A Study of Venetoclax in Combination With Bendamustine + Rituximab or Bendamustine + Obinutuzumab in Participants With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia (CLL)

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 of venetoclax (GDC-0199, ABT-199) administered in combination with bendamustine and rituximab (BR) (MabThera/Rituxan) or bendamustine and obinutuzumab (BG) to participants with first-line (1L)/previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). The study will explore two venetoclax combination regimens in participants with 1L CLL: BR+venetolax (V) and BG+V. Participants with R/R CLL will be administered BR+V.

Official Title
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A Phase IB, Open-Label Study Evaluating the Safety and Pharmacokinetics of Venetoclax (GDC-0199, ABT-199) in Combination With Bendamustine+Rituximab (BR) or Bendamustine+Obinutuzumab (BG) in Patients With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Obinutuzumab
* Drug: Rituximab
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of relapsing/refractory or previously untreated CLL Eastern Cooperative Oncology Group (ECOG) performance score of less than equal to (</=) 1 Adequate bone marrow function Adequate coagulation, renal and hepatic function Hematological values within the limits independent of growth factor support or transfusion unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g., myelodysplastic syndrome, hypoplastic bone marrow) Exclusion Criteria: Participants received an allogeneic stem cell transplant Known human immunodeficiency virus (HIV) positivity Uncontrolled autoimmune hemolytic anemia or thrombocytopenia Positive test results for chronic hepatitis B infection and hepatitis C virus (HCV) Received any anti-cancer therapy including chemotherapy or radiotherapy, steroid therapy for anti-neoplastic intent, and investigational therapy, including targeted small molecule agents within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy Significant history of 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1L CLL BR+V<br>Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician. | Drug: Bendamustine<br>* Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.<br>Drug: Rituximab<br>* Participants will receive IV infusion of rituximab (375 mg/m^2) on Day 1 of Cycle 1 and 500 mg/m^2 administered on Day 1 of Cycles 2-6.<br>* Other names: MabThera; Rituxan;Drug: Venetoclax<br>* Participants will receive multiple doses of venetoclax orally once daily.<br>* Other names: ABT-199; GDC-0199;|
| Experimental: 1L CLL BG+V<br>Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and obinutuzumab (BG). Participants received six 28-day cycles of BG+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician. | Drug: Bendamustine<br>* Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.<br>Drug: Obinutuzumab<br>* Participants will receive IV infusion of obinutuzumab (100 milligrams [mg]) on Day 1 of Cycle 1; 900 mg administered on Day 2 of Cycle 1; and 1000 mg administered 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: R/R CLL BR+V<br>Participants with relapsed/refractory (R/R) CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with R/R CLL continued single-agent venetoclax until disease progression, death, or unacceptable toxicity. | Drug: Bendamustine<br>* Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.<br>Drug: Rituximab<br>* Participants will receive IV infusion of rituximab (375 mg/m^2) on Day 1 of Cycle 1 and 500 mg/m^2 administered on Day 1 of Cycles 2-6.<br>* Other names: MabThera; Rituxan;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 |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | DLTs in this study were defined as specific adverse events (AEs) occurring during the DLT observation window: 1) Grade 4 neutropenia not responsive to granulocyte colony stimulating factors (G-CSF) lasting more than 14 days; 2) Grade 3 or 4 febrile neutropenia with fever lasting longer than 4 days; 3) Grade 4 thrombocytopenia resulting in bleeding, or that did not improve to Grade </=2 within 3 weeks; 4) Clinical tumor lysis syndrome (TLS) defined by the presence of laboratory TLS and one or more clinical manifestations related to the electrolyte abnormalities; 5) Grade 4 infusion-related reactions (IRRs) secondary to rituximab or obinutuzumab despite appropriate premedication and administration rate; 6) All other Grades 3, 4, or 5 AEs persisting for more than 2 weeks with or without treatment with some exceptions. | Schedule (Sch) A (venetoclax [V] introduced before other agents): Cycle 1 Day 1 (Cy1D1) to Cy1D21; Sch B (V introduced after other agents): Cy1D21 to Cy2D28; Cycle length = 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Venetoclax |  | Sch A: Ramp-up D1, 8, 15, 22, 29: predose (pd), 8 h; Cy1D1: pd; Cy1D3: pd, 2, 4, 6, 8, 10 h; Cy2D1, Cy4D1, Cy6D1: pd. Sch B: Cy1D1: pd; Cy1D22, Cy2D1, Cy2D8, Cy2D15, Cy2D22 (ramp-up): pd, 8 h; Cy3D1: pd, 2, 4, 6, 8 h; Cy4D1, Cy6D1: pd. | 
| Serum Concentrations of Rituximab |  | Sch A: Cy1D1, Cy2D1, Cy4D1, Cy6D1: predose, end of infusion. Sch B: Cy1D1: predose, end of infusion; Cy2D1, (ramp-up): predose, end of infusion; Cy3D1, Cy4D1, Cy6D1: predose. | 
| Serum Concentrations of Obinutuzumab |  | Sch A: Cy1D1, Cy1D2: pd, end of infusion (EoI); Cy1D3: pd; Cy1D8, Cy1D15, Cy2D1: pd, EoI; Cy3D1, Cy4D1, Cy5D1, Cy6D1: pd; Sch B: Cy1D1, Cy1D2, Cy1D8, Cy1D15: pd, EoI; Cy1D22 (ramp-up): pd; Cy2D1, Cy3D1, Cy4D1, Cy5D1, Cy6D1: pd, EoI. | 
| Plasma Concentrations of Bendamustine |  | Sch A: Cy1D2: predose, end of infusion. Sch B: Cy1D2, Cy3D2: predose, end of infusion. | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines | CR or CR with incomplete bone marrow recovery (CRi) or PR or nodular PR (nPR) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. | Baseline up to approximately 5.75 years | 
| Duration of Response According to IWCLL 2008 Guidelines | CR or CR with incomplete bone marrow recovery (CRi) or PR or nodular PR (nPR) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. | Baseline up to approximately 5.75 years | 
| Percentage of Participants with CR | CR or CR with incomplete bone marrow recovery (CRi) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri). | Baseline up to approximately 5.75 years | 
| Progression-Free Survival (PFS) According to IWCLL 2008 Guidelines | PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology. | Baseline up to approximately 5.75 years | 
| Overall Survival (OS) | OS was defined as the time from randomization to death from any cause. | Baseline up to approximately 5.75 years | 
| Number of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Up to approximately 5.75 years |