Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

Abstract

Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. Twenty-four patients were enrolled in the dose-escalation (<i>n</i> = 16) and dose-expansion (<i>n</i> = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (<i>n</i> = 2), fatigue (<i>n</i> = 1), hypertension (<i>n</i> = 1), pulmonary embolism (<i>n</i> = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (<i>n</i> = 12) revealed a mean <i>C</i> _max ^ss of 104 ± 45 ng/mL and AUC_τ ^ss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (<i>C</i> _max ^ss, 315 ng/mL and AUC_τ ^ss, 3,817 ng•h/mL). Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.