A Phase Ib Multicenter Dose-Finding and Safety Study of Venetoclax and Obinutuzumab in Patients With Relapsed or Refractory or Previously Untreated Chronic Lymphocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 82
- 试验地点
- 10
- 主要终点
- Percentage of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This multi-center, open-label, dose-finding study will evaluate the safety and pharmacokinetics as well as the preliminary efficacy of venetoclax (GDC-0199; ABT-199) administered in combination with obinutuzumab to participants with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL). The study is comprised of two stages for each participant population: a dose-finding stage and a safety-expansion stage. The dose-finding stage will explore multiple doses of venetoclax to be used in combination with a fixed dose of obinutuzumab. The dose-finding stage will also explore two schedules for drug administration, Schedule A (venetoclax introduced before obinutuzumab) and Schedule B (venetoclax introduced after obinutuzumab).
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
- •Diagnosis of relapsing/refractory or previously untreated chronic lymphocytic leukemia
- •Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1
- •Adequate bone marrow function
- •Adequate coagulation, renal and hepatic function
- •For all participants, agreement to remain abstinent or use contraceptive methods that result in a failure rate of less than (<) 1% per year during the treatment period and for at least 90 days (30 days for women) after the last dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer
排除标准
- •Participants who have undergone allogenic stem cell transplant are ineligible unless they meet the following criteria, a) participants who are off all immunosuppressive therapy, b) participants who have no signs and/or symptoms of acute or chronic graft versus host disease, or c) participants must have appropriate hematology counts
- •Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
- •Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
- •Investigational or anti-cancer therapy within 5 half-lives prior to the first dose of study drug
- •History of significant renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease
研究组 & 干预措施
Dose-Finding: Schedule A: Relapsed/Refractory CLL
All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Obinutuzumab (Drug)
Dose-Finding: Schedule A: Relapsed/Refractory CLL
All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Venetoclax (Drug)
Dose-Finding: Schedule B: Relapsed/Refractory CLL
In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Obinutuzumab (Drug)
Dose-Finding: Schedule B: Relapsed/Refractory CLL
In 4 cohorts of participants with relapsed/refractory CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Venetoclax (Drug)
Dose-Finding: Schedule A: Previously Untreated CLL
All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Obinutuzumab (Drug)
Dose-Finding: Schedule A: Previously Untreated CLL
All 4 cohorts will begin venetoclax administration after the ramp-up period of 5 weeks. In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule A, venetoclax will be introduced before obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Venetoclax (Drug)
Dose-Finding: Schedule B: Previously Untreated CLL
In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Obinutuzumab (Drug)
Dose-Finding: Schedule B: Previously Untreated CLL
In 4 cohorts of participants with previously untreated CLL escalating doses of venetoclax will be administered in combination with fixed dose obinutuzumab in the dose-finding stage. In Schedule B, venetoclax will be introduced after obinutuzumab. Schedule A will be explored prior to Schedule B.
干预措施: Venetoclax (Drug)
Safety Expansion: Relapsed/Refractory CLL
In participants with relapsed/refractory CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.
干预措施: Obinutuzumab (Drug)
Safety Expansion: Relapsed/Refractory CLL
In participants with relapsed/refractory CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.
干预措施: Venetoclax (Drug)
Safety Expansion: Previously Untreated CLL
In participants with previously untreated CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.
干预措施: Obinutuzumab (Drug)
Safety Expansion: Previously Untreated CLL
In participants with previously untreated CLL a recommended dose of venetoclax will be administered in combination with obinutuzumab in the safety expansion stage. Schedule A or B will be used for the expansion cohort after a review of available safety data from the dose finding stage.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Percentage of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Schedule (Sch) A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)
Maximum Tolerated Dose (MTD) of Venetoclax in Combination with Obinutuzumab
时间窗: Sch A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days)
次要结局
- Minimum Plasma Concentration (Cmin) of Venetoclax(Baseline up to Cycle 6 (1 Cycle=28 days))
- Percentage of Participants with Adverse Events(Baseline up to end of study (up to approximately 5 years and 5 months))
- Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) to Obinutuzumab(Baseline up to Cycle 6 (1 Cycle=28 days))
- Area Under the Concentration-Time Curve (AUC) of Venetoclax(Baseline up to Cycle 6 (1 Cycle=28 days))
- Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax(Baseline up to Cycle 6 (1 Cycle=28 days))
- Cmax of Obinutuzumab(Baseline up to Cycle 6 (1 Cycle=28 days))
- Percentage of Participants with Confirmed Complete Response (CR) as Determined by Standard CLL Response Criteria(Baseline up to end of study (up to approximately 5 years and 5 months))
- Percentage of Participants with Objective Response (Partial Response [PR] or CR [Including Cytopenic CR] as Determined by Standard CLL Response Criteria(Baseline up to end of study (up to approximately 5 years and 5 months))
- Duration of Objective Response as Determined by Standard CLL Response Criteria(Baseline up to end of study (up to approximately 5 years and 5 months))
- Change from Baseline in Number of B-Cells(Baseline up to end of study (up to approximately 5 years and 5 months))
- Change from Baseline in Number of T-Cells(Baseline up to end of study (up to approximately 5 years and 5 months))
- Change from Baseline in Number of Natural Killer (NK) Cells(Baseline up to end of study (up to approximately 5 years and 5 months))
- Cmin of Obinutuzumab(Baseline up to Cycle 6 (1 Cycle=28 days))
- Maximal Plasma Concentration (Cmax) of Venetoclax(Baseline up to Cycle 6 (1 Cycle=28 days))
- Change from Baseline in Serum Immunoglobulin Level(Baseline up to end of study (up to approximately 5 years and 5 months))
- Overall Survival(Baseline up to death or end of study (up to approximately 5 years and 5 months))
- Progression-Free Survival as Determined by Standard CLL Response Criteria(Baseline up to end of study (up to approximately 5 years and 5 months))