Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Antitumor Activity of TNG348 Single Agent and in Combination With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or Other HRD+ Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 7
- 试验地点
- 7
- 主要终点
- To determine dosing for TNG348 alone and in combination (Phase 1 only)
研究概览
简要总结
The goal of this interventional clinical trial is to learn about TNG348, a ubiquitin specific peptidase 1 (USP1) inhibitor, alone and in combination with olaparib in patients with BRCA 1/2 mutant or HRD+ solid tumors.
The main question[s] it aims to answer are:
- to evaluate the safety and tolerability of single agent and combination therapy
- to determine the recommended dose for Phase 2 of single agent and combination therapy
- to determine the pharmacokinetics of TNG348 as a single agent and in combination therapy
- to evaluate the initial antineoplastic activity as a single agent and in combination therapy
Participants will receive study treatment until they experience an undesirable side effect, their disease progresses or until they withdraw consent.
详细描述
This is a first-in-human Phase 1/2, open-label, multi-center, dose-escalation and expansion study designed to determine the maximum-tolerated dose (MTD) and recommended Phase 2 dose(s) (RP2D) and evaluate the safety, tolerability, and preliminary antitumor activity of TNG348 single agent and in combination with olaparib in participants with BRCA1/2 mutant or other HRD+ advanced or metastatic solid tumors.
In Phase 1 (dose escalation), the single agent component will explore escalating oral doses of TNG348 administered alone and in combination with olaparib.
Participants in Phase 2 (dose expansion) will be dosed at the RP2D(s) determined from Phase 1 based on safety and tolerability demonstrated, along with the available PK data and studied during Phase 1, as applicable.
In the Phase 2 portion of the study, both single agent and combination therapy may be evaluated to assess an early signal of clinical benefit, as well as for confirmation of safety and tolerability.
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
- •Is ≥18 years of age at the time of signature of the main study ICF.
- •Has ECOG performance status of 0 or
- •Has advanced or metastatic solid tumor with measurable disease based on RECIST v1.
- •All participants must have documented BRCA 1/2 mutant or other HRD+ in solid tumor, which is identified through a validated sequencing test
- •Adequate organ and bone marrow function per local labs
- •Negative serum pregnancy test result at screening
- •Written informed consent must be obtained according to local guidelines
排除标准
- •Known allergies, hypersensitivity, or intolerance to TNG348, olaparib or its excipients
- •Uncontrolled intercurrent illness that will limit compliance with the study requirements
- •Currently participating in or has planned participation in a study of another investigational agent or device
- •Impairment of GI function or disease that may significantly alter the absorption of study drug
- •Active prior or concurrent malignancy.
- •Central nervous system metastases associated with progressive neurological symptoms
- •Participant with MDS
- •Clinically relevant cardiovascular disease
- •Participant with known active or chronic infection
- •A female patient who is pregnant or lactating
研究组 & 干预措施
Single Agent Dose Escalation
Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 to estimate the MTD
干预措施: TNG348 (Drug)
Combination Dose Escalation
Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 in combination with olaparib to estimate the MTD
干预措施: TNG348 (Drug)
Combination Dose Escalation
Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 in combination with olaparib to estimate the MTD
干预措施: Olaparib (Drug)
Single agent dose expansion in breast cancer
Participants with BRCA 1/2 mutant breast cancer will receive TNG348 at the identified RP2D
干预措施: TNG348 (Drug)
Single agent dose expansion in ovarian cancer
Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 at the identified RP2D
干预措施: TNG348 (Drug)
Combination therapy dose expansion in breast cancer
Participants with BRCA 1/2 mutant breast cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: TNG348 (Drug)
Combination therapy dose expansion in breast cancer
Participants with BRCA 1/2 mutant breast cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: Olaparib (Drug)
Combination therapy dose expansion in ovarian cancer
Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: TNG348 (Drug)
Combination therapy dose expansion in ovarian cancer
Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: Olaparib (Drug)
Combination therapy dose expansion in pancreatic or prostate cancer
Participants with BRCA 1/2 mutant pancreatic or prostate cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: TNG348 (Drug)
Combination therapy dose expansion in pancreatic or prostate cancer
Participants with BRCA 1/2 mutant pancreatic or prostate cancer will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: Olaparib (Drug)
Combination therapy dose expansion in HRD+ advanced or metastatic solid tumors
Participants with HRD+ advanced or metastatic solid tumors will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: TNG348 (Drug)
Combination therapy dose expansion in HRD+ advanced or metastatic solid tumors
Participants with HRD+ advanced or metastatic solid tumors will receive TNG348 in combination with olaparib at the identified RP2D
干预措施: Olaparib (Drug)
结局指标
主要结局
To determine dosing for TNG348 alone and in combination (Phase 1 only)
时间窗: 21 days
• To determine the MTD, RP2D(s), and dosing schedule of TNG348 single agent and in combination with olaparib
Measure anti-tumor activity using RECIST 1.1 (Phase 2 only)
时间窗: 56 days
To assess the antitumor activity of TNG348 single agent and in combination using RECIST 1.1 per investigator assessment
次要结局
- Characterize the safety and tolerability profile(21 days)
- Characterize the plasma PK profile(16 days)
- Assess changes in levels of ubPCNA in response to TNG348 as single agent or in combination(22 days)
- Characterize olaparib concentrations when administered with TNG348(16 days)
- Measure anti-tumor activity using RECIST 1.1 (Phase 1 only)(56 days)