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 1 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 3 dose levels of crizotinib (250mg daily, 200mg BID, 250mg BID) with standard dose enzalutamide (160mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetic profile were secondary endpoints.24 patients were enrolled in the dose-escalation (n=16) and dose-expansion (n=8) phases. Two DLTs occurred in dose-escalation (grade 3 ALT elevation). The maximum tolerated dose (MTD) of crizotinib was 250mg BID. 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 (n=2), fatigue (n=1), hypertension (n=1), pulmonary embolism (n=1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95%CI: 2.8-21.2). Pharmacokinetic analysis at the MTD (n=12) revealed a mean Cmaxss of 104±45 ng/mL and AUCtss of 1,000±476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss: 315 ng/mL, AUCtss: 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 pharmacokinetic interactions when evaluating novel combination strategies in CRPC.

View details for DOI 10.1158/1078-0432.CCR-20-2306

View details for PubMedID 32943461