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)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Leukemia
• Intervention / Treatment: Procedure: Biospecimen Collection; Other: Survey Administration; Procedure: Computed Tomography; Procedure: Bone Marrow Aspiration; Drug: Zanubrutinib; Drug: Sonrotoclax

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.

• Study Type: Interventional
• Enrollment (Estimated): 466
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jayke Giese; Phone Number: 773-702-9171; Email: leukemiaprotocols@alliancenctn.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
• STEP 0: Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)
• STEP 0: Treatment with rituximab and/or high-dose corticosteroids for autoimmune complications of CLL must be completed prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
• STEP 0: Age ≥ 65 years
• STEP 0: ECOG performance status ≤ 2
• STEP 0: Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
• STEP 0: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• STEP 0: Patients with a history of hepatitis C virus (HCV), infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• STEP 0: Patients must not be receiving active systemic anticoagulation with warfarin. Patients must be off warfarin therapy for at least 5 half-lives washout and with normal INR prior to enrollment
• STEP 0: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better.

Patients with acute cardiac events within 6 months prior to registration should be carefully evaluated for their suitability for enrollment

• STEP 0: No patients with a history of a severe bleeding disorder or a history of hemorrhagic stroke or intracranial hemorrhage
• STEP 0: No patients with known active progressive central nervous system (CNS) disease
• STEP 0: No known medical condition causing an inability to swallow oral formulations of agents
• STEP 1: The adaptive report confirming a measurable and trackable B cell clone
• STEP 1: Patients may not have had major surgery within 7 days of enrollment, or minor surgery within 5 days of enrollment. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician
• STEP 1: No patients with ongoing active fungal, bacterial or viral infection requiring systemic therapy except those described in the protocol document
• STEP 1: Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily
• STEP 1: Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics
• STEP 1: Patients must not have continued requirement for therapy with a strong CYP3A4/5 inhibitor or inducer. Any such inhibitor or inducer must have been discontinued at least 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug
• STEP 1: Absolute neutrophil count (ANC) ≥ 1,000/mm3 unless due to marrow involvement
• STEP 1: Platelet count ≥ 30,000/mm3
• STEP 1: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless due to liver involvement, hemolysis or Gilbert's disease)
• STEP 1: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 x upper limit of normal (ULN) unless due to disease infiltration of the liver
• STEP 1: Calculated (calc.) creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) ≥ 30 mL/min
• STEP 1: Urine protein to creatinine ratio < 1 or urine protein ≤ 1+
• STEP 2: Detectable MRD ≥ 10 residual clonal cells per million nucleated cells in peripheral blood at the C15 restaging evaluation from ClonoSEQ
• STEP 2: Response of PR, PR-L, CR, CCR or CRi to zanubrutinib sonrotoclax therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 (zanubrutinib); 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.	Procedure: Biospecimen Collection; Undergo blood sample collection; Other: Survey Administration; Ancillary studies; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT Scan; Cat Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Drug: Zanubrutinib; Given PO
Experimental: Arm 2 (zanubrutinib and sonrotoclax); 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	Procedure: Biospecimen Collection; Undergo blood sample collection; Other: Survey Administration; Ancillary studies; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT Scan; Cat Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Drug: Zanubrutinib; Given PO; Drug: Sonrotoclax; Given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Undetectable (u) MRD will be defined as < 10 in 1,000,000 (less than 1 in 10^-5 [uMRD5]) on peripheral blood, and the depth of response below that level, (i.e. down to 10^-6 [uMRD6]), will also be collected. Kaplan-Meier will be used to estimate survival curves, log-rank tests to compare between survival curves, and hazard ration (HRs) and associated 95% CIs will be reported.	up to 10 years
Overall survival	OS will be summarized using Kaplan-Meier methodology, with hazard ratios from a stratified Cox proportional hazards model and log-rank test results provided.	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	Proportions of number of MRD+ to uMRD conversion by total number of evaluable patients will be estimated with their corresponding 95% CIs.	Up to 10 years
Overall response rate among treatment arms	Overall response rate is defined as the highest response achieved during the first 15 cycles of treatment. A response is defined as a patients achieving PR+.	Up to 10 years
Time to next CLL/SLL therapy	Kaplan-Meier estimates and 95% CIs of TTNT. Time is measured as the time from the end of initial treatment to the initiation of subsequent treatment.	Up to 10 years
Adverse Event Rates and Severity	Frequency and severity of adverse events and tolerability for each embedded treatment regimen will be collected and summarized using descriptive statistics.	Up to 10 years
Patient-reported symptomatic adverse events	As assessed by the Patient Reported Outcome-Common Terminology Criteria for Adverse Events, the frequency and proportion of patients with a maximum baseline-adjusted composite score greater than 0 will be compared between arms using Fisher's exact test. Similarly, the frequency and proportion of patients with a maximum baseline-adjusted composite score greater than or equal to 3 will be compared between arms using Fisher's exact test.	Up to 10 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Jennifer R Brown, MD, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): January 15, 2026
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2038

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 5, 2026
• First Posted (Actual): January 7, 2026

Study Record Updates

• Last Update Posted (Actual): January 7, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; zanubrutinib
• Other Study ID Numbers: A042302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No