A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Efficacy of ZN-A-1041 Enteric Capsules as a Single Agent or in Combination in Patients With HER2-Positive Advanced Solid Tumors
概览
- 阶段
- 1 期
- 干预措施
- ZN-A-1041
- 疾病 / 适应症
- 未指定
- 发起方
- Hoffmann-La Roche
- 入组人数
- 210
- 试验地点
- 42
- 主要终点
- The Incidence of Treatment-emergent Adverse Events of ZN-A-1041 as a Monotherapy in Phase 1a
- 状态
- 进行中（未招募）
- 最后更新
- 2个月前
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 participants with HER2-positive advanced solid tumors with or without brain metastases.
The study will consist of three phases: Phase 1a (dose escalation with ZN-A-1041 monotherapy), Phase 1b (dose escalation with ZN-A-1041 combination therapy) and Phase 1c (dose expansion with ZN-A-1041 combination therapy).
详细描述
This study is composed of three parts designed to evaluate the safety and efficacy of ZN-A-1041 in participants with HER2-positive advanced solid tumors. Phase 1a (Monotherapy Dose Escalation): In this first phase, participants will receive ZN-A-1041 alone. The study will begin with a low dose of ZN-A-1041, which will be gradually increased in new groups of participants to find the highest dose that can be given safely. This will establish the recommended dose for further study. Phase 1b (Combination Dose Escalation): In the second phase, the study will evaluate the safety of giving ZN-A-1041 together with established standard-of-care therapies for HER2-positive breast cancer. Participants will be enrolled into one of three combination arms to receive ZN-A-1041 with either T-DM1, T-DXd, or a pertuzumab/trastuzumab-based regimen. This phase will identify the recommended dose for these combination therapies. Phase 1c (Combination Dose Expansion): In the final phase, additional participants will be enrolled to receive ZN-A-1041 at the recommended combination doses identified in Phase 1b. This will allow for a more thorough evaluation of the safety and preliminary efficacy of these treatment regimens. Throughout the study, participants will undergo screening, treatment, and follow-up periods to collect comprehensive data on the safety, tolerability, pharmacokinetics, and anti-tumor activity of ZN-A-1041, both as a single agent and in combination.
研究者
入排标准
入选标准
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy of at least 6 months, as determined by the investigator
- •Histologically or cytologically confirmed with unresectable or metastatic HER2-positive advanced solid tumors
- •Must be relapsed or refractory after prior treatment for metastatic disease that included a taxane and trastuzumab or must have received first-line induction therapy for advanced disease a pertuzumab plus trastuzumab-based regimen or a T-DXd-based regimen
- •Participants with new, untreated, progressive, or stable brain metastases are eligible
排除标准
- •Participation in any other clinical study involving an investigational drug or device within 4 weeks prior to the first dose of study treatment
- •Any intracranial lesion (brain metastasis) that requires immediate local therapy, such as surgery or radiation, or systemic corticosteroids at the time of enrollment
研究组 & 干预措施
1a: ZN-A-1041
Phase 1a: Participants will receive escalating doses of ZN-A-1041 orally twice a day (BID) at pre-defined dosing regimens to determine the maximum tolerated dose (MTD).
干预措施: ZN-A-1041
1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv.
Phase 1b Arm1: 1. If the maximum tolerated dose (MTD) of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
干预措施: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1b
1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.
Phase 1b Arm2: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
干预措施: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1b
1b: ZN-A-1041 + PHESGO / Herceptin plus Perjeta
Phase 1b Arm3: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
干预措施: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1b
1c: ZN-A-1041 + T-DM1 3.6 mg/kg iv.
Phase 1c Arm1: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.
干预措施: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1c
1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.
Phase 1c Arm2: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.
干预措施: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1c
1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO
Phase 1c Arm3: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.
干预措施: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1c
结局指标
主要结局
The Incidence of Treatment-emergent Adverse Events of ZN-A-1041 as a Monotherapy in Phase 1a
时间窗: 23 days
Dose at which no more than one out of six participant at the same dose level experiences a probable drug-related DLT.
The Incidence of Treatment-emergent Adverse Events of ZN-A-1041 in Combination with T-DM1 or with T-DXd, or in Combination with PHESGO or Herceptin plus Perjeta
时间窗: 21 days
Dose at which no more than one out of six participant at the same dose level experiences a probable drug-related DLT.
RP2D
时间窗: Through study completion, an average of 1 year
To evaluate the safety of ZN-A-1041 in combination with T-DM1 or with T-DXd, or in combination with PHESGO or Herceptin plus Perjeta in participants on the RP2D.
次要结局
- Plasma, Urine and Potentially Cerebrospinal Fluid (CSF) Level of ZN-A-1041 and its Main Metabolites(From baseline to cycle 9 (each cycel is 21 days))
- Serum Level of Combination Drugs in Phase 1c(Through study completion, an average of 2 year)
- Anti-drug Antibodies (ADAs) Evaluation in Phase 1c(Through study completion, an average of 2 year)
- Overall Response Rate (ORR)(Through study completion, an average of 2 year)
- Progression Free Survival (PFS)(Through study completion, an average of 2 year)