Compositions including triciribine and trastuzumab and methods of use thereof

Abstract

This application relates to combination therapies including triciribine and related compounds and trastuzumab or a salt thereof 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:   
       
         
           
           
               
               
           
         
         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) trastuzumab or a salt thereof; 
       
       and
 (iii) a pharmaceutically acceptable earner. 
 
     
     
         2 . The composition of  claim 1 , wherein the compound of formula I is triciribine. 
     
     
         3 . The composition of  claim 1 , wherein the compound of formula I is triciribine phosphate. 
     
     
         4 . The composition of  claim 1 , wherein the compound of formula I is triciribine phosphonate. 
     
     
         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 1 , 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:   
       
         
           
           
               
               
           
         
         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) trastuzumab or a salt thereof. 
       
     
     
         16 . The method of  claim 15 , wherein a compound of formula I and trastuzumab or a salt thereof are administered simultaneously. 
     
     
         17 . The method of  claim 15 , wherein a compound of formula I is administered followed by the administration of trastuzumab or a salt thereof. 
     
     
         18 . The method of  claim 15 , wherein the trastuzumab or a salt thereof is administered followed by the administration of a compound of formula I. 
     
     
         19 . The method of  claim 15 , wherein the compound of formula I 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 trastuzumab 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 is administered. 
     
     
         25 . The method of  claim 15 , wherein at least 100 mg of trastuzumab or a salt thereof is administered. 
     
     
         26 . The method of  claim 15 , wherein at least 200 mg of trastuzumab or a salt thereof is administered. 
     
     
         27 . The method of  claim 15 , wherein at least 400 mg of trastuzumab or a salt thereof is administered.