A Phase 1a/b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GS-9716 as Monotherapy and in Combination With Anticancer Therapies in Subjects With Solid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 37
- 试验地点
- 14
- 主要终点
- Percentage of Patients Experiencing Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is a Phase I open-label, multi-center study of zamzetoclax (formerly GS-9716) tested either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies. Primary objectives are to define the maximum tolerated dose (MTD) or maximum administered dose of zamzetoclax, and characterize the safety and tolerability of zamzetoclax as monotherapy and in combination with anti-cancer therapies.
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
- •General Inclusion Criteria (all cohorts):
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Measurable disease per RECIST version 1.1
- •Adequate hematology, renal and hepatic function
- •Left ventricular ejection fraction (LVEF) ≥ 50%
- •Patients with brain metastases may be enrolled only if treated, nonprogressive, asymptomatic and not taking high dose steroids for at least 4 weeks prior to Cycle 1 Day 1 (C1D1)
- •Individuals of childbearing potential who engage in heterosexual intercourse must agree to use method(s) of contraception, per protocol.
- •Tissue criteria: must provide sufficient, and adequate tumor tissue sample or agree to have a biopsy taken.
- •Part A Specific Inclusion Criteria: zamzetoclax as monotherapy
- •Histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor for which no standard therapy is available, standard therapy has failed, or for whom standard-of-care therapy is contraindicated.
- •Cohorts B1 and C1 Specific Inclusion Criteria:
- •Histologically or cytologically confirmed unresectable metastatic or locally advanced disease following treatment for metastatic disease including an immune checkpoint inhibitor and a platinum-containing chemotherapy
- •Patients with actionable genomic alterations must have also received treatment with at least 1 approved therapy appropriate to the genomic alteration unless unavailable or contraindicated
- •Cohorts B4 and C4 Specific Inclusion Criteria:
- •Histologically or cytologically confirmed disease based on the most recent analyzed biopsy metastatic disease that is refractory to or relapsed after at least 2 prior standard-of-care chemotherapy regimens, one of which was a taxane (unless contraindicated).
排除标准
- •Prior systemic anti-cancer therapy must meet wash-out criteria outlined in protocol
- •Treatment with any high dose systemic corticosteroids or nonsystemic radiotherapy within 2 weeks of the first dose of zamzetoclax (low dose corticosteroids permitted).
- •Women who are pregnant or lactating
- •Patients with active ≥ Grade 2 nausea or vomiting, and/or signs of intestinal obstruction
- •Known active or chronic hepatitis B or C infection or HIV infection/ HIV positive
- •Known history of clinically significant cardiovascular disease or heart failure.
- •Known history of clinically significant active chronic obstructive pulmonary disease or other moderate to severe chronic respiratory illness present within 6 months prior to C1D1
- •Known history of other clinically significant pulmonary disease or evidence of active pneumonitis
- •Uncontrolled pleural effusion, pericardial effusion, or ascites
- •History of clinically significant bleeding, intestinal obstruction, or gastrointestinal (GI) perforation within 6 months prior to C1D1
- •Infection requiring intravenous anti-infective use within 2 weeks prior to C1D1
- •Active or history of autoimmune disease or immune deficiency
- •History of uncured coexisting cancer, not including uncured basal cell carcinoma, cervical cancer in situ, or superficial bladder cancer.
- •Cohort A Specific Exclusion Criteria: zamzetoclax as monotherapy:
- •Known heart failure or elevated cardiac biomarkers
- •Cohorts B1 and C1 Specific Exclusion Criteria:
- •Known hypersensitivity to excipients in study treatments.
- •Cohorts B4 and C4 Specific Exclusion Criteria:
- •Prior treatment with sacituzumab govitecan-hziy or a topoisomerase 1 inhibitor or agents targeting Trop-
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part C (Cohort C4): zamzetoclax + sacituzumab govitecan-hziy
Patients will receive ≤ MTD zamzetoclax in combination with sacituzumab govitecan-hziy.
干预措施: zamzetoclax (Drug)
Part C (Cohort C1): zamzetoclax + docetaxel
Patients will receive ≤ MTD zamzetoclax in combination with docetaxel.
干预措施: Docetaxel (Drug)
Part A: zamzetoclax Dose-Escalation
Patients will receive escalating doses of zamzetoclax to estimate MTD.
干预措施: zamzetoclax (Drug)
Part B (Cohort B1): Zamzetoclax + docetaxel
Patients will receive escalating doses of zamzetoclax in combination with docetaxel.
干预措施: Docetaxel (Drug)
Part C (Cohort C1): zamzetoclax + docetaxel
Patients will receive ≤ MTD zamzetoclax in combination with docetaxel.
干预措施: zamzetoclax (Drug)
Part B (Cohort B1): Zamzetoclax + docetaxel
Patients will receive escalating doses of zamzetoclax in combination with docetaxel.
干预措施: zamzetoclax (Drug)
Part B (Cohort B4): zamzetoclax + sacituzumab govitecan-hziy
Patients will receive escalating doses of zamzetoclax in combination with sacituzumab govitecan-hziy.
干预措施: sacituzumab govitecan-hziy (Drug)
Part A: zamzetoclax Dose-Expansion
Patients will receive ≤ MTD of zamzetoclax.
干预措施: zamzetoclax (Drug)
Part C (Cohort C4): zamzetoclax + sacituzumab govitecan-hziy
Patients will receive ≤ MTD zamzetoclax in combination with sacituzumab govitecan-hziy.
干预措施: sacituzumab govitecan-hziy (Drug)
Part B (Cohort B4): zamzetoclax + sacituzumab govitecan-hziy
Patients will receive escalating doses of zamzetoclax in combination with sacituzumab govitecan-hziy.
干预措施: zamzetoclax (Drug)
结局指标
主要结局
Percentage of Patients Experiencing Dose-Limiting Toxicities (DLTs)
时间窗: First dose date up to 28 days
Percentage of Patients Experiencing Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE), Version 5.0
时间窗: First dose date up to last dose date (Maximum: 105 weeks) plus 30 days
次要结局
- Maximum Observed Concentration (Cmax) for Zamzetoclax(Approximately 105 Weeks)
- Time to Maximum Observed Concentration (Tmax) for Zamzetoclax(Approximately 105 Weeks)
- Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) for Zamzetoclax(Approximately 105 Weeks)
- Parts B and C: Objective Response Rate (ORR)(Up to 105 weeks)
- Parts B and C: Disease Control Rate (DCR)(Up to 105 weeks)
- Parts B and C: Progression-Free Survival (PFS)(First dose date to PD or death, whichever occurs first (up to 39 months))
- Parts B and C: Time to Response (TTR)(First dose date to the first documentation of CR or PR (up to 105 weeks))
- Parts B and C: Duration of Response (DOR)(From first documentation of CR or PR to PD or death, whichever occurs first (up to 37 months))