A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Rituximab
* Drug: Ibrutinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Treatment Arm A<br> | Drug: Bendamustine<br>* 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6<br>Drug: Rituximab<br>* 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<br>Drug: Placebo<br>* 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<br>|
| Experimental: Treatment Arm B<br> | Drug: Bendamustine<br>* 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6<br>Drug: Rituximab<br>* 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<br>Drug: Ibrutinib<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) is 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 is first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD is 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). | Up to 97 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from the date of randomization to the date of the participant's death. | Up to 97 months | 
| Complete Response Rate | Complete response (CR) rate is 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. | 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. | Up to 97 months | 
| Percentage of Participants With Overall Response | Percentage of participants with overall response that is participants who achieved CR or PR was reported. 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. | 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. | 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 is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. | 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. | 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, for participants who achieved CR. | 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. | Up to 97 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Number of participants with TEAEs were reported. Treatment-emergent adverse events are 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. | Up to 97 months | 
| Oral Plasma Clearance (CL/F) of Ibrutinib | CL/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling). | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) | 
| Oral Volume of Distribution at Steady State of Ibrutinib | Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling. | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) | 
| 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. | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) | 
| Minimum Observed Plasma Concentration of Ibrutinib | Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling. | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) | 
| Maximum Observed Plasma Concentration of Ibrutinib | Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling. | Day 2 of Cycles 1, 2 and 3 (each cycle was of 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrutinib, Mantle cell lymphoma, Bruton's tyrosine kinase inhibitor, Bendamustine hydrochloride, Rituximab