A Phase 2b Study of ZEN003694 in Combination With Talazoparib in Patients With Triple-Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 115
- 试验地点
- 19
- 主要终点
- Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE)
研究概览
简要总结
This is a two-part open label, non-randomized, Phase 2, study of ZEN003694 in combination with Talazoparib in patients with TNBC without germline mutations of BRCA1 or BRCA2. Part 1 is a dose escalation and Part 2 is a Simon 2-Stage design. There are 3 expansion cohorts: Expansion Cohort A (combination treatment in post-TROP2-ADC patients), Expansion Cohort B (ZEN003694 monotherapy), and Expansion Cohort C (combination treatment in TROP2-ADC-naive patients).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
None (Open Label)
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
- •Females or males age ≥ 18 years (at time of signing informed consent)
- •Parts 1 and 2 only: Histologically confirmed metastatic or recurrent or locally advanced triple-negative breast cancer (estrogen receptor (ER) ≤10%; progesterone receptor (PR) ≤10%; and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH)
- •Expansion only: Histologically confirmed metastatic or recurrent, or locally advanced triple-negative breast cancer as defined by the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.
- •Patient is not a candidate for endocrine based therapy, based on Investigator judgement
- •Have a history of progressive disease despite prior therapy
- •Part 1: Have had at least 1 prior cytotoxic chemotherapy.
- •Part 2: Have had no more than 2 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease, unless approved by the Sponsor (no limit on prior targeted anticancer therapies such as mechanistic target or rapamycin (mTOR) or CDK4/6 inhibitors, immune-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF.)
- •Expansion Cohort A (combination treatment in post-TROP2-ADC patients): Have received TROP2-ADC therapy for unresectable locally advanced or metastatic disease.
- •Expansion Cohort B (ZEN003694 monotherapy): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease which may or may not have included a TROP2-ADC.
- •Expansion Cohort C (combination treatment in TROP2-ADC-naive patients): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease and who have not received prior TROP2-ADC therapy.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Part 2 and Expansion only: Measurable disease per RECIST version 1.1
排除标准
- •Documented germline mutations of BRCA1 or BRCA2
- •Parts 1 and 2 only: Evidence of disease progression during platinum treatment either in the neoadjuvant or in the metastatic setting. For patients receiving platinum in the neoadjuvant setting, at least 6 months must have elapsed between the last dose of platinum-based treatment and enrollment
- •Part 2 only: Patients with inflammatory breast cancer
- •Current or anticipated use of medications known to be strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows. Strong inhibitors, inducers or substrates must be discontinued at least 7 days prior to the first administration of study drug.
- •Current or anticipated use within 7 days prior to the first administration of study drug, or during the study, of strong P-gp inhibitors.
- •Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
- •Prior anticancer therapy (chemotherapy, radiation, hormone therapy, immunotherapy or investigational agent) within 3 weeks from the start of study drug (except for nitrosoureas and mitomycin C within 6 weeks from start of study drug)
- •Parts 1 and 2 only: Radiation to >25% of the bone marrow
- •Treatment with a bone-targeted radionuclide within 6 weeks of first dose of study drug
- •Have previously received an investigational BET inhibitor (including previous participation in studies with the Sponsor's drug, ZEN003694); except for patients in Expansion Cohort B who received ZEN003694 monotherapy and are eligible to cross-over to combination treatment
- •Prior treatment with a PARP inhibitor
- •QTcF interval > 470 msec
- •Insufficient recovery (i.e., has not recovered to at least Grade 1) from prior treatment-related toxicities except for alopecia, fatigue and Grade 2 neuropathy
- •Non-healing wound, ulcer or bone fracture (not including a pathological bone fracture caused by a pre-existing pathological bone lesion)
- •Parts 1 and 2 only: Brain metastases not adequately treated and clinically stable (at the discretion of the Investigator) for at least 3 months prior to the start of study treatment, unless a shorter interval is approved by the Sponsor's Medical Monitor
- •Expansion only: Progressive, symptomatic, or untreated brain metastases. CNS metastases treated definitively with surgery and/or radiation must be radiographically stable based on imaging at least 3 months after definitive treatment. CNS metastases requiring steroid doses equivalent to prednisone doses >10 mg daily or an increase in steroid doses due to CNS disease prior to consent are not eligible
- •Expansion only: Disease initially diagnosed with expression of estrogen receptor (ER) or progesterone receptor (PR) as ≥5%
- •Expansion only: Patients treated with prior endocrine therapy
研究组 & 干预措施
Part 1 and Part 2
ZEN003694 will be administered PO QD with Talazoparib PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU.
干预措施: ZEN003694 (Drug)
Part 1 and Part 2
ZEN003694 will be administered PO QD with Talazoparib PO QD in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU.
干预措施: Talazoparib (Drug)
Expansion Cohort A - Combination Treatment in post-TROP2-ADC patients
ZEN003694 will be administered PO QD with Talazoparib PO QD at the RP2D in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU.
干预措施: ZEN003694 (Drug)
Expansion Cohort A - Combination Treatment in post-TROP2-ADC patients
ZEN003694 will be administered PO QD with Talazoparib PO QD at the RP2D in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU.
干预措施: Talazoparib (Drug)
Expansion Cohort B - ZEN003694 Monotherapy
ZEN003694 will be administered PO QD as monotherapy at the RP2D in 28-day cycles with the option to cross-over to combination treatment of ZEN003694 PO QD with Talazoparib PO QD at the time of disease progression (but no sooner than after 6 weeks of monotherapy). Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in the US and EU.
干预措施: ZEN003694 (Drug)
Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve patients
ZEN003694 will be administered PO QD with Talazoparib PO QD at the RP2D in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in China only.
干预措施: ZEN003694 (Drug)
Expansion Cohort C - Combination Treatment in TROP2-ADC-naïve patients
ZEN003694 will be administered PO QD with Talazoparib PO QD at the RP2D in 28-day cycles. Patients have histologically confirmed Triple Negative Breast Cancer and have no documented germline mutations of BRCA1 or BRCA2. Includes sites in China only.
干预措施: Talazoparib (Drug)
结局指标
主要结局
Part 1 and Part 2: Number of Participants With Treatment-related Adverse Events (AE) and Treatment-related Serious Adverse Events (SAE)
时间窗: Cycle 1 Day 1 to 30 days post last dose (each cycle is 28 days) up to 22 months
Part 1: Number of Participants With Dose-limiting Toxicities (DLT)
时间窗: Cycle 1, Up to 1 month
Determination of DLT will be made during the first 28 days of treatment (i.e., Cycle 1) in the dose escalation phase. A DLT is defined as a clinically significant AE or laboratory abnormality that is considered possibly, probably or definitely related to study drug.
Part 2: Clinical Benefit Rate (CBR)
时间窗: From screening up to 18 months
Percentage of patients with a best overall response of confirmed complete response (CR), partial response (PR), or stable disease (SD ≥ 4 cycles) by RECIST v1.1
Expansion Cohort A: Objective Response Rate (ORR) by RECIST v1.1 (CR or PR)
时间窗: From screening up to 18 months
Percentage of participants with a confirmed complete response (CR) or partial response (PR) by RECIST 1.1
次要结局
- Part 1, Expansion Cohorts A and C: Clinical Benefit Rate (CBR)(From screening up to 18 months)
- Part 1, Part 2, and Expansion Cohort C: Objective Response Rate (ORR)(From screening up to 18 months)
- Part 2, Expansion Cohorts A and C: Safety Profile of ZEN003694 in Combination With Talazoparib.(From screening up to 18 months)
- Part 1, Part 2, Expansion Cohorts A & C: Evaluate Median Progression-free Survival(From screening up to 18 months)
- Part 2, Expansion Cohorts A and C: Evaluate Duration of Response (DOR)(From screening up to 18 months)
- Part 1 and Part 2: Measure the Pharmacokinetic Parameter (PK) of Cmax of ZEN003694 and ZEN003791 (Active Metabolite)(Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days))
- Part 1 and Part 2: Measure the Pharmacokinetic (PK) Parameter of Combined AUC(0-4h or 0-8h) of ZEN003694 and ZEN003791 (Active Metabolite)(Part 1: Cycle 1 Day 1: Pre-dose, 15 min, 30 min, 1 hour, 2 hour, 4 hour, 6 hour, and 8 hours post-dose. Parts 1 & 2: Cycle 2 Day 1: Pre-dose, 1 hour, 2 hour, and 4 hours post-dose. (cycles are 28 days))
- Part 1 & 2: Measure Plasma Concentrations of Talazoparib.(Part 1: Cycle 1 Day 15: Pre-dose; Parts 1& 2 Cycle 2 Day 1: Pre-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days))
- Expansion Cohorts A, B, and C: Measure Plasma Concentrations of ZEN003694 and the Active Metabolite ZEN003791.(Cycle 2 Day 1: Pre-dose, 1 hour, 2 hours, and 4 hours post-dose; Cycle 2 Day 15: Pre-dose (each cycle is 28 days))
- Expansion Cohorts A and C: Measure Plasma Concentrations of Talazoparib.(Cycle 2 Day 1: Pre-dose, Cycle 2 Day 15: Pre-dose (each cycle is 28 days))
- Part 2, Expansion Cohorts A and C: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by EORTC QLQ-C30 for Overall Duration(Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration))
- Part 2, Expansion Cohorts A and C: Change From Baseline in Breast Symptoms Scale as Assessed by the EORTC-QLQ-BR23(Screening and Day 1 of every 28-day Cycle, up to 18 months (Overall Duration))