Method for treatment and management of thyroid cancer using immunomodulatory compounds

Abstract

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

1 - 21 . (canceled) 
     
     
         22 . A method of treating thyroid cancer which comprises administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione having the formula:   
       
         
           
           
               
               
           
         
         3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione having the formula: 
       
       
         
           
           
               
               
           
         
         a compound of formula (I): 
       
       
         
           
           
               
               
           
         
       
       wherein one of X and Y is C═O, the other of X and Y is C═O or CH 2 , and R 2  is hydrogen or lower alkyl; and
 a compound of formula (II): 
 
       
         
           
           
               
               
           
         
       
       wherein
 one of X and Y is C═O and the other is CH 2  or C═O; 
 R 1  is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3 , C(S)NR 3 R 3′  or (C 1 -C 8 )alkyl-O(CO)R 5 ; 
 R 2  is H, F, benzyl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; 
 R 3  and R 3′  are independently (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; 
 R 4  is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-C 2 -C 5 )heteroaryl; 
 R 5  is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl; 
 each occurrence of R 6  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O—R 5  or the R 6  groups join to form a heterocycloalkyl group; 
 n is 0 or 1; and * represents a chiral-carbon center; 
 
       or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
         23 . The method of  claim 22 , wherein the compound is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 
     
     
         24 . The method of  claim 22 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         25 . The method of  claim 22 , wherein the compound is a pharmaceutically acceptable solvate. 
     
     
         26 . The method of  claim 22 , wherein the compound is a pharmaceutically acceptable stereoisomer. 
     
     
         27 . The method of  claim 26 , wherein the stereoisomer is an enantiomerically pure R isomer. 
     
     
         28 . The method of  claim 26 , wherein the stereoisomer is an enantiomerically pure S isomer. 
     
     
         29 . The method of  claim 22 , which further comprises administering a therapeutically effective amount of a second active agent. 
     
     
         30 . The method of  claim 29 , wherein the second active agent is hematopoietic growth factor, a cytokine, or an anti-cancer agent. 
     
     
         31 . The method of  claim 30 , wherein the second active agent is granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), interleukin (IL), interferon (IFN), or a pharmacologically active mutant or derivative thereof. 
     
     
         32 . The method of  claim 31 , wherein the second active agent is granulocyte-macrophage colony-stimulating factor (GM-CSF). 
     
     
         33 . The method of  claim 31 , wherein the second active agent is oblimersen, melphalan, topotecan, pentoxifylline, taxotere, irinotecan, ciprofloxacin, dexamethasone, doxorubicin, vincristine, dacarbazine, Ara-C, vinorelbine, prednisone, cyclophosphamide, bortezomib, arsenic trioxide or a combination thereof. 
     
     
         34 . The method of  claim 22 , which further comprises administering radiation therapy, hormonal therapy, biological therapy or immunotherapy. 
     
     
         35 . The method of  claim 22 , wherein the compound is administered orally. 
     
     
         36 . The method of  claim 35 , wherein the compound is administered in the form of a capsule or tablet. 
     
     
         37 . The method of  claim 22 , wherein the compound is administered in an amount of from about 0.1 to about 150 mg per day. 
     
     
         38 . The method of  claim 37 , wherein the compound is administered in an amount of from about 0.1 to about 50 mg per day. 
     
     
         39 . The method of  claim 38 , wherein the compound is administered in an amount of from about 5 to about 10 mg per day. 
     
     
         40 . The method of  claim 22 , wherein the compound is administered cyclically. 
     
     
         41 . The method of  claim 40 , wherein one cycle comprises four to six weeks. 
     
     
         42 . The method of  claim 40 , wherein one cycle comprises the administration of the compound for 21 days followed by seven days rest. 
     
     
         43 . The method of  claim 40 , wherein the compound is administered for four to twenty-four weeks with one to six weeks of rest. 
     
     
         44 . The method of  claim 40 , wherein the compound is administered in an amount of from about 0.1 to about 150 mg per day for 21 days every 28 days for sixteen to twenty-four weeks. 
     
     
         45 . The method of  claim 40 , wherein the compound is administered in an amount of from about 0.1 to about 50 mg per day for 21 days followed by seven days rest in a 28 day cycle. 
     
     
         46 . The method of  claim 40 , wherein the compound is administered in an amount of from about 5 to about 10 mg per day for 21 days followed by seven days rest in a 28 day cycle. 
     
     
         47 . The method of  claim 22 , wherein the cancer is papillary thyroid carcinoma, follicular thyroid carcinoma, or medullary thyroid carcinoma.