A Study of Venetoclax in Combination With Obinutuzumab in Participants With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Lymphocytic Leukemia, Chronic

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-Finding: Schedule A: Relapsed/Refractory CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|
| Experimental: Dose-Finding: Schedule B: Relapsed/Refractory CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|
| Experimental: Dose-Finding: Schedule A: Previously Untreated CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|
| Experimental: Dose-Finding: Schedule B: Previously Untreated CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|
| Experimental: Safety Expansion: Relapsed/Refractory CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|
| Experimental: Safety Expansion: Previously Untreated CLL<br>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. | Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab 100 milligrams (mg) on Day 1 of Cycle 1, 900 mg on Day 2 of Cycle 1, and 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.<br>* Other names: GA101; RO5072759;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199, GDC-0199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose Limiting Toxicities (DLTs) |  | 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 |  | Sch A (Cycle 1 Day 1 to Day 21), Sch B (Cycle 1 Day 22 to Cycle 2 Day 28) (1 Cycle=28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Maximal Plasma Concentration (Cmax) of Venetoclax |  | Baseline up to Cycle 6 (1 Cycle=28 days) | 
| Minimum Plasma Concentration (Cmin) of Venetoclax |  | Baseline up to Cycle 6 (1 Cycle=28 days) | 
| Cmax of Obinutuzumab |  | Baseline up to Cycle 6 (1 Cycle=28 days) | 
| Cmin 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) | 
| 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) | 
| 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) | 
| Change from Baseline in Serum Immunoglobulin Level |  | Baseline up to end of study (up to approximately 5 years and 5 months) |