A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of ZN-A-1041 Enteric Capsules as a Single Agent or in Combination in Patients With HER2-Positive Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 61
- 试验地点
- 1
- 主要终点
- The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a
研究概览
简要总结
This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination in patients with HER2-positive advanced solid tumors.
The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041 monotherapy), phase 1b (dose escalation with ZN-A-1041 in combination with Capecitabine and Trastuzumab) and phase 1c (dose expansion with ZN-A-1041 in combination with Capecitabine and Trastuzumab).
详细描述
Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7 planned dose levels. Patients with HER2-positive advanced solid tumor (including those with brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041 followed by multiple-dose administration of ZN-A-1041.
Phase 1b of the study will adopt the "traditional 3+3" dose escalation design. In phase 1b, patients with HER2-positive advanced breast cancer (including those with brain metastases) will be enrolled to receive multiple doses of ZN-A-1041 in combination with Capecitabine and Trastuzumab.
In phase 1c patients with HER2-positive breast cancer with brain metastases were planned to be enrolled to receive ZN-A-1041 in combination with Capecitabine and Trastuzumab The dose levels will be determined based on the recommended doses obtained from the Phase 1b study, and the possible changes in the dosage form and the food effect study, which will be decided by the sponsor and the investigator after discussion.
Each phase of the study includes a screening period, a treatment period and a follow-up period. During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as monotherapy and in combination with Capecitabine and Trastuzumab in the subjects will be collected and analyzed, thereby providing RP2D for the subsequent clinical trials.
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
ZN-A-1041 400mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 400mg BID (Drug)
ZN-A-1041 50mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 50mg BID (Drug)
ZN-A-1041 100mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 100mg BID (Drug)
ZN-A-1041 200mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 200mg BID (Drug)
ZN-A-1041 600mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 600mg BID (Drug)
ZN-A-1041 800mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 800mg BID (Drug)
ZN-A-1041 1000mg
Phase 1a:
Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle
干预措施: ZN-A-1041 1000mg BID (Drug)
ZN-A-1041 level 1+Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
Phase 1b:
ZN-A-1041 Level 1 (The previous dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
干预措施: ZN-A-1041 Level 1 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle (Drug)
ZN-A-1041 level 2+Capecitabine 1000 mg/m2+ Trastuzumab 8 mg/kg iv. First Cycle
Phase 1b:
ZN-A-1041 Level 2 ( dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
干预措施: ZN-A-1041 Level 2 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle (Drug)
ZN-A-1041 MAD+Capecitabine 1000 mg/m2+Trastuzumab 8 mg/kg iv. First Cycle
Phase 1b:
If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level (MAD) of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
干预措施: ZN-A-1041 MAD +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle (Drug)
ZN-A-1041+Capecitabine+Trastuzumab
Phase 1c:
The combined dose of ZN-A-1041 is based on the recommended combined dose in the Phase 1b and the possible changes in the dosage form and the results of the food effect study, which will be decided by the sponsor and the investigator after discussion
干预措施: ZN-A-1041+Capecitabine + Trastuzumab 8 mg/kg iv. First Cycle (Drug)
结局指标
主要结局
The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a
时间窗: 23days
Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
The safety/tolerability of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1b
时间窗: 21days
Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
The safety of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1c
时间窗: through study completion, an average of 3 year
To evaluate the safety of ZN-A-1041 in combination with Capecitabine in patients on the RP2D Dose
次要结局
- The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c(through study completion, an average of 3 year)
- Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c(From baseline to Day 8)
- Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c(From baseline to Day 8)
- Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c(From baseline to Day 8)