Zanubrutinib and Venetoclax as Initial Therapy for Chronic Lymphocytic Leukemia (CLL) With Response-based Obinutuzumab
- Conditions
- Leukemia, Lymphocytic, Chronic, B-Cell
- Interventions
- Registration Number
- NCT05650723
- Lead Sponsor
- Weill Medical College of Cornell University
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Double Therapy (Zanubrutinib plus Venetoclax) Zanubrutinib Pill 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. Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab) Zanubrutinib Pill 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. Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab) Venetoclax Pill 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. Triple Therapy (Zanubrutinib, Venetoclax, and Obinutuzumab) Obinutuzumab Injection 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. Double Therapy (Zanubrutinib plus Venetoclax) Venetoclax Pill 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.
- Primary Outcome Measures
Name Time Method Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via bone marrow aspirate Cycle 23 (Month 23) 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.
Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via peripheral blood Cycle 16 (Month 16) 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.
Percentage of total patients that have achieved undetectable minimal residual disease (MRD) at cycle 16, as assessed via bone marrow aspirate Cycle 16 (Month 23) 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.
Percentage of eligible patients that have achieved undetectable minimal residual disease (MRD) at cycle 23, as assessed via peripheral blood Cycle 23 (Month 23) 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.
- Secondary Outcome Measures
Name Time Method Percentage of total participants who experience adverse events (AEs) through cycle 16 Cycle 16 (Month 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.
Percentage of participants receiving triplet therapy who experience AEs through cycle 23 Cycle 23 (Month 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.
36-month Progression Free Survival (PFS) 36 months 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.
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 36 months 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-month Time to Next Treatment (TTNT) 36 months 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-month Overall Survival (OS) 36 months 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.
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 24 months 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.
Overall Response rate 36 months Overall response rate including all categories of response will be tabulated and calculated as total percentage of patients achieving a specific response on an intention to treat basis.
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 36 months 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.
Percentage Change in Tumor Lysis Syndrome (TLS) Risk Score From Baseline to Cycle 4 Baseline; Cycle 4, Day 1 (Month 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.
Trial Locations
- Locations (1)
Weill Cornell Medicine/NewYork-Presberteryian Hospital
🇺🇸New York, New York, United States