Recruiting
Phase 2

Venetoclax & Zanubrutinib

Sponsor:

Kerry Rogers

Code:

NCT07734038

Conditions

Chronic Lymphocytic Leukemia

Small Lymphocytic Lymphoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biospecimen Collection

Bone Marrow Aspiration

Bone Marrow Biopsy

Computed Tomography

Magnetic Resonance Imaging

Study Details

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

Study ID

NCT07734038

Start date

Oct 1, 2026

Status verified date

Aug, 2026

Completion date

Dec 31, 2027

Anticipated

Primary completion date

Dec 31, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • 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
  • Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented liver involvement and/or Gilbert's disease
  • Creatinine clearance (CrCl) ≥ 50 according to modified Cockcroft-Gault equation
  • Willing and able to complete study activities and treatment
  • Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
  • Willingness of men and women of reproductive potential and their partners to observe conventional and highly effective or acceptable birth control methods for the duration of treatment and for 1 week following the last dose of zanubrutinib or 30 days following the last dose of venetoclax, whichever is longer

Exclusion Criteria:

  • 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:

  • Unstable angina or acute coronary syndrome within the past 2 months
  • History of myocardial infarction within 3 months
  • Documented left ventricular ejection fraction (LVEF) by any method of ≤ 40% within 12 months
  • ≥ grade 3 New York Heart Association (NYHA) functional classification system of heart failure
  • Uncontrolled or symptomatic arrhythmias

  • Note: Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker
  • Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec. QTcF is calculated using Fridericia's Formula (QTcF)

  • Correction of suspected drug induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
  • Correction for underlying bundle branch block (BBB) allowed
  • Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below:

  • Hepatitis B virus (HBV): Patients with positive hepatitis B surface antibody (HBsAb) are not excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before inclusion. Patients who are hepatitis B PCR positive at time of screening will be excluded. Those who have hepatitis B core antibody positive and a negative PCR will be included if they are agreeable to receive antiviral prophylaxis
  • Hepatitis C virus (HCV): If hepatitis C antibody is positive, patients will need to have a negative result for hepatitis C ribonucleic acid (RNA) before inclusion. Patients who are hepatitis C RNA positive at time of screening will be excluded. Patients previously treated for hepatitis C > 6 months previously with a negative RNA test are eligible
  • Patients who are receiving intravenous immunoglobulin (IVIG) who test positive for any hepatitis B or C serologies and have a negative PCR and who are deemed likely to have received antibodies passively through IVIG and not from prior infection will be included without viral prophylaxis
  • Treatment with a strong cytochrome P450 (CYP)3A inhibitor or inducer and/or strong P-glycoprotein (P-gp) inhibitors within 3 days of starting and during study treatment
  • Patients may not plan to consume grapefruit or grapefruit products, Seville oranges or products from Seville oranges, or star fruit
  • Pregnancy, lactation, or plan to breastfeed during treatment with or within 2 weeks of the last dose of zanubrutinib or 1 month of the last dose of venetoclax
  • Major surgery within 4 weeks prior to screening
  • Vaccination with live vaccine within 28 days of screening
  • Currently incarcerated
  • Current central nervous system involvement by CLL/SLL

Study Design

Enrollment

155 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Cohort I (SOC zanubrutinib, venetoclax)

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.

experimental: Cohort II (SOC zanubrutinib, venetoclax)

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.

Interventions

Biospecimen Collection

Undergo blood sample collection

Bone Marrow Aspiration

Undergo bone marrow biopsy and aspiration

Bone Marrow Biopsy

Undergo bone marrow biopsy and aspiration

Computed Tomography

Undergo CT

Magnetic Resonance Imaging

Undergo MRI

Venetoclax

Given PO

Zanubrutinib

Given PO

Primary outcome measure

  • Rate of undetectable minimal residual disease (uMRD) (Firstline Cohort) [ Time Frame: At end of cycle 15 (cycle length = 28 days) ]
  • Rate of uMRD (Second Line Cohort) [ Time Frame: At end of cycle 27 (cycle length = 28 days) ]

Central Contacts and Locations

Central contacts

The Ohio State University Comprehensive Cancer Center

800-293-5066OSUCCCClinicaltrials@osumc.edu

Locations

Ohio State University Comprehensive Cancer Center

Recruiting

Columbus, Ohio, United States, 43210

Contacts

Kerry A. Rogers, MD

614-366-9338Kerry.Rogers@osumc.edu

Principal Investigator:

Kerry A. Rogers, MD

More Information

Sponsor

Kerry Rogers

Last update posted

Aug 31, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-06. This information was provided to ClinicalTrials.gov by Kerry Rogers on 2026-08-31.