Mutant selectivity and combinations of a phosphoinositide 3-kinase inhibitor compound and chemotherapeutic agents for the treatment of cancer

Abstract

Methods and compositions are provided for treating hyperproliferative disorders in patients with a PI3K inhibitor, GDC-0032 as a single agent or in combination with chemotherapeutic agents.

1 - 19 . (canceled) 
     
     
         20 . 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 GDC-0032 having the structure: 
       
         
           
           
               
               
           
         
         and a therapeutically effective amount of a chemotherapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole. 
       
     
     
         21 . The method of  claim 20  wherein the therapeutic combination further includes carboplatin. 
     
     
         22 . The method of  claim 20  wherein the therapeutic combination further includes an anti-VEGF antibody. 
     
     
         23 . The method of  claim 20  wherein the pharmaceutically acceptable salt of GDC-0032 is selected from a salt formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic 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. 
     
     
         24 . The method of  claim 20  wherein the therapeutically effective amount of GDC-0032, and the therapeutically effective amount of the chemotherapeutic agent are administered as a combined formulation. 
     
     
         25 . The method of  claim 20  wherein the therapeutically effective amount of GDC-0032, and the therapeutically effective amount of the chemotherapeutic agent are administered to a mammal by alternation. 
     
     
         26 . The method of  claim 25  wherein the mammal is administered the chemotherapeutic agent and subsequently administered GDC-0032. 
     
     
         27 . The method of  claim 25  wherein the therapeutic combination is administered by a dosing regimen where the therapeutically effective amount of GDC-0032 is administered in a range from twice daily to once every three weeks, and the therapeutically effective amount of the chemotherapeutic agent is administered in a range from twice daily to once every three weeks. 
     
     
         28 . The method of  claim 27  wherein the dosing regimen is repeated one or more times. 
     
     
         29 . The method of  claim 20  wherein administration of the therapeutic combination results in a synergistic effect. 
     
     
         30 . The method of  claim 29  wherein administration of the therapeutic combination results in a Combination Index value of less than about 0.7. 
     
     
         31 . The method of  claim 20  wherein the hyperproliferative disorder is cancer selected from breast, cervical, colon, endometrial, gastric, glioma, lung, melanoma, ovarian, pancreatic, and prostate. 
     
     
         32 . The method of  claim 31  wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R. 
     
     
         33 . The method of  claim 31  wherein the cancer expresses a PTEN mutant. 
     
     
         34 . The method of  claim 31  wherein the cancer is HER2 positive. 
     
     
         35 . The method of  claim 20  wherein the mammal is a breast cancer patient wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative. 
     
     
         36 . The method of  claim 35  wherein the breast cancer subtype is Basal or Luminal. 
     
     
         37 . The method of  claim 34  wherein the patient is administered GDC-0032 and eribulin. 
     
     
         38 . The method of  claim 20  wherein GDC-0032 and the chemotherapeutic agent are each administered in an amount from about 1 mg to about 1000 mg per unit dosage form. 
     
     
         39 . The method of  claim 20  wherein GDC-0032 and the chemotherapeutic agent are administered in a ratio of about 1:50 to about 50:1 by weight.