproteinase inhibitor; (ii) a melanoril; merbarone; 1, meperiline; methioninase (methylbutyronidase); metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; a mitotoxin fibroblast growth factor-saponin (mitotoxin growth factor-saporin); mitoxantrone; mofagotine; moraxest; erbitux, human chorionic gonadotropin; monophosphoryl lipid A + Mycobacterium cell wall SK (monophosphoryllipid A + Mycobacterium cell wall SK); mopidanol; mustard gas (mustard) anticancer agents; mycaperoxide B; mycobacterial cell wall extract (mycobactrial cell wall extract); myriaporone; n-acetyldinaline (acetyldinaline); n-substituted benzamides; nafarelin; spraying naretide; naloxone + pentazocine; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators (nitrooxide modulators); nitroxide antioxidants (nitroxide antioxidants); nitrulyn; oblimersen (Genasense *); o is⁶-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers (oral cytokine inducers); ormaplatin; an oxateclone; oxaliplatin; oxanonomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; palauamine; palmitoylrhizoxin; pamidronic acid; ginseng (alkyne) triol; panomifen; a parabencin; pazeliptin; a pemetrexed; pedunculing; a wood polysulphide sodium; pentostatin; (ii) pentazole; penflurron; cultivating phosphoramide; (ii) perilliylalycohol;phenazinomomycin; phenyl acetate; a phosphatase inhibitor; hemolytic streptococcus su; pirocarpine hydrochloride; pirarubicin; pirtroxine; placetin A; placentinB; a plasminogen activator inhibitor; platinum complexes (platinum complex); a platinum compound; platinum-triamine complex (platinum-triamine complex); porfimer sodium; a podomycin; prednisone; propyl bis-acridone; prostaglandin J2; a proteasome inhibitor; protein a-based immunomodulating agents (protein a-based immunomodulators); inhibitors of protein kinase C; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoline acridine; a polyhydroxyethylglycolate hemoglobin polyoxyethylene conjugate (pyridoxylated hemoglobin conjugate); a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated retetriptyline (retelliptinedemethylated); rhenium Re 1861-hydroxy-ethylene-1, 1-diphosphonic acid (rheniumRe 186 etronate); rhizomycin; a ribozyme; RII retinamide; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; saintopin; SarCNU; sarcophylol A; samustine; sdi 1 mimetics; methyl cyclohexylnitrosourea; aging derived inhibitor 1(senescence derived inhibitor 1); sense oligonucleotides (sense oligonucleotides); a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein (sonermin); (ii) solifenamine; phosphonowinter acid (spartic acid); spicamycin D; spiromustine; spleenetin; spongistatin 1; squalamine; stiiamide; matrix degrading enzyme inhibitors (stromelysin inhibitors); sulfinosine; potent vasoactive intestinal peptide antagonists (superactive vasoactive intestinal peptide antagonists); (ii) surfasta; suramin; aloperine; tamustine; methionine tamoxifen methiodide; bovine iodomustine; tazarotene; sodium tegafur; tegafur; telluropyrylium; inhibitors of telomerase; temoporfin; (ii) teniposide; tetrachlorodecaoxide; tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotreonam; thyroid stimulating hormone; a methylethyl iopurprisin; tirapazamine; cyclopentadienyl titanium dichloride (titanocenebichloride); topstein; toremifene; translation inhibitors (translionihibitors); tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; tyrphostins; an UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor (urogenic sinus-derived growth inhibitor factor); a urokinase receptor antagonist; vapreotide; variolin B; vilareol; veratramin; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.

Specific second active agents include, but are not limited to: oblimersen (Genasense)^*) Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron)^*) Steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa^*Taxol, taxotere, fluorouracil, leucovorin, irinotecan, receptacle, CPT-11, interferon-alphA, pegylated interferon-alphA (e.g., PEGINTRON-A), capecitabine, cisplatin, sertib, fludarabine, carboplatin, daunorubicin liposome (liposomal daunorubicin), ArA-C, doxolol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, clarithromycin (biaxin), busulfan, prednisone, A diphosphate compound, arsenic trioxide, vincristine, doxorubicin (Doxil)^*) Paclitaxel, ganciclovir, doxorubicin, estramustine sodium phosphate (Emoyt)^*) Sulindac, and etoposide.

5.3 Therapeutic and prophylactic methodsMethod of

The methods of the present invention include methods of treating, preventing and/or managing various types of cancers, as well as diseases and disorders associated with or characterized by undesired angiogenesis. As used herein, unless otherwise indicated, the term "treating" or "treatment" refers to the administration of a compound of the present invention or other additional active agent after the onset of symptoms of a particular disease or disorder. As used herein, unless otherwise indicated, the term "prevention" refers to administration prior to the onset of symptoms, particularly administration to patients at risk for diseases and conditions associated with or characterized by undesired angiogenesis, and cancer. The term "preventing" includes inhibiting the symptoms of a particular disease or disorder. Patients with a family history of cancer and diseases and disorders associated with or characterized by undesired angiogenesis are preferred candidates for prophylactic therapy. As used herein, unless otherwise indicated, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient having the particular disease or disorder, and/or extending the time to remission of a patient having the particular disease or disorder.

As used herein, the term "cancer" includes, but is not limited to, solid tumors and blood borne tumors (blood born tumors). The term "cancer" refers to skin tissue diseases, organ diseases, blood diseases, and vascular diseases, including but not limited to: bladder cancer, bone or blood cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colon cancer, endrometric cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, laryngeal cancer, and uterine cancer. Specific cancers include, but are not limited to: advanced malignancies (advanced malignant tumors), amyloidosis, neuroblastoma, brain [ spinal ] membrane tumor, hemangiopericyte tumor, multiple brain metastases (multiple malignant tumors), glioblastoma multiforme, brain stem glioma, poor prognosis malignant brain tumor (pore malignant brain tumor), malignant glioma, degenerative astrocytoma, degenerative oligodendroglioma, neuroendocrine tumor (neuroendocrine tumor), rectal adenocarcinoma (rectal adenocarcinoma), DukesC & D colorectal carcinoma, unresectable colorectal carcinoma (unresectable colorectal carcinoma), metastatic pancreatic carcinoma (metastatic pancreatic carcinoma), metastatic pancreatic carcinoma, Kajestic sarcoma), colorectal carcinoma (Kajejunoma's lymphoma), colorectal carcinoma (metastatic pancreatic carcinoma), metastatic carcinoma (metastatic carcinoma), metastatic carcinoma (Kaposi's lymphoma), malignant glioma (malignant lymphoma), malignant glioma, malignant lymphoma, colorectal carcinoma (malignant lymphoma, hemoprocytosis carcinoma (Kakaya, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma (diffluencelare B-Cell lymphoma), low-grade follicular lymphoma (low grade follicululariella), metastatic melanoma (localized melanoma), including but not limited to ocular melanoma (ocular melanoma), malignant mesothelioma (malignant mesothelioma), malignant pleural effusion mesothelioma syndrome (malignant pleural effusion mesothelioma), peritoneal carcinoma (peritoneal carcinosa), cancer of the blood serum (cervical serologic), gynecological sarcoma (gynecologic sarcoma), soft tissue sarcoma, scleroderma, skin vasculitis, Langerhans Cell histiocytosis, leiomyosarcoma, fibroplastic papilloma, refractory papillary cancer, refractory prostate cancer (refractory hepatocellular carcinoma), refractory prostate cancer (refractory prostate cancer), waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer (villopeian tube cancer), androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer (androgen dependent stage IV non-metastatic prostate cancer), hormone-insensitive prostate cancer (hormone-insensitive prostate cancer), chemotherapy-insensitive prostate cancer (chemo-intensive stage cancer), papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma. In a particular embodiment, the cancer is metastatic. In another scenario, the cancer is refractory or resistant to chemotherapy or radiation; particularly thalidomide, is refractory.

As used herein to refer to diseases and conditions other than cancer, the terms "disease or condition associated with or characterized by undesired angiogenesis", "disease or condition associated with undesired angiogenesis", and "disease or condition characterized by undesired angiogenesis" refer to diseases, disorders or conditions caused, regulated or implicated by undesired, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases (ocular neovascular diseases), choroidal neovascular diseases (choroid neovascular diseases), and retinal neovascular diseases (retina neovascular diseases).

Examples of such diseases or disorders associated with undesired angiogenesis include, but are not limited to: diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic pits, viral keratoconjunctivitis, atopy keratitis, hyperopic keratitis, pterygium keratitis (pulmonary keratitis), sjogrens, rosacea, phylectenulosis, syphilis, lipolysis (lipodegelation), bacterial ulcers (bacterial ulcers), fungal ulcers (fungal ulcers), Herpes simplex infections (Herpes simplex infections), Herpes zoster infections (Herpes zosterfection), protozoan infections (enzootic infections), systemic lupus erythematosus, rheumatoid arthritis, steven's Johnson disease, perphigoid radial keratopy, sickle cell anemia, sarcoid, elastopseudoxanthoma, Paget's disease, vein occlusion (vein occlusion), artery occlusion (arteocclusion), carotid obstructive disease (carotid obstructive disease), chronic uveitis (chronic uveitis), chronic vitritis (chronic vitritis), Lyme disease (Lyme's disease), Iris disease, Bechet's disease, retinitis, choroiditis, presumed ocular histoplasma disease (presupposed ocular fibrosis), Bests disease, Stargarts disease (Stargarts disease), pars plana, chronic retinal detachment syndrome, hyperviscosity syndrome (atherosclerosis), idiopathic pulmonary fibrosis, idiopathic fibrositis, osteoarthritis, retroviral replication, wasting, myelination, silica-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, 5q-syndrome, and veterinary conditions caused by feline immunodeficiency virus, equine infectious anemia virus, caprine arthritis virus, sheep myelinating virus, menidi virus, or lentivirus.

In particular embodiments of the invention, the disease or condition associated with undesired angiogenesis does not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated infectious shock, acute viral myocarditis, cardiac allograft rejection (cardiac allograft rejection), myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome (systemic fibrosis syndrome), bone resorption disease (bone-resorptive disease), chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease (chronic pulmonary inflammatory disease), dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock (hemodynamic shock), sepsis syndrome, prognostic ischemia reperfusion injury (post-ischemic reperfusion injury), fibrotic disease (fibrosis), spinal graft disease, rheumatoid arthritis, osteoporosis, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus proleocytosis (systemic lupus erythematosus), erythromatosis nodosum leprosy in leprosy, radiation injury, asthma, hyperoxic alveolars in jury, malaria, mycobacterial infection (mycobacteriol infection), and opportunistic infections caused by HIV.

The invention includes methods of treating patients who have been treated with a disease or condition that is previously due to cancer, or is associated with or characterized by undesired angiogenesis, but who are not susceptible to standard treatment, as well as those who have not previously been treated. The invention also includes methods of treating patients, regardless of the age of the patient, although certain diseases or conditions are more common in certain age groups. The invention further includes methods of treating a patient undergoing surgery in an attempt to treat the disease or condition in question, as well as diseases or disorders not in question. Because patients with cancer and diseases and conditions characterized by undesired angiogenesis have different clinical manifestations and different clinical outcomes, the treatment given to a patient may vary depending on his/her prognosis. A skilled clinician can readily determine without undue experimentation a specific second active agent, type of surgery, and type of non-drug-based standard treatment that can be effective in treating individual patients suffering from cancer and other diseases or conditions.

The invention encompasses methods comprising administering to a patient suffering from or likely to suffer from cancer or an undesirable disease or disorder modulated angiogenesis one or more immunomodulatory compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In one embodiment of the invention, it may be from about 0.10 to about 150 mg/dayIs administered orally in a single or divided daily dose. In one embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl) -isoindoline-1, 3-dione (Actimid) can be administered in an amount of about 0.1 to about 1mg per day, or alternatively in an amount of about 0.1 to about 5mg per day^TM). In a preferred embodiment, 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid) can be administered in an amount of 1 to 25mg per day, or alternatively in an amount of 10 to 50mg every other day^TM)。

In one embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl) -isoindoline-1, 3-dione (Actimid) can be administered to a patient with relapsed multiple myeloma (relapsedmultiple myelomas) in an amount of about 1,2, or 5mg per day^TM). In one embodiment, 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid) can be administered initially at a dose of 1 mg/day^TM) Then the dose was gradually increased to 10, 20, 25, 30 and 50 mg/day every week. In one embodiment, Revimid may be administered to a patient having a solid tumor in an amount of up to about 30 mg/day^TM. In one embodiment, Revimid can be administered to a patient having a glioma in an amount of up to about 40 mg/day^TM。

In a particular embodiment, 4- (amino) -2- (2, 6-dioxo (3-piperidyl) -isoindoline-1, 3-dione (Actimid) can be administered to a patient suffering from a disease or disorder associated with or characterized by undesired angiogenesis in an amount of about 0.1 to about 1mg per day, or alternatively in an amount of about 0.1 to about 5mg per every other day^TM) Diseases and conditions including, but not limited to: endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting (wasting), myelitis, silica-induced fibrosis (silica-induced fibrosis), asbestos-induced fibrosis (asbestos-induced fibrosis), veterinary disorders (veterinary disorder), malignancy-associated hypercalcemia, stroke, circulatory shock (circulatory shock), periodontitis, dental cariesGingivitis, macrocytic anemia, refractory anemia, and 5 q-syndrome.

In another embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid) can be administered to a patient having a disease or disorder associated with or characterized by undesired angiogenesis in an amount of about 1 to about 25mg per day, or alternatively in an amount of about 10 to about 50mg every other day^TM) The disease or condition includes but is not limited to: endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting (wasting), myelitis, silica-induced fibrosis (silica-induced fibrosis), asbestos-induced fibrosis (asbestos-induced fibrosis), veterinary disorders (veterinary disorder), malignancy-associated hypercalcemia, stroke, circulatory shock (circulatory shock), periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5 q-syndrome.

5.3.1 And a second active agent

Particular methods of the invention comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with one or more second active agents, and/or radiation therapy, transfusion or surgery. Examples of immunomodulatory compounds of the invention are disclosed herein (see, e.g., section 5.1). Examples of second active agents are also disclosed herein (see, e.g., section 5.2).

The selective cytokine inhibitory drug and the second active agent can be administered to the patient by the same or different routes of administration, either simultaneously or sequentially. Whether a particular route of administration is appropriate for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the blood) and the condition being treated. The preferred route of administration of the immunological compounds of the invention is oral. Preferred routes of administration for the second active agent or active ingredient of the invention are known to those skilled in the art, for example, see Physicians' desk reference, 1755-1760 (56 th edition, 2002).

In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously in an amount of from about 1 to about 1000mg, from about 5 to about 500mg, from about 10 to about 350mg, or from about 50 to about 250mg once a day or twice a day. The specific amount of the second active agent will depend upon the specific active agent employed, the type of disease being treated or controlled, the severity and stage of the disease, and the amount of immunomodulatory compounds of the invention and any optional additional active agents concurrently administered to the patient. In one embodiment, the second active agent is oblimersen (Genasense)^*) GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or combinations thereof.

In a particular embodiment, the dosage is from about 1 to about 750mg/m over a period of about 5 days in a four to six week cycle²Daily, preferably from about 25 to about 500mg/m²More preferably from about 50 to about 250mg/m²Daily, most preferably from about 50 to about 200mg/m²The amount per day GM-CSF, G-CSF or EPO are administered subcutaneously. In one aspect, it may be from about 60 to about 500mcg/m²Is administered intravenously over 2 hours, or at about 5 to about 12mcg/m²The amount per day was administered subcutaneously. In one embodiment, G-CSF can be initially administered subcutaneously in an amount of about 1 mcg/kg/day and then adjusted for an increase in total granulocytic count. Maintenance doses of G-CSF can be administered subcutaneously in amounts of about 300 (in smaller patients) or 480 mcg. In one embodiment, EPO can be administered subcutaneously in an amount of 10000 units, 3 times per week.

In another embodiment, an immunomodulatory compound is administered alone or in combination with a second active agent in an amount from about 0.1mg to about 150 mg/day to a patient suffering from metastatic melanoma (localized melanoma), including but not limited to ocular melanoma (oculeroma)The patient of (1). In one embodiment, Revimid is administered^TMIn an amount of about 1 to about 25 mg/day and dacarbazine in an amount of about 200 to 1,000mg/m²The daily amount is administered to a patient suffering from metastatic or localized melanoma (localized melanoma). In another embodiment, Revimid is administered^TMAdministering to a patient having metastatic or localized melanoma in an amount of about 1 to about 25 mg/day and temozolomide. In another embodiment, Revimid is administered^TMAdministering to a patient having metastatic or localized melanoma in an amount of about 1 to about 25 mg/day, the patient's disease progressing after treatment with dacarbazine IL-2 and/or IFN. In a specific embodiment, Revimid is administered^TMPatients with relapsed or refractory multiple myeloma are given twice a day in an amount of about 15 mg/day or four times a day in an amount of about 30 mg/day in combination with dexamethasone.

In another embodiment, an immunomodulatory compound and melphalan and dexamethasone are administered to a patient having an amyloid disease. In a particular embodiment, an immunomodulatory compound of the invention and a steroid may be administered to a patient having an amyloidosis.

In another embodiment, the selective cytokine inhibitory drug and gemcitabine and cisplatin are administered to a patient with locally advanced malignant or metastatic cell bladder cancer.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with a second active ingredient selected from the group consisting of: administering to a pediatric patient having a recurrent or progressive brain tumor or a recurrent neuroblastoma, in combination with temozolomide; in combination with celecoxib, etoposide and cyclophosphamide for recurrent or progressive central nervous system cancer; administering to a patient suffering from recurrent or progressive brain (spinal) meningioma, malignant meningioma, vascular integumentary tumor, multiple brain metastases (multiple brain tumors), recurrent brain tumor, or glioblastoma multiforme, or newly diagnosed; administering to a patient having a relapsed glioblastoma in combination with irinotecan; administering to a pediatric patient having brain stem glioma in combination with carboplatin; administering to a pediatric patient having a progressive malignant glioma in combination with procarbazine; administering to a patient having a malignant brain tumor with poor prognosis, a newly diagnosed or a relapsed glioblastoma multiforme in combination with cyclophosphamide; in combination with Gliadel * for advanced relapsing glioblastoma; in combination with temozolomide and tamoxifen for degenerative astrocytomas; or in combination with topotecan for glioma, glioblastoma, degenerative astrocytoma or degenerative oligodendroglioma.

In another embodiment, an immunomodulatory compound and methotrexate and cyclophosphamide are administered to a patient suffering from metastatic breast cancer.

In another embodiment, an immunomodulatory compound and temozolomide are administered to a patient having a neuroendocrine tumor.

In another embodiment, the immunomodulatory compound and gemcitabine are administered to a patient with recurrent or metastatic head or neck cancer. In another embodiment, the immunomodulatory compound and gemcitabine are administered to a patient with pancreatic cancer.

In another embodiment, the immunomodulatory compound is administered in combination with Arisa^*Taxol and/or taxotere are administered in combination to a patient suffering from colon cancer.

In another embodiment, the immunomodulatory compound and capecitabine are administered to a patient with refractory colorectal cancer or a patient who has failed first-line therapy or has poor performance in colon or rectal adenocarcinoma.

In another embodiment, an immunomodulatory compound is administered in combination with fluorouracil, folinic acid, and irinotecan to a patient having DukesC & D colorectal cancer or a patient previously treated for metastatic colorectal cancer.

In another embodiment, an immunomodulatory compound is administered in combination with capecitabine, Hirodade, and/or CPT-11 to a patient having refractory colorectal cancer.

In another embodiment, an immunomodulatory compound of the invention and capecitabine and irinotecan are administered to a patient having refractory colorectal cancer or a patient having unresectable or metastatic colorectal cancer.

In another embodiment, an immunomodulatory compound is administered alone or in combination with interferon-alpha or capecitabine to a patient having unresectable or metastatic hepatocellular carcinoma; or in combination with cisplatin and thiotepa, to patients with primary or metastatic liver cancer.

In another embodiment, an immunomodulatory compound is administered with pegylated alpha interferon to a patient with Kaposi's sarcoma.

In another embodiment, an immunomodulatory compound is administered in combination with fludarabine, carboplatin, and/or topotecan to a patient suffering from refractory or relapsed or high risk acute myeloid leukemia.

In another embodiment, an immunomodulatory compound is administered in combination with liposomal daunorubicin, topotecan, and/or Ara-C to a patient having worsening karotype acute myeloblastic leukemia.

In another embodiment, an immunomodulatory compound is administered in combination with gemcitabine and irinotecan to a patient having non-small cell lung cancer. In one embodiment, an immunomodulatory compound is administered in combination with carboplatin and irinotecan to a patient having non-small cell lung cancer. In one protocol, an immunomodulatory compound and doxetaxol are administered to a patient with non-small cell lung cancer who has previously been treated with carbo/VP 16 and radiation therapy.

In another embodiment, the immunomodulatory compound is administered to a patient having non-small cell lung cancer in combination with carboplatin and/or taxotere, or in combination with carboplatin, paclitaxel, and/or chest radiation. In one embodiment, an immunomodulatory compound is administered in combination with taxotere to a patient having stage IIIB or IV non-small cell lung cancer.

In another embodiment, an immunomodulatory compound of the invention is combined with an oblimersen (II)Genasenseo^*) In combination with administration to a patient suffering from small cell lung cancer.

In another embodiment, an immunomodulatory compound of the invention is administered to patients with different types of lymphomas including, but not limited to, hodgkin's lymphoma, non-hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse giant B-Cell lymphoma (difvuse large B-Cell lymphoma) or relapsed or refractory low-grade malignant follicular lymphoma, either alone or in combination with a second active ingredient, such as vinblastine or fludarabine.

In another embodiment, the selective cytokine inhibitory drugs are administered in combination with taxotere, IL-2, IFN, GM-CSF, and/or dacarbazine to patients with different types or stages of melanoma.

In another embodiment, an immunomodulatory compound is administered alone or in combination with vinorelbine to a patient having malignant mesothelioma or stage IIIB non-small cell lung cancer with pleural transplantation or malignant pleural effusion syndrome.

In another embodiment, an immunomodulatory compound is administered to A patient having multiple myelomA in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, A clarithromycin formulation, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, A dicarbonate compound, celecoxib, arsenic trioxide, PEG-INTRON-A, vincristine, or A combination thereof.

In another embodiment, the immunomodulatory compound is combined with doxorubicin (Doxil)^*) Vincristine and/or dexamethasone (Decardon)^*) In combination with patients with relapsed or refractory multiple myeloma.

In another embodiment, the immunomodulatory compound is administered in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, hiroda, paclitaxel, dexamethasone, or combinations thereof to a patient suffering from a different type or stage of ovarian cancer, such as peritoneal carcinoma (peritiealcanccinoma), papillary hematologic carcinoma (papillary serous carcinoma), refractory ovarian cancer, or recurrent ovarian cancer.

In another embodiment, the immunomodulatory compound is administered to a patient having a different type or stage of prostate cancer in combination with hiloda, 5FU/LV, gemcitabine, etidocitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, doxorubicin, docetaxel, estramustine, Emcyt, or a combination thereof.

In another embodiment, the immunomodulatory compound is administered in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex^*Or a combination thereof, to patients with different types or stages of renal cell carcinoma.

In another embodiment, an immunomodulatory compound is administered in combination with IFN, a COX-2 inhibitor such as Celebrex *, and/or sulindac to patients with different types or stages of gynecological, uterine or soft tissue sarcoma cancer.

In another embodiment, the immunomodulatory compound is administered to a patient having a solid tumor of a different type or stage in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apectibine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

In another embodiment, an immunomodulatory compound is administered to a patient having scelroderma or cutaneous vasculitis in combination with celecoxib, etoposide, cyclophosphamide, docetaxel, apectibine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

The invention also includes methods of increasing the dose of an anti-cancer agent or an anti-cancer agent that is safe and effective for administration to a patient, comprising administering to the patient (e.g., a human) a immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug of the invention. Patients who may benefit from this method are those who may experience adverse effects associated with anticancer drugs that treat skin cancer, subcutaneous tissue cancer, lymph node cancer, brain cancer, lung cancer, liver cancer, bone cancer, intestinal cancer, colon cancer, heart cancer, pancreatic cancer, adrenal cancer, kidney cancer, prostate cancer, breast cancer, colorectal cancer, or a combination thereof. Administration of the immunomodulatory compounds of the invention reduces or eliminates the above-mentioned adverse effects, which are so severe as to limit the amount of anticancer agent if not taken alone.

In one embodiment, an immunomodulatory compound of the invention can be administered orally in an amount of from about 0.1 to about 150mg, preferably from about 1 to about 50mg, more preferably from about 2 to about 25mg per day before, during, or after the occurrence of an adverse reaction associated with an anticancer agent administered to a patient. In one embodiment, the immunomodulatory compounds of the invention are administered in combination with specific active agents such as heparin, aspirin, coumarin, or G-CSF to avoid adverse effects associated with anticancer drugs, including but not limited to neutropenia or thrombocytopenia.

In one embodiment, the immunomodulatory compounds of the invention may be administered in combination with additional active ingredients, including but not limited to anti-cancer agents, anti-inflammatory agents, antihistamines, antibiotics, and steroids, to patients suffering from diseases and conditions associated with or characterized by undesired angiogenesis.

In another embodiment, the invention encompasses methods of treating, preventing and/or managing cancer, which comprise administering (e.g., before, during or after) an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with conventional therapy, including but not limited to surgery, immunotherapy, biotherapy, radiotherapy or other non-drug based therapy currently used to treat, prevent or manage diseases and disorders associated with or characterized by undesired angiogenesis. The combined use of the immunomodulatory compounds of the invention with conventional therapy in certain patients can provide unique therapeutic approaches with unexpected effectiveness. Without wishing to be bound by theory, it is believed that the immunomodulatory compounds of the invention may provide additive or synergistic effects when co-administered with conventional therapies.

In another aspect, the invention encompasses methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with (e.g., before, during or after) conventional therapy including, but not limited to, surgery, immunotherapy, biotherapy, radiation therapy or other non-drug-based therapy currently used to treat, prevent or manage diseases and disorders associated with or characterized by undesired angiogenesis. The combined use of the immunomodulatory compounds of the invention with conventional therapy in certain patients may provide an unexpectedly effective unique therapeutic approach. Without wishing to be bound by theory, it is believed that the immunomodulatory compounds of the invention may provide additive or synergistic effects when co-administered with conventional therapies.

As discussed elsewhere herein, the present invention includes methods of reducing, treating and/or preventing adverse or undesired reactions associated with conventional therapies including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy. One or more immunomodulatory compounds of the invention and other active ingredients may be administered to a patient before, during, or after the occurrence of adverse effects associated with conventional therapy.

In one embodiment, an immunomodulatory compound of the invention is administered orally, alone or in combination with a second active agent disclosed herein (see, e.g., section 5.2), in an amount of from about 0.1 to about 150mg, preferably from about 1 to about 25mg, more preferably from about 2 to about 10mg per day, before, during, or after use of conventional therapy.

In one embodiment of this method, an immunomodulatory compound of the invention and doxetaxol are administered to a patient having non-small cell lung cancer who has previously been treated with carboplatin/VP 16 and radiation therapy.

5.3.2 Used with transplantation therapy

Immunomodulatory compounds of the invention are useful for reducing the risk of Graft Versus Host Disease (GVHD). The invention therefore encompasses methods of treating, preventing and/or managing cancer, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with transplantation therapy.

As those skilled in the art are aware, treatment of cancer is often based on the stage and mechanism of the cancer. For example, transplantation of peripheral blood stem cells, hematopoietic stem cell preparations (hematopoietic stem cell preparations) or bone marrow may be necessary when inevitable leukemic transformation occurs at certain stages of cancer. The combined use of the immunomodulatory compounds of the invention and transplantation therapy can provide unique and unexpected synergistic effects. In particular, the immunomodulatory compounds of the invention are shown to provide additive or synergistic immunomodulatory activity when administered concurrently with transplantation therapy in patients with cancer.

The immunomodulatory compounds of the invention can work in combination with transplantation therapy to reduce the risk of complications associated with the invasive process of transplantation and GVHD. The invention encompasses methods of treating, preventing and/or managing cancer, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) prior to, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow. Stem cells suitable for use in the above-described methods of the invention are disclosed in U.S. patent application 10/411,655, filed on 11/4/2003 by r.haririi et al, which is incorporated herein by reference in its entirety.

In another embodiment, the invention encompasses methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, which comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) before, during or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow.

In one version of the method, an immunomodulatory compound of the invention is administered to a patient with multiple myeloma before, during, or after transplantation of autologous peripheral blood progenitor cells.

In another embodiment, an immunomodulatory compound of the invention is administered to a patient with relapsed multiple myeloma after stem cell transplantation.

In another embodiment, the immunomodulatory compounds of the invention and prednisone are administered as maintenance therapy to patients with multiple myeloma following autologous stem cell transplantation.

In another embodiment, an immunomodulatory compound of the invention and dexamethasone are administered as remedial therapy to patients with multiple myeloma to achieve low risk transplant prognosis.

In another embodiment, the immunomodulatory compounds of the invention and dexamethasone are administered as maintenance therapy to patients with multiple myeloma following autologous bone marrow transplantation.

In another embodiment, the immunomodulatory compound is administered to a patient with chemotherapy-responsive multiple myeloma after administration of a high dose of melphalan and autologous stem cell transplantation.

In another embodiment, an immunomodulatory compound and PEG INTRO-A are administered as maintenance therapy to patients with multiple myelomA following transplantation of autologous CD 34-selected peripheral stem cells.

In another embodiment, an immunomodulatory compound and post-transplant consolidation chemotherapy (posttransplantation consolidation chemotherapy) are administered to patients with newly diagnosed multiple myeloma to assess anti-angiogenic effects.

In another embodiment, the immunomodulatory compounds of the invention and dexamethasone are administered as maintenance therapy to patients 65 years or older with multiple myeloma following DCEP consolidation (DCEP consolidation), following high dose melphalan and peripheral blood stem cell transplantation therapy.

5.3.3 Circulatory therapy

In certain embodiments, the prophylactic or therapeutic agents of the invention are administered to the patient cyclically. Cycling therapy involves administering the active agent for a period of time, then stopping for a period of time, and then repeating this sequence of administrations. Cycling therapy may 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 efficiency of the therapy.

Thus, in one embodiment of the invention, the immunomodulatory compounds of the invention are administered in a single dose or in divided doses daily for a period of four to six weeks with a one to two week rest period. The invention further allows to increase the frequency, number and length of administration cycles. Thus, another embodiment of the invention includes administering an immunomodulatory compound of the invention for more cycles than is typical when the compound is administered alone. In another embodiment of the invention, an immunomodulatory compound of the invention is administered for a greater number of cycles, which typically causes dose-dependent toxicity in patients who have not been administered the second active ingredient.

In one embodiment, an immunomodulatory compound of the invention is administered daily at a dose of about 0.1 to about 150 mg/day for three to four weeks, followed by an interval of one or two weeks. Preferably, Actimid is administered continuously at an initial dose of 0.1 to 5 mg/day per day^TMThen the dose is increased (weekly) from 1 to 10 mg/day to a maximum dose of 50 mg/day, as long as the treatment is tolerated. In a specific directionIn one embodiment, Revimid is administered in an amount of about 1, 5, 10, or 25 mg/day, preferably about 10 mg/day^TMFor three to four weeks, followed by one or two week intervals, one cycle for four to six weeks.

In one embodiment of the invention, the immunomodulatory compound of the invention and the second active agent are administered orally during a cycle of four to six weeks, 30 to 60 minutes prior to the second active ingredient. In another embodiment of the invention, the combination of an immunomodulatory compound of the invention and a second active ingredient is administered by intravenous infusion over about 90 minutes per cycle. In one embodiment, a cycle comprises administering about 1 to about 25 mg/day of Revimid per day^TMAnd about 50 to about 200mg/m²The second active ingredient is administered three to four weeks a day, then one or two weeks off. In another embodiment, each cycle comprises administration of about 5 to about 10 mg/day of Actimid^TMAnd about 50 about 200mg/m²The second active ingredient is administered three to four weeks a day, then one or two weeks off. Typically, the number of cycles is from about 1 to about 24 cycles, more typically from about 2 to about 16 cycles, more typically from about four to three cycles, during administration of the combination therapy to a patient.

5.4 Pharmaceutical compositions and dosage forms

The pharmaceutical compositions may be presented in discrete, unitary unit dosage form. Pharmaceutical compositions and dosage forms of the invention include an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may further comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the present invention also include one or more additional active ingredients. The pharmaceutical compositions and dosage forms of the invention thus comprise the active ingredients (e.g., immunomodulatory compound and a second active ingredient) disclosed herein. Examples of optional or additional active ingredients are disclosed herein (see e.g., section 5.2).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, single bolus intravenous, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic formulations), transdermal or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as soft plastic gelatin capsules; a cachet; a lozenge; a lozenge; a dispersant; suppositories; powder preparation; aerosols (e.g., nasal sprays or inhalants); gelling; liquid dosage forms suitable for oral or mucosal administration to a patient include suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; a liquid dosage form suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solid formulations (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of the dosage form of the present invention typically may vary depending on its use. For example, a dosage form for the acute treatment of a disease may contain a greater amount of one or more active ingredients than a dosage form for the chronic treatment of the same disease. Similarly, parenteral dosage forms may contain smaller amounts of one or more active ingredients than their oral dosage forms for the treatment of the same disease. These and other ways of providing a particular dosage form encompassed by the present invention may vary, as will be apparent to those skilled in the art. See, for example, Remngton's pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in pharmacy. 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 route by which the dosage form is administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for parenteral dosage forms. The suitability of a particular excipient will also depend on the particular active ingredient in the dosage form. For example, the breakdown of certain active ingredients may be accelerated by certain excipients such as lactose or when exposed to water. Active ingredients containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the pharmaceutical compositions and dosage forms encompassed by the present invention contain little, if any, lactose and no other mono-or disaccharides. As used herein, the term "lactose-free" means that lactose is present in an amount that is insufficient, if at all, to significantly increase the rate of degradation of the active ingredient.

The lactose-free compositions of the invention may contain excipients well known in the art, for example, as exemplified in U.S. pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise an active ingredient, a binder/filler, and a pharmaceutically compatible and pharmaceutically acceptable amount of a lubricant. Preferred lactose-free dosage forms include the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention further includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water promotes the degradation of certain compounds. For example, the addition of water (e.g., 5%) as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of the dosage form over time is widely accepted in the pharmaceutical arts. See, e.g., Jens t. carstensen, "Drug Stability: principles & Practice, second edition, Marcel Dekker, NY, NY, 1995, pp.379-80. In fact, water and heat accelerate the decomposition of certain compounds. Thus, the effect of water on dosage forms can have great significance because moisture and/or humidity are commonly encountered during manufacture, processing, packaging, storage, shipment, and use of dosage forms.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low water content ingredients, low water or low moisture conditions. Pharmaceutical compositions and dosage forms containing lactose and at least one active ingredient containing a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacture, packaging and/or storage is expected.

Anhydrous pharmaceutical compositions should be prepared and stored such that their anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in a suitable regulatory (formulary) kit. Examples of suitable packages include, but are not limited to, sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further includes pharmaceutical compositions and dosage forms containing one or more compounds capable of reducing the rate of decomposition of an active ingredient. Such compounds are referred to herein as "stabilizers," which include, but are not limited to: antioxidants such as ascorbic acid, pH buffers or salt buffers.

The amount and specific type of active ingredient in a dosage form, like the amount and type of excipient, may vary depending on a variety of factors including, but not limited to, the route by which the active ingredient is administered to the patient. However, a typical dosage form of the invention comprises from about 0.10 to about 150mg of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. A typical dosage form comprises about 0.1, 1,2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, or 200mg of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In one embodiment, a preferred dosage form contains about 1,2, 5, 10, 25 or 50mg of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1-3-dione (Actimid)^TM). In one embodiment, a preferred dosage form contains about 5, 10, 25 or 50mg of 3- (4-amino-1-oxo-1, 3-dihydro-isoindolyl-2-yl) -piperidine-2, 6-dione (Revimid)^TM). Typical dosage forms contain from about 1 to about 1000mg, from about 5 to about 500mg, from about 10 to about 350mg, or from about 50 to about 200mg of the second active ingredient. The particular amount of the anti-cancer agent will, of course, depend on the particular active agent used, the type of cancer being treated or controlledAnd the amount of an immunomodulatory compound of the invention and, optionally, an additional active agent co-administered to the patient.

5.4.1 Oral dosage form

Pharmaceutical compositions of the present invention suitable for oral administration may be provided in discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and may be prepared by pharmaceutical methods known to those skilled in the art. See generally, Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms of the invention may be prepared by mixing the active ingredient and at least one excipient in intimate admixture using conventional pharmaceutical formulation techniques. Excipients may 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 excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) 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 administration unit form in which solid excipients are used. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such dosage forms may be prepared using any method of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredient with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product to the desired finished product specification.

For example, tablets may be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients. Molded tablets may be prepared by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.

Examples of excipients that may be used in the oral dosage forms of the present invention include, but are not limited to: a binder, a filler, a disintegrant, and a lubricant. 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 (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., 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 AVICELRC-581, AVICEL-PH-105 (commercially available from FMCCcorporation, American Viscose Division, Avicel Sales, MarcusHook, Pa.), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or adjuvants include AVICEL-PH-103^TMAnd Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to: talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler of the pharmaceutical composition of the present invention is typically present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants are used in the pharmaceutical compositions of the invention to disintegrate the tablet when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate upon storage, while those containing too little may not disintegrate at a desired rate or under desired conditions. Thus, a sufficient amount of disintegrant should be used to form the solid oral dosage form of the present invention that is not so much or so little as to adversely alter the release of the active ingredient. The amount of disintegrant used varies depending on the type of dosage form and is readily discernible to those skilled in the art. Typical pharmaceutical compositions include about 0.5 to about 15 weight percent of a disintegrant, preferably about 1 to about 5 weight percent of a disintegrant.

Disintegrants that may 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, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that may be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to: calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, silicate silica gel (AEROSIL200, manufactured by w.r. grace co., Baltimore, MD), coagulated aerosol of synthetic silica (sold by Degussa co., Plano, TX), CAB-O-SIL (a product of fumed silica sold by Cabot co., Boston, MA), and mixtures thereof. If used, lubricants typically incorporated into pharmaceutical compositions or dosage forms are used in amounts less than about 1 weight percent of the pharmaceutical composition or dosage form.

Preferred solid oral dosage forms of the invention include an immunomodulatory compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin.

5.4.2 Delayed release dosage form

The active ingredients of the present invention may also be administered by controlled release means or by delivery (delivery) devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. nos. 3,845,770; 3,916,899; 3,536,809, respectively; 3,598,123, respectively; 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 may be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide the desired release profiles in varying proportions. Suitable controlled release dosage forms are known to those of ordinary skill in the art and include those disclosed herein, and can be readily selected for use with the active ingredients of the present invention. The present invention thus encompasses single unit dosage forms suitable for oral administration, including, but not limited to, tablets, capsules, gelcaps, and caplets suitable for controlled release.

All controlled release drug products have a common goal of improved drug therapy beyond that achieved by their non-controlled release counterparts. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by a minimum of drug substance and a minimum of time for curing or controlling the condition. Advantages of controlled release dosage forms include prolonged drug activity, reduced frequency of administration, and increased patient compliance. In addition, controlled release dosage forms can be used to affect the onset time or other characteristics of an effect, such as the blood concentration of the drug, and thus the occurrence of side (e.g., adverse) effects.

Most controlled release dosage forms are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, followed by gradual and sustained release of other amounts of drug to maintain this level of therapeutic or prophylactic effect for an extended period of time. To maintain this steady level of drug in the body, the drug must be released from the dosage form at a rate that can replace the amount of drug that is metabolized and excreted by the body. The controlled release of the active ingredient may be stimulated by various conditions, including but not limited to: pH, temperature, enzyme, water or other physiological condition or compound.

5.4.3 Parenteral dosage form

Parenteral dosage forms can be administered to a patient by various routes including, but not limited to: subcutaneous, intravenous (including single bolus intravenous), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against poisons, parenteral dosage forms are preferably sterile or sterilizable prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to: ready-to-use solutions for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions ready for injection, and emulsions.

Suitable carriers for providing parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: water for injection of USP, aqueous carriers such as, but not limited to: sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water miscible carriers such as, but not limited to: ethanol, polyethylene glycol, and polypropylene glycol; 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 disclosed herein may also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof may be used to increase the solubility of the compounds of the present invention and derivatives thereof. See, e.g., U.S. Pat. No. 5,134,127, incorporated herein by reference.

5.4.4 Topical and mucosal dosage forms

Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic formulations, or other forms known to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th edition, Mack Publishing, Easton PA (1980& 1990); and Introduction to Pharmaceutical document Forms, fourth edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as mouthwashes or as mouth gels.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed by the present invention are well known to those skilled in the art of pharmaceutical formulation, depending on the particular tissue to which a given pharmaceutical composition or dosage form is to be administered. Based on the above facts, typical excipients include, but are not limited to: water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3 diol (butane-1, 3 diol), isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form a solution, emulsion or gel that is non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th edition, Mack Publishing, Easton PA (1980& 1990).

The pH of the pharmaceutical composition or dosage form may also be adjusted to enhance delivery of one or more active ingredients. Similarly, the ionic strength or tonicity of the solvent carrier can be adjusted to enhance delivery. Compounds such as stearic acid may also be added to pharmaceutical compositions or dosage forms to advantageously modify the hydrophilicity or hydrophobicity of one or more active ingredients to enhance delivery. In this regard, stearic acid may be used as a lipid carrier, emulsifier or surfactant, delivery enhancer or penetration enhancer for the dosage form. Different salts, hydrates or solvates of the active ingredient may be used to further tailor the properties of the resulting composition.

5.4.5 Reagent kit

Typically, the active ingredients of the present invention are preferably not administered to the patient at the same time or by the same route of administration. The invention therefore includes kits which, when used by a medical practitioner, can simplify the administration of appropriate amounts of the active ingredients to a patient.

A typical kit of the invention comprises a dosage form of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. The kit encompassed by the present invention may further comprise additional active ingredients such as oblimersen (Genasense)^*) Melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitors, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or pharmacologically active mutants or derivatives thereof, or combinations thereof. Examples of additional active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 5.2).

The kit of the invention may further contain a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags (drip bags), masks (patches), and inhalers.

The kit of the present invention may further contain cells or blood for transplantation and a pharmaceutically acceptable carrier, which may be used for administration of one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container containing a suitable carrier in which the active ingredient can be dissolved to form a sterile, particulate-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: water for injection of USP; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose-sodium chloride injection, and lactated ringer's injection; water miscible carriers such as, but not limited to, ethanol, 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.

6. Examples

Certain aspects of the invention are illustrated by the following non-limiting examples.

6.1 Modulation of cytokine production

A series of non-clinical pharmacological and toxicological studies have been conducted to support clinical evaluation of immunomodulatory compounds of the invention in human subjects. Unless otherwise indicated, these studies were conducted in accordance with internationally recognized study design guidelines and in compliance with the requirements of the drug safety test protocol (GLP).

4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (Actimid) was studied in vitro after stimulation with LPS on human PBMC and human whole blood^TM) 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM) And the inhibitory effect of thalidomide on TNF- α production (Muller et al, Bioorg med. chem. lett.9: 1625-1630, 1999). IC of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione for inhibition of TNF-alpha production following stimulation of PBMC and human whole blood with LPS₅₀These were-24 nM (6.55ng/mL) and-25 nM (6.83ng/mL), respectively. In vitro studies have demonstrated that 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione has a pharmacological activity profile similar to that of thalidomide, but at least 200-fold more potent than that of thalidomide. In vitro studies also demonstrated that concentrations of 2.73-27.3ng/ml (0.01 to 0.1. mu.M) of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione inhibited MM.IS and Hs Sultan cell proliferation by 50%.

After LPS stimulation of PBMC and human whole bloodIC for inhibition of TNF-alpha production by 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione₅₀These were-100 nM (25.9ng/mL) and-480 nM (103.6ng/mL), respectively. In contrast, thalidomide inhibits the IC of TNF- α production following LPS stimulation of PBMCs₅₀Was 194. mu.M (50.2. mu.g/mL). In vitro studies have demonstrated that 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione has a pharmacological activity profile similar to that of thalidomide, but 50-2000 times more potent than that of thalidomide. This indicates that the compounds of the invention stimulate T cell proliferation 50-100 fold more effectively than thalidomide following primary induction by T Cell Receptor (TCR) activation. 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is also about 50-100 fold more effective than thalidomide in increasing IL-2 and IFN- γ production following TCR activation of PBMC (IL-2) or T cells (IFN- γ). In addition, 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione showed a dose-dependent inhibition of LPS-stimulated pro-inflammatory response factors TNF-. alpha., IL-1. beta. and IL-6 produced by PBMC, but it increased the production of the anti-inflammatory cytokine IL-10.

6.2 Inhibition of MM cell proliferation

In vitro studies of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM) Studies were performed comparing the effect of thalidomide on the proliferative capacity of MM cell lines. The uptake of [ 2 ], [ 2 ] by different MM (MM.1S, Hs Sultan, U266 and RPMI-8226) cell lines was determined³H]Thymine as a marker of cell proliferation. Culturing the cells in the presence of the compound for 48 hours; the addition of [ 2 ] in the last 8 hours of the culture period³H]-thymine. Addition of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione to mm.is and Hs Sultan cells at concentrations of 0.4 and 1 μm, respectively, resulted in 50% inhibition of cell proliferation. In contrast, the addition of thalidomide at concentrations up to 100 μm produced only 15% and 20% inhibition of MM IS and Hs Sultan cells proliferation, respectively. These data are summarized in figure 1.

6.3 Toxicity Studies

3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid) was studied in anesthetized dogs^TM) Cardiovascular and respiratory system effects. Two groups of beagle dogs (2/gender/group) were used. One group received only three doses of vehicle and the other group received three increasing doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (2, 10, and 20 mg/kg). In all studies, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione or vehicle was administered continuously by infusion via the jugular vein at intervals of at least 30 minutes.

Cardiovascular and respiratory changes induced by 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione were minimal at all doses when compared to vehicle controls. The only statistically significant difference between the vehicle and treatment groups was a small increase in arterial blood pressure following administration of the low dose of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. This effect lasted about 15 minutes and was not observed at higher doses. Deviations in femoral blood flow (fermoral blood flow), respiratory parameters, and Qtc interval were identical for both the control and treated groups and were not considered treatment-related.

6.4 Cycling therapy in a patient

In one embodiment, the immunomodulatory compounds of the invention are cyclically administered to a patient suffering from cancer. Cycling therapy involves administering a first therapeutic agent for a period of time, then stopping for a period of time, and then repeating this sequence of administrations. Cycling therapy can reduce the occurrence of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies described above, and/or increase the efficiency of the therapy.

In a specific embodiment, the prophylactic or therapeutic agent is administered about 1 or 2 times per day over a period of about 4 to 6 weeks. One cycle includes administration of the therapeutic or prophylactic agent for 3 to 4 weeks, followed by a rest of at least 1 to 2 weeks. The number of cycles administered is from about 1 to 24 cycles, more typically from about 2 to about 16 cycles, more typically from about 4 to about 8 cycles.

For example, in one cycle of four weeks, on day 1, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered initially at 25 mg/day. Compound administration was discontinued for one week on day 22. On day 29, administration of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione at 25 mg/day was started.

6.5 Clinical study in patients

6.5.1 Treatment of relapsed multiple myeloma

4- (amino) -2- (2, 6-dioxy (3-piperidyl)) -isoindoline-1, 3-dione (Actimidm)^TM) Patients with relapsed/refractory multiple myeloma are given. The study was performed in compliance with good clinical trial protocol (GCP). Patients are at least 18 years old, have been diagnosed with multiple myeloma (by serum and or pathological proteins in the urine), and are considered refractory after at least two cycles of treatment, or relapse after two cycles of treatment.

Patients with progressive disease in their pretreatment are considered refractory to the Southwest Oncology Group (SWOG) criteria. Recurrence after remission was defined as a greater than 25% increase in M component from baseline levels; re-appearance of previously disappeared M lesion protein; or a clear increase in the size and number of bacteriolytic bone lesions identified on radiographs. The patient may be pre-treated with thalidomide, provided that it is able to tolerate such treatment. Zubrod performance status of 0 to 2 is required for all patients.

Administering 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione to the patient at a dose of 1,2, 5, or 10 mg/day for up to four weeks; three patients were initially enrolled (enroled) at each dose level. Administered at about the same time each morning; all doses were given in the fasted state (at least two hours before and two hours after dosing). Only after safety and tolerability was established at the current dose, 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione doses were given in an increasing fashion so that patients in the first group received the lowest dose of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (1 mg/day) and then escalated to the next higher dose level. If one of the three patients experiences Dose Limiting Toxicity (DLT) at any dose level, three additional patients will be enrolled at that dose. Increasing to the next dose level if none of the three additional patients experienced DLT; dose escalation was continued in a similar manner until the MTD was determined or the maximum daily dose (10 mg/day) was obtained. But if one of three additional patients enrolled experiences a DLT, the MTD is reached. If two or three of the three additional patients experience a DLT, the MTD is judged to have been exceeded, and three additional patients are enrolled at a previous dose level to determine the MTD. Once the MTD was determined, four additional patients were enrolled at that dose level to allow 10 patients to be treated entirely with MTD.

Blood sampling for pharmacokinetic parameter analysis was performed on days 1 and 28 according to the following sampling times: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4,6, 8, 10, 12, 18, and 24 hours post-dose. Additional blood samples were collected at weekly visits to determine 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione levels. Whole urine collection was also performed with urine pooled according to the following post-dose intervals: 0 to 4,4 to 8,8 to 12, and 12 to 24 hours. Safety assessments were performed by monitoring adverse reactions, vital signs, ECGs, clinical laboratory assessments (blood chemistry, hematology, lymphocyto-dominance, and urinalysis), and physical examination at specific times during the study.

The results of the intermediate pharmacokinetic analysis obtained after administration of a single dose or multiple doses of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione to patients with multiple myeloma are shown in tables 1 and 2 below. These data show that 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione is stably absorbed at all dose levels in patients with relapsed multiple myeloma. The maximum plasma concentrations occurred between 2.5-2.8 hours post-dose on day 1 of median Tmax and between 3 and 4 hours post-dose on week 4. Plasma concentrations decreased in a monophasic manner after Cmax was reached at all doses. The elimination phase occurred between 3 and 10 hours after the first and 4 week dosing, respectively.

These data also show that 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione accumulates to a small extent (C) 4 weeks after administration_max and AUC_(0-T)Average cumulative ratios of 1.02 to 1.52 and 0.94 to 1.62), respectively). AUC with dose increase_(0-T)And C_maxThe value of (a) increases almost in dose proportion. A5-fold higher dose of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione produces 3.2 and 2.2-fold C on the first day and at week 4, respectively_maxAnd (4) increasing. Similarly, a 5-fold increase in dose resulted in 3.6 and 2.3-fold AUC on day one and week 4, respectively_(0-T)And (4) increasing.

TABLE 1

Actimid in relapsed multiple myeloma patients^TMPharmacokinetic parameters of

Parameter(s)		1mg(N＝6)	2mg(N＝2)	5mg(N＝3)
					First of allSky
Cmax	ng/ml	15.03(4.04)	24.4*(12.1)	48.56(14.03)
					tmax	h	3.3(2.6)	2.7*(0.3)	2.3(0.3)
AUC(0-∞)	ng.h/ml	152.90(36.62)	279.18(51.10)	593.10(335.23)
					AUC(0-T)		134.21(27.14)	249.57(29.26)	520.94(267.32)
t1/2	h	7.3(3.4)	6.3(1.4)	6.5(2.2)
					CL/F	mL/min	114.75(29.20)	121.43(22.22)	182.31(117.06)
Vz/f	L	69.55(44.97)	65.31(2.80)	87.24(22.61)

t is 24 hours, and N/A is not detected.

TABLE 2

Multiple oral administrations (1, 2, and 5 mg/day) in patients with relapsed multiple myeloma

Posterior Actimid^TMPharmacokinetic parameters of

Parameter(s)		1mg(N＝5)	2mg(N＝2)	5mg(N＝3)
					The fourth side
Cmax	ng/ml	23.20(7.48)	30.05*(15.64)	58.07(38.08)
					tmax	h	3.6(1.5)	2.8*(0.3)	5.0(2.6)
AUC(0-∞)	ng.h/ml	N/A	N/A	N/A
					AUC(0-T)		239.31(122.59)	269.36(186.34)	597.24(354.23)
t1/2	h	6.2*(0.6)	7.7(2.8)	7.8(4.0)
					CL/F	mL/min	87.85(48.48)	162.68(112.54)	207.50(175.41)
Vz/f	L	41.35*(8.84)	95.04(35.39)	103.95(27.25)

t is 24 hours, N/A is not measured, N is 3 patients

6.5.2 Treatment of relapsed multiple myeloma

P-3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM) Two phase 1 clinical studies were performed to determine the Maximum Tolerated Dose (MTD) for patients with refractory or relapsed multiple myeloma. These data also characterize the safety profile of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione when given as an ascending dose of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione administered orally for up to 4 weeks. The patient was treated starting with 5 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione and increasing gradually to 10, 25 and 50 mg/day. Patients were enrolled for 28 days at their prescribed dose and extended treatment was selected for those patients who did not show disease progression or experienced dose-limiting toxicity (DLT). Adverse reactions of patients were assessed at each visit and were not treated according to the National Cancer Institute (NCI) general Toxicity guidelines (National Cancer Institute (NCI) Common susceptibility criterion)The severity of the good response was scored. If the patient experiences DLT (grade 3 or higher non-blood, or grade 4 hematological toxicity), the patient aborts the test.

In this study, 27 patients were enrolled, all with relapsed multiple myeloma and 18 (72%) were refractory to remedial therapy (salvage therapy). Of these patients, 15 had previously received autologous stem cell transplantation and 16 had previously received thalidomide therapy. The median value for the previous treatment was 3 (range 2 to 6).

Blood and urine samples were collected on days 1 and 28 for pharmacokinetic parameter analysis. Blood samples were collected according to the following sampling times: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4,6, 8, 10, 12, 18, and 24 hours post-dose. In addition, blood samples were collected at weekly clinical visits to determine 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Whole urine was collected and pooled according to the following post-dose intervals: 0 to 4,4 to 8,8 to 12, and 12 to 24 hours. Response to treatment was assessed by quantifying serum and collecting urine M-protein (using immunoelectrophoresis) at 24 hours, and creatinine clearance and 24 hour protein calculation were also used at screen, baseline, weeks 2 and 4, and each month thereafter (or terminated early). Bone marrow aspiration and/or tissue biopsy is also performed at months 3,6 and 12 if the patient's lesion protein serum concentration or 24 hour urinary protein excretion drops to the next lower level according to the optimal response criteria. Preliminary results for the 28-day treatment period are summarized below.

Preliminary pharmacokinetic analysis according to both studies showed that AUC and Cmax values increased with dose proportionally in multiple myeloma patients after single and multiple doses (also observed in healthy volunteers). Further, after the same dose of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione was administered, a single dose AUC (0- ∞) and multiple doses AUC_0-TThere is no evidence of multiple dose accumulation, as is comparable. A similar double peak was observed for the healthy volunteer study. When compared to a healthy maleExposure in multiple myeloma patients appeared to be slightly higher in terms of Cmax and AUC values, while clearance rates were lower in multiple myeloma patients than in healthy volunteers, consistent with their low renal function (as a result of their age and disease). Finally, the half-life of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in patients was shorter (8 hours on average, up to 17 hours) than in healthy volunteers.

In this study, the first group of 3 patients was treated at 5 mg/day for 28 days without any Dose Limiting Toxicity (DLT). The second group of 3 patients then began treatment at 10 mg/day. Patients in the second 10 mg/day group of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione are well tolerated for treatment.

6.5.3 Treatment of solid tumors

With 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM) Studies have been performed in patients with different types of solid tumors, including metastatic melanoma (13), pancreatic cancer (2), unknown primary carcinoids (1), renal cancer (1), breast cancer (1) and NSCLC (2). The patient received 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione at 5 mg/day for 7 days, then increased to 10 mg/day, 25 mg/day, and 50 mg/day every 7 days for a total of 4 weeks of treatment. Patients who experienced clinical benefit continued to be treated as indicated Patients (Named Patients).

This study initially enrolled 20 patients, then was modified at higher doses to enroll 16 additional patients (renal cancer, NSCLC, malignant mesothelioma, breast cancer, metastatic melanoma (8), renal cell carcinoma (4)). 16 additional patients were administered with weekly escalating doses of 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, and 150 mg/day over a 6 week period, and treatment continued for an additional six weeks.

A phase 1 study of this study was designed to determine the maximum tolerated dose of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in patients with refractory solid tumors and/or lymphomas, as well as to characterize the pharmacokinetics and side effect profile of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in such patients. This study design stipulates that treatment be completed for 28 days at least in 3 patients enrolled at one dose level and before enrollment at the next higher dose level in patients. Administration to patients in the first group was started at 5 mg/day of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. If there is no toxicity, the patient is gradually increased to 10, 20, 25, and 30 mg/day.

In this study, MTD was defined as the highest dose level at which less than two of the six patients treated did not experience grade 3 or greater non-hematologic toxicity or grade 4 or greater hematologic toxicity. If one of the three patients experienced toxicity at any given dose level in any study, three additional patients must be treated at that particular dose. But if two of the six patients experienced DLT, the MTD was judged to have been exceeded. No further dose escalation is required and additional patients are enrolled at the previous dose level. The dose of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione administered is escalated until the MTD is reached or the maximum daily dose is reached.

There were no reports of DLT in the initial group of 20 patients enrolled in this study. 13 of the 20 initial trial patients and 2 non-trial patients together were treated as assigned patients at doses up to 150 mg/day.

6.5.4 Treatment of glioma

This study was conducted to find toxicity in patients with recurrent high-grade glioma. The study was designed to allow patients to be given increasing higher doses of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione until the Maximum Tolerated Dose (MTD) was determined. This study also attempted to obtain preliminary toxicological information and pharmacokinetic data on 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, as well as preliminary data relating to surrogate end points of in vivo angiogenic activity developed using functional neuro-imaging studies (functional neuro-imaging studies) and in vitro analysis of serum angiogenic peptides.

Patients who were enrolled in the first group received 2.5mg/m²One cycle for 4 weeks/day. 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered once daily for three weeks during each 4-week treatment cycle, followed by one week of rest. If both criteria are met, a patient who completes one treatment cycle may receive another cycle of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. First, the patient must have a stable disease or experience a partial or complete response, or the patient benefits from treatment with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, as evidenced by a reduction in tumor-related symptoms, such as neurological deficit. Second, the patient must recover from 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione-related toxicity that occurred in the previous cycle, either before day 42 or earlier (28-day cycle plus 2-week recovery period), as evidenced by recovery to a grade 1 or less toxicity level. Patients who have experienced DLT in the previous cycle should be dose adjusted. The non-hematologic response to grade 3 or grade 4 toxicity considered to be associated with this study drug was defined as DLT. Patients who experienced DLT during the first cycle and were non-responsive to treatment were excluded from the study.

The 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione dose was then gradually increased to 5,8, 11, 15 and 20mg/m²Daily up to a maximum total daily dose of 40 mg. Patients continued to receive 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione at each dose level for a period of 4 weeks until one of the (off-study) criteria for discontinuation of the study was met.

Three patients were enrolled in each group. If at least one of the patients had a DLT, then three additional patients were added to the group at that particular dose level. If two patients develop DLT, then the MTD is considered to have been exceeded, defined as the dose at which less than one third of the patients experienced DLT at each dose level, then four more patients were treated with the previous dose.

Patients who experienced DLT during the first 4-week period were excluded from the study unless they responded to treatment. For patients who completed the first 4 week cycle without DLT, but who subsequently experienced grade 3 or grade 4 hematologic and/or non-hematologic toxicity, treatment was terminated for a minimum of one week. If the toxicity subsides to less than grade 2 within 3 weeks, the patient is treated at two dose levels lower than the dose that caused the toxicity (or a 50% reduction if the patient is treated at the first or second dose level). Patients who did not resolve grade 3 or grade 4 toxicity to less than grade 1 within three weeks, or those with additional grade 3 toxicity at reduced doses, were excluded from the study.

Pharmacokinetic sampling was performed before (day 1) and at 0.5, 1,2, 4,6, 8, 24, and 48 hours post-administration of the first dose of 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Samples were also taken on days 7 and 21 before and on days 21 after 0.5, 1,2, 4,6, 8, and 24 hours post-dose to determine steady-state levels of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione.

6.5.5 Treatment of metastatic melanoma

Starting with 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revmid)^TM) Patients with metastatic melanoma were treated at 5 mg/day for 7 days. The dose was then increased to 10 mg/day, 25 mg/day, and 50 mg/day, respectively, every 7 days for a total of four weeks of treatment. 5 of 13 metastatic melanoma patients receiving this treatment showed stable disease or partial response in the first four weeks of treatment. Tumor responses were observed in epidermal and subcutaneous lesions (5 patients), lymph nodes (two patients), and liver (one patient). The duration of response is about six months. The results prove thatThe compounds appear to be promising new anti-cancer agents and have anti-angiogenic and immunomodulatory properties.

6.5.6 Treatment of relapsed or refractory multiple myeloma

Patients with relapsed and refractory Dune-Salmon stage III multiple myeloma who are refractory to at least the first three treatments, are ineffectual or exhibit poor performance conditions, neutropenia or thrombocytopenia, are treated with a combination of melphalan (50mg intravenously) and an immunomodulatory compound of the invention (about 1 to 150mg orally per day) and dexamethasone (40 mg/day, orally on days 1-4) for up to four cycles, four to six weeks each. Maintenance therapy is the daily administration of an immunomodulatory compound of the invention and monthly administration of dexamethasone until disease progression. Treatment with the immunomodulatory compounds of the invention in combination with melphalan and dexamethasone is very effective and generally tolerated in heavily pretreated multiple myeloma patients whose prognosis is quite poor.

The above-described versions of the invention are intended to be merely exemplary, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of this invention and are encompassed by the appended claims.

Claims (32)

1. A method of 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 an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. A method of 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 an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient, radiation therapy, hormonal therapy, biological therapy or immunotherapy.

3. A method of treating, managing or preventing a disease associated with undesired angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

4. A method of treating, managing or preventing a disease associated with undesired angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient.

5. The method of claim 1, wherein the cancer is advanced malignancy, amyloidosis, neuroblastoma, brain [ crest ] meningioma, angiodermoma, multiple brain metastases, glioblastoma multiforme, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse giant B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, malignant mesothelioma, malignant pleural effusion syndrome, peritoneal cancer, papillary serum cancer, gynecological sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, langerhans 'cell histiocytosis, leiomyosarcoma, fibrosarcoma ossificane, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, waldenstrom's macroglobulinemia, congenital myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, non-hormone sensitive prostate cancer, non-chemotherapy sensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or leiomyoma.

6. The method of claim 2, wherein the cancer is advanced malignancy, locally advanced bladder cancer, metastatic transitional cell bladder cancer, recurrent brain tumor, progressive brain tumor, neuroblastoma, brain [ crest ] membrane tumor, hemangioblastoma, multiple brain metastases, glioblastoma multiforme, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, degenerative astrocytoma, degenerative oligodendroglioma, metastatic breast cancer, neuroendocrine tumors, rectal adenocarcinoma, DukesC & D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse giant B-cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, stage IIIB non-small cell lung cancer, malignant pleural effusion mesothelioma syndrome, multiple myeloma, peritoneal cancer, papillary serum carcinoma, gynecological sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, langerhans 'cell histiocytosis, leiomyosarcoma, fibrosaplastic tumors progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, waldenstrom's macroglobulinemia, negative myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or leiomyoma.

7. The method of claim 3 or 4, wherein the disease or disorder is diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic fovea, epidemic keratoconjunctivitis, atopic keratitis, hyperior limbitis, pterygium-drying keratitis, sjogrens, rosacea, phylectenulosis, syphilis, lipid degradation, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoan infections, Kaposi's sarcoma, sericultural corneal ulcers, Terrien's marginal degeneration, mariginnalkeratis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis, trauma, Wegeners sarcoma, stechouveitis, Stereo's disease, Peridiopathy, systemic lupus erythematosus, pseudosarcoma, pseudoxanthoma, systemic lupus erythematosus, paget's disease, venous occlusion, arterial occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, lyme disease, elshols disease, Bechet's disease, retinitis, choroiditis, presumed ocular histoplasmosis, Bests disease, Stargarts disease, pars plana ciliitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, sclerosing cholangitis, flushing, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, myelitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disease, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, or 5 q-syndrome.

8. The method of claim 2 or 4, wherein the second active ingredient is a hematopoietic growth factor, a cytokine, an anti-cancer drug, an antibiotic, a cox-2 inhibitor, an immunomodulator, an immunosuppressant, a corticosteroid, or a pharmacologically active mutant or derivative thereof, or a combination thereof.

9. 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, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmacologically active mutant or derivative thereof, or a combination thereof.

10. The method of any one of claims 1 to 4 wherein the immunomodulatory compound is 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione.

11. The method of claim 10, wherein the immunomodulatory compound is enantiomerically pure.

12. The method of any one of claims 1 to 4 wherein the immunomodulatory compound is 3- (4-amino-1-oxy-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione.

13. The method of claim 12, wherein the immunomodulatory compound is enantiomerically pure.

14. The method of any one of claims 1 to 4, wherein the immunomodulatory compound is of formula (I):

wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂，R²Is hydrogen or lower alkyl.

15. The method of claim 14, wherein the immunomodulatory compound is enantiomerically pure.

16. The method of any one of claims 1 to 4, wherein the immunomodulatory compound is of formula (II):

wherein

One of X and Y is C ═ O, and the other is CH₂Or C ═ O;

R¹is H, (C)₁-C₈) Alkyl radical (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³，C(S)R³，C(O)OR⁴，(C₁-C₈) alkyl-N (R)⁶)₂，(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，C(O)NHR³，C(S)NHR³，C(O)NR³R^3＇，C(S)NR³R^3＇Or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H, F, benzyl, (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl, or (C)₂-C₈) An alkynyl group;

R³and R^3＇Independently is (C)₁-C₈) Alkyl radical (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl group, (C)₀-C₈) alkyl-N (R)⁶)₂，(C₁-C₈) alkyl-OR⁵，(C₁-C₈) alkyl-C (O) OR⁵，(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵；

R⁴Is (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl (C)₁-C₄) alkyl-OR⁵Benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl, or (C)₀-C₄) Alkyl radical- (C)₂-C₅) A heteroaryl group;

R⁵is (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, or (C)₂-C₅) A heteroaryl group;

R⁶each occurrence is independently H, (C)₁-C₈) Alkyl radical (C)₂-C₈) Alkenyl (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₂-C₅) Heteroaryl, or (C)₀-C₈) alkyl-C (O) O-R⁵Or R⁶The groups are linked to form a heterocycloalkyl group;

n is 0 or 1; and is

^*Represents a chiral carbon center.

17. The method of claim 16, wherein the immunomodulatory compound is enantiomerically pure.

18. A method of treating, managing or preventing a specific cancer, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during or after surgery with the aim of alleviating, reducing or avoiding symptoms of the specific cancer in the patient.

19. A method of reducing or avoiding an adverse effect associated with administration of a second active ingredient in a patient suffering from a particular cancer, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

20. A method of reducing or avoiding adverse effects associated with radiation therapy, hormonal therapy, biological therapy or immunotherapy in a patient suffering from a particular cancer, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

21. A method of treating, preventing or managing a specific cancer that is refractory to conventional therapy, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

22. A method of treating, preventing or managing a specific cancer which is refractory to conventional therapy, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient.

23. A method of treating, preventing or managing a specific cancer, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow in the patient.

24. The method of claim 23, wherein the immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered before, during, or after transplanting umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow in the patient.

25. The method of any one of claims 1 to 4 wherein the selective cytokine inhibitory drug is administered in an amount of about 0.1 to about 150mg per day.

26. The method of claim 2, wherein the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered before, during, or after the administration of the second active ingredient, radiation therapy, hormonal therapy, biological therapy, or immunotherapy.

27. A pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active ingredient.

28. The pharmaceutical composition of claim 28, wherein the second active ingredient is a hematopoietic growth factor, a cytokine, an anticancer drug, an antibiotic, a cox-2 inhibitor, an immunomodulator, an immunosuppressant, a corticosteroid, or a pharmacologically active mutant or derivative thereof.

29. The pharmaceutical composition of claim 28, wherein the second active ingredient is oblimersen, melphalan, G-CSF, GM-CSF, EPO, a COX-2 inhibitor, topotecan, pentoxifylline, ciprofloxacin, taxotere, irinotecan, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmacologically active mutant or derivative thereof.

30. A kit, comprising:

a pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

pharmaceutical compositions comprising hematopoietic growth factors, cytokines, anti-cancer agents, antibiotics, cox-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids, or pharmacologically active mutants or derivatives thereof, or combinations thereof.

31. A kit, comprising:

a pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

a pharmaceutical composition comprising oblimersen, melphalan, G-CSF, GM-CSF, EPO, a COX-2 inhibitor, topotecan, pentoxifylline, taxotere, irinotecan, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmacologically active mutant or derivative thereof, or a combination thereof.

32. A kit, comprising:

a pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow.