Mantle Cell Lymphoma
Conditions
Keywords
Mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Bendamustine hydrochloride, Rituximab
Brief 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.
Detailed 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 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.
Interventions
DRUGBendamustine
90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6
DRUGRituximab
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
DRUGIbrutinib
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
DRUGPlacebo
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
Sponsors
Pharmacyclics LLC.
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 97 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Up to 97 months | 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-to-Next Treatment | Up to 97 months | 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. |
| Percentage of Participants With Overall Response | Up to 97 months | 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. |
| Minimal Residual Disease (MRD)-Negative Response Rate | Up to 97 months | 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 to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire | Up to 97 months | 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. |
| Duration of Response (DoR) | Up to 97 months | 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 |
| Duration of Complete Response (DoCR) | Up to 97 months | 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. |
| Overall Survival | From randomization (Day -3) up to 121 months | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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 | 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. |
| Oral Plasma Clearance (CL/F) of Ibrutinib | 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 | 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). |
| Oral Volume of Distribution at Steady State of Ibrutinib | 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 was determined using PopPK modeling. |
| Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State | 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 was determined using PopPK modeling. |
| Minimum Observed Plasma Concentration of Ibrutinib | 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 was determined using PopPK modeling. |
| Maximum Observed Plasma Concentration of Ibrutinib | 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 was determined using PopPK modeling. |
| Time to Response | Up to 97 months | Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Hungary, Ireland, Israel, Japan, Mexico, Netherlands, Poland, Puerto Rico, Russia, Slovakia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 523 subjects were randomized in this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Bendamustine and Rituximab (BR) (Treatment A) Participants received 4 capsules of ibrutinib-matching Placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square \[mg/m\^2\] intravenous \[IV\] infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m\^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a complete response (CR) or partial response (PR) continued to receive background therapy with rituximab maintenance (375 mg/m\^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Participants received treatment A up to 100.1 months. After treatment unblinding at the time of the primary analysis, participants randomized to Treatment A discontinued placebo treatment. | 262 |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) Participants received ibrutinib capsules 560 mg (4\*140 mg capsule) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m\^2 IV infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m\^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Participants with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m\^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Participants received treatment B up to 117.2 months. After treatment unblinding at the time of the primary analysis, participants randomized to Treatment B continued treatment with ibrutinib at the discretion of the investigator. | 261 |
| Total | 523 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 12 | 7 |
| Overall Study | Sponsor decision | 89 | 87 |
| Overall Study | Withdrawal by Subject | 32 | 48 |
Baseline characteristics
| Characteristic | Total | Placebo + Bendamustine and Rituximab (BR) (Treatment A) | Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) |
|---|---|---|---|
| Age, Continuous | 71.7 years STANDARD_DEVIATION 5.12 | 71.7 years STANDARD_DEVIATION 5.2 | 71.8 years STANDARD_DEVIATION 5.04 |
| Age, Customized < 70 years | 207 Participants | 108 Participants | 99 Participants |
| Age, Customized 70 years and over | 316 Participants | 154 Participants | 162 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 17 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 466 Participants | 234 Participants | 232 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 22 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 89 Participants | 42 Participants | 47 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 19 Participants | 9 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 405 Participants | 206 Participants | 199 Participants |
| Region of Enrollment ARGENTINA | 4 Participants | 0 Participants | 4 Participants |
| Region of Enrollment AUSTRALIA | 31 Participants | 12 Participants | 19 Participants |
| Region of Enrollment BELGIUM | 15 Participants | 10 Participants | 5 Participants |
| Region of Enrollment BRAZIL | 21 Participants | 10 Participants | 11 Participants |
| Region of Enrollment CANADA | 11 Participants | 7 Participants | 4 Participants |
| Region of Enrollment CHINA | 57 Participants | 26 Participants | 31 Participants |
| Region of Enrollment CZECH REPUBLIC | 15 Participants | 8 Participants | 7 Participants |
| Region of Enrollment FRANCE | 21 Participants | 13 Participants | 8 Participants |
| Region of Enrollment GERMANY | 8 Participants | 5 Participants | 3 Participants |
| Region of Enrollment GREECE | 7 Participants | 3 Participants | 4 Participants |
| Region of Enrollment HUNGARY | 10 Participants | 5 Participants | 5 Participants |
| Region of Enrollment IRELAND | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment ISRAEL | 14 Participants | 9 Participants | 5 Participants |
| Region of Enrollment ITALY | 26 Participants | 13 Participants | 13 Participants |
| Region of Enrollment JAPAN | 11 Participants | 4 Participants | 7 Participants |
| Region of Enrollment MEXICO | 3 Participants | 2 Participants | 1 Participants |
| Region of Enrollment NETHERLANDS | 8 Participants | 3 Participants | 5 Participants |
| Region of Enrollment POLAND | 35 Participants | 17 Participants | 18 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 27 Participants | 12 Participants | 15 Participants |
| Region of Enrollment SLOVAKIA | 3 Participants | 2 Participants | 1 Participants |
| Region of Enrollment SOUTH KOREA | 12 Participants | 6 Participants | 6 Participants |
| Region of Enrollment SPAIN | 20 Participants | 7 Participants | 13 Participants |
| Region of Enrollment SWEDEN | 18 Participants | 9 Participants | 9 Participants |
| Region of Enrollment TAIWAN | 6 Participants | 4 Participants | 2 Participants |
| Region of Enrollment TURKEY | 14 Participants | 6 Participants | 8 Participants |
| Region of Enrollment UKRAINE | 11 Participants | 5 Participants | 6 Participants |
| Region of Enrollment UNITED KINGDOM | 30 Participants | 16 Participants | 14 Participants |
| Region of Enrollment UNITED STATES | 83 Participants | 48 Participants | 35 Participants |
| Sex: Female, Male Female | 159 Participants | 76 Participants | 83 Participants |
| Sex: Female, Male Male | 364 Participants | 186 Participants | 178 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 129 / 262 | 120 / 261 |
| other Total, other adverse events | 255 / 260 | 256 / 259 |
| serious Total, serious adverse events | 157 / 260 | 201 / 259 |
Outcome results
Primary
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
Population: Intent-to-treat (ITT) analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (overall number of participants analyzed) signifies number of participants that were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Progression-free Survival (PFS) | 52.9 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Progression-free Survival (PFS) | 80.6 months |
p-value: 0.01195% CI: [0.59, 0.96]Log Rank
Secondary
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
Population: Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State | 425 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 267 |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Complete Response Rate | 57.6 percentage of participants |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Complete Response Rate | 65.5 percentage of participants |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a CR or better were included in the analysis of duration of complete response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Duration of Complete Response (DoCR) | 78.1 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Duration of Complete Response (DoCR) | NA months |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Duration of Response (DoR) | 63.5 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Duration of Response (DoR) | 81 months |
Secondary
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
Population: Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Maximum Observed Plasma Concentration of Ibrutinib | 74.5 ng/mL | Standard Deviation 48.3 |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. CR participants with missing MRD data and participants who did not achieve a CR were considered nonresponders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Minimal Residual Disease (MRD)-Negative Response Rate | 56.5 percentage of participants |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Minimal Residual Disease (MRD)-Negative Response Rate | 62.1 percentage of participants |
Secondary
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
Population: Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Minimum Observed Plasma Concentration of Ibrutinib | 3.90 nanograms per milliliter (ng/mL) | Standard Deviation 2.64 |
Secondary
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
Population: Safety analysis set included all randomized participants who received at least 1 dose of study drug (ibrutinib or placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 257 Participants |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 259 Participants |
Secondary
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
Population: Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Oral Plasma Clearance (CL/F) of Ibrutinib | 1123 liter per hour (L/h) | Standard Error 4.83 |
Secondary
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
Population: Pharmacokinetic-evaluable population included participants who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Oral Volume of Distribution at Steady State of Ibrutinib | 7286 liter | Standard Error 7.87 |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Overall Survival | 95.9 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Overall Survival | 104.3 months |
Secondary
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.
Time frame: Up to 97 months
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Percentage of Participants With Overall Response | 88.5 percentage of participants |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Percentage of Participants With Overall Response | 89.7 percentage of participants |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Here, N (number of participants analyzed) signifies number of participants that were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time-to-Next Treatment | 92.0 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time-to-Next Treatment | NA months |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received. Participants who achieved a PR or better were included in the analysis of time to response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time to Response | 2.79 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time to Response | 2.79 months |
Secondary
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
Population: ITT analysis set included all randomized participants and classified according to the assigned treatment group, regardless of the actual treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire | 22.2 months |
| Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) | Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire | 17.4 months |