A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration-resistant prostate cancer

作者：Choudhury Atish D; Gray Kathryn P; Supko Jeffrey G; Harshman Lauren C; Taplin Mary Ellen; Pace Amanda F; Farina Matthew; Zukotynski Katherine A; Bernard Brandon; Kantoff Philip W; Pomerantz Mark; Sweeney Christopher^*

来源：Prostate, 2018, 78(14): 1053-1062.

DOI：10.1002/pros.23662

• abiraterone
• cabozantinib
• castration-resistant
• prostate cancer
• XL184

BackgroundCabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone+cabozantinib in mCRPC.
MethodsPatients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000mg daily with prednisone 5mg BID in combination with cabozantinib at 20, 40, or 60mg daily in a dose-escalation 3+3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B).
ResultsThere were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40mg doses. Of the 12 patients treated at the 40mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20mg cohort and 22.01 months (95% CI:15.44-NE) in the 40mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20mg cohort and 39.08 months (95% CI:17.38-NE) in the 40mg cohort.
ConclusionsBased on tolerability and preliminary efficacy, 40mg cabozantinib plus 1000mg abiraterone daily is the RP2D.

• 出版日期2018-10-1