A Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

Study Overview
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Brief Summary
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This is a multi-cohort, open-label study in previously untreated participants with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), excluding those with the 17p deletion, to evaluate a debulking strategy that would enable all participants to receive subsequent venetoclax as outpatients, with lower risk of tumor lysis syndrome.

Detailed Description
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Safety and efficacy data through 13 October 2021 are included in the interim analysis, which was conducted after all participants completed the post-treatment Week 65 visit or discontinued from the study.

Official Title
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A Phase 3b Study in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Subjects, Excluding Those With the 17p Deletion, to Evaluate Debulking Regimens Prior to Initiating Venetoclax Combination Therapy

Conditions
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Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate hematology, kidney and liver function as described in the protocol Diagnosis of previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) according to 2008 Modified International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-sponsored Working Group (IWCLL NCI-WG) criteria Eastern Cooperative Oncology Group (ECOG) performance score of 0 - 1 CLL requires treatment according to the IWCLL criteria Medium tumor burden (any lymph node [LN] 5 to < 10 cm OR absolute lymphocyte count [ALC] ≥ 25 × 10^9/L) OR High tumor burden (any LN ≥ 10 cm OR ALC ≥ 25 × 10^9/L and LN ≥ 5 cm) Exclusion Criteria: Presence of 17p deletion at Screening Richter's syndrome (transformation of CLL/SLL to aggressive non-Hodgkin's lymphoma or Hodgkin's lymphoma) Prolymphocytic leukemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab<br>Obinutuzumab (100 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 Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. | Drug: Obinutuzumab<br>* Administered via intravenous infusion<br>* Other names: Gazyva;Drug: Venetoclax<br>* The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Participants were instructed to take venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.<br>* Other names: GDC-0199;|
| Experimental: Obinutuzumab/bendamustine<br>Obinutuzumab (100 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 Day 1 of Cycle 2; for Cycles 3 - 6 (1000 mg on Day 1) only as needed for participants to achieve low tumor burden) was administered via intravenous infusion during the debulking regimen. Bendamustine (90 mg/m^2 ) was to be administered to those with nodes or nodal mass > 10 cm, or with del(11q) and > 5 cm nodes, or at the discretion of the investigator as above, via intravenous infusion over 10 minutes on Days 1 and 2 (or Days 2 and 3 at the discretion of the investigator during Cycle 1) of each 28-day cycle for up to 6 cycles during the debulking regimen. After debulking, obinutuzumab (1000 mg) was administered via intravenous infusion on Day 1 of one 5-week and four 4-week cycles during the obinutuzumab/venetoclax combination part of the regimen. Venetoclax was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. | Drug: Obinutuzumab<br>* Administered via intravenous infusion<br>* Other names: Gazyva;Drug: Bendamustine<br>* Administered via intravenous infusion<br>* Other names: Bendeka;Drug: Venetoclax<br>* The venetoclax dose was administered according to a weekly ramp-up schedule over 5 weeks to the recommended daily dose of 400 mg. Participants were instructed to take venetoclax tablets with a meal and water at approximately the same time each day. Venetoclax tablets were to be swallowed whole and not chewed, crushed, or broken prior to swallowing.<br>* Other names: GDC-0199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Low Tumor Burden Status With Induction of Obinutuzumab or Obinutuzumab Plus Bendamustine (Debulking Period) | Low tumor burden is defined as absolute lymphocyte count (ALC) < 25 × 10^9 /L and all lymph nodes < 5 cm per computed tomography (CT) scans. | From Baseline to the end of Cycles 2, 4, and 6, up to approximately 24 weeks after initial dose of study drug | 
| Complete Response Rate | Complete response rate is defined as the percentage of participants achieving complete remission (CR) or complete remission with incomplete marrow recovery (CRi) as their best response based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: Peripheral blood lymphocytes <4000/μL Absence of lymphadenopathy by physical examination and computed tomography scan No hepatomegaly or splenomegaly by physical examination Absence of disease or constitutional symptoms (unexplained fevers >38°C, drenching night sweats, ≥10% weight loss in last 6 months) Blood counts above the following: Neutrophils >1500/μL Platelets >100,000/μL Hemoglobin >11.0 g/dL Bone marrow at least normocellular for age, <30% lymphocytes CRi was defined as participants with CR who had persistent cytopenia unrelated to CLL but related to drug toxicity. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieved a best response of complete remission (CR), complete remission with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) based on the 2008 Modified IWCLL NCI-WG criteria at any time during the study as assessed by investigator up through the completion of the 65-week disease response assessment after the start of venetoclax. Participants who did not respond were considered non-responders. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 
| Duration of Response (DoR) | DoR is defined as the number of days from the date of first response (CR, CRi, nPR, or PR per the 2008 Modified IWCLL NCI-WG criteria) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug (either venetoclax, obinutuzumab, or bendamustine). Duration of response was analyzed by Kaplan-Meier (K-M) methodology. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 
| Progression-Free Survival (PFS) | PFS is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of disease progression or death, whichever occurs first. All disease progression was to be included regardless whether the event occurred during or after the participant was taking any study drug. Progression-free survival was analyzed by Kaplan-Meier methodology. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 
| Time to Progression (TTP) | TTP is defined as the number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to date of disease progression. All disease progression was to be included regardless of whether the event occurred during or after the participant was taking any study drug.The distribution of the time to progression was estimated using Kaplan-Meier methodology. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 
| Overall Survival (OS) | OS is defined as number of days from the date of first dose of any study drug (either venetoclax, obinutuzumab, or bendamustine) to the date of death. If a participant had not died, their data was censored at the date when they were last known to be alive prior to the cutoff date.The distribution of OS was estimated using Kaplan-Meier methodology. | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021); overall median time on follow-up was up to 787 days | 
| Undetectable Minimal Residual Disease (UMRD) Rate | The level of MRD was assessed in the peripheral blood of all participants at 5 months after last dose of obinutuzumab, and at 3 months after last dose of venetoclax/end of treatment (including early study termination) to determine the rate of UMRD. Undetectable Minimal Residual Disease is defined as less than one CLL cell per 10,000 leukocytes (< 10^-4 ). | From first dose of study drug until the last participant completed Week 65 assessments (data cut-off date of 13 October 2021) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Chronic Lymphocytic Leukemia, 17p Deletion, Debulking, Obinutuzumab, Bendamustine, Tumor lysis syndrome, Venetoclax, Small Lymphocytic Lymphoma