A Phase 1, Open-Label, Non-Randomized, Safety, Tolerability and Pharmacokinetic Study of TAS3681 in Patients With Metastatic Castration Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 130
- 试验地点
- 33
- 主要终点
- Escalation Phase: Number of patients with treatment-emergent adverse events and significant ECG abnormalities
研究概览
简要总结
The purpose of this trial is to investigate the safety and tolerability of TAS3681, to find the maximum tolerated dose (MTD)/recommended dose of TAS3681 (Escalation Phase) and to further evaluate safety and preliminary efficacy of TAS3681 at the MTD/recommended dose (Expansion Phase).
详细描述
This is a first in human, multinational, Phase 1, open-label study of TAS3681 evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) for which there is no standard therapy. Eligible participants will be enrolled to evaluate safety and determine the MTD/recommended dose for TAS3681, including a preliminary evaluation of food effect and antitumor activity. The study will be conducted in 2 parts, Dose Escalation (Enrollment closed) and Expansion (Enrollment Closed). Patients who are continuing to receive clinical benefit may receive drug in the extension part of the study after escalation and expansion are completed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Male ≥18 years of age
- •Histological or cytological evidence of metastatic castrate resistant prostate cancer (excluding neuroendocrine differentiation and small cell histology) who are castration resistant and have:
- •Dose escalation: documented progression defined in PCWG3 and/or intolerance to abiraterone and/or enzalutamide therapy, as well as 1 or more chemotherapies.
- •I. Group A: documented progression after abiraterone or enzalutamide and chemotherapy consisting of no more than 2 prior taxane-based therapies
- •ii. Group B: documented progression after only abiraterone or enzalutamide therapy without any chemotherapy
- •iii. Measurable disease per RECIST 1.1 and/or bone metastases
- •ECOG performance status of ≤1 on Day 1 Cycle 1
- •Ongoing androgen deprivation with serum testosterone <50 ng/dL
- •Expansion Phase only: willingness to undergo baseline core biopsies, if feasible
- •Ability to take medication orally
- •Adequate organ function
- •Agree to use effective contraception during the study and for 30 days after the last dose of TAS3681
- •Willing to comply with scheduled visits and procedures
排除标准
- •QTcF ≥ 450 ms, history of QTc prolongation or predisposition for QTc prolongation or family history of sudden cardiac death or QT prolongation
- •History or presence of heart failure or left ventricular dysfunction with ejection fraction <40% within the previous 6 months; if >6 months cardiac function within normal limits and free of cardiac-related symptoms
- •History or presence of atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia; the presence or history of ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia
- •Presence of cardiac pacemaker or implantable cardioverter-defibrillator
- •History or presence of bradycardia or conduction abnormalities
- •History or presence of cardiac arrest or unexplained syncope
- •Hypokalemia
- •History of myocardial infarction or severe unstable angina
- •Any medication administered within 2 weeks prior to 1st dose of TAS3681 that is known to prolong the QT interval or be arrhythmogenic
- •Received G-CSF, radiotherapy for extended field, anticancer chemotherapy, investigational agents, or major surgery within 4 weeks of study drug administration; receipt of anticoagulant or CYP3A inhibitor within 2 weeks of study drug administration
- •Serious illness or medical condition that could affect the safety or tolerability of study treatments
- •Received prior treatment with TAS3681
- •User of herbal products
- •Any condition or reason that in the opinion of the investigator, interferes with the ability of the participant to participate in the trial
- •To be eligible to participate in the food effect assessment (Escalation Phase only), participants must not have a history or presence of any clinically significant abnormality involving the gastrointestinal tract and an inability to fast for a minimum of 8 hours
研究组 & 干预措施
TAS3681
All participants will receive TAS3681 in 28-day cycles. The Escalation phase includes participants who have progressed after abiraterone, enzalutamide and chemotherapy. Eleven dose escalation cohorts are planned, one of which includes a preliminary assessment of food effect. The MTD/recommended dose for further development will be used for participants in the Expansion Phase. The Expansion Phase will enroll participants who have progressed after abiraterone or enzalutamide with chemotherapy consisting of no more than 2 prior taxane-based therapies (Group A) or without any chemotherapy (Group B). Participants receive TAS3681 until discontinuation criteria are met.
干预措施: TAS3681 (Drug)
结局指标
主要结局
Escalation Phase: Number of patients with treatment-emergent adverse events and significant ECG abnormalities
时间窗: Through 6 months (or until patient discontinuation)
Based on treatment-emergent adverse events, serious adverse events (SAEs), clinical laboratory tests, vital signs, 12-lead electrocardiograms (ECGs)
Expansion Phase: Overall Response Rate (ORR)
时间窗: Through 6 months (or until patient discontinuation)
ORR based on investigator-assessed radiographic response per PCWG3/modified RECIST 1.1
Number of patients with dose-limiting toxicities
时间窗: Through 1 month
次要结局
- Escalation Phase: Accumulation ratio of TAS3681(Through Day 15 in Cycle 1 (each cycle is 28 days))
- Expansion:Tumor response measures including duration of response (DOR), radiologic progression-free survival (rPFS), overall survival (OS), clinical benefit rate (CBR; percentage of participants with complete response, partial response or stable disease)(Through 6 months (or until patient discontinuation))
- Escalation Phase: Area under the concentration-time curve of TAS3681(Through Day 15 in Cycle 1 (each cycle is 28 days))
- Escalation Phase: Time to PSA progression(Up to 6 months (or until patient discontinuation))
- Escalation Phase: Maximum concentration of TAS3681 in plasma(Through Day 15 in Cycle 1 (each cycle is 28 days))
- Escalation Phase: Time to reach maximum concentration of TAS3681(At Day 15 in Cycle 1 (each cycle is 28 days))
- Escalation Phase: Tumor response per PCWG3/RECIST 1.1 including ORR, and duration of response (DOR)(Through 6 months ( or until patient discontinuation))
- Expansion Phase: Prostate Specific Antigen (PSA) response(Up to 6 months (or until patient discontinuation))
- Escalation Phase: Prostate Specific Antigen (PSA) response(Up to 6 months (or until patient discontinuation))
- Escalation Phase: Terminal half-life time of TAS3681(Through Day 15 in Cycle 1 (each cycle is 28 days))
- Expansion Phase: Number of patients with treatment-emergent adverse events and significant ECG abnormalities(Through 6 months (or until patient discontinuation))
- Expansion Phase: Maximum concentration of TAS3681 in plasma(Through Day 15 during Cycle 1 (each cycle is 28 days))
- Expansion Phase: Time to reach maximum concentration of TAS3681(Through Day 15 during Cycle 1 (each cycle is 28 days))
- Expansion Phase: Area under the concentration-time curve of TAS3681(Through Day 15 during Cycle 1 (each cycle is 28 days))
- Expansion Phase: Terminal half-life time of TAS3681(Through Day 15 of Cycle 1 (each cycle is 28 days))