Abstract B29: A multicenter, open-label phase 1/2 study of oral CFG920, in combination with prednisone in adult patients with metastatic castration-resistant prostate cancer

Introduction CYP17 is a crucial enzyme in androgen synthesis. CYP17 inhibition results in virtually undetectable serum and intratumoral androgens and antitumor activity in metastatic castration-resistant prostate cancer (mCRPC). Abiraterone (ABI) acetate, a CYP17 inhibitor, is approved for mCRPC treatment. CFG920, a dual CYP17 and CYP11B2 inhibitor showed favorable efficacy and safety profile in repeat-dose toxicity studies in vivo. Here, we report data from the phase 1 part of the first-in-human study (CFG920×2101) of CFG920 and prednisone combination in patients with mCRPC. Methods Patients received escalating doses of CFG920 (50-200 mg twice daily [bid]) and prednisone (5 mg bid) in 28-day cycles. The primary objective was to determine maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Dose escalation decisions were made based on the synthesis of all relevant data, guided by an adaptive Bayesian logistic regression model (BLRM) with overdose control (EWOC) principle, based on the dose limiting toxicities (DLTs) data in cycle 1. Results Overall, 31 patients (median age 69 years) were enrolled and treated (median duration 18.6 weeks [range 1-96]). As of the data cut-off date, treatment was ongoing in 1 patient. DLTs (grade 3 hyponatremia, hyperkalemia, and hyperglycemia) occurred in 3 patients (at 100 mg bid, 150 mg bid and 200 mg bid) within the first 28 days of treatment; 2 patients permanently discontinued treatment, 1 in cycle 1 and 1 at the start of cycle 8. Serious adverse events (AEs), regardless of causality, occurred in 12 patients (38.7%); asthenia, confusional state, dehydration, and urosepsis occurred in 2 patients each. The common drug-related AEs (any grade) included fatigue (19.4%), nausea (19.1%), and thrombocytopenia (19.1%). Overall, 2 patients died during treatment; 1 due to cardiac arrest (100 mg bid; study drug unrelated), and 1 due to mCRPC (50 mg bid). Due to AEs, 7 patients discontinued treatment, and 6 patients had dose reductions. At ≥12 weeks after the first CFG920 dose, 8 patients (25.8%) had ≥50% decrease in prostate specific antigen (PSA). Serum testosterone and dehydroepiandrosterone-sulfate (DHEAS) levels were reduced markedly beyond castration levels at all doses, including in patients pretreated with abiraterone and ketoconazole. Reduction in serum aldosterone was also marked but transient. No clear dose-dependency was seen in PSA response or testosterone reduction. CFG920 was rapidly absorbed with Tmax of 0.5 to 2 hours after single or multiple doses. AUC increased dose-proportionally after a single dose and slightly more than dose-proportionally after repeat dose. Steady state was reached at cycle 1 day 15. The estimated half-life was 3 to 6 hours. As per the BLRM with EWOC principle, CFG920 300 mg bid dose had the highest probability to be in the target toxicity interval and satisfied the EWOC principle. Based on the available clinical safety, efficacy, pharmacokinetic, and pharmacodynamic data, 100 mg bid dose was declared as the RP2D of CFG920, without MTD declaration. Conclusion The safety profile was acceptable, and with the exception of unexplained thrombocytopenia, was in line with preclinical studies. The study was voluntarily terminated due to an already competitive prostate cancer landscape, and the phase 2 did not start. Citation Format: Sebastien J. Hotte, Joan Carles, John Sarantopoulos, Charles J. Ryan, Joshua M. Lang, Bruce Montgomery, Koichi Fukino, Gwendolyn Gobbo, Xiaoming Cui, Prakash Mistry, Chun Pan, Jean-Pascal Machiels. A multicenter, open-label phase 1/2 study of oral CFG920, in combination with prednisone in adult patients with metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B29.