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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

Phase 3
65 Years
Open (Enrolling)
Mantle Cell Lymphoma

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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.

Inclusion Criteria:

- Diagnosis of mantle cell lymphoma (MCL) reviewed and approved by central laboratory:
diagnosis must include morphology and expression of either cyclin D1 in association
with one B-cell marker (eg, CD19, CD20, or PAX5) and CD5 or evidence of t(11;14) as
assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase
chain reaction (PCR)

- Clinical Stage II, III, or IV by Ann Arbor Classification

- At least 1 measurable site of disease according to Revised Response Criteria for
Malignant Lymphoma

- No prior therapies for MCL

- Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1

- Hematology and biochemical laboratory values within protocol-defined limits

- Agrees to protocol-defined use of effective contraception

- Negative blood or urine pregnancy test at screening

Exclusion Criteria:

- Major surgery within 4 weeks of random assignment

- Known central nervous system lymphoma

- Diagnosed or treated for malignancy other than MCL, except: malignancy treated with
curative intent and with no known active disease present for >=3 years before random
assignment; adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease; adequately treated cervical carcinoma in situ without evidence
of disease

- Patients for whom the goal of therapy is tumor debulking prior to stem cell

- History of stroke or intracranial hemorrhage within 6 months prior to random

- Requires anticoagulation with warfarin or equivalent vitamin K antagonists

- Requires treatment with strong CYP3A4/5 inhibitors

- Clinically significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined
by the New York Heart Association Functional Classification

- Vaccinated with live, attenuated vaccines within 4 weeks of random assignment

- Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or
active hepatitis B virus infection or any uncontrolled active systemic infection
requiring intravenous antibiotics

- Any life-threatening illness, medical condition, or organ system dysfunction which,
in the investigator's opinion, could compromise the patient's safety, interfere with
the absorption or metabolism of ibrutinib capsules, or put the study outcomes at
undue risk

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

Up to the end-of-study visit until 265 progression-free survival events have been observed (up to 7 years after the last patient is randomized)

Safety Issue:


Principal Investigator

Janssen Research & Development, LLC Clinical Trial

Investigator Role:

Study Director

Investigator Affiliation:

Janssen Research & Development, LLC


United States: Food and Drug Administration

Study ID:




Start Date:

May 2013

Completion Date:

October 2019

Related Keywords:

  • Mantle Cell Lymphoma
  • Mantle cell lymphoma
  • Ibrutinib
  • Bruton's tyrosine kinase inhibitor
  • Bendamustine hydrochloride
  • Rituximab
  • Lymphoma
  • Lymphoma, Mantle-Cell



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