Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.
| Autor: | Tripathi A; University of Oklahoma Health Science Center, Oklahoma City, Oklahoma., Supko JG; Massachusetts General Hospital Cancer Center, Boston, Massachusetts., Gray KP; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Frontier Science Foundation, Boston, Massachusetts., Melnick ZJ; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Regan MM; Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts., Taplin ME; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Choudhury AD; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Pomerantz MM; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Bellmunt J; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Yu C; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Sun Z; Beckman Research Institute, City of Hope, California.; Stanford University, Stanford, California., Srinivas S; Stanford University, Stanford, California., Kantoff PW; Memorial Sloan Kettering Cancer Center, New York, New York., Sweeney CJ; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Harshman LC; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. lcharshman@gmail.com. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Dec 01; Vol. 26 (23), pp. 6122-6131. Date of Electronic Publication: 2020 Sep 17. |
| DOI: | 10.1158/1078-0432.CCR-20-2306 |
| Abstrakt: | Purpose: 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. Patients and Methods: 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. Results: Twenty-four patients were enrolled in the dose-escalation ( n = 16) and dose-expansion ( n = 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 ( 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% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD ( n = 12) revealed a mean C Conclusions: 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. (©2020 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|