Mantle Cell Lymphoma
Conditions
Keywords
Mantle cell lymphoma, Relapsed mantle cell lymphoma, Refractory mantle cell lymphoma, Ibrutinib, Bruton's tyrosine kinase inhibitor, Temsirolimus
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.
Detailed description
This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus \>=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Patients who receive treatment with temsirolimus and have disease progression (confirmed by an Independent Review Committee) may be eligible to crossover and receive treatment with ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression, unacceptable toxicity, or study end. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.
Interventions
DRUGIbrutinib
560 mg once daily continuous (without interruption) by mouth for 21-day cycles
DRUGTemsirolimus
175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle
Sponsors
Pharmacyclics LLC.
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of mantle cell lymphoma (MCL) * Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a \> 6 month treatment-free interval) * Documented relapse or disease progression following the last anti-MCL treatment * At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma * Eastern Cooperative Oncology Group performance status grade 0 or 1 * Protocol-defined hematology and biochemistry laboratory values
Exclusion criteria
* Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization * Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton's tyrosine kinase (BTK) inhibitors * Known central nervous system lymphoma * Received an allogeneic or autologous hematopoietic stem cell transplant \<=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease * 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 randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease * History of stroke or intracranial hemorrhage within 6 months prior to randomization * Requires anticoagulation with warfarin or equivalent vitamin K antagonist * Requires treatment with strong CYP3A inhibitor * 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 * Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics * Woman who is pregnant or breast-feeding * 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) | Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months) | PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to \[\>=\] 50 percent \[%\] of previously involved sites from nadir). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approximately up to 48 months | Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause. |
| Duration of Response | Approximately up to 48 months | Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. The analysis was based on the investigator assessment. |
| Time-to-Next Treatment | Approximately up to 48 months | Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment. |
| Overall Response Rate (ORR) | Approximately up to 48 months | ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment. CR is Disappearance of all target lesions while PR is greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is sum of CR and PR. |
| Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) | Approximately up to 48 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. Worsening was defined by a 5-point decrease from baseline. 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. |
| Number of Participants Affected With Treatment-emergent Adverse Events | Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier (Approximately up to 4 years) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Progression-Free Survival 2 | Approximately up to 48 months | Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent anti-neoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent anti-neoplastic therapy if no progressive disease was recorded after the first subsequent anti-neoplastic therapy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Response | Approximately up to 2.8 years | Time to response for participants with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response. |
| The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately up to 23 months) | The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state. |
| Extent of Exposure of Time | Approximately up to 46.8 months | Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment. |
| One Year Survival Rate | Month 12 | One -year survival rate, defined as the proportion of participants who were alive 1 year after randomization. |
| Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss) | Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr. postdose; Cycle 3 (day 1): Predose (Each cycle is of 21 days) | The AUC-ss is the area under the plasma concentration time curve observed during steady state. |
| Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib | Approximately up to 28.2 months | Biomarker evaluations to identify markers altering BCR signaling or activate alternative signaling pathways and explore their association with response or resistance to ibrutinib. Next-generation sequencing at baseline identifies possible primary resistance mutations and those found only at progression are acquired mutations on therapy. |
| Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI) | Approximately up to 28.2 months | Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study. |
| Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Approximately up to 28.2 months | Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study. |
| Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Approximately up to 28.2 months | Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study. |
Countries
Belgium, Brazil, Canada, Chile, Colombia, Czechia, France, Germany, Hungary, Ireland, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Sweden, Taiwan, Ukraine, United Kingdom
Participant flow
Pre-assignment details
139 participants were randomized and treated in the ibrutinib arm and 141 participants were randomized to the temsirolimus arm.
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib Participants received 560 milligram (mg) ibrutinib (4\*140 mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment during the 21 day cycle. | 139 |
| Temsirolimus Participants received Temsirolimus intravenous (IV) infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21 day cycle. Each temsirolimus dose is infused over a 30 to 60 minute period. | 141 |
| Total | 280 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 77 | 83 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Study Terminated by Sponsor | 50 | 41 |
| Overall Study | Withdrawal by Subject | 10 | 15 |
Baseline characteristics
| Characteristic | Ibrutinib | Temsirolimus | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 86 Participants | 87 Participants | 173 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 54 Participants | 107 Participants |
| Age, Continuous | 66.7 years STANDARD_DEVIATION 8.68 | 67.1 years STANDARD_DEVIATION 9.83 | 66.9 years STANDARD_DEVIATION 9.26 |
| Region of Enrollment Belgium | 7 participants | 10 participants | 17 participants |
| Region of Enrollment Brazil | 5 participants | 10 participants | 15 participants |
| Region of Enrollment Canada | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Colombia | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Czech Republic | 7 participants | 7 participants | 14 participants |
| Region of Enrollment France | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Germany | 12 participants | 11 participants | 23 participants |
| Region of Enrollment Hungary | 5 participants | 7 participants | 12 participants |
| Region of Enrollment Ireland | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Italy | 6 participants | 8 participants | 14 participants |
| Region of Enrollment Mexico | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Netherlands | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Poland | 9 participants | 14 participants | 23 participants |
| Region of Enrollment Portugal | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Russian Federation | 18 participants | 11 participants | 29 participants |
| Region of Enrollment South Korea | 11 participants | 3 participants | 14 participants |
| Region of Enrollment Spain | 5 participants | 14 participants | 19 participants |
| Region of Enrollment Sweden | 10 participants | 8 participants | 18 participants |
| Region of Enrollment Taiwan | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Ukraine | 6 participants | 4 participants | 10 participants |
| Region of Enrollment United Kingdom | 11 participants | 16 participants | 27 participants |
| Sex/Gender, Customized Female | 39 participants | 33 participants | 72 participants |
| Sex/Gender, Customized Male | 100 participants | 108 participants | 208 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 130 / 139 | 137 / 139 |
| other Total, other adverse events | 130 / 139 | 137 / 139 |
| serious Total, serious adverse events | 79 / 139 | 83 / 139 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to \[\>=\] 50 percent \[%\] of previously involved sites from nadir).
Time frame: Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months)
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Progression Free Survival (PFS) | 15.6 Months |
| Temsirolimus | Progression Free Survival (PFS) | 6.2 Months |
p-value: <0.000195% CI: [0.35, 0.6]Log Rank
Secondary
Duration of Response
Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. The analysis was based on the investigator assessment.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received. The 'N' (number of participants analyzed) signifies the number of participants responded for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Duration of Response | 23.1 Months |
| Temsirolimus | Duration of Response | 6.3 Months |
Secondary
Number of Participants Affected With Treatment-emergent Adverse Events
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier (Approximately up to 4 years)
Population: Safety population included all randomized participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib | Number of Participants Affected With Treatment-emergent Adverse Events | 139 Participants |
| Temsirolimus | Number of Participants Affected With Treatment-emergent Adverse Events | 138 Participants |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment. CR is Disappearance of all target lesions while PR is greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is sum of CR and PR.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Overall Response Rate (ORR) | 77.0 Percentage of participants |
| Temsirolimus | Overall Response Rate (ORR) | 46.8 Percentage of participants |
Secondary
Overall Survival (OS)
Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Overall Survival (OS) | 30.3 Months |
| Temsirolimus | Overall Survival (OS) | 23.5 Months |
p-value: =0.062195% CI: [0.54, 1.02]Log Rank
Secondary
Progression-Free Survival 2
Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent anti-neoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent anti-neoplastic therapy if no progressive disease was recorded after the first subsequent anti-neoplastic therapy.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Progression-Free Survival 2 | 26.2 Months |
| Temsirolimus | Progression-Free Survival 2 | 15.4 Months |
Secondary
Time-to-Next Treatment
Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Time-to-Next Treatment | 31.8 Months |
| Temsirolimus | Time-to-Next Treatment | 11.6 Months |
Secondary
Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym)
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. Worsening was defined by a 5-point decrease from baseline. 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.
Time frame: Approximately up to 48 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) | NA Weeks |
| Temsirolimus | Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) | 10.6 Weeks |
Other Pre-specified
Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss)
The AUC-ss is the area under the plasma concentration time curve observed during steady state.
Time frame: Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr. postdose; Cycle 3 (day 1): Predose (Each cycle is of 21 days)
Population: Pharmacokinetic analysis set included the participants who had received one dose of study drug had at least 1 pharmacokinetic sample obtained post-treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib | Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss) | 561.6 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 448 |
Other Pre-specified
Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time frame: Approximately up to 28.2 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibrutinib | Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Mean days of hospitalization | 19.7 Days | Standard Deviation 20.5 |
| Ibrutinib | Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Mean days of emergency room visits | 1.8 Days | Standard Deviation 1.3 |
| Temsirolimus | Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Mean days of hospitalization | 20.3 Days | Standard Deviation 22.4 |
| Temsirolimus | Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | Mean days of emergency room visits | 1.6 Days | Standard Deviation 1.3 |
Other Pre-specified
Extent of Exposure of Time
Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment.
Time frame: Approximately up to 46.8 months
Population: Safety Analyses Set (SAS) population includes all the randomized participants who received at least 1 dose of study agent (ibrutinib or temsirolimus) during the treatment phase.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Extent of Exposure of Time | 14.39 Months |
| Temsirolimus | Extent of Exposure of Time | 3.02 Months |
Other Pre-specified
Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time frame: Approximately up to 28.2 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received. The 'N' (number of participants analyzed) signifies the number of participants responded for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib | Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | 1.2 Emergency room visits | Standard Deviation 0.4 |
| Temsirolimus | Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) | 1.2 Emergency room visits | Standard Deviation 0.4 |
Other Pre-specified
Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI)
Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
Time frame: Approximately up to 28.2 months
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received. The 'N' (number of participants analyzed) signifies the number of participants responded for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibrutinib | Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI) | 3.1 Hospitalizations | Standard Deviation 4.6 |
| Temsirolimus | Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI) | 2.8 Hospitalizations | Standard Deviation 4.3 |
Other Pre-specified
Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib
Biomarker evaluations to identify markers altering BCR signaling or activate alternative signaling pathways and explore their association with response or resistance to ibrutinib. Next-generation sequencing at baseline identifies possible primary resistance mutations and those found only at progression are acquired mutations on therapy.
Time frame: Approximately up to 28.2 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib | 61 Participants |
| Temsirolimus | Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib | 53 Participants |
Other Pre-specified
One Year Survival Rate
One -year survival rate, defined as the proportion of participants who were alive 1 year after randomization.
Time frame: Month 12
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | One Year Survival Rate | 0.68 Proportion of participants |
| Temsirolimus | One Year Survival Rate | 0.61 Proportion of participants |
Other Pre-specified
The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment
The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state.
Time frame: Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately up to 23 months)
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received. The 'N' (number of participants analyzed) signifies the number of participants evaluated for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 5 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 11 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 2 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 14 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 6 | 0.1 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 17 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 4 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 20 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 7 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 28 | -0.1 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 3 | 0.1 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 36 | 0.0 Units on scale | Standard Deviation 0.3 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 8 | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at End of treatment | 0.0 Units on scale | Standard Deviation 0.2 |
| Ibrutinib | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Baseline | 0.7 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at End of treatment | -0.1 Units on scale | Standard Deviation 0.3 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Baseline | 0.7 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 2 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 3 | -0.1 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 4 | 0.0 Units on scale | Standard Deviation 0.3 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 5 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 6 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 7 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 8 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 11 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 14 | 0.0 Units on scale | Standard Deviation 0.1 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 17 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 20 | 0.0 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 28 | 0.1 Units on scale | Standard Deviation 0.2 |
| Temsirolimus | The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment | Change at Cycle 36 | -0.1 Units on scale | Standard Deviation 0.2 |
Other Pre-specified
Time to Response
Time to response for participants with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response.
Time frame: Approximately up to 2.8 years
Population: The Intent-to-Treat (ITT) population included all participants randomized into the study regardless of treatment actually received. The 'N' (number of participants analyzed) signifies the number of participants responded for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Time to Response | 2.15 Months |
| Temsirolimus | Time to Response | 2.14 Months |