Zanubrutinib and Venetoclax in CLL (ZANU-VEN)

NCT05168930 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 21-279
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 4

Brief Summary

This study is being done to test the effectiveness of zanubrutinib in combination with venetoclax in participants with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Conditions

Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL)

Keywords

Zanubrutinib; Venetoclax

Outcome Measures

Primary Outcomes (1)

• Rate of undetectable minimal residual disease (uMRD)

  Assessed by flow cytometry (FC)

  At the end of cycle 15 (each cycle is 28 days)

Secondary Outcomes (6)

• Overall response Rate (ORR)

  At the end of cycle 15 (each cycle is 28 days)

• Complete Response (CR) Rate

  At the end of cycle 15 (each cycle is 28 days)

• Percentage of undetectable minimal residual disease (uMRD) in bone marrow with CR

  At the end of cycle 15 (each cycle is 28 days)

• Percentage of uMRD in peripheral blood

  After cycle 15At the end of cycle 15 (each cycle is 28 days)

• Progression-free survival (PFS)

  1 and 3 years after treatment initiation

Study Arms (3)

Cohort A: BTKi and BCL2i naive

EXPERIMENTAL

Participants who have never received a BTK inhibitor or a BCL-2 inhibitor

Drug: Venetoclax; Drug: Zanubrutinib

Cohort B: BTKi or BCL2i exposed without disease progression

EXPERIMENTAL

Participants who have received prior treatment with a BTK or BCL-2 inhibitor and discontinued treatment for any reason other than disease progression

Drug: Venetoclax; Drug: Zanubrutinib

Cohort C: BTKi exposed and with disease progression

EXPERIMENTAL

Participants who experienced disease progression on a prior BTK inhibitor. Participants with BTK C481X mutation at enrollment will be excluded.

Drug: Venetoclax; Drug: Zanubrutinib

Interventions

Zanubrutinib DRUG

C1-15

Also known as: Brukinsa

Cohort A: BTKi and BCL2i naive; Cohort B: BTKi or BCL2i exposed without disease progression; Cohort C: BTKi exposed and with disease progression

Venetoclax DRUG

C4-15

Also known as: Venclexta

Cohort A: BTKi and BCL2i naive; Cohort B: BTKi or BCL2i exposed without disease progression; Cohort C: BTKi exposed and with disease progression

Eligibility Criteria

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

You may qualify if:

• Confirmed diagnosis of CLL or SLL as per 2018 International Workshop on CLL (IWCLL) criteria.
• Participants must have relapsed after at least one prior line of therapy and must currently require therapy by 2019 IWCLL criteria.
• For enrollment to Cohort A: Participants must be covalent BTK and BCL-2 inhibitor naïve. Participants who have received prior therapy with a covalent BTK or BCL-2 inhibitor are not eligible, including but not limited to prior treatment with ibrutinib or acalabrutinib.
• For enrollment to Cohort B: Participants must have had prior treatment with a BTK inhibitor or a BCL-2 inhibitor, but not both, and must not have experienced disease progression as defined by iwCLL criteria while receiving therapy.
• For enrollment to Cohort C: participants must have a disease that progressed during therapy with a covalent BTK inhibitor, not including zanubrutinib.
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of zanubrutinib and venetoclax in participants \< 18 years of age and CLL/SLL is extremely rare in this population, children are excluded from this study.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).
• Participants must have adequate organ function as defined below:
• Platelet count ≥ 20,000/mcL
• Total bilirubin ≤ 2 × institutional upper limit of normal (ULN) (unless due to controlled hemolysis, Gilbert's disease, or is of non-hepatic origin)
• AST (SGOT) and ALT (SGPT) ≤ 4 × institutional ULN
• Serum Creatinine ≤ 1.5 × institutional ULN, OR
• Calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-Gault formula)
• The effects of zanubrutinib or venetoclax on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study agent administration.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Known BTK C481X mutation.
• For enrollment to Cohort B: participants who have received prior treatment with both a BTK inhibitor and BCL-2 inhibitor.
• Participants who have had previous anti-cancer therapy (e.g., chemotherapy, radiotherapy, immunotherapy, biologic therapy, hormonal therapy, surgery, investigational agents, and/or tumor embolization) within 2 weeks of Cycle 1 Day 1 with the following exceptions:
• Hormonal therapy given in the adjuvant setting
• Corticosteroid therapy (prednisone or equivalent ≤ 20 mg daily) is allowed as clinically warranted as long as the dose is stabilized at least for 7 days prior to initial dosing. Topical, inhaled, intra-articular, or ophthalmologic corticosteroids are permitted
• Participants enrolling to Cohort C may remain on prior BTK inhibitor therapy up until 2 days prior to Cycle 1 Day 1
• History of a prior allogeneic hematologic stem cell transplant.
• Participants with known central nervous system (CNS) involvement, because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with no known history of CNS involvement are not required to undergo CT scan or lumbar puncture (LP) for trial eligibility unless the participant is symptomatic as judged by the treating investigator.
• Participants who are receiving any other investigational agents at the time of study entry.
• History of other malignancies, with the following exceptions:
• Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
• Low-risk prostate cancer on active surveillance
• Participants who have been vaccinated with live, attenuated vaccines \< 4 weeks prior to Cycle 1 Day 1.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• BeiGene: collaborator

Study Sites (4)

New England Cancer Specialists

Scarborough, Maine, 04074, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

South Shore Hospital

South Weymouth, Massachusetts, 02190, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

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

Study Officials

• Inhye E Ahn, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

DFCI Clinical Trials Hotline

CONTACT

877-DF-TRIAL; DFCILymphomaResearchNurses@partners.org

Study Design

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

Study Record Dates

• First Submitted: December 9, 2021
• First Posted: December 23, 2021
• Study Start: February 18, 2022
• Primary Completion (Estimated): October 28, 2026
• Study Completion (Estimated): October 28, 2028
• Last Updated: December 5, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (4)