Overview

This trial is active, not recruiting.

Condition mantle cell lymphoma
Treatments bendamustine, rituximab, ibrutinib, placebo
Phase phase 3
Targets BTK, CD20
Sponsor Janssen Research & Development, LLC
Collaborator Pharmacyclics LLC.
Start date May 2013
End date March 2018
Trial size 524 participants
Trial identifier NCT01776840, 2012-004056-11, CR100967, PCI-32765MCL3002, U1111-1137-0389

Summary

The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator)
Primary purpose treatment
Arm
(Placebo Comparator)
bendamustine
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
rituximab
375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses
placebo
4 capsules administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or the final analysis of progression-free survival
(Experimental)
bendamustine
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
rituximab
375 mg/m2 administered intravenously on Day 1, Cycles 1-6; if complete response or partial response is achieved, 375 mg/m2 is administered on Day 1 of every second cycle for a maximum of 12 additional doses
ibrutinib
560 mg (4 x 140 mg capsules) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end

Primary Outcomes

Measure
Progression-free survival
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)

Secondary Outcomes

Measure
Overall survival
time frame: Up to the end-of-study visit until 60% of all enrolled patients have died (up to 7 years after the last patient is randomized)
Overall response rate
time frame: Up to the end-of-study visit up to 7 years after the last patient is randomized
Number of participants with change in Lym subscale scores of the Functional Assessment of Cancer Therapy-Lymphoma (FACT Lym)
time frame: Screening, Day 1 of the first 6 cycles, then every 12 weeks in the first 12 months, thereafter every 16 weeks up to 7 years after the last patient is randomized
Minimal residual disease negative rate
time frame: For participants with complete response, every 12 weeks in the first 12 months, thereafter every 16 weeks and at disease progression or up to the end-of-study visit (up to 7 years after the last patient is randomized)
Duration of response
time frame: Up to the end-of-study visit up to 7 years after the last patient is randomized
Time-to-next treatment
time frame: Up to the end-of-study visit up to 7 years after the last patient is randomized
Number of participants affected by an adverse event
time frame: Up to 30 days after the last dose of any study treatment
Oral plasma clearance of ibrutinib as derived from population pharmacokinetics
time frame: Predose on Day 2 Cycles 1-3, postdose on Day 2 Cycles 1 and 2 at 1, 2, and 4 hours after administration of ibrutinib study dose
Oral volume of distribution at steady state of ibrutinib as derived from population pharmacokinetics
time frame: Predose on Day 2 Cycles 1-3, postdose on Day 2 Cycles 1 and 2 at 1, 2, and 4 hours after administration of ibrutinib study dose
Area under the concentration curve of ibrutinib as derived from population pharmacokinetics
time frame: Predose on Day 2 Cycles 1-3, postdose on Day 2 Cycles 1 and 2 at 1, 2, and 4 hours after administration of ibrutinib study dose
Minimum observed plasma concentration of ibrutinib as derived from population pharmacokinetics
time frame: Predose on Day 2 Cycles 1-3, postdose on Day 2 Cycles 1 and 2 at 1, 2, and 4 hours after administration of ibrutinib study dose
Maximum observed plasma concentration of ibrutinib as derived from population pharmacokinetics
time frame: Predose on Day 2 Cycles 1-3, postdose on Day 2 Cycles 1 and 2 at 1, 2, and 4 hours after administration of ibrutinib study dose

Eligibility Criteria

Male or female participants at least 65 years old.

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 other relevant markers (eg, CD19, CD20, 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 transplant - History of stroke or intracranial hemorrhage within 6 months prior to random assignment - Requires anticoagulation with warfarin or equivalent vitamin K antagonists - Requires treatment with strong CYP3A 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

Additional Information

Official title 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
Description 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 discontinuation of all study treatment 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. Four clinical cutoffs are planned. The first 3 clinical cutoffs will occur when approximately 134, 180, and 265 PFS events have been observed, respectively. The interim analyses and the final analysis of PFS will take place at these 3 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Janssen Research & Development, LLC.