Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use

Abstract

Combinations of PI3K inhibitor compounds having Formulas I and II and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hyperproliferative disorders such as cancer. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

1 - 10 . (canceled) 
     
     
         11 . A method for the treatment of a hyperproliferative disorder comprising administering a therapeutic combination as a combined formulation or by alternation to a mammal, wherein the therapeutic combination comprises a therapeutically effective amount of a compound having Formula Ia and a therapeutically effective amount of XL-518: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of Ia and/or XL-518. 
     
     
         12 . The method of  claim 11  wherein the therapeutically effective amount of a compound having Formula Ia, and the therapeutically effective amount of XL-518 are administered as a combined formulation. 
     
     
         13 . The method of  claim 11  wherein the therapeutically effective amount of a compound having Formula Ia, and the therapeutically effective amount of XL-518 are administered to a mammal by alternation. 
     
     
         14 . The method of  claim 13  wherein the mammal is administered with XL-518 and subsequently administered with the Formula Ia compound. 
     
     
         15 . The method of  claim 13  wherein the therapeutic combination is administered by a dosing regimen where the therapeutically effective amount of a compound having Formula Ia is administered in a range from twice daily to once every three weeks, and the therapeutically effective amount of XL-518 is administered in a range from twice daily to once every three weeks. 
     
     
         16 . The method of  claim 15  wherein the dosing regimen is repeated one or more times. 
     
     
         17 . The method of  claim 11 , wherein said patient is administered the compounds for 21 consecutive days. 
     
     
         18 . The method of  claim 11  wherein administration of the therapeutic combination results in a synergistic effect. 
     
     
         19 . The method of  claim 11  wherein the hyperproliferative disorder is cancer selected from breast, cervical, colon, endometrial, glioma, lung, melanoma, ovarian, pancreatic, and prostate. 
     
     
         20 . The method of  claim 19  wherein the cancer expresses a K-ras mutant. 
     
     
         21 . The method of  claim 19 , wherein the cancer expresses a B-raf mutant. 
     
     
         22 . The method of  claim 19 , wherein the cancer expresses a PI3K mutant. 
     
     
         23 . The method of  claim 19 , wherein the cancer exhibits a loss of the tumor suppressor phosphatase and tensin homolog (PTEN). 
     
     
         24 . The method of  claim 11 , wherein the hyperproliferative disorder is modulated by PI3 kinases. 
     
     
         25 . The method of  claim 11 , wherein the hyperproliferative disorder is characterized by activation of the PI3 kinase pathway. 
     
     
         26 . The method of  claim 11  wherein the mammal is a breast cancer patient wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative. 
     
     
         27 . The method of  claim 11  wherein the Formula Ia compound and XL-518 are each administered in an amount from about 1 mg to about 1000 mg per unit dosage form. 
     
     
         28 . The method of  claim 11 , wherein the Formula Ia compound and XL-518 are each administered in an amount from about 10 mg to about 100 mg per unit dosage form. 
     
     
         29 . The method of  claim 11 , wherein the Formula Ia compound is administered in an amount from about 100 mg to about 300 mg per unit dosage form. 
     
     
         30 . The method of  claim 11  wherein the Formula Ia compound and XL-518 are administered in a ratio of about 1:50 to about 50:1 by weight. 
     
     
         31 . The method of  claim 11  wherein the Formula Ia compound and XL-518 are administered in a ratio of about 1:10 to about 10:1 by weight. 
     
     
         32 . A pharmaceutical formulation comprising a compound of Formula Ia and XL-518, or pharmaceutically acceptable salts thereof; wherein Formula Ia and XL-518 have the structures: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The pharmaceutical formulation of  claim 32  that comprises a pharmaceutically acceptable salt of the Formula Ia compound selected from a salt formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid. 
     
     
         34 . The pharmaceutical formulation of  claim 32  that comprises a pharmaceutically acceptable salt of XL-518 selected from a salt formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid. 
     
     
         35 . The pharmaceutical formulation of  claim 34  wherein the pharmaceutically acceptable salt of XL-518 is a salt formed with fumaric acid. 
     
     
         36 . The pharmaceutical formulation of  claim 32  comprising a pharmaceutically, acceptable glidant selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof. 
     
     
         37 . The pharmaceutical formulation of  claim 32  wherein the Formula Ia compound and XL-518 each comprise an amount from about 1 mg to about 1000 mg per unit dosage form. 
     
     
         38 . The pharmaceutical formulation of  claim 32  for use in a method of treatment of cancer. 
     
     
         39 . An article of manufacture for treating a hyperproliferative disorder comprising:
 a) a therapeutic combination of  claim 11 ; and   b) instructions for use.   
     
     
         40 . An article of manufacture for treating a hyperproliferative disorder comprising:
 a) a compound of Formula Ia or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
         b) XL-518 or a pharmaceutically acceptable salt thereof: 
       
       
         
           
           
               
               
           
         
       
       and
 c) instructions for use. 
 
     
     
         41 . The article of manufacture of  claim 41 , further comprising:
 a) a first container with the compound of Formula Ia or pharmaceutically acceptable salt thereof; and   b) a second container with the XL-518 or pharmaceutically acceptable salt thereof.