Zanubrutinib and Venetoclax as Initial Therapy for Chronic Lymphocytic Leukemia (CLL) With Response-based Obinutuzumab

Study Overview
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Brief Summary
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Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and the B cell lymphoma 2 inhibitor (BCL-2i) venetoclax are drug classes used to treat patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). Anti-CD20 therapy may not be required for all patients. The investigators hypothesis is that it may be better to give anti-CD20 therapy (obinutuzumab) only to patients that still have detectable cancer in their blood (minimal residual disease [MRD]) after being treated with a combination of two oral medications, zanubrutinib (a BTKi ) and venetoclax (a BCL-2i), instead of giving a combination of three drugs to all patients from the start of treatment. This strategy, if effective, will prevent overtreatment with anti-CD20 antibodies; reduce side effects of treatment while potentially increasing MRD negativity rates; and will possibly make the anti-CD20 antibody therapy more effective given the low tumor burden present when utilized. This study will test this hypothesis by treating subjects with 3 cycles of a zanubrutinib monotherapy lead-in, in order to debulk and mitigate tumor lysis risk, followed by 13 cycles of zanubrutinib and venetoclax combination therapy. Subjects who are both peripheral blood and bone marrow MRD negative at the completion of the 13 cycles of combination therapy will stop treatment and enter an observation phase every 3 months. Subjects that are MRD positive will continue combination therapy with zanubrutinib and venetoclax for an additional 6 cycles but also receive 6 cycles of obinutuzumab in order to augment response and increase MRD negative rates for the overall treated cohort.

Detailed Description
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This is an open label, phase II, investigator-initiated clinical trial of 50 subjects. Subjects with CLL/SLL who have treatment indications per the 2018 International Workshop for CLL (iwCLL) will be eligible to enroll. The investigators hypothesize that anti-CD20 therapy may not be required for all patients and a response-adapted strategy will prevent over treatment of a significant number of patients and reduce toxicity of treatment while still achieving a high rate of MRD negativity. The investigators also hypothesize that late addition of anti-CD20 therapy can eliminate low burden residual disease in subjects and maximize undetectable MRD negativity in subjects who remain MRD positive. All subjects will initiate induction therapy with 3 cycles of zanubrutinib monotherapy in order to debulk subjects and mitigate tumor lysis risk. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination. Standard ramp-up protocols for venetoclax based on TLS risk assessed prior to C4D1 will be utilized. All subjects will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD assessments will occur at C16D1. Subjects will continue on combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all subjects will be on treatment for at least 16 full cycles. Subjects that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Subjects that meet definition of MRD positivity will continue combination therapy with zanubrutinib and venetoclax, but will also receive 6 cycles of obinutuzumab starting at C17D1. In this subgroup, peripheral blood and bone marrow MRD assessments will occur after an additional 6 cycles of the triplet combination therapy (C23D1) at which point all subjects will stop study treatment regardless of MRD status.

Official Title
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Zanubrutinib and Venetoclax as Initial Therapy for CLL With Obinutuzumab Consolidation in Patients With Minimal Residual Disease Positivity (BruVenG)

Conditions
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Leukemia, Lymphocytic, Chronic, B-Cell

Intervention / Treatment
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* Drug: Zanubrutinib Pill
* Drug: Venetoclax Pill
* Drug: Obinutuzumab Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have confirmed diagnosis of CLL/SLL Participant must have indications for treatment Participants of childbearing potential must be willing to comply with pregnancy prevention interventions Exclusion Criteria: Previous exposure to any systemic anti-cancer therapy as a treatment for CLL/SLL, including but not limited to chemotherapy, immunotherapy, radiotherapy, hormone therapy (other than contraceptives, hormone-replacement therapy or megestrol acetate) or investigational therapy. History of malignancy except for non-melanoma skin cancers. Participants treated with curative intent via methods of local resection and or locally targeted anticancer treatment and are free of malignancy for at least 5 years from treatment end will be allowed to enroll. Requires chronic immunosuppressive therapy for any reason or was treated with immunosuppressive therapy within 6 months of study entry. Participants with active autoimmune hemolytic anemia or immune thrombocytopenia purpura. Prolymphocytic leukemia or Richter's Transformation. Active bleeding, or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease). Participant requires warfarin or equivalent vitamin K antagonist. Uncontrolled or active significant infection requiring systemic treatment History of suspected or confirmed PML Myocardial infarction within 6 months before screening. Unstable angina within 3 months before screening. New York Heart Association class III or IV congestive heart failure History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes). Patients with stroke or CNS hemorrhage within 6 months. Pregnant or breastfeeding. Major surgical procedure within 28 days of first dose of study drug. Has difficulty with or is unable to swallow oral medication or has significant gastrointestinal disease that would limit absorption of oral medication. Participant is positive for human immunodeficiency virus (HIV). Known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use. Vaccination with live vaccine ≤28 days prior to start of treatment.

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: Double Therapy (Zanubrutinib plus Venetoclax)<br>All participants will receive an initial 3 cycles of zanubrutinib monotherapy. This lead-in period will then be followed by 12 cycles of zanubrutinib and venetoclax combination therapy. All participants will complete 12 cycles of zanubrutinib and venetoclax combination therapy or 15 cycles of total treatment. Peripheral blood and bone marrow MRD assessments will occur at C16D1. Participants will continue on double combination treatment for an additional 1 month while results of MRD testing are obtained. In total, all participants will be on treatment for at least 16 full cycles. Participants that meet definition of MRD negativity will stop therapy at C17D1 and enter an observation phase with study visits every 3 months. Participants that remain MRD positive at C16D1 will enter the triple therapy (zanubrutinib, venetoclax, and obinutuzumab) arm. | Drug: Zanubrutinib Pill<br>* 320 mg once per day by mouth<br>* Other names: Brukinsa;Drug: Venetoclax Pill<br>* 400 mg once per day by mouth following the standard ramp-up schedule (20mg daily PO week 1, 50mg daily PO week 2, 100mg daily PO week 3, 200mg daily PO week 4, followed by 400mg PO daily week 5)<br>* Other names: Venclexta;|
| Experimental: Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab)<br>Participants that meet definition of MRD positivity at C16D1 will enter the triple therapy arm (zanubrutinib, venetoclax, and obinutuzumab). These participants will continue combination therapy with zanubrutinib and venetoclax, but will also receive 6 cycles of obinutuzumab starting at C17D1. In this subgroup, peripheral blood and bone marrow MRD assessments will occur after an additional 6 cycles of the triplet combination therapy (C23D1) at which point all participants will stop study treatment regardless of MRD status. | Drug: Zanubrutinib Pill<br>* 320 mg once per day by mouth<br>* Other names: Brukinsa;Drug: Venetoclax Pill<br>* 400 mg once per day by mouth following the standard ramp-up schedule (20mg daily PO week 1, 50mg daily PO week 2, 100mg daily PO week 3, 200mg daily PO week 4, followed by 400mg PO daily week 5)<br>* Other names: Venclexta;Drug: Obinutuzumab Injection<br>* 1000 mg IV given every 28 days<br>* Other names: Gazyva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via peripheral blood | The primary endpoint of C16 peripheral blood MRD negativity at cycle 16 will be represented as a percentage of total patients. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. A cycle is defined as 28 days. | Cycle 16 (Month 16) | 
| Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via bone marrow aspirate | The primary endpoint of C16 bone marrow MRD negativity at cycle 16 will be represented as a percentage of total patients. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. | Cycle 16 (Month 23) | 
| Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via peripheral blood | The co-primary endpoint of C23 peripheral blood MRD negativity rate will be presented as a percentage of patients that achieve undetectable MRD at C23, who were found to be MRD positive at C16 and went on to receive at least one dose of obinutuzumab. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. | Cycle 23 (Month 23) | 
| Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via bone marrow aspirate | The co-primary endpoint of C23 bone marrow MRD negativity rate will be presented as a percentage of patients that achieve undetectable MRD at C23, who were found to be MRD positive at C16 and went on to receive at least one dose of obinutuzumab. This will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. | Cycle 23 (Month 23) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of total participants who experience adverse events (AEs) through cycle 16 | The secondary endpoints measuring toxicity will be tabulated using CTCAE 5.0. Numbers of participants experiencing adverse events (AEs) will be represented as a percentage through cycle 16. | Cycle 16 (Month 16) | 
| Percentage of participants receiving triplet therapy who experience AEs through cycle 23 | The secondary endpoints measuring toxicity will be tabulated using CTCAE 5.0. Participants who were MRD positive at cycle 16 and who receive obinutuzumab will have AEs tabulated as a percentage of total patients in the obinutuzumab consolidation phase of the study. | Cycle 23 (Month 23) | 
| 36-month Progression Free Survival (PFS) | Thirty-six-month PFS will be determined via Kaplan-Meier methods. PFS will be defined as the time from first treatment day until progression or death from any cause, as assessed at 36 months. Patients who do not experience an event or lost to follow-up will be censored. | 36 months | 
| 36-month Overall Survival (OS) | 36-month OS will be determined via Kaplan-Meier methods. OS will be defined as the time from first treatment day until death from any cause as assessed at 36-months. Patients who do not experience an event or lost to follow-up will be censored. | 36 months | 
| Percentage of patients treated with doublet therapy (zanubrutinib and venetoclax) that have achieved undetectable minimal residual disease (MRD) at 24-months, as assessed via peripheral blood | The percentage of patients who were treated with doublet therapy of zanubrutinib and venetoclax who achieve undetectable MRD at 24 months, as assessed with via peripheral blood, will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. A cycle is defined as 28 days. | 24 months | 
| Percentage of patients treated with doublet therapy (zanubrutinib and venetoclax) that have achieved undetectable minimal residual disease (MRD) at 36-months, as assessed via peripheral blood | The percentage of patients who were treated with doublet therapy of zanubrutinib and venetoclax who achieve undetectable MRD at 36 months, as assessed with via peripheral blood, will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. A cycle is defined as 28 days. | 36 months | 
| Percentage of patients treated with triplet therapy (zanubrutinib and venetoclax) that have achieved undetectable minimal residual disease (MRD) at 36-months, as assessed via peripheral blood | The percentage of patients who were treated with triplet therapy who achieve undetectable MRD at 36 months, as assessed with via peripheral blood, will be calculated on both efficacy evaluable and intention to treat basis. These will be estimated with a 90% confidence interval using Clopper-Pearson method based on exact binomial distribution. A cycle is defined as 28 days. | 36 months | 
| 36-month Time to Next Treatment (TTNT) | 36-month TTNT will be determined via Kaplan-Meier methods. TTNT will be measured from the start of treatment to the date of next line of treatment after stopping therapy. Obinutuzumab consolidation will not be considered a second line of treatment. Any treatment directed at CLL after stopping therapy will be considered a next therapy. Subjects will be followed prospectively and for 36 months from start of initial therapy to calculate a 3 year TTNT. Subjects that die will be censored at time of death. | 36 months | 
| Percentage Change in Tumor Lysis Syndrome (TLS) Risk Score From Baseline to Cycle 4 | Tumor lysis risk of high, medium, or low will be collected at baseline/screening. After 3 cycles of zanubrutinib debulking, TLS risk will be reassessed prior to Cycle 4 day 1. Subjects will have their new assessment, high, medium, or low recorded. Change in TLS risk category will be reported in aggregate and as a percentage change after debulking. | Baseline; Cycle 4, Day 1 (Month 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia, CLL, Small Lymphocytic Lymphoma, SLL