A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>/= 65 Years of Age) With Chronic Lymphocytic Leukemia (CLL)
I. To determine whether progression free survival (PFS) is superior after therapy with
bendamustine (bendamustine hydrochloride) in combination with rituximab, ibrutinib alone, or
ibrutinib in combination with rituximab in patients age 65 or older with previously
untreated chronic lymphocytic leukemia (CLL).
I. To determine 2-year PFS in each of the three treatment arms. II. To determine which
treatment arm produces superior overall survival (OS). III. To determine the complete
response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall
response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.
IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR
documentation and at 2 years on PFS and overall survival (OS) in each of the treatment arms.
V. To determine duration of response after each of the three treatments and compare these
VI. To determine toxicity and tolerability of the three treatment regimens. VII. To
determine response and PFS of patients initially on the bendamustine in combination with
rituximab arm who cross over to ibrutinib.
VIII. To determine whether baseline cytogenetic markers, zeta-chain (TCR) associated protein
kinase 70kDa (Zap-70) methylation, immunoglobulin variable region (IgVH) mutational status,
or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response in
these three arms.
IX. To determine whether local fluorescent in situ hybridization (FISH) results for
del(11q22.3) and del(17p13.1) are consistent with central analysis.
X. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers
are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2
years versus not), as well as to explore changes in microRNA expression from baseline to
post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.
XI. To determine whether eradication of MRD predicts longer duration of response with
standard therapy and ibrutinib-based regimens.
XII. To describe the baseline functional status, comorbid medical conditions, and number of
medications of older CLL patients who meet criteria for therapy.
XIII. To determine how functional status changes with therapy using baseline to 3-month
evaluation and end-of-study/2-year evaluation; to determine whether this change is different
among the treatment groups.
XIV. To determine whether geriatric assessment variables known to be associated with
chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity
in the CLL population.
XV. To assess whether the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) (FCGR3A)
polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus
rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and
progression-free survival (PFS).
XVI. To assess whether complement component 1, q subcomponent, A chain (C1QA) polymorphism
(rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and
bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days
for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
experiencing disease progression may crossover to Arm II.
ARM II: Patients receive ibrutinib orally (PO) daily. Treatment continuous in the absence of
disease progression or unacceptable toxicity.
ARM III: Patients receive ibrutinib as in Arm II. Beginning in course 2, patients receive
rituximab IV on days 1, 8, 15, and 22 and on day 1 of courses 3-6. Treatment with rituximab
repeats every 28 days for 5 courses in the absence of disease progression or unacceptable
After completion of study treatment, patients are followed up for 24 months.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Log-rank statistics will be used to compare the PFS distributions of the different treatment arms. The methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, and PFS medians along with their 95% confidence intervals.
Time from study entry to the time of documented disease progression or death, assessed up to 2 years
Cancer and Leukemia Group B
United States: Food and Drug Administration
|Cancer and Leukemia Group B||Chicago, Illinois 60606|