NCT07321652

Testing the Addition of Anti-Cancer Drug Sonrotoclax, to the Standard Treatment Zanubrutinib, for Previously Untreated CLL/SLL

Phase III Evaluation of Fixed Duration Zanubrutinib Plus Sonrotoclax-Based Therapy Compared to Continuous Zanubrutinib in Previously Untreated Older Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

• Status: Not Yet Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 466 (estimated)
• Sponsor: Alliance for Clinical Trials in Oncology · Academic / Other
• Sex: All
• Age: 65 Years
• Healthy volunteers: Not accepted

Summary

This phase III trial compares the effect of adding sonrotoclax to zanubrutinib versus zanubrutinib alone for the treatment of patients with untreated chronic lymphoblastic leukemia (CLL)/small lymphocytic lymphoma (SLL). Sonrotoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Zanubrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. Giving sonrotoclax and zanubrutinib may be more effective than zanubrutinib alone for the treatment of untreated CLL/SLL.

Detailed description

PRIMARY OBJECTIVES: I. To compare the progression free survival (PFS) between minimal residual disease (MRD)-guided zanubrutinib sonrotoclax therapy to continuous zanubrutinib as control. II. To determine the PFS comparing fixed duration zanubrutinib sonrotoclax therapy to continuous zanubrutinib as control. SECONDARY OBJECTIVES: I. To compare the PFS between the patients with MRD-detectable disease treated with fixed duration zanubrutinib sonrotoclax to the PFS of the patients with MRD detectable disease who receive one additional year of combination therapy. II. To determine the overall survival of all arms of the study. III. To determine the frequency of patients with MRD-detectable disease who convert to undetectable MRD, and at what depth and for how long, after receiving an extra year of combination therapy on the MRD-guided zanubrutinib sonrotoclax therapy arm. IV. To determine and compare the overall response rate (ORR defined as PR, CR, CCR, CRi) and complete remission rate (CR) after 14 cycles of therapy among the three arms. V. To compare time to the next CLL/SLL therapy among treatment arms. VI. To determine the rates and severity of toxicity in each arm, with a particular focus on adverse events of special interest that include infections, cardiovascular events (arrhythmias, heart failure, hypertension), tumor lysis syndrome, bleeding events, cytopenias, and second malignancies. VII. To compare patient-reported symptomatic adverse events as assessed by the Patient Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) between arms 1 and 2. EXPLORATORY OBJECTIVES: I. To compare the best achieved rate of undetectable MRD (uMRD) between the fixed duration zanubrutinib sonrotoclax arm and the MRD guided zanubrutinib sonrotoclax arm. II. To compare rates of undetectable MRD measured by the immunoglobulin heavy chain (IGH) sequencing assay ClonoSeq (sensitivity 1 in 10\^-6) to undetectable MRD measured by standard six-color flow cytometry (uMRD4), and to compare results from bone marrow to peripheral blood. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive zanubrutinib orally (PO) twice daily (BID) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo restaging starting at cycle 15 day 1. Patients with at least partial remission continue therapy as described above. Patients with progressive disease proceed to follow up. Patients undergo computed tomography (CT) scan, bone marrow aspiration and blood sample collection throughout the study. ARM 2: Patients receive zanubrutinib PO BID on days 1-28 of each cycle. Starting cycle 4 day 1 patients also receive sonrotoclax PO daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo restaging starting at cycle 15 day 1. Patients with undetectable MRD and a response of PR, partial response with persistent lymphocytosis (PR-L), CR, CCR or CRi stop therapy at cycle 15 day 28 and proceed to follow up. Patients with detectable MRD and an objective response to therapy are re-randomized to arm 2B or arm 2C. ARM 2B: Patients continue zanubrutinib PO BID sonrotoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for an additonal 12 cycles in the absence of disease progression or unacceptable toxicity. ARM 2C: Patients discontinue therapy starting at cycle 15 day 28 and proceed to follow up. Patients undergo CT scan, bone marrow aspiration and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 3 years then every 6 months until 10 years for study registration. Patients with progression or the start of non protocol CLL directed therapy are followed every 6 months for 10 years from registration.

Conditions

• Chronic Lymphocytic Leukemia
• Small Lymphocytic Leukemia

Interventions

Type	Name	Description
DRUG	Zanubrutinib	Given PO
DRUG	Sonrotoclax	Given PO
PROCEDURE	Computed Tomography	Undergo CT scan
PROCEDURE	Bone Marrow Aspiration	Undergo bone marrow aspiration
PROCEDURE	Biospecimen Collection	Undergo blood sample collection
OTHER	Survey Administration	Ancillary studies

Timeline

• Start date: 2026-01-15
• Primary completion: 2028-09-30
• Completion: 2038-09-30
• First posted: 2026-01-07
• Last updated: 2026-01-07