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Signed, informed consent |
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Ability and willingness to comply with the requirements of the study protocol |
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Age ≥18 years |
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Diagnosis of the following histories according to the WHO criteria |
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CLL or SLL |
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MCL |
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For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like |
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No prior systemic therapy for disease under study except |
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cells accounting for at least 1% of circulating WBC |
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prior local radiation for symptomatic disease is permitted |
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ECOG performance status of 0 to 2 |
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Short course systemic corticosteroids is permissible for disease control, improvement of performance status or non-cancer indication (must be ≤ 7 days and < 100 mg/day prednisone or ≤ 20 mg/day dexamethasone). Steroids must be discontinued prior to study treatment. Inhaled steroids for asthma, topical steroids, and replacement/Stress corticosteroids are permitted. Low-dose steroids for ITP are also permitted up to the equivalent prednisone 20mg/daily at time of eligibility review |
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Adequate hematologic parameters unless due to disease under study |
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Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion) |
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Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion) |
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Adequate renal and hepatic function, per laboratory reference range at Screening as |
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Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement due to disease under study (per investigator discretion) |
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follows |
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AST/SGOT, ALT/SGPT ≤2.0 x ULN b. Total bilirubin ≤ 2.0 x ULN unless |
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Considered secondary to Gilbert"s syndrome, in which case ≤3 x ULN ii. Considered due to disease under study (Per PI or Co-PI discretion) |
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Creatinine clearance of eGFR>30 mL/min according to the Cockcroft-Gault Equation |
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For females of childbearing potential, a negative serum pregnancy test within 7 days |
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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) |
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of study treatment |
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A woman is considered to be of childbearing potential if she is postmenarcheal, has not |
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reached a postmenopausal state (>/= 12 continuous months of amenorrhea with no identified |
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cause other than menopause), and it not permanently infertile due to surgery (i.e., removal |
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of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the |
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investigator (e.g., Mullerian agenesis). The definition of childbearing potential may be |
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adapted for alignment with local guidelines or regulations |
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Examples of contraceptive methods with a failure rate of <1% per year include bilateral |
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tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation |
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hormone-releasing intrauterine devices, and copper intrauterine devices. Hormonal |
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contraceptive methods must be supplemented by a barrier method |
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The reliability of sexual abstinence should be evaluated in relation to the duration |
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of the clinical trial and the preferred and usual lifestyle of the patient. Periodic |
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abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and |
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withdrawal are not acceptable methods of contraception |
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For men with a female partner of childbearing potential or a pregnant female |
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partnet: agreement to remain abstinent (refrain from heterosexual intercourse) or |
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use a condom during the treatment period and to continue its use for 90 days |
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after the last dose of zanubrutinib, or venetoclax AND for 18 months after the |
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last dose of obinutuzumab (whichever date is later) |
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Additional Eligibility Criteria for CLL Cohort |
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The reliability of sexual abstinence should be evaluated in relation duration of the |
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clinical trial and the preferred and usual lifestyle of the patient. Periodic |
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abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and |
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withdrawal are not acceptable methods of contraception - Willingness to not donate or |
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bank sperm or oocytes during the entire study treatment period and after treatment |
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discontinuation for 90 days after the last dose of zanubrutinib AND 30 days after the |
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Diagnosis of untreated stage II-IV mantle cell lymphoma |
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last dose of venetoclax AND for 18 months after the last dose of obinutuzumab |
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(whichever date is later) |
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Diagnosis of untreated CLL or SLL according to WHO criteria 2. For patients with |
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SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting |
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for at least 1% of circulating WBC 3. No prior systemic therapy for CLL: prior single |
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site of local radiation for symptomatic disease is permitted 4. Subject requires |
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treatment according to IWCLL guidelines (See Appendix A) |
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Additional Eligibility Criteria for TP53 Mutant MCL cohorts |
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a. Prior radiotherapy for localized disease is permitted 2. Presence of TP53 mutation |
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irrespective of variant allele frequency (TP53 cohort) |
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OR |
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Presence of p53 overexpression by immunohistochemistry defined as strong nuclear staining |
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of >30% positive nuclei |
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Additional Eligibility Criteria for Transplant Ineligible MCL cohort |
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Diagnosis of untreated stage II-IV mantle cell lymphoma |
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a. Prior radiotherapy for localized disease is permitted |
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Patients must meet one of the following criteria (a or b) |
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Age ≥65 years If age <65 years of age, then patients must be ineligible for |
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HDT/ASCT on the basis of comorbidity or organ dysfunction |
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Specifically, patients must meet at least one of the following criteria below |
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dysfunction, precluding high dose therapy secondary to expected increased morbidity |
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i.. Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidney |
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and mortality. ii. ECOG 2 iii. Ejection fraction ≥35% and <45% iv. Impaired pulmonary |
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function test with DLCO <50% expected v. Medical conditions which in the opinion of |
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the treating physician in consultation with the study PI or Co-PI and DMT preclude |
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HDT/ASCT |
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Other malignancies
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Other diagnosis of active cancer
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Co-morbidities
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Known bleeding diathesis
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Known CNS hemorrhage or stroke within 6 months of the study
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History of progressive multifocal leukoencephalopathy (PML)
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Congestive heart failure, New York Heart Association classification III/IV
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Known condition or other clinical situation that would affect oral absorption
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Psychiatric illness/social situations that would interfere with study compliance
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Inability to swallow a large number of tablets
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Concomitant medications and drug interactions
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Live-virus vaccines given within 28 days prior to the initiation of study treatment
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Immunotherapy
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Prior therapy
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Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
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Radiation therapy intended to treat MCL or CLL/SLL
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Known active histological transformation from CLL to an aggressive lymphoma (i.e
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Warfarin or warfarin derivatives
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Richter"s transformation)
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Active malignancy or systemic therapy for another malignancy within 3 years
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local/regional therapy with curative intent such as surgical resection or
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Other
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localized radiation within 3 years of treatment is permitted
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Females who are currently pregnant or breastfeeding
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Any uncontrolled illness that in the opinion of the investigator would preclude
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administration of study therapy (e.g. significant active infections
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hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction)
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Known active bacterial, viral, fungal, mycobacterial, parasitic, or other
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infection (excluding fungal infections of nail beds) at study enrollment, or any
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major episode of infection requiring treatment with IV antibiotics or
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hospitalization (relating to the completion of the course of antibiotics) within
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weeks prior to Cycle 1, Day 1
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Prior major surgical procedure within 4 weeks of study, or anticipation of need
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for a major surgical procedure during the course of the study
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History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
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infection
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a. Patients with occult or prior HBV infection (defined as positive total
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hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA
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is undetectable. These patients must be willing to take appropriate anti-viral
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prophylaxis as indicated and undergo monthly DNA testing
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b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
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polymerase chain reaction (PCR) is negative for HCV RNA
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Clinically significant history of liver disease, including viral or other
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hepatitis, current alcohol abuse, or cirrhosis
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Receipt of live-virus vaccines within 28 days prior to the initiation of study
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treatment or need for live-virus vaccines at any time during study treatment
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Administration within 7 days prior to the first dose of study drug or concurrent
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therapy with strong inhibitors or inducers of CYP3A, CYP2C8, CYP2C9 and CYP2C19. The
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same applied for moderate inhibitors or inducers of CY_3A
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Hormone therapy (other than contraceptives, hormone replacement therapy, or
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megestrol acetate)
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Any therapies intended for the treatment of lymphoma/leukemia whether FDA
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approved or experimental (outside of this study)
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Consumption of one or more of the following within 3 days prior to the first dose
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of study drug
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Grapefruit or grapefruit products Seville oranges, including marmalade containing
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Seville oranges Star Fruit (carambola)
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Obinutuzumab is contraindicated in patients with a known hypersensitivity
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(IgE-mediated) reaction to obinutuzumab or to any of its excipients
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Prior systemic therapy for CLL; prior single site of local radiation for
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symptomatic disease is permitted
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Participation in a separate investigational therapeutic study unless authorized
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by the investigator
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