MURANO: A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Study Details
Study Description
Brief Summary
The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).
Condition or Disease | Intervention/Treatment | Phase |
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Phase 3 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Active Comparator: Bendamustine + Rituximab Participants will receive bendamustine 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6. | Drug: Bendamustine Bendamustine will be administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. Drug: Rituximab Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle. |
Experimental: Venetoclax + Rituximab Participants will be initially placed on a venetoclax 5 weeks ramp-up period, and will receive an initial dose of 20 milligrams (mg) via tablet orally once daily (QD). Then the dose will be incremented weekly up to a maximum dose of 400 mg. Participants will then continue receiving venetoclax 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards, as directed by the investigator, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6. | Drug: Venetoclax Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first.
R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.
Other Names: Drug: Rituximab Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle. |
Experimental: Bendamustine + Rituximab Crossover Substudy Participants entering the Crossover Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Crossover Day 1 of the Substudy. | Drug: Venetoclax Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first.
R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.
Other Names: Drug: Rituximab Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle. |
Experimental: Venetoclax + Rituximab Re-Treatment Participants entering the Re-Treatment Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Re-Treatment Day 1 of the Substudy. | Drug: Venetoclax Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first.
R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.
Other Names: Drug: Rituximab Rituximab will be administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle. |
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death [Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)]
Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 grams per deciliter (g/dL) or to less than [<] 10 g/dL.
- Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley.
Secondary Outcome Measures
- Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL.
- PFS as Assessed by the IRC Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence In-situ Hybridization (FISH) Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL.
- PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL.
- PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]
PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With Best Overall Response of Complete Response (CR), CR With Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines [Baseline up to last follow-up visit (FUV) (maximum up to data cut-off date, overall approximately 3 years)]
Response was assessed by the investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.
- Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines [Baseline up to last FUV (maximum up to data cut-off date, overall approximately 3 years)]
Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.
- Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines [End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days]
Response was assessed by the investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.
- Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines [EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days]
Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.
- Percentage of Participants Who Died [Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)]
Percentage of participants who died from any cause, during the study, was reported.
- Overall Survival (OS) [Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)]
OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With PD/Relapse, Start of a New Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines [Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)]
Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL.
- Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines [Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)]
EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. The median EFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines [From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)]
Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines or death from any cause during the study was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint.
- Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines [From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)]
DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. The median DOR was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint.
- Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator [Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)]
Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported.
- Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator [Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)]
TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.
- Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit [EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days]
MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method.
- Plasma Venetoclax Concentrations [Pre-dose (0 hour, anytime before venetoclax administeration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days]
- Change From Baseline in Lymphocyte Subset Counts at Specified Time Points [Baseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days]
- Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores [Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days]
MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13; total 13 items: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness) and Module Symptom Severity (average of Questions 14 to 19; total 6 items: night sweats, fevers and chills, lymph node swelling, diarrhea, bruising easy or bleeding, and constipation). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25; total 6 items: general activity, walking, work, mood, relations with other people, and enjoyment of life). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL).
- Change From Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score [Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days]
The EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Functional scales score and global health status/global QoL scale score are reported. Scores were averaged, transformed to 0-100 scale; where higher score for functional scales = poor level of functioning and higher score for global health status/global QoL = better HRQoL.
- Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score [Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days]
The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines
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Previously treated with 1-3 lines of therapy (example: completed greater than or equal to [>/=] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen
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Participants previously treated with bendamustine only if their duration of response was >/= 24 months
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Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1
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Adequate bone marrow function
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Adequate renal and hepatic function
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Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding
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For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy
Inclusion Criteria R/C Substudy:
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Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria
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Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B
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Adequate renal and hepatic function per laboratory reference range
Exclusion Criteria:
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Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL
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Undergone an allogenic stem cell transplant
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A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease
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Hepatitis B or C or known human immunodeficiency virus (HIV) positive
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Receiving warfarin treatment
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Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug
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Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
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Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax
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History of prior venetoclax treatment
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Participants with another cancer, history of another cancer considered uncured on in complete remission for <5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved
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Malabsorption syndrome or other condition that precludes enteral route of administration
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Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal)
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Vaccination with a live vaccine within 28 days prior to randomization
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Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment
-
A cardiovascular disability status of New York Heart Association Class >/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain
-
Major surgery within 30 days prior to the first dose of study treatment
-
A participant who is pregnant or breastfeeding
-
Known allergy to both xanthine oxidase inhibitors and rasburicase
Exclusion Criteria R/C Substudy:
-
Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL
-
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
-
Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
-
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
-
History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab
-
Known HIV positivity
-
Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HbsAg] serology)
-
Positive test results for hepatitis C virus (HCV; HCV antibody serology testing)
-
Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin)
-
Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy
-
Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment
-
Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment
-
Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment
-
A cardiovascular disability status of New York Heart Association Class >/= 3
-
A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes
-
Major surgery within 30 days prior to the first dose of study treatment
-
A participant who is pregnant or breastfeeding
-
Malabsorption syndrome or other condition that precludes enteral route of administration
-
Known allergy to both xanthine oxidase inhibitors and rasburicase
-
Vaccination with a live vaccine within 28 days prior to randomization
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of California San Diego Medical Center | La Jolla | California | United States | 92093-5354 |
2 | Henry Ford Health System | Detroit | Michigan | United States | 48202 |
3 | Memorial Sloan Kettering Cancer Center; Clinical Trials Office | New York | New York | United States | 10021 |
4 | Perlmutter Cancer Center NYU Langone Health | New York | New York | United States | 10032 |
5 | Huntsman Cancer Institute; University of Utah | Salt Lake City | Utah | United States | 84112 |
6 | The Canberra Hospital | Garran | Australian Capital Territory | Australia | 2065 |
7 | Concord Repatriation General Hospital | Concord | New South Wales | Australia | 2139 |
8 | St George Hospital | Kogarah, New South Wales | New South Wales | Australia | 2217 |
9 | Princess Alexandra Hospital | Woolloongabba | Queensland | Australia | 4102 |
10 | Royal Adelaide Hospital | Adelaide | South Australia | Australia | 5000 |
11 | Flinders Medical Centre | Bedford Park | South Australia | Australia | 5042 |
12 | Royal Hobart Hospital | Hobart | Tasmania | Australia | 7000 |
13 | Peter MacCallum Cancer Center | East Melbourne | Victoria | Australia | 3002 |
14 | Frankston Hospital | Frankston | Victoria | Australia | 3199 |
15 | Monash Medical Centre; Haematology | Melbourne | Victoria | Australia | 3168 |
16 | Slade Health Pharmacy | Mount Waverley | Victoria | Australia | 3149 |
17 | Royal Melbourne Hospital | Parkville | Victoria | Australia | 3050 |
18 | The Perth Blood Institute | Nedlands | Western Australia | Australia | 6009 |
19 | Medizinische Universität Innsbruck | Innsbruck | Austria | 6020 | |
20 | LKH - Universitätsklinikum der PMU Salzburg | Salzburg | Austria | 5020 | |
21 | Medizinische Universität Wien | Wien | Austria | 1090 | |
22 | Klinik Ottakring | Wien | Austria | 1160 | |
23 | ZNA Antwerpen; Department Hematology | Antwerpen | Belgium | 2060 | |
24 | Cliniques Universitaires Saint-Luc; Hematology | Bruxelles | Belgium | 1200 | |
25 | AZ Groeninge | Kortrijk | Belgium | 8500 | |
26 | UZ Leuven; Department Hematology | Leuven | Belgium | 3000 | |
27 | CHU UCL Mont-Godinne | Mont-godinne | Belgium | 5530 | |
28 | AZ Delta (Campus Rumbeke) | Roeselare | Belgium | 8800 | |
29 | Foothills Medical Centre; Centre Dept of Medical Clinical Neuroscience | Calgary | Alberta | Canada | T2N 2T9 |
30 | Juravinski Cancer Clinic | Hamilton | Ontario | Canada | L8N 3Z5 |
31 | Jewish General Hospital | Montreal | Quebec | Canada | H3T 1E2 |
32 | Saskatoon City Hospital;Saskatchewan Cancer Centre | Saskatoon | Saskatchewan | Canada | S7N 4H4 |
33 | Fakultni nemocnice Brno | Brno | Czechia | 613 00 | |
34 | Fakultni nemocnice Hradec Kralove | Hradec Kralove | Czechia | 500 05 | |
35 | Fakultní nemocnice Olomouc | Olomouc | Czechia | 775 20 | |
36 | Fakultni nemocnice Ostrava | Ostrava - Poruba | Czechia | 708 52 | |
37 | Vseobecna fakultni nemocnice v Praze | Praha 2 | Czechia | 128 08 | |
38 | Fakultni nemocnice Kralovske Vinohrady | Praha | Czechia | 100 34 | |
39 | Herlev Hospital | Herlev | Denmark | 2730 | |
40 | Rigshospitalet | København Ø | Denmark | 2100 | |
41 | Odense Universitetshospital | Odense C | Denmark | 5000 | |
42 | Sjællands Universitetshospital, Roskilde | Roskilde | Denmark | 4000 | |
43 | Sygehus Lillebælt, Vejle | Vejle | Denmark | 7100 | |
44 | Hôpital Morvan | Brest | France | 29609 | |
45 | Centre Hospitalier Départemental Les Oudairies | La Roche sur Yon | France | 85025 | |
46 | Hopital Claude Huriez - CHU Lille | Lille | France | 59037 | |
47 | Hopital Saint Eloi | Montpellier | France | 34295 | |
48 | CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation | Nantes | France | 44093 | |
49 | Hopital Robert Debre | Paris | France | 75019 | |
50 | Centre Hospitalier Lyon Sud | Pierre Benite | France | 69495 | |
51 | CHU Poitiers - Hopital La Miletrie | Poitiers | France | 86000 | |
52 | CHU de Rennes - Hopital de Pontchaillo | Rennes | France | 35033 | |
53 | Centre Henri Becquerel | Rouen | France | 76038 | |
54 | Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O) | Toulouse | France | 31059 | |
55 | CHU Tours - Hôpital Bretonneau | Tours | France | 37044 | |
56 | Hôpital de Brabois Adultes | Vandoeuvre-les-nancy | France | 54511 | |
57 | Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden | Dresden | Germany | 01307 | |
58 | Universitaetsklinikum Freiburg | Freiburg | Germany | 79106 | |
59 | Universitätsklinikum Tübingen | Tuebingen | Germany | 72076 | |
60 | Semmelweis Egyetem | Budapest | Hungary | 1083 | |
61 | Orszagos Onkologiai Intezet | Budapest | Hungary | 1122 | |
62 | Debreceni Egyetem Klinikai Központ; Bőrgyógyászati Klinika | Debrecen | Hungary | 4012 | |
63 | Somogy Megyei Kaposi Mor Oktato Korhaz | Pecs | Hungary | 7624 | |
64 | Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp. | Szeged | Hungary | 6720 | |
65 | Azienda Ospedaliera Città della Salute e della Scienza di Torino; Radiology | Torino | Abruzzo | Italy | 10126 |
66 | Azienda Ospedaliero Universitaria San Martino | Genova | Liguria | Italy | 16132 |
67 | Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII) | Bergamo | Lombardia | Italy | 24127 |
68 | Ospedale San Raffaele | Milano | Lombardia | Italy | 20132 |
69 | Asst Grande Ospedale Metropolitano Niguarda; SC Farmacia Ospedale | Milano | Lombardia | Italy | 20162 |
70 | Azienda Ospedaliero Universitaria Ospedali Riuniti | Torrette Di Ancona | Marche | Italy | 60126 |
71 | Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari | Bari | Puglia | Italy | 70124 |
72 | Azienda Ospedaliera Universitaria Careggi | Florence | Toscana | Italy | 50134 |
73 | Azienda Ospedaliera Di Padova | Padova | Veneto | Italy | 35128 |
74 | Seoul National University Bundang Hospital | Seongnam-si | Korea, Republic of | 13605 | |
75 | Severance Hospital, Yonsei University Health System | Seoul | Korea, Republic of | 03722 | |
76 | Konkuk University Medical Center | Seoul | Korea, Republic of | 05030 | |
77 | The Catholic University of Korea Seoul St. Mary's Hospital | Seoul | Korea, Republic of | 137-701 | |
78 | Amsterdam UMC, Locatie VUMC; Neurology | Amsterdam | Netherlands | 1081 HV | |
79 | Amsterdam UMC Location AMC | Amsterdam | Netherlands | 1105 AZ | |
80 | Albert Schweitzer Ziekenhuis, Dordwijk; Internal Medicine, Hemato-Oncology | Dordrecht | Netherlands | 3318 AT | |
81 | Medisch Spectrum Twente | Enschede | Netherlands | 7512 KZ | |
82 | Leids Universitair Medisch Centrum; Cardiology | Leiden | Netherlands | 2333 ZA | |
83 | Erasmus Medisch Centrum Rotterdam; Lokatie Daniel den Hoed | Rotterdam | Netherlands | 3015 GD | |
84 | UMC Utrecht | Utrecht | Netherlands | 3508 GA | |
85 | North Shore Hospital; Haematolgy | Auckland | New Zealand | 1309 | |
86 | Middlemore Hospital | Auckland | New Zealand | ||
87 | Christchurch Hospital NZ | Christchurch | New Zealand | 8011 | |
88 | Baxter Healthcare | Mount Wellington | New Zealand | 1060 | |
89 | SP ZOZ Zespol Szpitali Miejskich w Chorzowie | Chorzow | Poland | 41-500 | |
90 | Uniwersyteckie Centrum Kliniczne | Gdansk | Poland | 80-214 | |
91 | Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi | Lodz | Poland | 93-513 | |
92 | Szpital Wojewodzki w Opolu | Opole | Poland | 45-061 | |
93 | MTZ Clinical Research Sp. z o.o. | Warszawa | Poland | 02-106 | |
94 | Samodzielny Publiczny Szpital Kliniczny nr 1 | Zabrze | Poland | 44803 | |
95 | Kemerovo Regional Clinical Hospital | Kemerovo | Russian Federation | 650066 | |
96 | FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin" | Moscow | Russian Federation | 115478 | |
97 | BHI of Omsk region Clinical Oncology Dispensary | Omsk | Russian Federation | 644013 | |
98 | SRI of Hematology and Transfusiology | St. Petersburg | Russian Federation | 191024 | |
99 | North-West Federal Medical Research Center n.a. V.A. Almazov | St. Petersburg | Russian Federation | 197341 | |
100 | Complejo Hospitalario de Navarra | Pamplona | Navarra | Spain | 31008 |
101 | Hospital Universitari Vall d'Hebron | Barcelona | Spain | 08035 | |
102 | Hospital Clinic i Provincial de Barcelona; Hematology | Barcelona | Spain | 08036 | |
103 | Hospital Universitario 12 de Octubre | Madrid | Spain | 28041 | |
104 | Hospital Clinico Universitario de Salamanca | Salamanca | Spain | 37007 | |
105 | Skånes Universitetssjukhus | Lund | Sweden | 221 85 | |
106 | Akademiska Sjukhuset | Uppsala | Sweden | 751 85 | |
107 | National Taiwan University Hospital | Taipei | Taiwan | 10002 | |
108 | Bristol Haematology and Oncology Centre | Bristol | United Kingdom | BS2 8ED | |
109 | The Christie | Manchester | United Kingdom | M20 4BX | |
110 | Southampton General Hospital | Southampton | United Kingdom | SO16 6YD | |
111 | Singleton Hospital; Pharmacy Department | Swansea | United Kingdom | SA2 8QA |
Sponsors and Collaborators
- Hoffmann-La Roche
- AbbVie
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
More Information
Publications
None provided.- GO28667
- 2013-002110-12
Study Results
Participant Flow
Recruitment Details | A total of 489 participants were screened, out of which, 389 participants were enrolled into the study. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 milligrams (mg) via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Period Title: Overall Study | ||
STARTED | 195 | 194 |
Treated | 188 | 194 |
COMPLETED | 0 | 0 |
NOT COMPLETED | 195 | 194 |
Baseline Characteristics
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab | Total |
---|---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Total of all reporting groups |
Overall Participants | 195 | 194 | 389 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] | 64.4
(9.6)
| 63.9
(10.5)
| 64.1
(10.1)
|
Sex: Female, Male (Count of Participants) | |||
Female | 44 22.6% | 58 29.9% | 102 26.2% |
Male | 151 77.4% | 136 70.1% | 287 73.8% |
Ethnicity (NIH/OMB) (Count of Participants) | |||
Hispanic or Latino | 3 1.5% | 4 2.1% | 7 1.8% |
Not Hispanic or Latino | 186 95.4% | 186 95.9% | 372 95.6% |
Unknown or Not Reported | 6 3.1% | 4 2.1% | 10 2.6% |
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native | 0 0% | 0 0% | 0 0% |
Asian | 4 2.1% | 6 3.1% | 10 2.6% |
Native Hawaiian or Other Pacific Islander | 0 0% | 0 0% | 0 0% |
Black or African American | 2 1% | 0 0% | 2 0.5% |
White | 178 91.3% | 181 93.3% | 359 92.3% |
More than one race | 0 0% | 0 0% | 0 0% |
Unknown or Not Reported | 11 5.6% | 7 3.6% | 18 4.6% |
Outcome Measures
Title | Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death |
---|---|
Description | Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 grams per deciliter (g/dL) or to less than [<] 10 g/dL. |
Time Frame | Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number [percentage of participants] | 58.5 30% | 16.5 8.5% |
Title | Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines |
---|---|
Description | PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Median (95% Confidence Interval) [months] | 17.0 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.17 | |
Confidence Interval |
(2-Sided) 95% 0.11 to 0.25 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.17 | |
Confidence Interval |
(2-Sided) 95% 0.12 to 0.26 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines |
---|---|
Description | Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number [percentage of participants] | 54.4 27.9% | 18.0 9.3% |
Title | PFS as Assessed by the IRC Using Standard iwCLL Guidelines |
---|---|
Description | PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Median (95% Confidence Interval) [months] | 18.1 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.19 | |
Confidence Interval |
(2-Sided) 95% 0.13 to 0.28 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.20 | |
Confidence Interval |
(2-Sided) 95% 0.14 to 0.30 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence In-situ Hybridization (FISH) Test |
---|---|
Description | Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants with 17p deletion as identified by FISH test. |
Arm/Group Title | Bendamustine + Rituximab 17p Del. Population | Venetoclax + Rituximab 17p Del. Population |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. | Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. |
Measure Participants | 46 | 46 |
Number [percentage of participants] | 58.7 30.1% | 15.2 7.8% |
Title | PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test |
---|---|
Description | PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants with 17p deletion as identified by FISH test. |
Arm/Group Title | Bendamustine + Rituximab 17p Del. Population | Venetoclax + Rituximab 17p Del. Population |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. | Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. |
Measure Participants | 46 | 46 |
Median (95% Confidence Interval) [months] | 15.4 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factor: geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.13 | |
Confidence Interval |
(2-Sided) 95% 0.05 to 0.31 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.13 | |
Confidence Interval |
(2-Sided) 95% 0.05 to 0.29 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test |
---|---|
Description | Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants with 17p deletion as identified by FISH test. |
Arm/Group Title | Bendamustine + Rituximab 17p Del. Population | Venetoclax + Rituximab 17p Del. Population |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. | Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. |
Measure Participants | 46 | 46 |
Number [percentage of participants] | 47.8 24.5% | 19.6 10.1% |
Title | PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test |
---|---|
Description | PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to PD or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants with 17p deletion as identified by FISH test. |
Arm/Group Title | Bendamustine + Rituximab 17p Del. Population | Venetoclax + Rituximab 17p Del. Population |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. | Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included. |
Measure Participants | 46 | 46 |
Median (95% Confidence Interval) [months] | 16.1 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factor: geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.21 | |
Confidence Interval |
(2-Sided) 95% 0.09 to 0.49 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.21 | |
Confidence Interval |
(2-Sided) 95% 0.09 to 0.46 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With Best Overall Response of Complete Response (CR), CR With Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | Response was assessed by the investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method. |
Time Frame | Baseline up to last follow-up visit (FUV) (maximum up to data cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number (95% Confidence Interval) [percentage of participants] | 67.7 34.7% | 93.3 48.1% |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Cochran-Mantel-Haenszel | |
Comments | ||
Method of Estimation | Estimation Parameter | Difference in Response Rates |
Estimated Value | 25.61 | |
Confidence Interval |
(2-Sided) 95% 17.88 to 33.33 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | The 95% CI was computed using Anderson-Hauck method. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
Estimated Value | 7.81 | |
Confidence Interval |
(2-Sided) 95% 3.97 to 15.37 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | OR was estimated using logistic regression model. The 95% CI was computed using Wald test. |
Title | Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines |
---|---|
Description | Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method. |
Time Frame | Baseline up to last FUV (maximum up to data cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number (95% Confidence Interval) [percentage of participants] | 72.3 37.1% | 92.3 47.6% |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Cochran-Mantel-Haenszel | |
Comments | ||
Method of Estimation | Estimation Parameter | Difference in Response Rates |
Estimated Value | 19.96 | |
Confidence Interval |
(2-Sided) 95% 12.36 to 27.56 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | The 95% CI was computed using Anderson-Hauck method. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
Estimated Value | 4.79 | |
Confidence Interval |
(2-Sided) 95% 2.56 to 8.99 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | OR was estimated using logistic regression model. The 95% CI was computed using Wald test. |
Title | Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | Response was assessed by the investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method. |
Time Frame | End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number (95% Confidence Interval) [percentage of participants] | 62.6 32.1% | 88.1 45.4% |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Cochran-Mantel-Haenszel | |
Comments | ||
Method of Estimation | Estimation Parameter | Difference in Response Rates |
Estimated Value | 25.58 | |
Confidence Interval |
(2-Sided) 95% 17.13 to 34.03 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | The 95% CI was computed using Anderson-Hauck method. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
Estimated Value | 4.75 | |
Confidence Interval |
(2-Sided) 95% 2.76 to 8.16 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | OR was estimated using logistic regression model. The 95% CI was computed using Wald test. |
Title | Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines |
---|---|
Description | Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method. |
Time Frame | EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number (95% Confidence Interval) [percentage of participants] | 62.6 32.1% | 87.1 44.9% |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Cochran-Mantel-Haenszel | |
Comments | ||
Method of Estimation | Estimation Parameter | Difference in Response Rates |
Estimated Value | 24.55 | |
Confidence Interval |
(2-Sided) 95% 16.00 to 33.10 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | The 95% CI was computed using Anderson-Hauck method. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
Estimated Value | 4.59 | |
Confidence Interval |
(2-Sided) 95% 2.68 to 7.85 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | OR was estimated using logistic regression model. The 95% CI was computed using Wald test. |
Title | Percentage of Participants Who Died |
---|---|
Description | Percentage of participants who died from any cause, during the study, was reported. |
Time Frame | Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number [percentage of participants] | 13.8 7.1% | 7.7 4% |
Title | Overall Survival (OS) |
---|---|
Description | OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Median (95% Confidence Interval) [months] | NA | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region. | |
Statistical Test of Hypothesis | p-Value | 0.0186 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.48 | |
Confidence Interval |
(2-Sided) 95% 0.25 to 0.90 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0190 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.48 | |
Confidence Interval |
(2-Sided) 95% 0.25 to 0.90 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With PD/Relapse, Start of a New Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. |
Time Frame | Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number [percentage of participants] | 60.5 31% | 17.0 8.8% |
Title | Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. The median EFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Median (95% Confidence Interval) [months] | 16.4 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.17 | |
Confidence Interval |
(2-Sided) 95% 0.11 to 0.25 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.18 | |
Confidence Interval |
(2-Sided) 95% 0.12 to 0.26 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines or death from any cause during the study was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint. |
Time Frame | From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 132 | 181 |
Number [percentage of participants] | 53.8 27.6% | 11.0 5.7% |
Title | Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines |
---|---|
Description | DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. The median DOR was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint. |
Time Frame | From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 132 | 181 |
Median (95% Confidence Interval) [months] | 19.4 | NA |
Title | Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator |
---|---|
Description | Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. |
Time Frame | Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number [percentage of participants] | 42.6 21.8% | 11.9 6.1% |
Title | Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator |
---|---|
Description | TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. |
Time Frame | Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years) |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Median (95% Confidence Interval) [months] | 26.4 | NA |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.19 | |
Confidence Interval |
(2-Sided) 95% 0.12 to 0.31 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | Unstratified Analysis | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.19 | |
Confidence Interval |
(2-Sided) 95% 0.12 to 0.31 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | Hazard ratio was estimated by Cox regression model. |
Title | Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit |
---|---|
Description | MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method. |
Time Frame | EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on ITT population. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 195 | 194 |
Number (95% Confidence Interval) [percentage of participants] | 13.3 6.8% | 62.4 32.2% |
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <.0001 |
Comments | ||
Method | Chi-squared | |
Comments | ||
Method of Estimation | Estimation Parameter | Difference in MRD Negativity Rates |
Estimated Value | 49.04 | |
Confidence Interval |
(2-Sided) 95% 40.44 to 57.64 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | The 95% CI was computed using Anderson-Hauck method. |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Bendamustine + Rituximab, Venetoclax + Rituximab |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
Estimated Value | 10.77 | |
Confidence Interval |
(2-Sided) 95% 6.50 to 17.85 | |
Parameter Dispersion |
Type: Value: | |
Estimation Comments | OR was estimated using logistic regression model. The 95% CI was computed using Wald test. |
Title | Plasma Venetoclax Concentrations |
---|---|
Description | |
Time Frame | Pre-dose (0 hour, anytime before venetoclax administeration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on Pharmacokinetic (PK)-Evaluable population, which included all participants in the 'Venetoclax + Rituximab' arm and who received at least one dose of venetoclax with at least one post-dose PK concentration result available. Here 'Number Analyzed' signifies the number of participants evaluable at specified time point. |
Arm/Group Title | Venetoclax + Rituximab |
---|---|
Arm/Group Description | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 184 |
C1D1, Pre-dose | 0.626
(0.540)
|
C1D1, 4 hours Post-Dose | 1.34
(0.881)
|
C4D1, Pre-dose | 0.681
(0.745)
|
C4D1, 4 hours Post-Dose | 1.34
(0.905)
|
Title | Change From Baseline in Lymphocyte Subset Counts at Specified Time Points |
---|---|
Description | |
Time Frame | Baseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Title | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores |
---|---|
Description | MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13; total 13 items: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness) and Module Symptom Severity (average of Questions 14 to 19; total 6 items: night sweats, fevers and chills, lymph node swelling, diarrhea, bruising easy or bleeding, and constipation). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25; total 6 items: general activity, walking, work, mood, relations with other people, and enjoyment of life). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL). |
Time Frame | Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on patient reported outcome (PRO)-evaluable population, which included all participants with baseline and at least one post-baseline PRO assessment. Here, 'Overall Number of Participants Analyzed' = participants evaluable for this outcome measure and 'Number Analyzed' = participants evaluable at specified time point. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 117 | 42 |
Baseline; Mean core symptom severity | 1.76
(1.55)
| 1.55
(1.31)
|
Change at C1D1; Mean core symptom severity | 0.00
(0.00)
| -0.08
(0.98)
|
Change at C1D8; Mean core symptom severity | 0.26
(1.34)
| -0.30
(0.84)
|
Change at C1D15; Mean core symptom severity | 0.00
(1.31)
| -0.27
(0.93)
|
Change at C2D1; Mean core symptom severity | -0.23
(1.30)
| -0.33
(0.91)
|
Change at C2D8; Mean core symptom severity | 0.17
(1.59)
| -0.45
(0.91)
|
Change at C2D15; Mean core symptom severity | -0.13
(1.53)
| -0.53
(0.90)
|
Change at C3D1; Mean core symptom severity | -0.26
(1.60)
| -0.40
(1.13)
|
Change at C3D8; Mean core symptom severity | -0.13
(1.63)
| -0.66
(1.20)
|
Change at C3D15; Mean core symptom severity | -0.42
(1.52)
| -0.53
(1.05)
|
Baseline; Mean module symptom severity | 1.60
(1.46)
| 1.57
(1.11)
|
Change at C1D1; Mean module symptom severity | 0.00
(0.00)
| -0.19
(0.96)
|
Change at C1D8; Mean module symptom severity | -0.22
(1.40)
| -0.53
(0.96)
|
Change at C1D15; Mean module symptom severity | -0.43
(1.51)
| -0.73
(1.13)
|
Change at C2D1; Mean module symptom severity | -0.49
(1.46)
| -0.65
(0.92)
|
Change at C2D8; Mean module symptom severity | -0.46
(1.63)
| -0.77
(0.87)
|
Change at C2D15; Mean module symptom severity | -0.69
(1.47)
| -0.94
(0.93)
|
Change at C3D1; Mean module symptom severity | -0.65
(1.48)
| -0.81
(0.97)
|
Change at C3D8; Mean module symptom severity | -0.51
(1.58)
| -0.83
(0.97)
|
Change at C3D15; Mean module symptom severity | -0.83
(1.51)
| -0.92
(0.97)
|
Baseline; Mean interference | 1.81
(2.05)
| 1.90
(2.25)
|
Change at C1D1; Mean interference | 0.00
(0.00)
| -0.13
(1.49)
|
Change at C1D8; Mean interference | 0.45
(1.78)
| -0.29
(2.14)
|
Change at C1D15; Mean interference | 0.36
(1.85)
| 0.01
(2.04)
|
Change at C2D1; Mean interference | 0.01
(1.73)
| -0.34
(1.78)
|
Change at C2D8; Mean interference | 0.58
(2.20)
| -0.58
(1.81)
|
Change at C2D15; Mean interference | 0.06
(1.84)
| -0.64
(1.59)
|
Change at C3D1; Mean interference | -0.02
(2.02)
| -0.73
(2.06)
|
Change at C3D8; Mean interference | 0.15
(1.91)
| -0.82
(2.09)
|
Change at C3D15; Mean interference | -0.07
(2.01)
| -0.55
(2.18)
|
Title | Change From Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score |
---|---|
Description | The EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Functional scales score and global health status/global QoL scale score are reported. Scores were averaged, transformed to 0-100 scale; where higher score for functional scales = poor level of functioning and higher score for global health status/global QoL = better HRQoL. |
Time Frame | Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on PRO-evaluable population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable at specified time point. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 177 | 69 |
Baseline; Physical functioning | 82.59
(17.46)
| 83.77
(15.27)
|
Change at C1D1; Physical functioning | 0.0
(0.0)
| 1.39
(12.90)
|
Change at C2D1; Physical functioning | 0.31
(15.81)
| 2.99
(12.83)
|
Change at C3D1; Physical functioning | 0.22
(16.43)
| 1.46
(14.76)
|
Change at C4D1; Physical functioning | 2.11
(14.95)
| 5.54
(14.17)
|
Change at C5D1; Physical functioning | 2.44
(18.19)
| 4.62
(15.27)
|
Change at C6D1; Physical functioning | 2.25
(16.82)
| 4.51
(16.59)
|
Change at STC/EW; Physical functioning | 1.68
(18.76)
| 4.53
(16.04)
|
Change at EoCTR; Physical functioning | 2.92
(18.03)
| 4.34
(16.12)
|
Change at FUV1; Physical functioning | 2.27
(18.86)
| 3.81
(16.27)
|
Change at FUV2; Physical functioning | 2.40
(19.21)
| 2.75
(17.17)
|
Change at FUV3; Physical functioning | 2.54
(17.83)
| 3.44
(17.31)
|
Change at FUV4; Physical functioning | 4.74
(20.14)
| 0.85
(21.06)
|
Change at FUV5; Physical functioning | 1.90
(17.68)
| -1.75
(19.35)
|
Change at FUV6; Physical functioning | -1.41
(15.34)
| 1.33
(5.58)
|
Change at FUV7; Physical functioning | -3.08
(11.74)
| 0.00 |
Change at FUV8; Physical functioning | -9.33
(23.38)
| 0.00 |
Change at FUV9; Physical functioning | -10.00
(33.0)
| |
Baseline; Role functioning | 78.25
(25.67)
| 83.82
(21.00)
|
Change at C1D1; Role functioning | 0.0
(0.0)
| -1.74
(23.23)
|
Change at C2D1; Role functioning | -1.26
(27.45)
| 2.49
(23.07)
|
Change at C3D1; Role functioning | -0.10
(29.64)
| 1.82
(26.08)
|
Change at C4D1; Role functioning | 0.87
(29.01)
| 5.13
(22.03)
|
Change at C5D1; Role functioning | 0.45
(30.75)
| 4.36
(23.44)
|
Change at C6D1; Role functioning | 0.70
(29.92)
| 1.79
(25.71)
|
Change at STC/EW; Role functioning | -0.41
(32.91)
| 2.60
(25.58)
|
Change at EoCTR; Role functioning | 3.26
(29.95)
| 2.12
(26.69)
|
Change at FUV1; Role functioning | 2.93
(32.31)
| 2.65
(27.47)
|
Change at FUV2; Role functioning | 3.07
(32.63)
| -1.85
(31.84)
|
Change at FUV3; Role functioning | 5.26
(31.16)
| 1.88
(28.17)
|
Change at FUV4; Role functioning | 5.41
(33.16)
| -0.35
(30.39)
|
Change at FUV5; Role functioning | 2.34
(29.79)
| 1.75
(34.20)
|
Change at FUV6; Role functioning | -4.04
(27.01)
| -13.33
(32.06)
|
Change at FUV7; Role functioning | 2.56
(29.54)
| -16.67 |
Change at FUV8; Role functioning | 0.00
(23.57)
| 16.67 |
Change at FUV9; Role functioning | -16.67
(23.57)
| |
Baseline; Emotional functioning | 78.98
(22.47)
| 82.13
(15.80)
|
Change at C1D1; Emotional functioning | 0.0
(0.0)
| 4.35
(15.17)
|
Change at C2D1; Emotional functioning | 2.24
(20.07)
| 5.60
(14.68)
|
Change at C3D1; Emotional functioning | 2.99
(20.06)
| 5.34
(19.09)
|
Change at C4D1; Emotional functioning | 2.61
(18.35)
| 4.19
(15.45)
|
Change at C5D1; Emotional functioning | 1.14
(18.79)
| 3.97
(17.37)
|
Change at C6D1; Emotional functioning | 2.06
(18.74)
| 3.08
(17.96)
|
Change at STC/EW; Emotional functioning | 2.43
(20.61)
| 5.34
(18.69)
|
Change at EoCTR; Emotional functioning | 2.58
(19.45)
| 3.49
(17.83)
|
Change at FUV1; Emotional functioning | 3.49
(20.91)
| 4.37
(18.50)
|
Change at FUV2; Emotional functioning | 4.39
(20.33)
| 0.66
(21.02)
|
Change at FUV3; Emotional functioning | 0.63
(19.97)
| 2.82
(17.66)
|
Change at FUV4; Emotional functioning | 4.82
(19.73)
| 1.95
(18.41)
|
Change at FUV5; Emotional functioning | 3.13
(17.95)
| 2.63
(20.61)
|
Change at FUV6; Emotional functioning | 2.27
(21.78)
| 5.00
(17.28)
|
Change at FUV7; Emotional functioning | 5.77
(17.48)
| -8.33 |
Change at FUV8; Emotional functioning | 3.33
(28.01)
| 0.00 |
Change at FUV9; Emotional functioning | -16.67
(11.79)
| |
Baseline; Cognitive functioning | 86.55
(16.78)
| 89.86
(14.91)
|
Change at C1D1; Cognitive functioning | 0.0
(0.0)
| -1.24
(14.01)
|
Change at C2D1; Cognitive functioning | -0.19
(15.34)
| 0.25
(14.06)
|
Change at C3D1; Cognitive functioning | -0.32
(16.34)
| -1.56
(17.50)
|
Change at C4D1; Cognitive functioning | -1.54
(17.41)
| -0.26
(17.05)
|
Change at C5D1; Cognitive functioning | -1.94
(18.10)
| -0.26
(14.28)
|
Change at C6D1; Cognitive functioning | -2.68
(16.97)
| -0.77
(15.98)
|
Change at STC/EW; Cognitive functioning | -2.19
(17.65)
| 1.04
(18.28)
|
Change at EoCTR; Cognitive functioning | -2.23
(18.11)
| -0.27
(16.94)
|
Change at FUV1; Cognitive functioning | -2.02
(17.21)
| -0.26
(15.98)
|
Change at FUV2; Cognitive functioning | 1.32
(16.16)
| -2.38
(18.17)
|
Change at FUV3; Cognitive functioning | -1.63
(14.84)
| -2.96
(18.24)
|
Change at FUV4; Cognitive functioning | 0.44
(17.63)
| -1.77
(19.11)
|
Change at FUV5; Cognitive functioning | -1.49
(15.66)
| -6.14
(21.67)
|
Change at FUV6; Cognitive functioning | -0.51
(14.72)
| 0.00
(0.00)
|
Change at FUV7; Cognitive functioning | -1.28
(14.37)
| 0.00 |
Change at FUV8; Cognitive functioning | 0.00
(23.57)
| 0.00 |
Change at FUV9; Cognitive functioning | 16.67
(23.57)
| |
Baseline; Social functioning | 82.48
(22.06)
| 85.51
(21.18)
|
Change at C1D1; Social functioning | 0.0
(0.0)
| -1.74
(19.92)
|
Change at C2D1; Social functioning | -2.44
(21.44)
| 0.25
(18.46)
|
Change at C3D1; Social functioning | -2.32
(22.61)
| 3.65
(25.45)
|
Change at C4D1; Social functioning | -0.55
(22.15)
| 4.62
(20.09)
|
Change at C5D1; Social functioning | -5.48
(26.49)
| 2.56
(20.46)
|
Change at C6D1; Social functioning | -5.13
(24.80)
| 3.85
(24.61)
|
Change at STC/EW; Social functioning | -4.06
(27.71)
| 1.04
(19.22)
|
Change at EoCTR; Social functioning | -0.47
(24.95)
| 1.88
(20.49)
|
Change at FUV1; Social functioning | -1.08
(26.09)
| 1.59
(24.27)
|
Change at FUV2; Social functioning | 0.58
(24.68)
| 1.32
(27.97)
|
Change at FUV3; Social functioning | -0.91
(24.00)
| 1.88
(25.98)
|
Change at FUV4; Social functioning | 1.97
(27.35)
| 1.06
(32.12)
|
Change at FUV5; Social functioning | 1.79
(26.72)
| 0.00
(33.79)
|
Change at FUV6; Social functioning | 1.52
(29.27)
| 10.00
(14.91)
|
Change at FUV7; Social functioning | -2.56
(23.42)
| 33.33 |
Change at FUV8; Social functioning | -10.00
(22.36)
| 33.33 |
Change at FUV9; Social functioning | -25.00
(35.36)
| |
Baseline; Global health status/QoL | 63.02
(21.45)
| 67.39
(22.17)
|
Change at C1D1; Global health status/QoL | 0.0
(0.0)
| 6.34
(18.41)
|
Change at C2D1; Global health status/QoL | 2.73
(21.69)
| 5.35
(20.14)
|
Change at C3D1; Global health status/QoL | 2.34
(24.66)
| 2.21
(23.58)
|
Change at C4D1; Global health status/QoL | 3.84
(22.26)
| 7.05
(21.05)
|
Change at C5D1; Global health status/QoL | 7.36
(24.20)
| 7.18
(21.94)
|
Change at C6D1; Global health status/QoL | 4.25
(25.00)
| 5.90
(25.16)
|
Change at STC/EW; Global health status/QoL | 4.32
(26.20)
| 6.51
(23.22)
|
Change at EoCTR; Global health status/QoL | 6.10
(23.65)
| 7.66
(24.11)
|
Change at FUV1; Global health status/QoL | 5.91
(24.57)
| 7.01
(25.01)
|
Change at FUV2; Global health status/QoL | 6.94
(24.81)
| 4.50
(26.51)
|
Change at FUV3; Global health status/QoL | 4.80
(25.30)
| 6.32
(27.36)
|
Change at FUV4; Global health status/QoL | 7.35
(26.77)
| 6.38
(27.60)
|
Change at FUV5; Global health status/QoL | 4.46
(23.89)
| 4.39
(18.08)
|
Change at FUV6; Global health status/QoL | 1.01
(24.00)
| 5.00
(7.45)
|
Change at FUV7; Global health status/QoL | 8.33
(25.69)
| 16.67 |
Change at FUV8; Global health status/QoL | 6.67
(16.03)
| 8.33 |
Change at FUV9; Global health status/QoL | 0.00
(0.00)
|
Title | Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score |
---|---|
Description | The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL. |
Time Frame | Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
Analysis was performed on PRO-evaluable population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable at specified time point. |
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab |
---|---|---|
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. |
Measure Participants | 175 | 69 |
Baseline; TRSE | 14.29
(13.95)
| 9.42
(8.80)
|
Change at C1D1; TRSE | 0.0
(0.0)
| 0.12
(10.10)
|
Change at C2D1; TRSE | 1.62
(13.82)
| 0.62
(12.76)
|
Change at C3D1; TRSE | -0.26
(13.76)
| 1.98
(14.72)
|
Change at C4D1; TRSE | -0.49
(13.97)
| 0.52
(11.87)
|
Change at C5D1; TRSE | -0.51
(14.57)
| 0.64
(10.02)
|
Change at C6D1; TRSE | 0.46
(15.51)
| -0.13
(10.04)
|
Change at STC/EW; TRSE | 0.81
(18.11)
| 0.13
(10.76)
|
Change at EoCTR; TRSE | -0.88
(16.06)
| 0.26
(12.61)
|
Change at FUV1; TRSE | -1.20
(14.87)
| 1.19
(12.24)
|
Change at FUV2; TRSE | -1.70
(15.28)
| 2.65
(14.03)
|
Change at FUV3; TRSE | -2.08
(12.64)
| -0.13
(13.70)
|
Change at FUV4; TRSE | -1.97
(12.76)
| 2.84
(15.18)
|
Change at FUV5; TRSE | -2.68
(11.02)
| 1.32
(10.49)
|
Change at FUV6; TRSE | -1.01
(12.10)
| -1.67
(3.73)
|
Change at FUV7; TRSE | 2.56
(22.67)
| -8.33 |
Change at FUV8; TRSE | 1.67
(13.69)
| 0.00 |
Change at FUV9; TRSE | 8.33
(11.79)
| |
Baseline; DRS | 19.57
(16.81)
| 16.95
(17.37)
|
Change at C1D1; DRS | 0.0
(0.0)
| -2.74
(16.18)
|
Change at C2D1; DRS | -3.33
(16.05)
| -4.77
(16.84)
|
Change at C3D1; DRS | -4.77
(16.49)
| -3.35
(17.48)
|
Change at C4D1; DRS | -6.03
(16.51)
| -5.12
(17.72)
|
Change at C5D1; DRS | -5.90
(16.73)
| -4.79
(17.50)
|
Change at C6D1; DRS | -6.40
(17.26)
| -5.30
(16.72)
|
Change at STC/EW; DRS | -5.80
(18.52)
| -6.51
(18.45)
|
Change at EoCTR; DRS | -6.57
(17.21)
| -5.86
(20.38)
|
Change at FUV1; DRS | -6.55
(15.73)
| -5.82
(19.20)
|
Change at FUV2; DRS | -8.63
(14.39)
| -3.57
(18.31)
|
Change at FUV3; DRS | -7.37
(14.88)
| -3.76
(19.25)
|
Change at FUV4; DRS | -8.55
(18.56)
| -2.66
(20.49)
|
Change at FUV5; DRS | -8.33
(16.13)
| -2.19
(19.41)
|
Change at FUV6; DRS | -6.31
(16.01)
| -3.33
(13.94)
|
Change at FUV7; DRS | -15.38
(20.08)
| -8.33 |
Change at FUV8; DRS | -10.00
(16.03)
| -8.33 |
Change at FUV9; DRS | -4.17
(5.89)
| |
Baseline; Fatigue | 28.76
(24.66)
| 21.74
(20.67)
|
Change at C1D1; Fatigue | 0.0
(0.0)
| -2.24
(20.29)
|
Change at C2D1; Fatigue | -2.55
(22.86)
| -5.47
(21.40)
|
Change at C3D1; Fatigue | -2.83
(25.17)
| -3.17
(23.73)
|
Change at C4D1; Fatigue | -3.18
(23.23)
| -4.17
(22.02)
|
Change at C5D1; Fatigue | -2.38
(27.52)
| -4.36
(20.89)
|
Change at C6D1; Fatigue | -2.66
(26.35)
| -2.31
(21.42)
|
Change at STC/EW; Fatigue | -3.11
(28.64)
| -4.69
(21.30)
|
Change at EoCTR; Fatigue | -6.69
(26.78)
| -3.97
(24.27)
|
Change at FUV1; Fatigue | -6.37
(26.61)
| -4.23
(22.99)
|
Change at FUV2; Fatigue | -6.64
(24.55)
| -1.85
(24.70)
|
Change at FUV3; Fatigue | -5.79
(23.29)
| -2.42
(23.73)
|
Change at FUV4; Fatigue | -9.65
(26.84)
| -0.35
(25.18)
|
Change at FUV5; Fatigue | -6.55
(25.56)
| 3.51
(23.95)
|
Change at FUV6; Fatigue | -5.05
(24.82)
| 3.33
(24.72)
|
Change at FUV7; Fatigue | -10.26
(30.08)
| -33.33 |
Change at FUV8; Fatigue | -6.67
(19.00)
| 0.00 |
Change at FUV9; Fatigue | -8.33
(11.79)
| |
Baseline; Infection | 15.92
(17.63)
| 14.01
(18.99)
|
Change at C1D1; Infection | 0.0
(0.0)
| -2.24
(20.03)
|
Change at C2D1; Infection | -0.02
(19.98)
| -3.61
(21.72)
|
Change at C3D1; Infection | -1.66
(19.21)
| -1.32
(20.48)
|
Change at C4D1; Infection | -1.44
(22.07)
| -3.13
(21.28)
|
Change at C5D1; Infection | -1.91
(24.00)
| -2.56
(23.47)
|
Change at C6D1; Infection | -1.09
(20.66)
| -2.95
(20.54)
|
Change at STC/EW; Infection | -0.12
(23.28)
| -1.69
(23.34)
|
Change at EoCTR; Infection | -0.55
(21.73)
| -3.44
(25.78)
|
Change at FUV1; Infection | 1.08
(18.77)
| -2.65
(26.51)
|
Change at FUV2; Infection | 0.05
(23.29)
| -0.53
(25.74)
|
Change at FUV3; Infection | -1.90
(16.97)
| -0.54
(26.48)
|
Change at FUV4; Infection | -4.24
(16.71)
| 0.53
(25.56)
|
Change at FUV5; Infection | -4.51
(22.66)
| 7.46
(27.20)
|
Change at FUV6; Infection | -1.60
(18.90)
| 8.33
(15.59)
|
Change at FUV7; Infection | -0.43
(21.84)
| -16.67 |
Change at FUV8; Infection | 8.89
(23.36)
| -25.00 |
Change at FUV9; Infection | -2.78
(3.93)
|
Title | Euro QoL 5 Dimension (EQ-5D) Questionnaire Score |
---|---|
Description | |
Time Frame | Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title |
---|
Arm/Group Description |
Adverse Events
Time Frame | Baseline up to Follow-up (maximum up to Data Cut-off date, overall approximately 3 years) | |||
---|---|---|---|---|
Adverse Event Reporting Description | Analysis was performed on safety evaluable (SE) population, which included all randomized participants who received at least one dose of study treatment (venetoclax, rituximab, or bendamustine), with participants grouped according to the actual treatment received. | |||
Arm/Group Title | Bendamustine + Rituximab | Venetoclax + Rituximab | ||
Arm/Group Description | Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. | ||
All Cause Mortality | ||||
Bendamustine + Rituximab | Venetoclax + Rituximab | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 27/188 (14.4%) | 15/194 (7.7%) | ||
Serious Adverse Events | ||||
Bendamustine + Rituximab | Venetoclax + Rituximab | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 81/188 (43.1%) | 90/194 (46.4%) | ||
Blood and lymphatic system disorders | ||||
Anaemia | 5/188 (2.7%) | 3/194 (1.5%) | ||
Autoimmune haemolytic anaemia | 3/188 (1.6%) | 3/194 (1.5%) | ||
Disseminated intravascular coagulation | 0/188 (0%) | 1/194 (0.5%) | ||
Febrile neutropenia | 16/188 (8.5%) | 7/194 (3.6%) | ||
Immune thrombocytopenic purpura | 0/188 (0%) | 1/194 (0.5%) | ||
Leukocytosis | 1/188 (0.5%) | 0/194 (0%) | ||
Neutropenia | 3/188 (1.6%) | 3/194 (1.5%) | ||
Pancytopenia | 0/188 (0%) | 1/194 (0.5%) | ||
Thrombocytopenia | 2/188 (1.1%) | 2/194 (1%) | ||
Cardiac disorders | ||||
Acute myocardial infarction | 1/188 (0.5%) | 0/194 (0%) | ||
Angina pectoris | 0/188 (0%) | 1/194 (0.5%) | ||
Atrial fibrillation | 1/188 (0.5%) | 0/194 (0%) | ||
Cardiac failure | 0/188 (0%) | 1/194 (0.5%) | ||
Coronary artery disease | 1/188 (0.5%) | 0/194 (0%) | ||
Myocardial infarction | 0/188 (0%) | 2/194 (1%) | ||
Ventricular tachycardia | 0/188 (0%) | 1/194 (0.5%) | ||
Ear and labyrinth disorders | ||||
Deafness | 0/188 (0%) | 1/194 (0.5%) | ||
Vertigo | 0/188 (0%) | 1/194 (0.5%) | ||
Eye disorders | ||||
Eye haemorrhage | 0/188 (0%) | 1/194 (0.5%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 0/188 (0%) | 1/194 (0.5%) | ||
Anal fistula | 1/188 (0.5%) | 0/194 (0%) | ||
Ascites | 0/188 (0%) | 1/194 (0.5%) | ||
Colitis | 1/188 (0.5%) | 0/194 (0%) | ||
Crohn's disease | 0/188 (0%) | 1/194 (0.5%) | ||
Diarrhoea | 0/188 (0%) | 2/194 (1%) | ||
Dyspepsia | 0/188 (0%) | 1/194 (0.5%) | ||
Gastrointestinal haemorrhage | 0/188 (0%) | 1/194 (0.5%) | ||
Nausea | 1/188 (0.5%) | 0/194 (0%) | ||
Oesophageal obstruction | 0/188 (0%) | 1/194 (0.5%) | ||
Small intestinal obstruction | 0/188 (0%) | 1/194 (0.5%) | ||
Vomiting | 1/188 (0.5%) | 1/194 (0.5%) | ||
General disorders | ||||
Asthenia | 1/188 (0.5%) | 0/194 (0%) | ||
Hyperpyrexia | 1/188 (0.5%) | 1/194 (0.5%) | ||
Malaise | 1/188 (0.5%) | 0/194 (0%) | ||
Pyrexia | 13/188 (6.9%) | 5/194 (2.6%) | ||
Sudden cardiac death | 0/188 (0%) | 1/194 (0.5%) | ||
Sudden death | 1/188 (0.5%) | 0/194 (0%) | ||
Unevaluable event | 1/188 (0.5%) | 0/194 (0%) | ||
Hepatobiliary disorders | ||||
Bile duct obstruction | 0/188 (0%) | 1/194 (0.5%) | ||
Infections and infestations | ||||
Abscess neck | 1/188 (0.5%) | 0/194 (0%) | ||
Appendicitis | 0/188 (0%) | 2/194 (1%) | ||
Atypical pneumonia | 1/188 (0.5%) | 0/194 (0%) | ||
Bronchitis | 2/188 (1.1%) | 0/194 (0%) | ||
Bronchopulmonary aspergillosis | 1/188 (0.5%) | 0/194 (0%) | ||
Campylobacter gastroenteritis | 0/188 (0%) | 1/194 (0.5%) | ||
Cellulitis | 1/188 (0.5%) | 0/194 (0%) | ||
Clostridium difficile colitis | 1/188 (0.5%) | 0/194 (0%) | ||
Cystitis | 0/188 (0%) | 1/194 (0.5%) | ||
Diverticulitis | 0/188 (0%) | 1/194 (0.5%) | ||
Erysipelas | 0/188 (0%) | 1/194 (0.5%) | ||
Escherichia sepsis | 1/188 (0.5%) | 0/194 (0%) | ||
Gastroenteritis rotavirus | 0/188 (0%) | 1/194 (0.5%) | ||
Gastroenteritis viral | 1/188 (0.5%) | 0/194 (0%) | ||
Haemophilus infection | 0/188 (0%) | 1/194 (0.5%) | ||
Hepatitis B | 1/188 (0.5%) | 0/194 (0%) | ||
Herpes simplex otitis externa | 0/188 (0%) | 1/194 (0.5%) | ||
Herpes zoster | 0/188 (0%) | 1/194 (0.5%) | ||
Influenza | 2/188 (1.1%) | 3/194 (1.5%) | ||
Listeria sepsis | 1/188 (0.5%) | 0/194 (0%) | ||
Localised infection | 1/188 (0.5%) | 0/194 (0%) | ||
Lung infection | 0/188 (0%) | 3/194 (1.5%) | ||
Meningitis | 0/188 (0%) | 1/194 (0.5%) | ||
Moraxella infection | 0/188 (0%) | 1/194 (0.5%) | ||
Neutropenic sepsis | 1/188 (0.5%) | 0/194 (0%) | ||
Peritoneal tuberculosis | 0/188 (0%) | 1/194 (0.5%) | ||
Pharyngitis | 2/188 (1.1%) | 0/194 (0%) | ||
Pneumococcal bacteraemia | 1/188 (0.5%) | 0/194 (0%) | ||
Pneumocystis jirovecii pneumonia | 1/188 (0.5%) | 0/194 (0%) | ||
Pneumonia | 15/188 (8%) | 16/194 (8.2%) | ||
Pneumonia influenzal | 0/188 (0%) | 1/194 (0.5%) | ||
Pneumonia legionella | 1/188 (0.5%) | 0/194 (0%) | ||
Pneumonia streptococcal | 0/188 (0%) | 1/194 (0.5%) | ||
Respiratory tract infection | 0/188 (0%) | 2/194 (1%) | ||
Respiratory tract infection fungal | 0/188 (0%) | 1/194 (0.5%) | ||
Respiratory tract infection viral | 0/188 (0%) | 1/194 (0.5%) | ||
Rhinovirus infection | 0/188 (0%) | 1/194 (0.5%) | ||
Scedosporium infection | 1/188 (0.5%) | 0/194 (0%) | ||
Sepsis | 4/188 (2.1%) | 1/194 (0.5%) | ||
Septic shock | 1/188 (0.5%) | 0/194 (0%) | ||
Sinusitis | 1/188 (0.5%) | 2/194 (1%) | ||
Staphylococcal infection | 1/188 (0.5%) | 0/194 (0%) | ||
Tooth abscess | 0/188 (0%) | 1/194 (0.5%) | ||
Upper respiratory tract infection | 2/188 (1.1%) | 3/194 (1.5%) | ||
Urinary tract infection | 1/188 (0.5%) | 1/194 (0.5%) | ||
Urinary tract infection pseudomonal | 0/188 (0%) | 1/194 (0.5%) | ||
Urosepsis | 1/188 (0.5%) | 0/194 (0%) | ||
Varicella zoster virus infection | 1/188 (0.5%) | 0/194 (0%) | ||
Viral infection | 0/188 (0%) | 1/194 (0.5%) | ||
Viral upper respiratory tract infection | 0/188 (0%) | 1/194 (0.5%) | ||
Lower respiratory tract infection | 1/188 (0.5%) | 0/194 (0%) | ||
Parainfluenzae virus infection | 1/188 (0.5%) | 0/194 (0%) | ||
Injury, poisoning and procedural complications | ||||
Humerus fracture | 0/188 (0%) | 1/194 (0.5%) | ||
Infusion related reaction | 6/188 (3.2%) | 1/194 (0.5%) | ||
Tendon rupture | 1/188 (0.5%) | 0/194 (0%) | ||
Investigations | ||||
Body temperature increased | 1/188 (0.5%) | 0/194 (0%) | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 0/188 (0%) | 1/194 (0.5%) | ||
Dehydration | 0/188 (0%) | 2/194 (1%) | ||
Diabetes mellitus | 0/188 (0%) | 1/194 (0.5%) | ||
Fluid overload | 0/188 (0%) | 1/194 (0.5%) | ||
Hyperkalaemia | 0/188 (0%) | 2/194 (1%) | ||
Hyperphosphataemia | 0/188 (0%) | 2/194 (1%) | ||
Tumour lysis syndrome | 1/188 (0.5%) | 4/194 (2.1%) | ||
Musculoskeletal and connective tissue disorders | ||||
Intervertebral disc protrusion | 1/188 (0.5%) | 0/194 (0%) | ||
Musculoskeletal chest pain | 1/188 (0.5%) | 0/194 (0%) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
Acute myeloid leukaemia | 1/188 (0.5%) | 0/194 (0%) | ||
Adenocarcinoma gastric | 0/188 (0%) | 1/194 (0.5%) | ||
Adenocarcinoma of colon | 1/188 (0.5%) | 0/194 (0%) | ||
Basal cell carcinoma | 0/188 (0%) | 1/194 (0.5%) | ||
Colon cancer | 0/188 (0%) | 1/194 (0.5%) | ||
Colorectal cancer | 0/188 (0%) | 2/194 (1%) | ||
Lung neoplasm malignant | 2/188 (1.1%) | 0/194 (0%) | ||
Lymphoma | 1/188 (0.5%) | 0/194 (0%) | ||
Malignant melanoma | 0/188 (0%) | 1/194 (0.5%) | ||
Medullary thyroid cancer | 1/188 (0.5%) | 0/194 (0%) | ||
Metastatic malignant melanoma | 0/188 (0%) | 1/194 (0.5%) | ||
Myelodysplastic syndrome | 0/188 (0%) | 2/194 (1%) | ||
Pancreatic carcinoma | 0/188 (0%) | 1/194 (0.5%) | ||
Prostate cancer | 1/188 (0.5%) | 0/194 (0%) | ||
Prostatic adenoma | 0/188 (0%) | 1/194 (0.5%) | ||
Skin cancer | 0/188 (0%) | 1/194 (0.5%) | ||
Squamous cell carcinoma | 1/188 (0.5%) | 3/194 (1.5%) | ||
Transitional cell carcinoma | 1/188 (0.5%) | 0/194 (0%) | ||
Nervous system disorders | ||||
Dizziness | 0/188 (0%) | 1/194 (0.5%) | ||
Haemorrhagic stroke | 1/188 (0.5%) | 0/194 (0%) | ||
Lacunar infarction | 0/188 (0%) | 1/194 (0.5%) | ||
Polyneuropathy | 1/188 (0.5%) | 0/194 (0%) | ||
Status epilepticus | 0/188 (0%) | 1/194 (0.5%) | ||
Syncope | 1/188 (0.5%) | 0/194 (0%) | ||
Renal and urinary disorders | ||||
Acute kidney injury | 1/188 (0.5%) | 1/194 (0.5%) | ||
Nephrolithiasis | 0/188 (0%) | 1/194 (0.5%) | ||
Renal impairment | 1/188 (0.5%) | 0/194 (0%) | ||
Reproductive system and breast disorders | ||||
Cervical dysplasia | 0/188 (0%) | 1/194 (0.5%) | ||
Uterine haemorrhage | 0/188 (0%) | 1/194 (0.5%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Acute respiratory failure | 0/188 (0%) | 1/194 (0.5%) | ||
Bronchiectasis | 0/188 (0%) | 1/194 (0.5%) | ||
Lung disorder | 0/188 (0%) | 1/194 (0.5%) | ||
Pulmonary embolism | 1/188 (0.5%) | 1/194 (0.5%) | ||
Skin and subcutaneous tissue disorders | ||||
Dermatitis allergic | 1/188 (0.5%) | 0/194 (0%) | ||
Vascular disorders | ||||
Aortic stenosis | 1/188 (0.5%) | 0/194 (0%) | ||
Deep vein thrombosis | 1/188 (0.5%) | 1/194 (0.5%) | ||
Embolism | 1/188 (0.5%) | 0/194 (0%) | ||
Hypotension | 5/188 (2.7%) | 0/194 (0%) | ||
Other (Not Including Serious) Adverse Events | ||||
Bendamustine + Rituximab | Venetoclax + Rituximab | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 176/188 (93.6%) | 190/194 (97.9%) | ||
Blood and lymphatic system disorders | ||||
Anaemia | 40/188 (21.3%) | 28/194 (14.4%) | ||
Neutropenia | 82/188 (43.6%) | 118/194 (60.8%) | ||
Thrombocytopenia | 42/188 (22.3%) | 24/194 (12.4%) | ||
Gastrointestinal disorders | ||||
Abdominal pain | 6/188 (3.2%) | 13/194 (6.7%) | ||
Constipation | 39/188 (20.7%) | 27/194 (13.9%) | ||
Diarrhoea | 31/188 (16.5%) | 76/194 (39.2%) | ||
Nausea | 64/188 (34%) | 41/194 (21.1%) | ||
Vomiting | 22/188 (11.7%) | 15/194 (7.7%) | ||
General disorders | ||||
Chills | 16/188 (8.5%) | 8/194 (4.1%) | ||
Fatigue | 39/188 (20.7%) | 34/194 (17.5%) | ||
Oedema peripheral | 7/188 (3.7%) | 11/194 (5.7%) | ||
Pyrexia | 33/188 (17.6%) | 27/194 (13.9%) | ||
Infections and infestations | ||||
Bronchitis | 13/188 (6.9%) | 20/194 (10.3%) | ||
Conjunctivitis | 5/188 (2.7%) | 10/194 (5.2%) | ||
Lower respiratory tract infection | 4/188 (2.1%) | 11/194 (5.7%) | ||
Nasopharyngitis | 10/188 (5.3%) | 22/194 (11.3%) | ||
Oral herpes | 12/188 (6.4%) | 8/194 (4.1%) | ||
Pharyngitis | 1/188 (0.5%) | 13/194 (6.7%) | ||
Pneumonia | 11/188 (5.9%) | 5/194 (2.6%) | ||
Sinusitis | 5/188 (2.7%) | 17/194 (8.8%) | ||
Upper respiratory tract infection | 28/188 (14.9%) | 41/194 (21.1%) | ||
Urinary tract infection | 7/188 (3.7%) | 11/194 (5.7%) | ||
Injury, poisoning and procedural complications | ||||
Infusion related reaction | 40/188 (21.3%) | 15/194 (7.7%) | ||
Investigations | ||||
Alanine aminotransferase increased | 10/188 (5.3%) | 9/194 (4.6%) | ||
Neutrophil count decreased | 13/188 (6.9%) | 11/194 (5.7%) | ||
Metabolism and nutrition disorders | ||||
Decreased appetite | 17/188 (9%) | 8/194 (4.1%) | ||
Hyperkalaemia | 0/188 (0%) | 11/194 (5.7%) | ||
Hypokalaemia | 7/188 (3.7%) | 12/194 (6.2%) | ||
Musculoskeletal and connective tissue disorders | ||||
Arthralgia | 10/188 (5.3%) | 12/194 (6.2%) | ||
Back pain | 11/188 (5.9%) | 15/194 (7.7%) | ||
Muscle spasms | 11/188 (5.9%) | 4/194 (2.1%) | ||
Nervous system disorders | ||||
Dizziness | 10/188 (5.3%) | 12/194 (6.2%) | ||
Headache | 19/188 (10.1%) | 21/194 (10.8%) | ||
Psychiatric disorders | ||||
Insomnia | 12/188 (6.4%) | 21/194 (10.8%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Cough | 31/188 (16.5%) | 35/194 (18%) | ||
Dyspnoea | 14/188 (7.4%) | 11/194 (5.7%) | ||
Oropharyngeal pain | 7/188 (3.7%) | 10/194 (5.2%) | ||
Productive cough | 4/188 (2.1%) | 12/194 (6.2%) | ||
Skin and subcutaneous tissue disorders | ||||
Pruritus | 8/188 (4.3%) | 10/194 (5.2%) | ||
Rash | 24/188 (12.8%) | 14/194 (7.2%) | ||
Vascular disorders | ||||
Hypertension | 7/188 (3.7%) | 12/194 (6.2%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title | Medical Communications |
---|---|
Organization | Hoffmann-La Roche |
Phone | 800-821-8590 |
genentech@druginfo.com |
- GO28667
- 2013-002110-12