Sonrotoclax + Zanubrutinib vs Venetoclax + Obinutuzumab for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
+222 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: BeiGene
Disqualifiers: Previous CLL treatment, Prolymphocytic leukemia, CNS involvement, PML, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The main objective of this study is to compare the efficacy of sonrotoclax plus zanubrutinib versus venetoclax plus obinutuzumab in participants with chronic lymphocytic leukemia (CLL)
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug combination Venetoclax and Obinutuzumab for treating Chronic Lymphocytic Leukemia?
Research shows that the drug combination of Venetoclax and Obinutuzumab is effective for treating Chronic Lymphocytic Leukemia (CLL). In the CLL14 trial, this combination led to longer progression-free survival and higher response rates compared to another treatment, chlorambucil plus obinutuzumab. It also maintained improvements in clinical outcomes during long-term follow-up.
12345Is the combination of Venetoclax and Obinutuzumab safe for treating chronic lymphocytic leukemia?
The combination of Venetoclax and Obinutuzumab has been shown to have an acceptable safety profile in treating chronic lymphocytic leukemia, with common side effects including neutropenia (a low level of white blood cells) and some infections, but no fatal infections were reported in first-line treatment. Most side effects can be managed with supportive care and dose adjustments.
12456What makes the combination of Sonrotoclax + Zanubrutinib unique for treating chronic lymphocytic leukemia?
The combination of Sonrotoclax + Zanubrutinib is unique because it pairs a novel BCL2 inhibitor (Sonrotoclax) with a Bruton’s tyrosine kinase (BTK) inhibitor (Zanubrutinib), potentially offering a new mechanism of action compared to the established venetoclax + obinutuzumab regimen, which is already known for its chemotherapy-free approach and effectiveness in improving progression-free survival in chronic lymphocytic leukemia.
12347Eligibility Criteria
This trial is for adults who haven't been treated for chronic lymphocytic leukemia (CLL) yet. They should be able to perform daily activities with ease or have only slight limitations (ECOG score 0-2), have measurable disease visible on scans, and their liver and kidneys must work well enough based on specific blood tests.Inclusion Criteria
I can take care of myself and am up and about more than half of my waking hours.
My kidneys work well enough (creatinine clearance ≥ 50 mL/min).
My liver tests are within the normal range set by the hospital.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either venetoclax plus obinutuzumab or sonrotoclax plus zanubrutinib. Venetoclax plus obinutuzumab involves intravenous administration and dose escalation over 12 cycles. Sonrotoclax plus zanubrutinib involves oral administration with dose escalation starting from Cycle 4 over 15 cycles.
48 weeks (12 cycles) for venetoclax plus obinutuzumab, 60 weeks (15 cycles) for sonrotoclax plus zanubrutinib
Follow-up
Participants are monitored for safety and effectiveness after treatment, with assessments including quality of life and disease progression.
Up to approximately 9 years
Open-label extension (optional)
Participants may opt into continuation of treatment long-term to assess overall survival and long-term safety.
Long-term
Participant Groups
The study aims to see which treatment works better for CLL: Sonrotoclax with Zanubrutinib or Venetoclax with Obinutuzumab. Participants will receive one of these combinations to compare their effectiveness in treating the condition.
2Treatment groups
Experimental Treatment
Active Control
Group I: Sonrotoclax Plus ZanubrutinibExperimental Treatment2 Interventions
Participants will receive from start of Cycle 1 a standard dose of zanubrutinib once or twice daily orally and in combination with sonrotoclax starting from Cycle 4 onwards at increasing doses until target dose is reached and continuing until end of Cycle 15 (each cycle is 28 days)
Group II: Venetoclax Plus ObinutuzumabActive Control2 Interventions
Participants will receive obinutuzumab 100mg intravenously on Day 1 Cycle 1, followed by 900 mg on Day 2 Cycle 1 (or alternatively receive 1000 mg intravenously on Day 1), followed by 1000 mg on Days 8 and 15 of Cycle 1 and thereafter on Day 1 of Cycles 2 through 6 (each cycle is 28 days) in combination with venetoclax at increasing doses until target dose is reached from Day 22 Cycle 1 until end of Cycle 12 (each cycles is 28 days)
Obinutuzumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
🇪🇺 Approved in European Union as Gazyva for:
- Chronic Lymphocytic Leukemia (CLL)
- Follicular Lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mount Sinai Comprehensive Cancer CenterMiami Beach, FL
Southeastern Regional Medical CenterNewnan, GA
James Cancer Hospital and Solove Research InstituteColumbus, OH
Cisss Des LaurentidesMontreal SaintJerome, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
BeiGeneLead Sponsor
References
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. [2020]Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.
Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.
Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting.
Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10-4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.
Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. [2022]This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.
Venetoclax Data Prompt Rethink of CLL Therapy. [2021]The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease.