This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.
PRIMARY OBJECTIVE: I. To evaluate whether early treatment with venetoclax and obinutuzumab (V-O) extends overall survival (OS) compared with delayed treatment with V-O in high-risk (Chronic Lymphocytic Leukemia \[CLL\] International Prognostic Indicator \[CLL-IPI\] \>= 4 or complex cytogenetics), newly diagnosed asymptomatic CLL/small lymphocytic lymphoma (SLL) participants. SECONDARY OBJECTIVES: I. To compare overall response rates (complete response \[CR\] + partial response \[PR\]), CR rates, progression-free survival (PFS), and event-free survival (EFS) between arms. II. To evaluate safety and tolerability of each arm. III. To compare time to second CLL-directed treatment (from randomization and from response) between arms. IV. To compare relapse-free survival (RFS) and time to second objective disease progression (PFS2) between arms. V. To compare the rates of Richter's transformation between arms. VI. To describe distribution of Cumulative Illness Rating Scale across the study, in each treatment arm, and to estimate the interaction between the scale and treatment arm and OS. PATIENT-REPORTED OUTCOMES OBJECTIVES: I. To assess the impact of early intervention with V-O versus delayed therapy with V-O in CLL participants in relation to Health-Related Quality of Life (HRQoL) using the Functional Assessment of Cancer Therapy (FACT)-Leukemia scale. II. To assess the impact of the two treatment arms on the specific domains of the FACT-Leukemia, including physical, social, emotional, and functional well-being and leukemia-specific HRQoL. TRANSLATIONAL MEDICINE OBJECTIVES (INTEGRATED): I. To evaluate the prognostic association between OS and measurable residual disease (MRD) undetectable disease state at 15 months after treatment initiation, across and between treatment arms. (Primary) II. To describe the prognostic association between the endpoints RFS and OS and MRD undetectable disease state at all measured time points (cycle \[C\]7 day\[D\]1, C9D1, C12D1, and 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 87, 93, and 99 months after treatment initiation) using landmark analyses, across and between treatment arms. (Secondary) III. To evaluate the prognostic association of MRD undetectable disease state over time in each treatment arm with respect to OS and RFS using time-dependent covariate analyses. (Secondary) IV. To describe the proportion of variation in OS and RFS explained by MRD sampling schemes with the goal of providing information on how much additional variation in OS and RFS is explained by additional MRD sampling for future trial designs. (Secondary) V. To compare the rate of MRD undetectable disease state at 15 months after initiation of treatment between treatment arms. (Secondary) VI. To compare duration of MRD undetectable disease state between treatment arms. (Secondary) VII. To describe associations between pretreatment stimulated karyotype risk, p53 mutation, IGHV mutational analysis, fluorescence in situ hybridization (FISH) for del(13q), del(11q), trisomy 12, and del(17p), and beta-2-microglobulin levels and other biomarkers with OS, PFS, overall and complete response rates, achievement of MRD undetectable disease state, and Richter's transformation. (Secondary) VIII. To describe associations between clinical complete or partial response (by International Workshop on Chronic Lymphocytic Leukemia \[IWCLL\] 2018 criteria) and response as assessed by MRD status and CT scans at 15 months after treatment initiation. (Secondary) OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (DELAYED V-O): Treatment begins once 2018 IWCLL indications are met. Patients receive obinutuzumab intravenously (IV) over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax orally (PO) once daily (QD) on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration and biopsy throughout the trial. ARM II (EARLY V-O): Treatment begins as soon as eligibility criteria are met. Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, collection of blood samples, and bone marrow aspiration and biopsy throughout the trial. After completion of study treatment, patients are followed up for 10 years after registration.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
247
Undergo collection of blood samples
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Undergo CT
Given IV
Ancillary studies
Given PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
ACTIVE_NOT_RECRUITINGAnchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
SUSPENDEDAnchorage Radiation Therapy Center
Anchorage, Alaska, United States
SUSPENDEDAlaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
SUSPENDEDOverall survival (OS)
The final analysis will use stratified Cox proportional hazards regression stratified by Chronic Lymphocytic Leukemia \[CLL\] International Prognostic Indicator Risk score status (high risk versus very high risk) with a two-sided alpha of 0.042. The final analysis will occur after 58 OS events have been observed, or at 4 years after accrual completes, whichever occurs first. Under the alternative hypothesis, the final analysis is expected to occur at approximately 7.9 years after study activation (about 3.8 years after accrual completes).
Time frame: From the day of registration on study until death from any cause with observations censored on the day of last contact for participants not known to have died, assessed up to 10 years
Functional Assessment of Cancer Therapy (FACT)-Leukemia total score
A single comparison in the FACT-Leukemia total scores between patients randomized to early V-O versus delayed V-O will be conducted at the alpha=.05 level. The analysis of the 2-year FACT-Leukemia Total score will be conducted using multiple linear regression analysis, adjusting for stratification factor and the baseline FACT-Leukemia Total score as covariates. Will also conduct longitudinal modeling of the outcome measures over time.
Time frame: At 2 years
Incidence of adverse events
Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting.
Time frame: Up to 10 years
Overall Response rate
Will be compared using Fisher's exact test.
Time frame: Up to 10 years
Progression free survival
Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Time frame: From the day of registration on study until the first of: relapse from complete response, progression, or death from any cause, assessed up to 10 years
Event free survival
Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Time frame: From the day of registration on study until the first of: relapse from complete response, death from any cause, start of new (non-protocol) therapy, or completion of protocol therapy without documentation of complete response, assessed up to 10 years
Relapse free survival
Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Time frame: From the date the participant first achieves complete response until relapse from complete response or death from any cause, assessed up to 10 years
Time to second treatment
Will be defined as the next CLL treatment the patient receives after removal from protocol therapy. Will be estimated using the Kaplan-Meier method and will be compared using log-rank tests and Cox regression models.
Time frame: Up to 10 years
Patient compliance
Will be reported descriptively by arm.
Time frame: Up to 10 years
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Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
SUSPENDEDAlaska Women's Cancer Care
Anchorage, Alaska, United States
SUSPENDEDAnchorage Oncology Centre
Anchorage, Alaska, United States
SUSPENDEDKatmai Oncology Group
Anchorage, Alaska, United States
SUSPENDEDProvidence Alaska Medical Center
Anchorage, Alaska, United States
SUSPENDEDFairbanks Memorial Hospital
Fairbanks, Alaska, United States
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