Lymphoma
Conditions
Keywords
Lymphoma, Follicular lymphoma, Marginal zone lymphoma, Indolent Non-Hodgkin lymphoma, PCI-32765, Ibrutinib, Bendamustine, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, R-CHOP
Brief summary
The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered in combination with either bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in adult participants with previously treated indolent Non-Hodgkin lymphoma.
Detailed description
This is a randomized (individuals assigned to study treatment by chance), double-blind (individuals and study personnel will not know the identity of study treatments), 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 in approximately 400 adult participants with follicular lymphoma or marginal zone lymphoma. The study will include the following phases: Screening, Treatment, and a Post-treatment Follow-up. Eligible participants will be randomly assigned in a 1:1 ratio to either treatment Arm A (background immune-chemotherapy + placebo) or treatment Arm B (background immune-chemotherapy + 560 milligram \[mg\] of ibrutinib). All participants will receive 6 cycles of background immune-chemotherapy with either BR or R-CHOP in combination with either placebo (Arm A) or ibrutinib (Arm B). Selection of background immune-chemotherapy will be based on prior treatment history and cardiac function. After completion of background immune-chemotherapy, study drug (ibrutinib or placebo) will continue until disease progression, unacceptable toxicity, or study end, whichever comes first. Assessment of tumor response and progression will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Serial pharmacokinetic (study of what a drug does to the body) blood samples will be collected. Safety will be assessed throughout the study.
Interventions
DRUGBendamustine
90 milligram per meter square (mg/m\^2) administered intravenously on Days 1 to 2 of Cycles 1 to 6.
DRUGRituximab
375 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6.
DRUGCyclophosphamide
750 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6.
DRUGDoxorubicin
50 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6.
DRUGVincristine
1.4 mg/m\^2 (maximum total 2 mg) administered intravenously on Day 1 of Cycles 1 to 6.
DRUGPrednisone
100 mg administered orally on Days 1 to 5 of Cycles 1 to 6.
560 mg (4\*140 mg) capsules administered orally once daily, continuously starting on Cycle 1, Day 1.
DRUGPlacebo
Placebo (4 capsules) matched to ibrutinib administered orally once daily, continuously starting on Cycle 1, Day 1.
Sponsors
Pharmacyclics LLC.
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of B-cell indolent Non-Hodgkin lymphoma with histological subtype limited to follicular lymphoma or marginal zone lymphoma, at initial diagnosis and without evidence of pathological transformation or clinical signs suggesting transformation * At least 1 prior treatment with a CD20 antibody combination chemo-immunotherapy regimen * Disease that has relapsed or was refractory after prior chemo-immunotherapy * At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma 2007 * Eastern Cooperative Oncology Group performance status grade 0 or 1 * Laboratory values within protocol-defined parameters * Agrees to protocol-defined use of effective contraception * Men must agree not to donate sperm during and after the study for 6 months after the last dose of bendamustine, 12 months after the last dose of rituximab, or 3 months after the last dose of study medication, whichever is later * Women of childbearing potential must have a negative serum or urine pregnancy test at Screening
Exclusion criteria
* Prior treatment according to protocol-defined criteria * Unable to receive background chemotherapy based on prior treatment history and cardiac function * Known central nervous system lymphoma * Diagnosed or treated for malignancy other than indolent Non-Hodgkin lymphoma * History of stroke or intracranial hemorrhage within 6 months prior to randomization * Requires anticoagulation with warfarin or equivalent Vitamin K antagonists * Requires treatment with strong CYP3A inhibitors * Clinically significant cardiovascular disease * Known history of human immunodeficiency virus or active hepatitis C virus (HCV; ribonucleic acid \[RNA\] polymerase chain reaction \[PCR\]-positive) or active hepatitis B virus (HBV; DNA PCR-positive) 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 participant's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk * Women who are pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Analysis: Progression Free Survival (PFS): Stratified Analysis | Up to 8 years | PFS was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from complete response (CR) or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by greater than or equal to (\>=) 50 percent (%) of previously involved sites from nadir disease progression 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. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. |
| Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Participants With Marginal Zone Lymphoma (MZL) | Up to 8 years | PFS in MZL participants was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from CR or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by \>=50% of previously involved sites from nadir disease progression criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Primary Analysis: Complete Response Rate (CRR): Stratified Analysis | Up to 8 years | CRR was defined as the percentage of participants who achieved a complete response (CR); (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma 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 CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. |
| Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Participants With MZL | Up to 8 years | CRR in MZL participants was defined as the percentage of participants who achieved a CR (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma therapy. 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 and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL. |
| Primary Analysis: Overall Response Rate (ORR): Stratified Analysis | Up to 8 years | ORR was defined as the percentage of participants who achieved a CR or partial response (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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. |
| Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Participants With MZL | Up to 8 years | ORR in MZL participants was defined as the percentage of participants who achieved a 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL. |
| Primary Analysis: Duration of Response (DOR): Stratified Analysis | Up to 8 years | DOR was defined as the interval (in months) between the date of initial documentation of response (CR or PR) and the date of first documented evidence of progressive disease (or relapse for participants who experienced CR during the study) or death, whichever occurred first. 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. |
| Primary Analysis: Overall Survival (OS): Stratified Analysis | Up to 8 years | OS was defined as the interval (in months) between the date of randomization and the date of the participant's death due to any cause. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. |
| Primary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire | Up to 8 years | Time-to-worsening in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomization to the start date of the worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline in participant symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. |
| Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Participants With MZL | Up to 8 years | TTW in MZL participants in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomization to the start date of the worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline in participant symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months) | Number of participants with TEAEs were reported. Adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs 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. |
| Number of Participants With TEAEs: Participants With MZL | Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months) | Number of MZL participants with TEAEs were reported. AE was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs 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. |
| Supplementary Analysis: Duration of Response: Unstratified Analysis - Participants With MZL | Up to 8 years | DOR in MZL participants was defined as the interval (in months) between the date of initial documentation of response (CR or PR) and the date of first documented evidence of progressive disease (or relapse for participants who experienced CR during the study) or death, whichever occurred first. 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL. |
| Supplementary Analysis: Overall Survival: Unstratified Analysis - Participants With MZL | Up to 8 years | OS in MZL participants was defined as the interval (in months) between the date of randomization and the date of the participant's death due to any cause. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL. |
Countries
Argentina, Australia, Belgium, Brazil, China, France, Germany, Israel, Japan, Poland, Puerto Rico, Russia, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were stratified by background chemotherapy treatment (bendamustine and rituximab \[BR\] or combination or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone \[R-CHOP\]), refractory versus relapsed disease, Indolent non-Hodgkin lymphoma histology, and number of prior lines of therapy.
Pre-assignment details
Placebo+CIT arm participants discontinued the study treatment post the primary analysis but were assessed for the safety till the end of the study. No further efficacy analyses were done after the primary analysis.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Chemoimmunotherapy (CIT) Participants received 4 capsules of placebo matching to ibrutinib orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 milligrams per meter square (mg/m\^2) intravenously (IV) on Days 1 and 2 of each cycle and rituximab 375 mg/m\^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m\^2 IV on Day 1, cyclophosphamide 750 mg/m\^2 IV on Day 1, doxorubicin 50 mg/m\^2 IV on Day 1, vincristine 1.4 mg/m\^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, participants randomized to arm Placebo + CIT discontinued placebo treatment. | 201 |
| Ibrutinib + CIT Participants received ibrutinib 560 mg capsules (4 capsules of 140 mg) orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All participants also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 mg/m\^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m\^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m\^2 IV on Day 1, cyclophosphamide 750 mg/m\^2 IV on Day 1, doxorubicin 50 mg/m\^2 IV on Day 1, vincristine 1.4 mg/m\^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, participants randomized to arm Ibrutinib + CIT continued/stopped treatment with ibrutinib at the discretion of the treating physician. | 202 |
| Total | 403 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 7 | 7 |
| Overall Study | Sponsor decision | 109 | 110 |
| Overall Study | Withdrawal by Subject | 24 | 20 |
Baseline characteristics
| Characteristic | Placebo + Chemoimmunotherapy (CIT) | Total | Ibrutinib + CIT |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 12.7 | 58.8 years STANDARD_DEVIATION 12.27 | 58.9 years STANDARD_DEVIATION 11.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 30 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 173 Participants | 351 Participants | 178 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants | 22 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 59 Participants | 127 Participants | 68 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 10 Participants | 4 Participants |
| Race (NIH/OMB) White | 135 Participants | 261 Participants | 126 Participants |
| Region of Enrollment ARGENTINA | 2 Participants | 10 Participants | 8 Participants |
| Region of Enrollment AUSTRALIA | 21 Participants | 37 Participants | 16 Participants |
| Region of Enrollment BELGIUM | 4 Participants | 13 Participants | 9 Participants |
| Region of Enrollment BRAZIL | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment CHINA | 31 Participants | 57 Participants | 26 Participants |
| Region of Enrollment FRANCE | 13 Participants | 21 Participants | 8 Participants |
| Region of Enrollment GERMANY | 5 Participants | 13 Participants | 8 Participants |
| Region of Enrollment ISRAEL | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment ITALY | 6 Participants | 11 Participants | 5 Participants |
| Region of Enrollment JAPAN | 15 Participants | 42 Participants | 27 Participants |
| Region of Enrollment POLAND | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 11 Participants | 20 Participants | 9 Participants |
| Region of Enrollment SOUTH KOREA | 12 Participants | 26 Participants | 14 Participants |
| Region of Enrollment SPAIN | 13 Participants | 20 Participants | 7 Participants |
| Region of Enrollment SWEDEN | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment TURKEY | 11 Participants | 20 Participants | 9 Participants |
| Region of Enrollment UKRAINE | 6 Participants | 8 Participants | 2 Participants |
| Region of Enrollment UNITED KINGDOM | 10 Participants | 20 Participants | 10 Participants |
| Region of Enrollment UNITED STATES | 19 Participants | 40 Participants | 21 Participants |
| Sex: Female, Male Female | 102 Participants | 191 Participants | 89 Participants |
| Sex: Female, Male Male | 99 Participants | 212 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 61 / 201 | 65 / 202 |
| other Total, other adverse events | 196 / 199 | 198 / 201 |
| serious Total, serious adverse events | 76 / 199 | 113 / 201 |
Outcome results
Primary
Primary Analysis: Progression Free Survival (PFS): Stratified Analysis
PFS was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from complete response (CR) or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by greater than or equal to (\>=) 50 percent (%) of previously involved sites from nadir disease progression 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. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
Time frame: Up to 8 years
Population: Intent-to-treat (ITT) population included all randomized participants who were enrolled with follicular lymphoma (FL) or marginal zone lymphoma (MZL) and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Progression Free Survival (PFS): Stratified Analysis | 23.75 months |
| Ibrutinib + CIT | Primary Analysis: Progression Free Survival (PFS): Stratified Analysis | 40.51 months |
p-value: 0.092295% CI: [0.626, 1.037]Log Rank
Primary
Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Participants With Marginal Zone Lymphoma (MZL)
PFS in MZL participants was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from CR or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by \>=50% of previously involved sites from nadir disease progression criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Participants With Marginal Zone Lymphoma (MZL) | 91.63 months |
| Ibrutinib + CIT | Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Participants With Marginal Zone Lymphoma (MZL) | NA months |
p-value: 0.450595% CI: [0.312, 1.682]Log Rank
Secondary
Number of Participants With TEAEs: Participants With MZL
Number of MZL participants with TEAEs were reported. AE was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs 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.
Time frame: Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months)
Population: Safety analysis population included all randomized participants with MZL who received at least 1 dose of study drug, and were analyzed according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Number of Participants With TEAEs: Participants With MZL | 28 Participants |
| Ibrutinib + CIT | Number of Participants With TEAEs: Participants With MZL | 28 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Number of participants with TEAEs were reported. Adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs 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.
Time frame: Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months)
Population: Safety analysis population included all randomized participants who received at least 1 dose of study drug, and were analyzed according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 197 Participants |
| Ibrutinib + CIT | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 199 Participants |
Secondary
Primary Analysis: Complete Response Rate (CRR): Stratified Analysis
CRR was defined as the percentage of participants who achieved a complete response (CR); (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma 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 CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
Time frame: Up to 8 years
Population: ITT population included all randomized participants who were enrolled with FL or MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Complete Response Rate (CRR): Stratified Analysis | 50.2 percentage of participants |
| Ibrutinib + CIT | Primary Analysis: Complete Response Rate (CRR): Stratified Analysis | 55 percentage of participants |
Secondary
Primary Analysis: Duration of Response (DOR): Stratified Analysis
DOR was defined as the interval (in months) between the date of initial documentation of response (CR or PR) and the date of first documented evidence of progressive disease (or relapse for participants who experienced CR during the study) or death, whichever occurred first. 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
Time frame: Up to 8 years
Population: ITT population included all randomized participants who were enrolled with FL or MZL and were analyzed according to the treatment to which they were randomized. Participants who achieved a PR or better were included in the analysis of duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Duration of Response (DOR): Stratified Analysis | 21.68 months |
| Ibrutinib + CIT | Primary Analysis: Duration of Response (DOR): Stratified Analysis | 44.32 months |
Secondary
Primary Analysis: Overall Response Rate (ORR): Stratified Analysis
ORR was defined as the percentage of participants who achieved a CR or partial response (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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
Time frame: Up to 8 years
Population: ITT population included all randomized participants who were enrolled with FL or MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Overall Response Rate (ORR): Stratified Analysis | 90.5 percentage of participants |
| Ibrutinib + CIT | Primary Analysis: Overall Response Rate (ORR): Stratified Analysis | 91.6 percentage of participants |
Secondary
Primary Analysis: Overall Survival (OS): Stratified Analysis
OS was defined as the interval (in months) between the date of randomization and the date of the participant's death due to any cause. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
Time frame: Up to 8 years
Population: ITT population included all randomized participants who were enrolled with FL or MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Overall Survival (OS): Stratified Analysis | NA months |
| Ibrutinib + CIT | Primary Analysis: Overall Survival (OS): Stratified Analysis | NA months |
Secondary
Primary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire
Time-to-worsening in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomization to the start date of the worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline in participant symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
Time frame: Up to 8 years
Population: ITT population included all randomized participants who were enrolled with FL or MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Primary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire | 37.03 months |
| Ibrutinib + CIT | Primary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire | 24.84 months |
Secondary
Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Participants With MZL
CRR in MZL participants was defined as the percentage of participants who achieved a CR (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma therapy. 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 and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Participants With MZL | 60.7 percentage of participants |
| Ibrutinib + CIT | Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Participants With MZL | 64.3 percentage of participants |
Secondary
Supplementary Analysis: Duration of Response: Unstratified Analysis - Participants With MZL
DOR in MZL participants was defined as the interval (in months) between the date of initial documentation of response (CR or PR) and the date of first documented evidence of progressive disease (or relapse for participants who experienced CR during the study) or death, whichever occurred first. 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized. Participants who achieved a PR or better were included in the analysis of duration of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Duration of Response: Unstratified Analysis - Participants With MZL | 89.17 months |
| Ibrutinib + CIT | Supplementary Analysis: Duration of Response: Unstratified Analysis - Participants With MZL | NA months |
Secondary
Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Participants With MZL
ORR in MZL participants was defined as the percentage of participants who achieved a 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 and no new sites of disease detected during assessment. Criteria for PR: \>=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. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Participants With MZL | 82.1 percentage of participants |
| Ibrutinib + CIT | Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Participants With MZL | 89.3 percentage of participants |
Secondary
Supplementary Analysis: Overall Survival: Unstratified Analysis - Participants With MZL
OS in MZL participants was defined as the interval (in months) between the date of randomization and the date of the participant's death due to any cause. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Overall Survival: Unstratified Analysis - Participants With MZL | NA months |
| Ibrutinib + CIT | Supplementary Analysis: Overall Survival: Unstratified Analysis - Participants With MZL | NA months |
Secondary
Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Participants With MZL
TTW in MZL participants in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomization to the start date of the worsening of participant symptoms. Worsening was defined by a 5-point decrease from baseline in participant symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
Time frame: Up to 8 years
Population: All randomized participants who were enrolled with MZL and were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo + Chemoimmunotherapy (CIT) | Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Participants With MZL | 36.83 months |
| Ibrutinib + CIT | Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Participants With MZL | 58.91 months |