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.

We claim: 
     
         1 . A method of treating a hyperproliferative disorder in a patient comprising administering a therapeutically effective amount of GDC-0032 as a single agent or a combination of GDC-0032 and a chemotherapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole to the patient, wherein a biological sample obtained from the patient, prior to administration to the patient of GDC-0032 as a single agent or the combination of GDC-0032 and the chemotherapeutic agent, has been tested for PIK3CA or PTEN mutation status, and wherein PIK3CA or PTEN mutation status is indicative of therapeutic responsiveness by the patient to GDC-0032 as a single agent or the combination of GDC-0032 and the chemotherapeutic agent. 
     
     
         2 . The method of  claim 1  wherein the patient is administered a therapeutically effective amount of GDC-0032 as a single agent. 
     
     
         3 . The method of  claim 1  wherein the patient is administered a therapeutically effective amount of the combination of GDC-0032 and a chemotherapeutic agent. 
     
     
         4 . The method of  claim 1  wherein the hyperproliferative disorder is metastatic breast cancer, hormone receptor positive (HR+) breast cancer, HER2 expressing breast cancer, or estrogen receptor positive (ER+) breast cancer. 
     
     
         5 . The method of  claim 4  wherein the patient has been previously treated with tamoxifen, fulvestrant, or letrozole. 
     
     
         6 . The method of  claim 1  wherein the PIK3CA or PTEN mutation is the H1047R, H1047L, E542K, E545K or Q546R mutation of PIK3CA. 
     
     
         7 . The method of  claim 1  wherein a biological sample has been tested by measuring functional PI3K protein level after administration of GDC-0032 or the combination of GDC-0032 and the chemotherapeutic agent, wherein a change in the level of functional PI3K protein indicates that the patient will be resistant or responsive to GDC-0032 or the combination of GDC-0032 and a chemotherapeutic agent. 
     
     
         8 . A method of monitoring whether a patient with a hyperproliferative disorder will respond to treatment with GDC-0032 as a single agent or a combination of GDC-0032 and a chemotherapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole, the method comprising:
 (a) detecting a PIK3CA or PTEN mutation in a biological sample obtained from the patient following administration of at least one dose of GDC-0032 or the combination of GDC-0032 and the chemotherapeutic agent; and   (b) comparing PIK3CA or PTEN mutation status in a biological sample obtained from the patient prior to administration of GDC-0032 or the combination of GDC-0032 and the chemotherapeutic agent to the patient,   wherein a change or modulation of PIK3CA or PTEN mutation status in the sample obtained following administration of GDC-0032 or the combination of GDC-0032 and the chemotherapeutic agent identifies a patient who will respond to treatment with GDC-0032 or the combination of GDC-0032 and the chemotherapeutic agent.   
     
     
         9 . The method of  claim 8  wherein the hyperproliferative disorder is metastatic breast cancer, hormone receptor positive (HR+) breast cancer, HER2 expressing breast cancer, or estrogen receptor positive (ER+) breast cancer. 
     
     
         10 . The method of  claim 8  wherein the patient has been previously treated with tamoxifen, fulvestrant, or letrozole. 
     
     
         11 . The method of  claim 8  wherein the PIK3CA or PTEN mutation is the H1047R, H1047L, E542K, E545K or Q546R mutation of PIK3CA. 
     
     
         12 . A method of optimizing therapeutic efficacy of GDC-0032 single agent or the combination of GDC-0032 and a chemotherapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole in the treatment of a hyperproliferative disorder, the method comprising:
 (a) detecting a PIK3CA or PTEN mutation in a biological sample obtained from a patient following administration of at least one dose of GDC-0032 single agent or the combination of GDC-0032 and the chemotherapeutic agent; and   (b) comparing the PIK3CA or PTEN status in a biological sample obtained from the patient prior to administration of GDC-0032 single agent or the combination of GDC-0032 and the chemotherapeutic agent to the patient,   wherein a change or modulation of PIK3CA or PTEN in the sample obtained following administration of GDC-0032 single agent or the combination of GDC-0032 and the chemotherapeutic agent identifies a patient who has an increased likelihood of benefit from treatment with GDC-0032 single agent or the combination of GDC-0032 and the chemotherapeutic agent.   
     
     
         13 . The method of  claim 12  wherein the hyperproliferative disorder is metastatic breast cancer, hormone receptor positive (HR+) breast cancer, HER2 expressing breast cancer, or estrogen receptor positive (ER+) breast cancer. 
     
     
         14 . The method of  claim 13  wherein the patient has been previously treated with tamoxifen, fulvestrant, or letrozole. 
     
     
         15 . The method of  claim 12  wherein the PIK3CA or PTEN mutation is the H1047R, H1047L, E542K, E545K or Q546R mutation of PIK3CA. 
     
     
         16 . A method of treating a hyperproliferative disorder in a patient, comprising administering a therapeutically effective amount of GDC-0032 single agent or the combination of GDC-0032 and a chemotherapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole to the patient, wherein treatment is based upon a sample from the patient having a PIK3CA or PTEN mutation. 
     
     
         17 . The method of  claim 16  wherein the PIK3CA or PTEN mutation is the H1047R, H1047L, E542K, E545K or Q546R mutation of PIK3CA. 
     
     
         18 . The method of  claim 16  wherein the hyperproliferative disorder is metastatic breast cancer, hormone receptor positive (HR+) breast cancer, HER2 expressing breast cancer, or estrogen receptor positive (ER+) breast cancer. 
     
     
         19 . The method of  claim 18  wherein the patient has been previously treated with tamoxifen, fulvestrant, or letrozole.