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Zanubrutinib + Venetoclax in CLL/SLL

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05168930
Recruitment Status : Recruiting
First Posted : December 23, 2021
Last Update Posted : March 31, 2022
Sponsor:
Collaborator:
BeiGene
Information provided by (Responsible Party):
Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute

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).

The names of the study drugs involved in this study are:

  • zanubrutinib (BGB-3111)
  • venetoclax

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma Drug: Venetoclax Drug: Zanubrutinib Phase 2

Detailed Description:

This is an open label, non-randomized phase 2 trial assessing the combination of zanubrutinib and venetoclax in adult participants with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have relapsed after at least one prior therapy.

The U.S. Food and Drug Administration (FDA) has approved zanubrutinib as a treatment for mantle cell lymphoma (MCL) but not previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The U.S. Food and Drug Administration (FDA) has approved venetoclax as a treatment option for previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, the U.S. Food and Drug Administration (FDA) has not approved these two drugs together as a treatment for any disease. Zanubrutinib is a type of investigational drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL/SLL cells live and grow. By blocking BTK, zanubrutinib may kill cancer cells or stop them from growing. As of July 2020 about 2000 patients with CLL/SLL have been treated with zanubrutinib as a single drug and some of these participants had improvement of their cancer with this treatment. Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL/SLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing.Venetoclax has been shown to be safe and effective when given alone or in combination with obinutuzumab to treat patients with CLL/SLL and is FDA approved for patients with CLL/SLL.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

Participants will receive study treatment for 15 months initially. There is an option for an additional 12 months of therapy at disease recurrence, if indicated by their treating physician. Participants will be followed for 36 months after they discontinue the study drugs.

It is expected that about 45 people will take part in this research study.

BeiGene Ltd. is providing funding for the trial and the study drug zanubrutinib.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Trial of Zanubrutinib and Venetoclax in Previously Treated CLL/SLL Patients
Actual Study Start Date : February 18, 2022
Estimated Primary Completion Date : October 28, 2025
Estimated Study Completion Date : October 28, 2028


Arm Intervention/treatment
Experimental: Venetoclax + Zanubrutinib

Participants will be enrolled to one of three treatment cohorts: Cohort A: Participants who are bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitor naïve; Cohort B: Participants who have received treatment with a prior BTK or BCL-2 inhibitor who discontinued treatment for any reason other than progressive disease; Cohort C (Exploratory): Participants who experienced disease progression on a prior BTK inhibitor who do not have a Cys481X mutation.

Study cycles are 28 days and all participants will receive:

  • Zanubrutinib 2x daily for 16 cycles with option to retreat
  • Venetoclax: 1x daily starting day 1 of cycle 4 for 16 cycles with option to retreat
Drug: Venetoclax
Capsule/Tablet taken orally
Other Name: Venclexta

Drug: Zanubrutinib
Capsule/Tablet taken orally
Other Names:
  • BGB-3111
  • Brukinsa

Experimental: Venetoclax + Zanubrutinib Retreatment

Based on determination of their treating physician, participants will be enrolled to receive:

  • Zanubrutinib 2x daily and Venetoclax 1x daily for 12 cycles
Drug: Venetoclax
Capsule/Tablet taken orally
Other Name: Venclexta

Drug: Zanubrutinib
Capsule/Tablet taken orally
Other Names:
  • BGB-3111
  • Brukinsa




Primary Outcome Measures :
  1. Rate of undetectable minimal residual disease (uMRD) [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by flow cytometry (FC)


Secondary Outcome Measures :
  1. Overall response Rate (ORR), [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by iwCLL 2018 criteria

  2. Complete response (CR), [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by iwCLL 2018 criteria

  3. Complete response (CR) with incomplete count recovery (CRi) [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by iwCLL 2018 criteria

  4. Percentage of Bone marrow undetectable minimal residual disease (uMRD) with CR [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by flow cytometry (FC)

  5. Percentage of bone marrow undetectable minimal residual disease with CRi [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by flow cytometry (FC)

  6. Percentage of Peripheral blood undetectable minimal residual disease [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Assessed by flow cytometry (FC)

  7. Progression free survival (PFS) [ Time Frame: 1 year and 3 years post-treatment ]
    Time from enrollment to the earlier of progression or death due to any cause; participants alive without disease progression will be censored at date of last disease evaluation) at 1 yr after cycle 15

  8. Overall survival (OS) rates [ Time Frame: 1 year and 3 years post-treatment ]
    Time from enrollment to death due to any cause or censored at date last known alive

  9. Median time to MRD recurrence [ Time Frame: Up to 27 months ]
    Defined as at least 2 consecutive positive PB MRD tests by flow cytometry (FC)

  10. Median time to re-treatment [ Time Frame: Time from discontinuation of initial therapy to the time of the first re-treatment up to 17 months ]
    Time from discontinuation of initial therapy to the time of the first re-treatment; patients who do not receive re-treatment will be censored at the time of their last known visit

  11. Median time to next different therapy [ Time Frame: Time from initiation of first zanubrutinib venetoclax therapy to the time of first treatment with alternative therapy up to 17 months ]
    time from initiation of first zanubrutinib venetoclax therapy to the time of first treatment with alternative therapy; patients who have not had alternative therapy will be censored at the time of their last known visit

  12. The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade. [ Time Frame: Up to 27 months ]
    Assessed by CTCAE version 5.0

  13. Compare Rate of uMRD between bone marrow and peripheral blood at the primary endpoint evaluation [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Flow cytometry (FC) by McNemar's test

  14. Evaluate the association of established CLL prognostic factors including FISH cytogenetics, IGHV mutation status, and TP53 mutation status with clinical response [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    ORR, CR and uMRD rates in patients with deletion 17p, TP53 mutation or both

  15. Evaluate the association of established CLL prognostic factors including FISH cytogenetics, IGHV mutation status, and TP53 mutation status with uMRD [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    ORR, CR and uMRD rates in patients with unmutated and mutated IGHV

  16. Difference in undetectable MRD between cohorts A and B [ Time Frame: Two months after completion of initial 15 treatment cycles ]
    Compared using Fisher's exact test. Median PFS and OS will be estimated with 95% CI for each cohort. Survival distributions will be estimated using the Kaplan Meier method and compared using the log-rank test.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) as per International Workshop on CLL (iwCLL) 2018 criteria.
  • Participants must have relapsed after at least one prior line of therapy and must currently require therapy by iwCLL 2018 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 disease that progressed during therapy with a covalent BTK inhibitor, not including zanubrutinib.
  • For retreatment in patients who had residual MRD positivity at end of cycle 15 restaging: disease that has now progressed according to iwCLL criteria. Please note these patients do NOT need to meet iwCLL criteria for treatment, just for disease progression
  • For retreatment in patients who had BM uMRD at end of cycle 15 restaging: two consecutive positive PB MRD tests, with confirmed MRD positivity in BM.
  • 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 Cys481X 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05168930


Contacts
Layout table for location contacts
Contact: Jennifer R Brown, MD, PhD 617-632-4564 Jennifer_Brown@dfci.harvard.edu
Contact: Kim E Pena del Aguila 857-215-1707 kime_penadelaguila@dfci.harvard.edu

Locations
Layout table for location information
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Jennifer R Brown, MD, PhD    617-632-4564    Jennifer_Brown@dfci.harvard.edu   
Principal Investigator: Jennifer R Brown, MD, PhD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Jennifer R Brown, MD, PhD    617-632-4564    Jennifer_Brown@dfci.harvard.edu   
Principal Investigator: Jennifer R Brown, MD, PhD         
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Jon Arnason, MD    617-667-9920    jarnason@bidmc.harvard.edu   
Principal Investigator: Jon Arnason, MD         
Sponsors and Collaborators
Jennifer R. Brown, MD, PhD
BeiGene
Investigators
Layout table for investigator information
Principal Investigator: Jennifer R Brown, MD, PhD Dana-Farber Cancer Institute
Layout table for additonal information
Responsible Party: Jennifer R. Brown, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT05168930    
Other Study ID Numbers: 21-279
First Posted: December 23, 2021    Key Record Dates
Last Update Posted: March 31, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute:
Chronic Lymphocytic Leukemia (CLL)
Small Lymphocytic Lymphoma
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Leukemia, B-Cell
Venetoclax
Zanubrutinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action