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

NCT07321652 | Not Yet Recruiting Phase 3

• 1 other identifier: A042302
• Study Type: interventional
• Target: 466
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  From initial randomization date until the earlier of disease progression or death from any cause. PFS estimates for zanubrutinib plus sonrotoclax therapy to continuous Zanubrutinib.

  From initial randomization date until the earlier of disease progression or death from any cause, up to 10 years

Other Outcomes (7)

• PFS for patients with MRD detectable disease treated with fixed duration zanubrutinib sonrotoclax versus patients with MRD detectable disease who receive one additional year of combination therapy

  up to 10 years

• Overall survival

  Up to 10 years

• Percentage of patients with MRD detectable disease who convert to uMRD after receiving an extra year of combination therapy on the MRD-guided Zanubrutinib sonrotoclax therapy arm

  Up to 10 years

Study Arms (2)

Arm 1 (zanubrutinib)

ACTIVE COMPARATOR

Patients receive zanubrutinib PO 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 CT scan, bone marrow aspiration and blood sample collection throughout the study.

Drug: Zanubrutinib; Procedure: Computed Tomography; Procedure: Bone Marrow Aspiration; Procedure: Biospecimen Collection; Other: Survey Administration

Arm 2 (zanubrutinib and sonrotoclax)

EXPERIMENTAL

Patients receive zanubrutinib PO BID on days 1-28 of each cycle. Starting cycle 4 day 1 patients also receive sonrotoclax PO 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, 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

Drug: Zanubrutinib; Drug: Sonrotoclax; Procedure: Computed Tomography; Procedure: Bone Marrow Aspiration; Procedure: Biospecimen Collection; Other: Survey Administration

Interventions

Zanubrutinib DRUG

Given PO

Arm 1 (zanubrutinib); Arm 2 (zanubrutinib and sonrotoclax)

Sonrotoclax DRUG

Given PO

Arm 2 (zanubrutinib and sonrotoclax)

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CT Scan, Cat Scan

Arm 1 (zanubrutinib); Arm 2 (zanubrutinib and sonrotoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Arm 1 (zanubrutinib); Arm 2 (zanubrutinib and sonrotoclax)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Arm 1 (zanubrutinib); Arm 2 (zanubrutinib and sonrotoclax)

Survey Administration OTHER

Ancillary studies

Arm 1 (zanubrutinib); Arm 2 (zanubrutinib and sonrotoclax)

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• STEP 0: This bone marrow or peripheral blood submission to Adaptive is mandatory prior to registration/randomization for real-time identification of the clone needed for MRD testing. The bone marrow sample should be from the first aspiration (i.e., first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be obtained as soon after pre-registration as possible to confirm registration eligibility
• STEP 0: Patients must be diagnosed with CLL/SLL according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria that includes all of the following:
• ≥ 5 x10\^9 /L B lymphocytes (5000/μL) in the peripheral blood (CLL) or a lymph node biopsy demonstrating SLL with the below immunophenotype (SLL)
• On morphologic review, the leukemic cells must be small mature lymphocytes
• Immunophenotype of CLL cells (performed locally) must reveal a clonal B-cell population, which coexpress the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in \> 10% of cells must lack t(11;14) translocation by interphase cytogenetics
• STEP 0: Patients must meet criteria for treatment as defined by IWCLL 2018 guidelines which includes at least one of the following criteria:
• Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia), typically hemoglobin (Hb) \< 10 g/dL, platelet count \< 100,000/mm\^3
• Massive (\> 6 cm below the costal margin), progressive or symptomatic splenomegaly
• Massive nodes (ie, \> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
• Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
• Constitutional symptoms, which include any of the following:
• Unintentional weight loss of ≥ 10% within the previous 6 months
• Significant fatigue (ie. Eastern Cooperative Oncology Group \[ECOG\] performance status \[PS\] ≥ 2)
• Fevers \>100.5 °F or 38.0°C for 2 weeks or more without evidence of infection
• Night sweats \> 1 month without evidence of infection

Sponsors & Collaborators

• Alliance for Clinical Trials in Oncology: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

zanubrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Jennifer R Brown, MD

  Alliance for Clinical Trials in Oncology

  STUDY CHAIR

Central Study Contacts

Jayke Giese

CONTACT

773-702-9171; leukemiaprotocols@alliancenctn.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2026
• First Posted: January 7, 2026
• Study Start: January 15, 2026
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2038
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share