Chronic Lymphocytic Leukemia (CLL)Phase 2NCT05168930
Zanubrutinib and Venetoclax in CLL (ZANU-VEN)
A Phase 2 study testing Venetoclax and Zanubrutinib in people with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL), run by Dana-Farber Cancer Institute at 4 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
- What is being tested?
- Venetoclax and Zanubrutinib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 4 sitesUnited States
- Study dates
- 18 Feb 2022to 28 Oct 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 16Show fewer
- 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.
- Ability to swallow and retain oral medication.
Who cannot join
- 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
Show all 28Show fewer
- 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.
- Recent infection requiring intravenous antibiotics completed ≤ 7 days before the first dose of study drug, or any uncontrolled active systemic infection.
- Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.
- History of stroke, intracranial hemorrhage, or recent major bleed within 6 months prior to study entry.
- Participants who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed with approval from the overall principal investigator).
- Participants who are known at the time of study entry to require concomitant treatment with any medications or substances that are moderate or strong CYP3A inhibitors or inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
- Known history of human immunodeficiency virus (HIV), active hepatitis C virus (HCV), or hepatitis B virus (HBV).
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to zanubrutinib or venetoclax.
- Participants with psychiatric illness/social situations that would limit compliance with study requirements.
- Pregnant women are excluded from this study because zanubrutinib and venetoclax are anti-cancer agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with zanubrutinib or venetoclax, breastfeeding should be discontinued if the mother is treated with zanubrutinib or venetoclax.
- Participants with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to study entry.
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the treating investigator's opinion, could compromise the participant's safety or the integrity of the trial.
- Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia.
Trial locations and contacts
4 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States4 sites, 4 recruiting
- Recruiting
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Jon Arnason, MD
Jon Arnason, MD
- Recruiting
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Inhye E Ahn, MD
Inhye E Ahn, MD
- Recruiting
New England Cancer Specialists
Scarborough, Maine, 04074
Patricia Collins, 207-303-3429, collip@newecs.org
John P Winters, III, MD
- Recruiting
South Shore Hospital
South Weymouth, Massachusetts, 02190
Nicole Hixon, RN, Nicole_Hixon@DFCI.HARVARD.EDU
Nancy Kaddis, MD, MPH
About this study
Official title: A Phase 2 Trial of Zanubrutinib and Venetoclax in Previously Treated CLL/SLL Patients
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).
Read the detailed description
This is an open-label, non-randomized phase 2 trial assessing the combination of zanubrutinib and venetoclax in adult participants with CLL or SLL who have relapsed after at least one prior therapy.
Participants will receive study treatment for 15 months initially. There is an option for an additional 12 months of re-treatment with study therapy at the time of disease recurrence. Participants will be followed for 36 months after they discontinue the study drugs.
The study will enroll up to 45 participants. BeiGene Ltd. is providing funding for the trial and the study drug zanubrutinib.
- Being tested
- Venetoclax, Zanubrutinib
- Keywords
- Zanubrutinib, Venetoclax
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VenetoclaxDrug
Also called Venclexta
C4-15
ZanubrutinibDrug
Also called Brukinsa
C1-15
| Study group | Role | What they receive |
|---|---|---|
| Cohort A: BTKi and BCL2i naive | Experimental | Participants who have never received a BTK inhibitor or a BCL-2 inhibitor Receives: 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 Receives: 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. Receives: Drug: Venetoclax; Drug: Zanubrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of undetectable minimal residual disease (uMRD)
Assessed by flow cytometry (FC)
Measured: At the end of cycle 15 (each cycle is 28 days)
Secondary outcomes (6)
Overall response Rate (ORR)
Assessed by 2018 IWCLL criteria
Measured: At the end of cycle 15 (each cycle is 28 days)
Complete Response (CR) Rate
Assessed by 2018 IWCLL criteria
Measured: At the end of cycle 15 (each cycle is 28 days)
Percentage of undetectable minimal residual disease (uMRD) in bone marrow with CR
Assessed by flow cytometry (FC)
Measured: At the end of cycle 15 (each cycle is 28 days)
Percentage of uMRD in peripheral blood
Assessed by flow cytometry (FC)
Measured: After cycle 15At the end of cycle 15 (each cycle is 28 days)
Progression-free survival (PFS)
Time since treatment initiation and alive without disease progression
Measured: 1 and 3 years after treatment initiation
Overall survival (OS)
Time since treatment initiation and alive
Measured: 1 and 3 years after treatment initiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2021
- Study start18 Feb 2022
- Primary completion28 Oct 2026 (estimated)
- Study completion28 Oct 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Lymphocytic Leukemia (CLL)Studies of the same condition, open and under way.
- More trials run by Dana-Farber Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dana-Farber Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- BeiGene
- Responsible party
- Principal investigator, Inhye Ahn, Dana-Farber Cancer Institute
- Investigators
- Inhye E Ahn, MD, Principal investigator, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05168930
- Sponsor's protocol ID
- 21-279
- Status last verified
- Dec 2025
- First submitted
- 9 Dec 2021
- Last updated
- 5 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Study at a glance
From the registry record, last updated by the sponsor on 5 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Trial of Zanubrutinib and Venetoclax in Previously Treated CLL/SLL Patients
- ClinicalTrials.gov ID
- NCT05168930
- Acronym / sponsor ID
- 21-279
- Keywords
- Zanubrutinib, Venetoclax
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Dana-Farber Cancer InstituteUniversity, hospital or other
- Collaborators
- BeiGene
- Study start
- 18 Feb 2022 (actual)
- Primary completion
- 28 Oct 2026 (estimated)
- Study completion
- 28 Oct 2028 (estimated)
- First posted
- 23 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
This is an open-label, non-randomized phase 2 trial assessing the combination of zanubrutinib and venetoclax in adult participants with CLL or SLL who have relapsed after at least one prior therapy.
Participants will receive study treatment for 15 months initially. There is an option for an additional 12 months of re-treatment with study therapy at the time of disease recurrence. Participants will be followed for 36 months after they discontinue the study drugs.
The study will enroll up to 45 participants. BeiGene Ltd. is providing funding for the trial and the study drug zanubrutinib.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort A: BTKi and BCL2i naive | Experimental | Drug: Venetoclax, Drug: ZanubrutinibParticipants who have never received a BTK inhibitor or a BCL-2 inhibitor |
| Cohort B: BTKi or BCL2i exposed without disease progression | Experimental | Drug: Venetoclax, Drug: ZanubrutinibParticipants who have received prior treatment with a BTK or BCL-2 inhibitor and discontinued treatment for any reason other than disease progression |
| Cohort C: BTKi exposed and with disease progression | Experimental | Drug: Venetoclax, Drug: ZanubrutinibParticipants who experienced disease progression on a prior BTK inhibitor. Participants with BTK C481X mutation at enrollment will be excluded. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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.
Key exclusion criteria (28 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VenetoclaxAlso: VenclextaC4-15 | Drug | Cohort A: BTKi and BCL2i naive, Cohort B: BTKi or BCL2i exposed without disease progression, Cohort C: BTKi exposed and with disease progression |
| ZanubrutinibAlso: BrukinsaC1-15 | Drug | Cohort A: BTKi and BCL2i naive, Cohort B: BTKi or BCL2i exposed without disease progression, Cohort C: BTKi exposed and with disease progression |
Primary outcome
Rate of undetectable minimal residual disease (uMRD)
Time frame: At the end of cycle 15 (each cycle is 28 days)
Assessed by flow cytometry (FC)
6 secondary outcomes
Overall response Rate (ORR)
Time frame: At the end of cycle 15 (each cycle is 28 days)
Complete Response (CR) Rate
Time frame: At the end of cycle 15 (each cycle is 28 days)
Percentage of undetectable minimal residual disease (uMRD) in bone marrow with CR
Time frame: At the end of cycle 15 (each cycle is 28 days)
Percentage of uMRD in peripheral blood
Time frame: After cycle 15At the end of cycle 15 (each cycle is 28 days)
Progression-free survival (PFS)
Time frame: 1 and 3 years after treatment initiation
Overall survival (OS)
Time frame: 1 and 3 years after treatment initiation
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Dec 2025.
- Individual participant dataSharing planned: Yes. The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Related trials for Chronic Lymphocytic Leukemia (CLL)
RecruitingPhase 2
Tafasitamab With Acalabrutinib and Venetoclax for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Not yet recruitingPhase 2
Nemtabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) Refractory to Covalent Bruton Tyrosine Kinase Inhibitor or Pirtobrutinib and Previously Treated With a BCL2 Inhibitor
Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia
RecruitingObservational study
Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)
Waldenstrom Macroglobulinemia, Lymphoplasmacytic Lymphoma
RecruitingPhase 3
A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010).
Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Chronic Lymphocytic
RecruitingObservational study
HPC Offered for PRESERVE Expansion
Bone Marrow Transplant (BMT)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Inhye E Ahn, MD principal investigator
Dana-Farber Cancer Institute
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Venetoclax and Zanubrutinib in people with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL), run by Dana-Farber Cancer Institute at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 5 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact DFCI Clinical Trials Hotline (877-DF-TRIAL, DFCILymphomaResearchNurses@partners.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of undetectable minimal residual disease (uMRD) (time frame: At the end of cycle 15 (each cycle is 28 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Dec 2025.