A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT3789 as Monotherapy and in Combination With Docetaxel in Participants With Advanced or Metastatic Solid Tumors With a SMARCA4 Mutation
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 135
- 试验地点
- 32
- 主要终点
- Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: AEs, CTCAE Assessments
研究概览
简要总结
This is a Phase 1 dose-escalation study of PRT3789, a SMARCA2 degrader, in participants with advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of PRT3789 monotherapy and in combination with docetaxel, describe any dose limiting toxicities (DLTs), define the dosing schedule, and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) to be used in subsequent development of PRT3789.
详细描述
This is an open-label, multi-center, dose-escalation, first in human, Phase 1 study of PRT3789 as monotherapy and in combination with docetaxel, a SMARCA2 degrader, evaluating participants with advanced or metastatic solid tumors with loss of SMARCA4 due to truncating mutation and/or deletion. The study will evaluate escalating doses of PRT3789 until the MTD or RP2D is determined. Taking into account pharmacokinetic and pharmacodynamic data from the preceding dose levels, the dose may be escalated until a dose limiting toxicity is identified. Approximately 186 participants will be enrolled in monotherapy, dose escalation, backfill, and combination cohorts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures
- •Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy with any mutation of SMARCA4 (dose escalation and combination cohorts) and loss of function mutation of SMARCA4 (backfill cohorts) by local testing that have either progress on or ineligible for standard of care therapy
- •Must have measurable or non-measureable (but evaluable) disease per RECIST v1.1 for dose escalation and combination cohorts
- •Must have measureable diseases per RECIST v1.1 for backfill cohort
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Willing to provide either archival or fresh tumor tissue sample
- •Adequate organ function (hematology, renal, and hepatic)
排除标准
- •Participants with solid tumors with known concomitant SMARCA2 mutation or loss of protein expression
- •Clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, uncontrolled or symptomatic central nervous system (CNS) metastases or leptomeningeal disease
- •History of another malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancies, or malignancies previously treated with curative intent and not on active therapy or expected to require treatment or recurrence during the study
- •Concurrent treatment with strong or moderate CYP3A4 inhibitor or inducer
研究组 & 干预措施
PRT3789 Monotherapy
PRT3789 will be administered by intravenous infusion
干预措施: PRT3789 (Drug)
PRT3789/Docetaxel Combination
PRT3789 and Docetaxel will be administered by intravenous infusions
干预措施: PRT3789 (Drug)
PRT3789/Docetaxel Combination
PRT3789 and Docetaxel will be administered by intravenous infusions
干预措施: Docetaxel (Drug)
结局指标
主要结局
Safety and tolerability of PRT3789 monotherapy and in combination with docetaxel: AEs, CTCAE Assessments
时间窗: Baseline through approximately 3 years
Safety and tolerability will be evaluated by incidence of DLTs, laboratory measurements, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
Dose limiting toxicity (DLT) of PRT3789 monotherapy and in combination with docetaxel
时间窗: Baseline through Day 21
Dose limiting toxicities will be evaluated over the 21-day observation period
Maximum tolerated dose (MTD)/ Recommended phase 2 dose (RP2D) of PRT3789 monotherapy and in combination with docetaxel
时间窗: Baseline through approximately 3 years
The MTD/RP2D will be established for further investigation in participants with advanced solid tumors
次要结局
- Pharmacodynamic effect of PRT3789 monotherapy and in combination with docetaxel: Target engagement(Baseline through approximately 3 years)
- Efficacy of PRT3789 monotherapy and in combination with docetaxel: Objective response rate (ORR)(Baseline through approximately 3 years)
- Efficacy of PRT3789 monotherapy and in combination with docetaxel: Duration of response (DOR)(Baseline through approximately 3 years)
- Efficacy of PRT3789 monotherapy and in combination with docetaxel: Progression-free survival (PFS)(Baseline through approximately 3 years)
- Efficacy of PRT3789 monotherapy and in combination with docetaxel: Clinical benefit rate (CBR)(Baseline through approximately 3 years)
- Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Maximum observed plasma concentration(Baseline through approximately 3 years)
- Pharmacokinetic profile of PRT3789 monotherapy and in combination with docetaxel: Area under the curve(Baseline through approximately 3 years)