A Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Study Overview
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Brief Summary
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The purpose of this study is to assess progression-free survival (PFS) from treatment with ibrutinib plus venetoclax (I+VEN) compared with obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review Committee (IRC).

Official Title
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A Randomized, Open-label, Phase 3 Study of the Combination of Ibrutinib Plus Venetoclax Versus Chlorambucil Plus Obinutuzumab for the First-line Treatment of Subjects With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL).

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Venetoclax
* Drug: Chlorambucil
* Drug: Obinutuzumab
* Drug: Ibrutinib (as Subsequent Therapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants who are: (a) greater than or equal to (>=) 65 years old or, (b) 18 to 64 years old and have at least 1 of the following: Cumulative Illness Rating Scale (CIRS) score > 6 Creatinine clearance (CrCl) estimated less than (<) 70 milliliter per minute (mL/min) using Cockcroft-Gault equation Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that meets International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria Measurable nodal disease (by computed tomography [CT]), defined as at least one lymph node > 1.5 centimeter (cm) in longest diameter Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Grade less than or equal to (<=) 2 Active CLL/SLL requiring treatment per the iwCLL criteria Exclusion Criteria: Prior anti-leukemic therapy for CLL or SLL Presence of deletion of the short arm of chromosome 17 (del17p) or known TP53 mutation detected at a threshold of >10 percent (%) variable allele frequency (VAF) Major surgery within 4 weeks of first dose of study treatment Known bleeding disorders (example, von Willebrand's disease or hemophilia) Central nervous system (CNS) involvement or suspected Richter's syndrome

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A: Ibrutinib and Venetoclax (I+VEN)<br>Participants will initially receive ibrutinib (420 mg [milligrams]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. | Drug: Ibrutinib<br>* Participants will receive ibrutinib 420 mg orally once daily up to 15 cycles.<br>Drug: Venetoclax<br>* Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 to 400 mg.<br>Drug: Ibrutinib (as Subsequent Therapy)<br>* Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.<br>|
| Active Comparator: Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb)<br>Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. | Drug: Chlorambucil<br>* Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6.<br>Drug: Obinutuzumab<br>* Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6.<br>Drug: Ibrutinib (as Subsequent Therapy)<br>* Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes >15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; >=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi >15 mm) or >=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi >15 mm); >=50% increase from nadir in enlargement of liver/spleen; >=50% increase from baseline in lymphocyte count (ALC; to >=5*10^9/L); or >=50% increase from nadir in ALC in >=2 serial assessments if ALC is >=30000*10^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology. | Up to 2 years 10 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) Negative Rate | MRD-negative rate is defined as the percentage of participants who achieved MRD-negative status (that is, less than [<] 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes or <0.01 percentage [%]) in the bone marrow as assessed by next-generation sequencing (NGS). Participants with missing MRD data were considered MRD positive. | Up to 2 years 10 months | 
| Complete Response Rate (CRR) | Complete response rate is defined as the percentage of participants who achieved complete response or complete response with an incomplete marrow recovery (CRi) on or prior to initiation of subsequent anti-leukemic therapy per the IRC assessment. International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL), absolute lymphocyte count <4000/microliter (mcL) and normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow. | Up to 2 years 10 months | 
| Overall Response Rate (ORR) | ORR: percentage of participants who achieved best overall response of either CR, CRi, nodular PR (nPR) and partial response (PR). iWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 g/dL and ALC <4000/mcL, normocellular bone marrow with <30% lymphocytes and no B lymphoid nodules; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but bone marrow biopsy shows B-lymphoid nodules (reflecting residual disease); PR-2 of following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum of products of multiple nodes, >=50% decrease in enlargement of spleen or liver; and 1 of following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; 50% reduction in bone marrow infiltrates or B lymphoid nodules; no new enlarged nodes or new hepatosplenomegaly. | Up to 2 years 10 months | 
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death from any cause. | Up to 4 years 10 months | 
| Duration of Response (DOR) | DOR is defined as the interval between the date of initial documentation of a response including partial response with lymphocytosis (PRL) and the date of first documented evidence of PD or death or date of censoring per the IRC assessment. iWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other organ infiltrates; >= 50% increase from nadir in existing lymph node or >=50% increase from nadir in sum of product of diameters of multiple nodes; >=50% increase from nadir in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b or platelets) attributable to CLL; transformation to a more aggressive histology. | Up to 2 years 10 months | 
| Time-to-Next Treatment | Time-to-next treatment was measured from the date of randomization to the start date of any subsequent anti-leukemic therapy. | Up to 2 years 10 months | 
| Time to Worsening as Measured by Using EuroQol 5 Dimension 5 Level Questionnaire (EQ-5D-5L) | Time to worsening= time interval (months) from randomization to first observation of deterioration. EQ-5D-5L consists of a 5-item descriptive system and the EuroQol visual analog scale (EQ-5D VAS). EQ-5D-VAS self-rating records respondent's own assessment of his/her overall health status at time of completion, on scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Worsening is defined as a decrease of >= 7 points (on a 0-100 scale). EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self -care, usual activities, pain/discomfort, and anxiety/depression) to describe participant's current health state. Responses for 5 dimensions are combined into a 5-digit number describing respondents health state that can be converted into a single index value or utility score (using the United Kingdom weights), ranging from -1 to 1, where lower scores indicate a worse health status. Worsening is defined as a decrease of >=0.08 points (on a 0-1 scale). | Up to 2 years 10 months | 
| Time to Worsening Measured by European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30) | Time to worsening= time interval from randomization to first observation of deterioration. EORTC QLQ-C30 includes 30 separate items: 5 functional scales (physical, role, emotional, cognitive, and social Functioning), 1 global health status (GHS) and QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Each item, except GHS, is answered on 4-point scale (1=not at all to 4=very much) and GHS is measured on 1-7 scale: 1=very poor and 7=excellent. Scores derived using validated scoring algorithms as per EORTC QLQ-C30 Manual and linearly transformed in a range from 0-100. For functional and global QoL scales, higher scores=better level of functioning/QoL. For symptom-oriented scales, higher score=more severe symptoms. Worsening in functional and global health scores=decrease of >=10 points (on 0-100 scale) and in symptom scores=increase of >=10 points (on 0-100 scale). | Up to 2 years 10 months | 
| Time to Worsening and Time to Improvement as Measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Total Score | Responses to the 13-item FACIT Fatigue Scale are reported on a 5-point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). Time to Worsening is defined as time interval (months) from randomization to first observation of deterioration. Worsening is defined as a decrease >= 3 points (on a 0-52 scale). Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. Improvement is defined as an increase >=3 points (on a 0-52 scale). | Up to 2 years 10 months | 
| Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability | An adverse event (AE) is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to 4 years 10 months | 
| Number of Participants With Abnormal Clinical Laboratory Findings | Number of participants with abnormal clinical laboratory findings (hematology and serum chemistry) were reported. | Up to 4 years 10 months | 
| Percentage of Participants With Sustained Hemoglobin Improvement | Sustained hemoglobin improvement is defined as the percentage of participants who achieved an increase in hemoglobin levels from baseline by >= 2 grams per deciliter (g/dL) and lasts for at least 56 days without blood transfusion or growth factors. | Up to 2 years 10 months | 
| Percentage of Participants With Sustained Platelet Improvement | Sustained platelet improvement is defined as the percentage of participants who achieved an increase in platelet levels from baseline by >= 50% and lasts for at least 56 days without blood transfusion or growth factors. | Up to 2 years 10 months | 
| Plasma Concentration of Ibrutinib and Venetoclax | Plasma concentrations of ibrutinib and venetoclax were determined by validated liquid chromatography-tandem mass spectrometry. | Ibrutinib: Pre-dose-Day 1 of Cycles 2, 3, 5 and 6 (each cycle is defined as 28 days), Venetoclax: Pre-dose-Day 1 of Cycles 5 and 6 |