Zanubrutinib, Obinutuzumab, and Venetoclax in Treating Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Status: Active

Description

This phase II trial studies how well zanubrutinib, obinutuzumab, and venetoclax work in treating patients with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Zanubrutinib and venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Giving zanubrutinib, obinutuzumab, and venetoclax together may work better in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to standard therapy, including antibody therapy (a treatment that targets cancer cells) plus chemotherapy.

Eligibility Criteria

Inclusion Criteria

  • Signed, informed consent
  • Ability and willingness to comply with the requirements of the study protocol
  • Diagnosis of CLL or small lymphocytic lymphoma (SLL) according to World Health Organization (WHO) criteria
  • For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting for at least 1% of circulating white blood cells (WBC)
  • No prior systemic therapy for CLL; prior single site of local radiation for symptomatic disease is permitted
  • Subject requires treatment according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L unless neutropenia is clearly due to disease under study (per investigator discretion)
  • Platelet count > 75,000/mm^3 OR platelet count >= 20,000/mm^3 if thrombocytopenia is clearly due to disease under study (per investigator discretion)
  • Hemoglobin >= 9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion)
  • Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) =< 2.0 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.0 x ULN
  • Total bilirubin =< 2.0 x ULN unless considered secondary to Gilbert's syndrome, in which case =< 3 x ULN
  • Creatinine clearance of estimated glomerular filtration rate (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) * 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

  • 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
  • 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 central nervous system (CNS) hemorrhage or stroke within 6 months of the study
  • History of progressive multifocal leukoencephalopathy (PML)
  • History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic or acute) or hepatitis C infection * Patients with occult or prior hepatitis B virus (HBV) infection (defined as positive total hepatitis B core antibody [HBcAb] and negative hepatitis B surface antigen [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 * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (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
  • Concurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19
  • Requires aspirin and P2Y inhibitors (clopidogrel, ticagrelor).
  • Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
  • Obinutuzumab is contraindicated in patients with a known hypersensitivity (immunoglobulin [Ig]E-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
  • Females who are currently pregnant or breastfeeding
  • Participation in a separate investigational therapeutic study unless authorized by the investigator

Locations & Contacts

Massachusetts

Boston
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Jacob D. Soumerai
Phone: 617-724-4000

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Andrew D. Zelenetz
Phone: 212-639-2656

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the rate of minimum residual disease (MRD) undetectable response.

SECONDARY OBJECTIVES:

I. To determine the time to MRD undetectable response (defined using flow cytometry, with a sensitivity of 1 chronic lymphocytic leukemia (CLL) cell in 10,000 cells or 10^-4).

II. To establish the recommended phase 2/3 duration of therapy.

III. To determine the proportion of patients who successfully discontinue therapy after achieving an MRD undetectable response.

IV. To determine the durability of clinical benefit after treatment discontinuation as measured by duration of peripheral blood MRD response and treatment-free survival.

V. To assess safety and tolerability.

VI. To determine whether induction therapy with 2 cycles of zanubrutinib and obinutuzumab prior to venetoclax reduces tumor lysis syndrome (TLS) risk assignment.

EXPLORATORY OBJECTIVES:

I. To cross validate MRD testing using multiparameter flow cytometry with deoxyribonucleic acid (DNA) sequencing-based MRD assays in peripheral blood and bone marrow.

II. To evaluate clonal evolution of CLL in serial patient samples on therapy with zanubrutinib, obinutuzumab, and venetoclax, during posttreatment surveillance, and at progression.

III. To investigate the effects of zanubrutinib, obinutuzumab, and venetoclax on immune responses.

OUTLINE:

Patients receive zanubrutinib orally (PO) twice daily (BID) on days 1-28. Patients also receive obinutuzumab intravenously (IV) on days 1 (may be split over days 1 and 2), 8, and 15 of cycle 1, and on day 1 of cycles 2-8. Beginning in cycle 3, patients receive venetoclax PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Andrew D. Zelenetz

Trial IDs

Primary ID 18-427
Secondary IDs NCI-2019-01323
Clinicaltrials.gov ID NCT03824483