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Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)

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ClinicalTrials.gov Identifier: NCT03824483
Recruitment Status : Recruiting
First Posted : January 31, 2019
Last Update Posted : May 16, 2019
Sponsor:
Collaborators:
BeiGene USA, Inc.
Roche-Genentech
Massachusetts General Hospital
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Brief Summary:
The purpose of this study is to determine the rate of minimum residual disease (MRD) negative response (i.e. the rate of no evidence of disease) of the study drugs, zanubrutinib, obinutuzumab, and venetoclax, given in combination as a treatment for CLL and/or SLL.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Patients will be enrolled in a single-stage phase 2 design.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Actual Study Start Date : February 22, 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021


Arm Intervention/treatment
Experimental: BOVEN regimen
Patients will be given zanubrutinib (160mg by mouth BID) and obinutuzumab (1000mg IVPB on Days 1*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). * On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC >25,000 cells/ul or baseline lymph nodes >5 cm diameter). Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.
Drug: Zanubrutinib
zanubrutinib (160mg by mouth BID)

Drug: Obinutuzumab
obinutuzumab (1000mg IVPB on Days 1*, 8 and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8) starting on Cycle 1 (28-day cycles). * On Cycle 1, obinituzumab will be administered in "split dose" at 100mg IVPB on Day 1 and 900mg IVPB on Day 2 in patients at increased risk for IRR (ALC >25,000 cells/ul or baseline lymph nodes >5 cm diameter).
Other Name: GA101

Drug: Venetoclax
Venetoclax will be added to the regimen starting on Cycle 3, and will be incorporated into the regimen using the 5-week ramp-up schedule to mitigate the risk of tumor lysis syndrome (beginning at 20mg and gradually increasing to 400mg), and venetoclax will be administered a ta fixed dose level of 400mg by mouth daily of 28-day cycles thereafter.
Other Name: ABT-199




Primary Outcome Measures :
  1. establish the rate of minimum residual disease (MRD) undetectable response [ Time Frame: 1 year ]
    Patients will have their minimum residual disease (MRD) response classified by bone marrow peripheral blood flow cytometry with a sensitivity of 10-4.



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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:

  • Signed, informed consent
  • Ability and willingness to comply with the requirements of the study protocol
  • Age ≥18 years
  • Diagnosis of CLL or SLL according to WHO criteria.
  • For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting for at least 1% of circulating WBC.
  • No prior systemic therapy for CLL; prior single site of local radiation for symptomatic disease is permitted
  • Subject requires treatment according to IWCLL guidelines
  • ECOG performance status of 0 to 2
  • Adequate hematologic parameters unless due to disease under study:

    1. Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion)
    2. Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion)
    3. Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion)
  • Adequate renal and hepatic function, per laboratory reference range at Screening as follows:

    1. AST/SGOT, ALT/SGPT ≤2.0 x ULN
    2. Total bilirubin ≤ 2.0 x ULN unless considered secondary to Gilbert‟s syndrome, in which case ≤3 x ULN
    3. Creatinine clearance of eGFR>50 mL/min according to the Cockcroft-Gault Equation
  • QT-interval corrected according to Fridericia‟s formula (QTcF) ≤450 milliseconds (ms)
  • For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment
  • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of zanubrutinib or venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later)

    a. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

  • Willingness to not donate sperm or oocytes during the entire study treatment period and after treatment discontinuation

Exclusion Criteria:

Other malignancies:

  • Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter‟s transformation)
  • Active malignancy or systemic therapy for another malignancy within 3 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 3 years of treatment is permitted
  • Other diagnosis of active cancer

Co-morbidities:

  • Any uncontrolled illness that in the opinion of the investigator would preclude administration of study therapy (e.g. significant active infections, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction)
  • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1
  • Known bleeding diathesis
  • Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study
  • Known CNS hemorrhage or stroke within 6 months of the study
  • History of progressive multifocal leukoencephalopathy (PML)
  • History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection

    1. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing.
    2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • Congestive heart failure, New York Heart Association classification III/IV
  • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
  • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment
  • Known condition or other clinical situation that would affect oral absorption
  • Psychiatric illness/social situations that would interfere with study compliance

Concomitant medications and drug interactions:

  • Concurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19
  • Requires aspirin and P2Y inhibitors (clopidogrel, ticagrelor)

Prior therapy:

  • Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
  • Obinutuzumab is contraindicated in patients with a known hypersensitivity (IgE-mediated) reaction to obinutuzumab or to any of its excipients
  • Prior systemic therapy for CLL; prior single site of local radiation for symptomatic disease is permitted

Other:

  • Females who are currently pregnant or breastfeeding
  • Participation in a separate investigational therapeutic study unless authorized by the investigator

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): NCT03824483


Contacts
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Contact: Andrew Zelenetz, MD, PhD 212-639-2656 zeleneta@mskcc.org
Contact: Anthony Mato, MD 212-639-8596

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Jacob D Soumerai, MD    617-724-4000      
United States, New Jersey
Memorial Sloan Kettering at Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Andrew Zelenetz, MD    212-639-2656      
Memoral Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Andrew Zelenetz, MD, PhD    212-639-2656      
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Helena Yu, MD    646-888-4274      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Andrew Zelenetz, MD, PhD    212-639-2656      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Andrew Zelenetz, MD, PhD    212-639-2656      
Contact: Anthony Mato, MD    212-639-8596      
Principal Investigator: Andrew Zelenetz, MD, PhD         
Memorial Sloan Kettering Nassau Recruiting
Uniondale, New York, United States, 11553
Contact: Andrew Zelenetz, MD, PhD    212-639-2656      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
BeiGene USA, Inc.
Roche-Genentech
Massachusetts General Hospital
Investigators
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Principal Investigator: Andrew Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03824483     History of Changes
Other Study ID Numbers: 18-427
First Posted: January 31, 2019    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
Supporting Materials: Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)

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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 Memorial Sloan Kettering Cancer Center:
Zanubrutinib
Obinutuzumab
Venetoclax
18-427

Additional relevant MeSH terms:
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Venetoclax
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Obinutuzumab
Zanubrutinib
Antineoplastic Agents
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action