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) patients.
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
patients 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 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 throughout the trial.
After completion of study treatment, patients are followed up for 10 years after
registration.