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.
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 and placebo treatment will be stopped at the clinical cutoff for the final analysis of PFS. Treatment unblinding and stopping of placebo treatment could occur before the planned final analysis of PFS if recommended by the independent Data Monitoring Committee (DMC) after an interim analysis. 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
523
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
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
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
Progression-free Survival (PFS)
Progression-free survival (PFS) was defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever was first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD was defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters \[cm\] in any axis, 50% increase in sum of product of diameters \[SPD\] of greater than \[\>\] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis).
Time frame: Up to 97 months
Overall Survival
Overall survival was defined as the time from the date of randomization to the date of the participant's death. Kaplan-Meier estimate was used.
Time frame: From randomization (Day -3) up to 121 months
Complete Response Rate
Complete response (CR) rate was defined as the percentage of participants who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Time frame: Up to 97 months
Time-to-Next Treatment
Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment.
Time frame: Up to 97 months
Percentage of Participants With Overall Response
Percentage of participants with overall response was defined as the portion of participants who achieved CR or PR. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. Criteria for PR: greater than or equal to (\>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions.
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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
Unnamed facility
Tucson, Arizona, United States
Unnamed facility
Burbank, California, United States
Unnamed facility
La Jolla, California, United States
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Stanford, California, United States
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Denver, Colorado, United States
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New Haven, Connecticut, United States
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Stamford, Connecticut, United States
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Chicago, Illinois, United States
Unnamed facility
Maywood, Illinois, United States
Unnamed facility
Niles, Illinois, United States
...and 191 more locations
Time frame: Up to 97 months
Minimal Residual Disease (MRD)-Negative Response Rate
Minimal residual disease negative rate was defined as the percentage of participants with a best overall response of CR with MRD-negative disease status (that is, \<5 mantle cell lymphoma \[MCL\] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample.
Time frame: Up to 97 months
Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline, death, or a missing assessment due to being "too ill", whichever occurred first. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score was the total of reverse scores, ranged 0 to 60. Higher scores indicated a better quality of life.
Time frame: Up to 97 months
Duration of Response (DoR)
Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death
Time frame: Up to 97 months
Duration of Complete Response (DoCR)
Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first.
Time frame: Up to 97 months
Time to Response
Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response.
Time frame: Up to 97 months
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Number of participants with TEAEs were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. Treatment-emergent adverse events were defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier.
Time frame: Placebo + BR (Treatment A): From first dose of study treatment (Day 1) up to 100.1 months; Ibrutinib + BR (Treatment B): From first dose of study treatment (Day 1) up to 117.2 months
Oral Plasma Clearance (CL/F) of Ibrutinib
CL/F was defined as apparent total systemic clearance of ibrutinib after extravascular administration. Cl/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling).
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Oral Volume of Distribution at Steady State of Ibrutinib
Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling.
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State
Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling.
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Minimum Observed Plasma Concentration of Ibrutinib
Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
Maximum Observed Plasma Concentration of Ibrutinib
Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling.
Time frame: Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2