Phase I trial of TAK‐385 in hormone treatment‐naïve Japanese patients with nonmetastatic prostate cancer

Abstract

This open‐label, phase I dose‐finding study evaluated the gonadotropin‐releasing hormone antagonist, TAK‐385, in Japanese patients with nonmetastatic prostate cancer. In a two‐part design, patients received daily oral TAK‐385 at doses of 320 (loading, day 1)/80 (maintenance, day 2 and thereafter), 320/120, 320/160, or 360/120 mg for 28 days in a dose‐escalation phase (part A, n = 13), and at 320/80 or 320/120 mg for up to 96 weeks in a randomized expansion phase (part B, n = 30). Primary endpoint in both parts was safety, including dose‐limiting toxicity in part A. Secondary endpoints included pharmacokinetics, pharmacodynamics, and prostate‐specific antigen concentration. Ten (77%) patients in part A and all patients in part B experienced an adverse event; hot flush (part A, n = 4; part B, n = 15), viral upper respiratory tract infection (part A, n = 1; part B, n = 10), and diarrhea (part B, n = 8) were most frequent. No dose‐limiting toxicities were observed (part A). In 12 evaluable patients (part A), TAK‐385 was rapidly absorbed after a single loading dose; on day 28 (maintenance dose), median steady‐state T _max was ~1‐2 hours and mean t _1/2z was 67‐79 hours. All doses rapidly reduced testosterone concentrations to castration levels within 1 week. Durable reductions in prostate‐specific antigen of >90% from baseline were observed through 96 weeks. TAK‐385 appeared tolerable and resulted in sustained reductions in testosterone to castration levels at all doses. The lowest loading/maintenance dose required for a clinical effect was 320/80 mg.

http://ClinicalTrials.gov: NCT02141659.

Abstract

TAK‐385 is an orally active gonadotropin‐releasing hormone (GnRH) antagonist with rapid testosterone‐lowering effects in clinical studies, achieving effective and sustained castration in patients with prostate cancer without the initial testosterone surge observed with GnRH agonists. To date, clinical trials of TAK‐385 for the treatment of prostate cancer have been conducted in a predominantly Western patient population. Building on these data, the current study establishes an appropriate dose range for TAK‐385 in Japanese patients with non‐metastatic prostate cancer, and evaluates safety, pharmacokinetics, pharmacodynamics and preliminary efficacy in this population.