Venetoclax Plus Zanubrutinib for the Treatment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

NCT07734038 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: OSU-25150NCI-2026-05223STUDY20251617
• Study Type: interventional
• Target: 155
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial tests the effect of venetoclax in combination with standard of care (SOC) zanubrutinib in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax 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 blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. It is a type of tyrosine kinase inhibitor. Giving venetoclax in combination with SOC zanubrutinib may be safe and tolerable and may reduce the number of cancer cells that remain in the body in patients with CLL or SLL that have not previously received treatment or at least two years have passed since completing initial treatment.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (2)

• Rate of undetectable minimal residual disease (uMRD) (Firstline Cohort)

  Will be defined as \< 1 x 10\^-4 by ClonoSEQ in the peripheral blood, after 12 cycles of combined venetoclax plus zanubrutinib assessed by ClonoSEQ. Will be calculated separately in each cohort among all eligible patients who start any amount of study drug, and the 95% exact confidence interval will be provided with the estimated rate.

  At end of cycle 15 (cycle length = 28 days)

• Rate of uMRD (Second Line Cohort)

  Will be defined at \< 1 x 10\^-4 by ClonoSEQ in the peripheral blood, after 24 cycles of combined venetoclax plus zanubrutinib. Will be calculated separately in each cohort among all eligible patients who start any amount of study drug, and the 95% exact confidence interval will be provided with the estimated rate.

  At end of cycle 27 (cycle length = 28 days)

Secondary Outcomes (13)

• Overall response rate (Frontline Cohort)

  Up to 5 years

• Rate of complete remission (Frontline Cohort)

  Up to 5 years

• Duration of clinical response (Frontline Cohort)

  From date of achieving response to progression or death, assessed up to 5 years

• Duration of uMRD if achieved (Frontline Cohort)

  From date of achieving uMRD to progression or death, assessed up to 5 years

• Time to next treatment (Frontline Cohort)

  From date of treatment start to the start date of the next treatment, assessed up to 5 years

Study Arms (2)

Cohort I (SOC zanubrutinib, venetoclax)

EXPERIMENTAL

Patients receive SOC zanubrutinib PO QD or BID per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow biopsy and aspiration, and CT or MRI throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Venetoclax; Drug: Zanubrutinib

Cohort II (SOC zanubrutinib, venetoclax)

EXPERIMENTAL

Patients receive SOC zanubrutinib PO QD or BID per physician discretion on days 1-28 of each cycle. Starting with cycle 4, patients also receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, bone marrow biopsy and aspiration, and CT or MRI throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Venetoclax; Drug: Zanubrutinib

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow biopsy and aspiration

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy and aspiration

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Venetoclax DRUG

Given PO

Also known as: ABT 199, ABT-0199, ABT-199, ABT199, GDC 0199, GDC-0199, GDC0199, RG7601, Venclexta, Venclyxto

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Zanubrutinib DRUG

Given PO

Also known as: BGB 3111, BGB-3111, BGB3111, Brukinsa, BTK-InhB

Cohort I (SOC zanubrutinib, venetoclax); Cohort II (SOC zanubrutinib, venetoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of CLL/SLL meeting criteria established in International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria
• Age ≥ 18 years
• Indications for treatment as defined by the iwCLL 2018 Guidelines
• Received prior treatment or not depending on cohort
• Frontline cohort:
• CLL/SLL who are treatment-naïve and have met criteria 1 through 3 above
• Second line cohort:
• Must have received time-limited venetoclax based therapy in the front line. This is defined as treatment with venetoclax and an-anti-CD20 antibody, venetoclax and a BTKi, or treatment with venetoclax and a BTKi, and an anti-CD20 monoclonal antibody that was given for a fixed-duration. Patients who discontinue ibrutinib, due to intolerance, in a BTKi and venetoclax +/- obinutuzumab combination are eligible provided they completed other drugs in the regimen and in the opinion of the treating investigator the intolerance will not limit treatment with zanubrutinib and venetoclax. Patients who discontinued BTKi other than ibrutinib or who discontinued venetoclax due to intolerance will be excluded
• At least 2 years since completion of initial CLL treatment
• Only 1 prior line of therapy. Treatment with rituximab or other anti-CD20 monoclonal antibody for idiopathic thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) is not considered a prior line of CLL/SLL therapy
• Eastern Cooperative Oncology Group (ECOG) performance 0-2
• Absolute neutrophil count (ANC) \> 1000/mm\^3 (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Platelets \> 30,000/mm\^3 at screening (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Hemoglobin \> 7 g/dL (independent of growth factor support at screening, unless cytopenias are due to marrow involvement by CLL/SLL)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) or ≤ 5 x ULN with documented liver involvement

You may not qualify if:

• Second line arm only: Patients who progressed per iwCLL 2018 criteria on therapy or within two years of completing time-limited, venetoclax based treatment
• Frontline arm only: Patients with deletion 17p and/or TP53 mutation
• Active Richter's transformation
• Prior zanubrutinib exposure
• Known hypersensitivity to any of the excipients of zanubrutinib or venetoclax
• Need for treatment with warfarin or other vitamin K antagonist during study treatment
• History of stroke or intracranial hemorrhage within 6 months
• Known bleeding diathesis
• Inability to take pills or oral medications
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of either zanubrutinib or venetoclax
• Active second malignancy unless in remission and with life expectancy \> 2 years. Adjuvant endocrine therapy for breast or prostate cancer that is expected to be cured is allowed. Non-melanoma skin cancers are permitted if adequately treated
• Psychiatric illness, or social situations that would limit compliance with study requirements
• Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia \[AIHA\], idiopathic thrombocytopenic purpura \[ITP\]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrollment to maintain adequate blood counts
• Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator may pose a risk for patient participation. Screening for chronic conditions is not required
• Significant cardiovascular disease defined as:

Sponsors & Collaborators

• Kerry Rogers: lead
• AbbVie: collaborator

Study Sites (1)

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Links

• The Jamesline

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Specimen Handling; Biopsy; Magnetic Resonance Spectroscopy; venetoclax; 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

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Kerry A Rogers, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

The Ohio State University Comprehensive Cancer Center

CONTACT

800-293-5066; OSUCCCClinicaltrials@osumc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 24, 2026
• First Posted: July 29, 2026
• Study Start (Estimated): October 7, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: July 29, 2026

Record last verified: 2026-07

Locations

US (1)