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Phase I trial of TAK-385 in hormone treatment-naive 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 Tmax was ~1-2 hours and mean t1/2z 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. ClinicalTrials.gov: NCT02141659.

SUBMITTER: Suzuki H

PROVIDER: S-EPMC6792482 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Suzuki Hiroyoshi H Uemura Hiroji H Mizokami Atsushi A Hayashi Narihiko N Miyoshi Yasuhide Y Nagamori Satoshi S Enomoto Yutaka Y Akaza Hideyuki H Asato Takayuki T Kitagawa Tadayuki T Suzuki Kazuhiro K

Cancer medicine 20190819 13

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 endpoin ...[more]

PMID: 31429205

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Project description:ObjectivesTo evaluate the prognosis of newly diagnosed patients with metastatic hormone-naïve prostate cancer (mHNPC) and develop a novel prognostic model based on ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) risk classifications.Patients and methodsWe retrospectively analyzed the data of 578 newly diagnosed mHNPC patients initially treated with androgen deprivation therapy. We evaluated three clinical factors, namely, CHAARTED risk classifications (high-volume disease [HVD] vs low-volume disease [LVD]), Gleason scores (GS, 9-10 vs ≤8), and hemoglobin (Hb, ≤13.0 g/dL vs >13.0 g/dL), for their prognostic potential in predicting time to castration-resistant prostate cancer (TTC) and overall survival (OS) of mHNPC patients by multivariate analysis. Moreover, we developed a novel prognostic model that consisted of significant prognostic factors.ResultsOf the entire cohort, the median TTC and OS values were 18.3 and 67.5 months, respectively. HVD, GS 9-10, and Hb ≤13.0 g/dL were independent poor prognostic factors for both TTC and OS. We developed a novel prognostic model which could stratify mHNPC patients into four risk groups according to the numbers of poor prognostic factors: group 1, LVD with low-risk (LVD patients without GS 9-10 and Hb ≤13.0 g/dL); group 2, LVD with high-risk (LVD patients with GS 9-10, Hb ≤13.0 g/dL, or both); group 3, HVD with low-risk (HVD patients without GS 9-10 with or without Hb ≤13.0 g/dL); and group 4, HVD with high-risk (HVD patients with GS 9-10 with or without Hb ≤13.0 g/dL). The median TTC and OS of groups 1, 2, 3, and 4 were 124.8, 36.4, 17.9, and 11.2 months, and 117.2, 94.2, 67.9, and 46.2 months, respectively. A significant difference in TCC and OS was found between all groups.ConclusionWe developed a prognostic model for mHNPC patients that consisted of CHAARTED risk classifications, GS, and Hb. Our prognostic model could significantly stratify the prognosis of patients with LVD and HVD into two groups each. This model might be a good reference for shared decision making between patients and physicians on the initial treatment for mHNPC.

Dataset Information

Phase I trial of TAK-385 in hormone treatment-naive Japanese patients with nonmetastatic prostate cancer.

Publications

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

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