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Zanubrutinib and Venetoclax in CLL (ZANU-VEN)

Primary Purpose

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

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Venetoclax
Zanubrutinib
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia (CLL) focused on measuring Zanubrutinib, Venetoclax

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  • 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.
  • Ability to swallow and retain oral medication.

Exclusion Criteria:

  • 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.
  • 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.

Sites / Locations

  • New England Cancer SpecialistsRecruiting
  • Beth Israel Deaconess Medical CenterRecruiting
  • Dana-Farber Cancer InstituteRecruiting
  • South Shore HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort A: BTKi and BCL2i naive

Cohort B: BTKi or BCL2i exposed without disease progression

Cohort C: BTKi exposed and with disease progression

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Rate of undetectable minimal residual disease (uMRD)
Assessed by flow cytometry (FC)

Secondary Outcome Measures

Overall response Rate (ORR)
Assessed by 2018 IWCLL criteria
Complete Response (CR) Rate
Assessed by 2018 IWCLL criteria
Percentage of undetectable minimal residual disease (uMRD) in bone marrow with CR
Assessed by flow cytometry (FC)
Percentage of uMRD in peripheral blood
Assessed by flow cytometry (FC)
Progression-free survival (PFS)
Time since treatment initiation and alive without disease progression
Overall survival (OS)
Time since treatment initiation and alive

Full Information

First Posted
December 9, 2021
Last Updated
October 2, 2023
Sponsor
Dana-Farber Cancer Institute
Collaborators
BeiGene
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1. Study Identification

Unique Protocol Identification Number
NCT05168930
Brief Title
Zanubrutinib and Venetoclax in CLL (ZANU-VEN)
Official Title
A Phase 2 Trial of Zanubrutinib and Venetoclax in Previously Treated CLL/SLL Patients
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 18, 2022 (Actual)
Primary Completion Date
October 28, 2025 (Anticipated)
Study Completion Date
October 28, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
BeiGene

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Keywords
Zanubrutinib, Venetoclax

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort A: BTKi and BCL2i naive
Arm Type
Experimental
Arm Description
Participants who have never received a BTK inhibitor or a BCL-2 inhibitor
Arm Title
Cohort B: BTKi or BCL2i exposed without disease progression
Arm Type
Experimental
Arm Description
Participants who have received prior treatment with a BTK or BCL-2 inhibitor and discontinued treatment for any reason other than disease progression
Arm Title
Cohort C: BTKi exposed and with disease progression
Arm Type
Experimental
Arm Description
Participants who experienced disease progression on a prior BTK inhibitor. Participants with BTK C481X mutation at enrollment will be excluded.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
Venclexta
Intervention Description
C4-15
Intervention Type
Drug
Intervention Name(s)
Zanubrutinib
Other Intervention Name(s)
Brukinsa
Intervention Description
C1-15
Primary Outcome Measure Information:
Title
Rate of undetectable minimal residual disease (uMRD)
Description
Assessed by flow cytometry (FC)
Time Frame
At the end of cycle 15 (each cycle is 28 days)
Secondary Outcome Measure Information:
Title
Overall response Rate (ORR)
Description
Assessed by 2018 IWCLL criteria
Time Frame
At the end of cycle 15 (each cycle is 28 days)
Title
Complete Response (CR) Rate
Description
Assessed by 2018 IWCLL criteria
Time Frame
At the end of cycle 15 (each cycle is 28 days)
Title
Percentage of undetectable minimal residual disease (uMRD) in bone marrow with CR
Description
Assessed by flow cytometry (FC)
Time Frame
At the end of cycle 15 (each cycle is 28 days)
Title
Percentage of uMRD in peripheral blood
Description
Assessed by flow cytometry (FC)
Time Frame
After cycle 15At the end of cycle 15 (each cycle is 28 days)
Title
Progression-free survival (PFS)
Description
Time since treatment initiation and alive without disease progression
Time Frame
1 and 3 years after treatment initiation
Title
Overall survival (OS)
Description
Time since treatment initiation and alive
Time Frame
1 and 3 years after treatment initiation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria 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. Ability to swallow and retain oral medication. Exclusion Criteria: 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Heather Walker, MPH
Phone
877-DF-TRIAL
Email
heathera_walker@dfci.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Inhye E Ahn, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
New England Cancer Specialists
City
Scarborough
State/Province
Maine
ZIP/Postal Code
04074
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rachel Farris
Phone
207-303-3429
Email
farrir@newecs.org
First Name & Middle Initial & Last Name & Degree
John P Winters, III, MD
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jon Arnason, MD
First Name & Middle Initial & Last Name & Degree
Jon Arnason, MD
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Inhye E Ahn, MD
First Name & Middle Initial & Last Name & Degree
Inhye E Ahn, MD
Facility Name
South Shore Hospital
City
South Weymouth
State/Province
Massachusetts
ZIP/Postal Code
02190
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicole Hixon, RN
Email
Nicole_Hixon@DFCI.HARVARD.EDU
First Name & Middle Initial & Last Name & Degree
Nancy Kaddis, MD, MPH

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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.
IPD Sharing Time Frame
Data can be shared no earlier than 1 year following the date of publication
IPD Sharing Access Criteria
Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Learn more about this trial

Zanubrutinib and Venetoclax in CLL (ZANU-VEN)

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