Trial Information

A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma

This is a randomized (individuals assigned to study treatment by chance), double blind
(neither physician nor participant knows the treatment that the participant receives),
placebo (an inactive substance that is compared with a drug to test whether the drug has a
real effect in a clinical trial)-controlled study to compare the efficacy and safety of
ibrutinib given in combination with bendamustine and rituximab (BR) with BR alone in
participants newly diagnosed with mantle cell lymphoma (MCL) who are 65 years of age or
older. Approximately 520 participants will be randomly assigned in a 1:1 ratio and
stratified by simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score
(low risk [0-3] versus intermediate risk [4-5] versus high risk [6-11]). The treatment phase
will extend from randomization until study drug discontinuation or the clinical cutoff for
the end of study. A cycle is defined as 28 days. All participants will receive open-label
(identity of assigned study drug will be known) BR background therapy for a maximum of 6
cycles; participants with a complete response or partial response will continue to receive
open-label background therapy with rituximab maintenance every second cycle for a maximum of
12 additional doses. In addition to the background therapy, all participants will receive
blinded study drug (ibrutinib or placebo). Participants randomized to treatment Arm A will
receive placebo capsules and participants randomized to treatment Arm B will receive
ibrutinib capsules. Study drug will be administered daily and continuously until disease
progression, unacceptable toxicity, or study end. Participants with stable disease after
initial chemoimmunotherapy (BR+ibrutinib/placebo) should continue treatment with
ibrutinib/placebo until disease progression, unacceptable toxicity, or study end.
Participants with progressive disease must discontinue all study treatment. For participants
who discontinue background therapy and do not have progressive disease, treatment with study
drug will continue until disease progression or unacceptable toxicity or the clinical cutoff
for the final analysis of progression-free survival (PFS). Participants receiving BR,
rituximab, or ibrutinib at the clinical cutoff for the final analysis of PFS will continue
open-label treatment until disease progression or unacceptable toxicity. Placebo will be
stopped when the study is unblinded for the clinical cutoff for the final analysis of PFS.
The posttreatment follow-up phase will begin once a participant discontinues bendamustine
and rituximab and study drug. Participants who discontinue for reasons other than disease
progression must continue to have disease evaluations as outlined in the protocol.
Participants who discontinue due to disease progression will be followed for survival and
subsequent anti-MCL therapy. The posttreatment follow-up phase will continue until death,
lost to follow up, consent withdrawal, or study end, whichever occurs first. Three clinical
cutoffs are planned. The first 2 clinical cutoffs will occur when approximately 134 and 265
PFS events have been observed, respectively. The interim analysis and the final analysis of
PFS will take place at these 2 clinical cutoffs, respectively; participant treatment
assignment will be unblinded at the clinical cutoff for the final analysis of PFS. The last
cutoff will occur at the end of study, when 60% of the randomized participants have died or
the Sponsor terminates the study, whichever comes first. Efficacy assessments will be
conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Safety
will be monitored throughout the study and summarized. Blood samples will be drawn for
assessment of pharmacokinetic parameters. Blood and bone marrow will be collected for
assessment of minimal residual disease and biomarker studies.