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

  • STATUS
    Recruiting
  • days left to enroll
    11
  • participants needed
    127
  • sponsor
    Memorial Sloan Kettering Cancer Center
Updated on 7 October 2022
platelet count
cancer
corticosteroids
lymphoid leukemia
anemia
chronic lymphocytic leukemia
lymphoma
flow cytometry
thrombocytopenia
residual tumor
venetoclax
TP53
neutrophil count
mantle cell lymphoma
obinutuzumab

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.

Details
Condition Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Leukemia (SLL)
Treatment Obinutuzumab, venetoclax, Zanubrutinib
Clinical Study IdentifierNCT03824483
SponsorMemorial Sloan Kettering Cancer Center
Last Modified on7 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Signed, informed consent
Ability and willingness to comply with the requirements of the study protocol
Age ≥18 years
Diagnosis of the following histories according to the WHO criteria
CLL or SLL
MCL
For patients with SLL, peripheral blood flow cytometry must be positive with CLL-like
No prior systemic therapy for disease under study except
cells accounting for at least 1% of circulating WBC
prior local radiation for symptomatic disease is permitted
ECOG performance status of 0 to 2
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
Adequate hematologic parameters unless due to disease under study
Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion)
Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion)
Adequate renal and hepatic function, per laboratory reference range at Screening as
Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement due to disease under study (per investigator discretion)
follows
AST/SGOT, ALT/SGPT ≤2.0 x ULN b. Total bilirubin ≤ 2.0 x ULN unless
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)
Creatinine clearance of eGFR>30 mL/min according to the Cockcroft-Gault Equation
For females of childbearing potential, a negative serum pregnancy test within 7 days
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)
of study treatment
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 it 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
partnet: 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)
Additional Eligibility Criteria for CLL Cohort
The reliability of sexual abstinence should be evaluated in relation 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 or
bank 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
Diagnosis of untreated stage II-IV mantle cell lymphoma
last dose of venetoclax AND for 18 months after the last dose of obinutuzumab
(whichever date is later)
Diagnosis of untreated CLL or SLL according to WHO criteria 2. For patients with
SLL, peripheral blood flow cytometry must be positive with CLL-like cells accounting
for at least 1% of circulating WBC 3. No prior systemic therapy for CLL: prior single
site of local radiation for symptomatic disease is permitted 4. Subject requires
treatment according to IWCLL guidelines (See Appendix A)
Additional Eligibility Criteria for TP53 Mutant MCL cohorts
a. Prior radiotherapy for localized disease is permitted 2. Presence of TP53 mutation
irrespective of variant allele frequency (TP53 cohort)
OR
Presence of p53 overexpression by immunohistochemistry defined as strong nuclear staining
of >30% positive nuclei
Additional Eligibility Criteria for Transplant Ineligible MCL cohort
Diagnosis of untreated stage II-IV mantle cell lymphoma
a. Prior radiotherapy for localized disease is permitted
Patients must meet one of the following criteria (a or b)
Age ≥65 years If age <65 years of age, then patients must be ineligible for
HDT/ASCT on the basis of comorbidity or organ dysfunction
Specifically, patients must meet at least one of the following criteria below
dysfunction, precluding high dose therapy secondary to expected increased morbidity
i.. Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidney
and mortality. ii. ECOG 2 iii. Ejection fraction ≥35% and <45% iv. Impaired pulmonary
function test with DLCO <50% expected v. Medical conditions which in the opinion of
the treating physician in consultation with the study PI or Co-PI and DMT preclude
HDT/ASCT

Exclusion Criteria

Other malignancies
Other diagnosis of active cancer
Co-morbidities
Known bleeding diathesis
Known CNS hemorrhage or stroke within 6 months of the study
History of progressive multifocal leukoencephalopathy (PML)
Congestive heart failure, New York Heart Association classification III/IV
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
Concomitant medications and drug interactions
Live-virus vaccines given within 28 days prior to the initiation of study treatment
Immunotherapy
Prior therapy
Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
Radiation therapy intended to treat MCL or CLL/SLL
Known active histological transformation from CLL to an aggressive lymphoma (i.e
Warfarin or warfarin derivatives
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
Other
localized radiation within 3 years of treatment is permitted
Females who are currently pregnant or breastfeeding
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
weeks prior to Cycle 1, Day 1
Prior major surgical procedure within 4 weeks of study, or anticipation of need
for a major surgical procedure during the course of the study
History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
infection
a. 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
b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA
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
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 applied for moderate inhibitors or inducers of CY_3A
Hormone therapy (other than contraceptives, hormone replacement therapy, or
megestrol acetate)
Any therapies intended for the treatment of lymphoma/leukemia whether FDA
approved or experimental (outside of this study)
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)
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
Participation in a separate investigational therapeutic study unless authorized
by the investigator
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