Compositions including triciribine and epidermal growth factor receptor inhibitor compounds or salts thereof and methods of use thereof

Abstract

This application relates to combination therapies including triciribine compounds and epidermal growth factor receptor inhibitor compounds, particularly erlotinib-like compounds and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.

1 . A composition comprising:
 (i) a compound of the formula I-IV:   
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; 
         (ii) epidermal growth factor receptor inhibitor or a salt thereof; 
       
       and
 (iii) a pharmaceutically acceptable carrier. 
 
     
     
         2 . The composition of  claim 1 , wherein the compound of formula I-IV is triciribine, triciribine phosphate, triciribine phosphate monohydrate, or combination thereof. 
     
     
         3 . The composition of  claim 1 , wherein the epidermal growth factor receptor inhibitor gefitinib. 
     
     
         4 . The composition of  claim 1 , wherein the epidermal growth factor receptor inhibitor erlotinib. 
     
     
         5 . The composition of  claim 1 , wherein the compound of formula I is present in a dose amount of at least 20 mg/m 2 . 
     
     
         6 . The composition of  claim 1 , wherein the compound of formula I is present in an amount of at least 10 mg/m 2 . 
     
     
         7 . The composition of  claim 1 , suitable for parenteral administration. 
     
     
         8 . The composition of  claim 7 , wherein the parenteral administration is intravenous administration. 
     
     
         9 . The composition of  claim 1 , suitable for oral administration. 
     
     
         10 . The composition of  claim 1 , suitable for topical administration. 
     
     
         11 . The composition of  claim 1 , wherein the trastuzumab or a salt thereof is present in an amount from about 1 mg to about 1000 mg. 
     
     
         12 . The composition of  claim 1 , wherein the trastuzumab or a salt thereof is present in an amount from about 100 mg to about 500 mg. 
     
     
         13 . The composition of  claim 1 , wherein the trastuzumab or a salt thereof is present in an amount from about 200 mg to about 450 mg. 
     
     
         14 . The composition of  claim 1 , wherein the trastuzumab or a salt thereof is present in an amount of about 440 mg. 
     
     
         15 . A method of treating a tumor or cancer in a mammal comprising administering to the mammal an effective amount of a composition comprising:
 (i) a compound of formula I-IV:   
       
         
           
           
               
               
           
         
         wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
         wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
         R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; and 
         (ii) epidermal growth factor receptor inhibitor or a salt thereof. 
       
     
     
         16 . The method of  claim 15 , wherein the compound of formula I-IV and the epidermal growth factor receptor inhibitor or a salt thereof are administered simultaneously. 
     
     
         17 . The method of  claim 15 , wherein the compound of formula I-IV is administered followed by the administration of trastuzumab or a salt thereof. 
     
     
         18 . The method of  claim 15 , wherein the epidermal growth factor receptor inhibitor or a salt thereof is administered followed by the administration of a compound of formula I-IV. 
     
     
         19 . The method of  claim 15 , wherein the compound of formula I-IV is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
     
     
         20 . The method of  claim 15 , wherein the epidermal growth factor receptor inhibitor or a salt thereof is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
     
     
         21 . The method of  claim 20 , wherein the dosing schedule is repeated at least twice. 
     
     
         22 . The method of  claim 20 , wherein the dosing schedule is repeated at least 4 times. 
     
     
         23 . The method of  claim 15 , wherein the tumor treated is breast, pancreatic, ovarian and colorectal tumors. 
     
     
         24 . The method of  claim 15 , wherein at least 10 mg/m 2  of the compound of formula I-IV is administered. 
     
     
         25 . The method of  claim 15 , wherein at least 100 mg of epidermal growth factor receptor inhibitor or a salt thereof is administered. 
     
     
         26 . The method of  claim 15 , wherein at least 200 mg of epidermal growth factor receptor inhibitor or a salt thereof is administered. 
     
     
         27 . The method of  claim 15 , wherein at least 400 mg of epidermal growth factor receptor inhibitor or a salt thereof is administered.