Clinical Trials /

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

NCT03824483

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Richter Syndrome
  • Small Lymphocytic Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL)
  • Official Title: Phase 2 Study of Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated Patients With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Clinical Trial IDs

  • ORG STUDY ID: 18-427
  • NCT ID: NCT03824483

Conditions

  • Chronic Lymphocytic Leukemia (CLL)
  • Small Lymphocytic Leukemia (SLL)

Interventions

DrugSynonymsArms
ZanubrutinibBOVEN regimen
ObinutuzumabGA101BOVEN regimen
VenetoclaxABT-199BOVEN regimen

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
BOVEN regimenExperimentalPatients 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.
  • Zanubrutinib
  • Obinutuzumab
  • Venetoclax

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Zanubrutinib
  • Obinutuzumab
  • Venetoclax
  • 18-427

Last Updated

July 12, 2019