Zanubrutinib, Obinutuzumab, and Venetoclax in Treating Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma and Mantle Cell Lymphoma
- Signed, informed consent
- Ability and willingness to comply with the requirements of the study protocol
- Diagnosis of the following histologies according to World Health Organization (WHO) criteria: * CLL or small lymphocytic lymphoma (SLL) * MCL with TP53 mutation irrespective of variant allele frequency
- 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; except: * Prior local radiation for symptomatic disease is permitted * Short course systemic corticosteroids is permissible for disease control, improvement of performance status or non-cancer indication if < 7 days and must be discontinued prior to study treatment
- 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: agreement 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) or remain abstinent (refrain from heterosexual intercourse) during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later). A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal contraceptive methods must be supplemented by a barrier method. * 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
- For men with a female partner of childbearing potential or a pregnant female partner: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom during the treatment period 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 for 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (w hichever date is later)
- ADDITIONAL ELIGIBILITY CRITERIA FOR CLL COHORT
- Diagnosis of untreated 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 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines
- ADDITIONAL ELIGIBILITY CRITERIA FOR MCL COHORT:
- Diagnosis of untreated stage II-IV mantle cell lymphoma * Prior radiotherapy for localized disease is permitted
- Presence of TP53 mutation irrespective of variant allele frequency
- 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
- Inability to swallow a large number of tablets
- Administration within 7 days prior to the first dose of study drug or concurrent therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19. The same applies for moderate inhibitors or inducers of CYP3A
- Requires aspirin and P2Y inhibitors (clopidogrel, ticagrelor).
- Consumption of one or more of the following within 3 days prior to the first dose of study drug: * Grapefruit or grapefruit products * Seville oranges, including marmalade containing Seville oranges * Star fruit (carambola)
- 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
I. To determine the rate of minimum residual disease (MRD) undetectable response in patients with chronic lymphocytic leukemia (CLL).
II. To establish the 2-year progression-free survival in patients with mantle cell lymphoma (MCL).
I. To determine the time to MRD undetectable response (defined using flow cytometry, with a sensitivity of 1 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 of the of zanubrutinib, obinutuzumab, and venetoclax regimen in the first-line setting.
VI. To determine whether induction therapy with 2 cycles of zanubrutinib and obinutuzumab prior to venetoclax reduces tumor lysis syndrome (TLS) risk assignment.
VII. Estimate the overall response rate (ORR), complete response rate (CR), partial response rate (PR), the duration of response (DOR), event free survival (EFS), overall survival (OS), and rate of conversion to undetectable MRD in patients with MCL.
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 and MCL 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.
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, every 12 weeks for 2 years, then every 24 weeks thereafter.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Andrew D. Zelenetz
- Primary ID 18-427
- Secondary IDs NCI-2019-01323
- Clinicaltrials.gov ID NCT03824483