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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 : July 15, 2019
Sponsor:
Collaborators:
BeiGene USA, Inc.
Roche-Genentech
Massachusetts General Hospital
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE January 29, 2019
First Posted Date  ICMJE January 31, 2019
Last Update Posted Date July 15, 2019
Actual Study Start Date  ICMJE February 22, 2019
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 29, 2019)
establish the rate of minimum residual disease (MRD) negative 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.
Change History Complete list of historical versions of study NCT03824483 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)
Official Title  ICMJE Phase 2 Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE
  • Chronic Lymphocytic Leukemia (CLL)
  • Small Lymphocytic Leukemia (SLL)
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Zanubrutinib
  • Drug: Obinutuzumab
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 29, 2019)
37
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andrew Zelenetz, MD, PhD 212-639-2656 zeleneta@mskcc.org
Contact: Anthony Mato, MD 212-639-8596
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03824483
Other Study ID Numbers  ICMJE 18-427
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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)
Supporting Materials: Informed Consent Form (ICF)
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE
  • BeiGene USA, Inc.
  • Roche-Genentech
  • Massachusetts General Hospital
Investigators  ICMJE
Principal Investigator: Andrew Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP