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) (MURANO)

• ClinicalTrials.gov Identifier: NCT02005471
• Recruitment Status: Completed
• First Posted: December 9, 2013
• Results First Posted: October 1, 2018
• Last Update Posted: October 17, 2023
• Sponsor: Hoffmann-La Roche
• Collaborator: AbbVie
• Information provided by (Responsible Party): Hoffmann-La Roche

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
Chronic Lymphocytic Leukemia	Drug: Bendamustine; Drug: Venetoclax; Drug: Rituximab	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 389 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab
• Actual Study Start Date: March 17, 2014
• Actual Primary Completion Date: May 8, 2017
• Actual Study Completion Date: August 3, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Bendamustine + Rituximab; Participants will receive bendamustine 70 milligrams per meter square (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 Name: GDC-0199, ABT-199; 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 Name: GDC-0199, ABT-199; 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 Name: GDC-0199, ABT-199; 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 :

1. Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death [ Time Frame: Baseline up to PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months) ]
   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. Percentages are rounded off.
2. Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines [ Time Frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months) ]
   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 :

1. Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines [ Time Frame: 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. No new IRC data was generated post the primary analysis.
2. PFS as Assessed by the IRC Using Standard iwCLL Guidelines [ Time Frame: 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. No new IRC data was generated post the primary analysis.
3. 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 [ Time Frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months) ]
   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. Percentages are rounded off.
4. PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [ Time Frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months) ]
   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.
5. 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 [ Time Frame: 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. No new IRC data was generated post the primary analysis.
6. PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [ Time Frame: 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. No new IRC data was generated post the primary analysis.
7. 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 [ Time Frame: Baseline up to approximately 8 years 5 months ]
   Response was assessed by investigator according to 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 following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of 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. 95% CI was computed using Pearson-Clopper method.Percentages are rounded off.
8. Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines [ Time Frame: Baseline up to last FUV (up to approximately 3 years) ]
   Response was assessed by IRC according to 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, 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 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; 1 of 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. 95% CI was computed using Pearson-Clopper method.No new IRC data was generated post primary analysis.
9. 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 [ Time Frame: 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 investigator according to 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 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of 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. 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.
10. 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 [ Time Frame: 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.
11. Percentage of Participants Who Died [ Time Frame: Baseline up to approximately 8 years 5 months ]
    Percentage of participants who died from any cause, during the study, was reported. Percentage is rounded off.
12. Overall Survival (OS) [ Time Frame: Baseline up to approximately 8 years 5 months ]
    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.
13. 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 [ Time Frame: Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months) ]
    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. Percentages are rounded off.
14. Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines [ Time Frame: Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months) ]
    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.
15. 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 [ Time Frame: From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months) ]
    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. Percentage is rounded off.
16. Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines [ Time Frame: From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months) ]
    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.
17. Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator [ Time Frame: Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months) ]
    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. Percentage is rounded off.
18. Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator [ Time Frame: Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months) ]
    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.
19. Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood [ Time Frame: 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 was reported. The 95% CI was computed using Pearson-Clopper method. Percentage is rounded off.
20. Percentage of Participants With MRD Negativity in Bone Marrow [ Time Frame: 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 flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.
21. Plasma Venetoclax Concentrations [ Time Frame: Pre-dose (0 hour, anytime before venetoclax administration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days ]
22. Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores [ Time Frame: 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).
23. 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 [ 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 ]
    EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into 5 functional scales (Physical, Role, Cognitive, Emotional, and Social), 3 symptom scales (fatigue, pain, nausea, and vomiting), 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'). Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL.
24. Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score [ 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 ]
    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.
25. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From signing of informed consent form up to approximately 8 years 5 months ]
    An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A Serious Adverse Event (SAE) is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)
26. Number of Participants With Grade 3 or Higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs) [ Time Frame: From signing of informed consent form up to approximately 8 years 5 months ]
    An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A SAE is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. TLS and IRRs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening; Grade 5 = Death. A higher grade indicates a worse outcome.

Other Outcome Measures:

1. Change From Baseline in Lymphocyte Subset Counts at Specified Time Points [ 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines
• 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
• Participants previously treated with bendamustine only if their duration of response was >/= 24 months
• Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (</=) 1
• Adequate bone marrow function
• Adequate renal and hepatic function
• 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
• 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:

• Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria
• Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B
• Adequate renal and hepatic function per laboratory reference range

Exclusion Criteria:

• Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL
• Undergone an allogenic stem cell transplant
• A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease
• Hepatitis B or C or known human immunodeficiency virus (HIV) positive
• Receiving warfarin treatment
• Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug
• 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
• 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
• History of prior venetoclax treatment
• 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
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal)
• Vaccination with a live vaccine within 28 days prior to randomization
• 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

United States, California

University of California San Diego Medical Center

La Jolla, California, United States, 92093-5354

United States, Michigan

Henry Ford Health System

Detroit, Michigan, United States, 48202

United States, New York

Memorial Sloan Kettering Cancer Center; Clinical Trials Office

New York, New York, United States, 10021

Perlmutter Cancer Center NYU Langone Health

New York, New York, United States, 10032

United States, Utah

Huntsman Cancer Institute; University of Utah

Salt Lake City, Utah, United States, 84112

Australia, Australian Capital Territory

The Canberra Hospital

Garran, Australian Capital Territory, Australia, 2065

Australia, New South Wales

Concord Repatriation General Hospital

Concord, New South Wales, Australia, 2139

St George Hospital

Kogarah, New South Wales, New South Wales, Australia, 2217

Australia, Queensland

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia, 4102

Australia, South Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia, 5000

Flinders Medical Centre

Bedford Park, South Australia, Australia, 5042

Australia, Tasmania

Royal Hobart Hospital

Hobart, Tasmania, Australia, 7000

Australia, Victoria

Frankston Hospital

Frankston, Victoria, Australia, 3199

Monash Medical Centre; Haematology

Melbourne, Victoria, Australia, 3168

Slade Health Pharmacy

Mount Waverley, Victoria, Australia, 3149

Peter MacCallum Cancer Center

North Melbourne, Victoria, Australia, 3051

Royal Melbourne Hospital

Parkville, Victoria, Australia, 3050

Australia, Western Australia

The Perth Blood Institute

Nedlands, Western Australia, Australia, 6009

Austria

Medizinische Universität Innsbruck

Innsbruck, Austria, 6020

LKH - Universitätsklinikum der PMU Salzburg

Salzburg, Austria, 5020

Medizinische Universität Wien

Wien, Austria, 1090

Klinik Ottakring

Wien, Austria, 1160

Belgium

ZNA Antwerpen; Department Hematology

Antwerpen, Belgium, 2060

Cliniques Universitaires Saint-Luc; Hematology

Bruxelles, Belgium, 1200

AZ Groeninge

Kortrijk, Belgium, 8500

UZ Leuven; Department Hematology

Leuven, Belgium, 3000

CHU UCL Mont-Godinne

Mont-godinne, Belgium, 5530

AZ Delta (Campus Rumbeke)

Roeselare, Belgium, 8800

Canada, Alberta

Foothills Medical Centre; Centre Dept of Medical Clinical Neuroscience

Calgary, Alberta, Canada, T2N 2T9

Canada, Ontario

Juravinski Cancer Clinic

Hamilton, Ontario, Canada, L8N 3Z5

Canada, Quebec

Jewish General Hospital

Montreal, Quebec, Canada, H3T 1E2

Canada, Saskatchewan

Saskatoon City Hospital;Saskatchewan Cancer Centre

Saskatoon, Saskatchewan, Canada, S7N 4H4

Czechia

Fakultni nemocnice Brno

Brno, Czechia, 613 00

Fakultni nemocnice Hradec Kralove

Hradec Kralove, Czechia, 500 05

Fakultní nemocnice Olomouc

Olomouc, Czechia, 775 20

Fakultni nemocnice Ostrava

Ostrava - Poruba, Czechia, 708 52

Vseobecna fakultni nemocnice v Praze

Praha 2, Czechia, 128 08

Fakultni nemocnice Kralovske Vinohrady

Praha, Czechia, 100 34

Denmark

Herlev Hospital

Herlev, Denmark, 2730

Rigshospitalet

København Ø, Denmark, 2100

Odense Universitetshospital

Odense C, Denmark, 5000

Sjællands Universitetshospital, Roskilde

Roskilde, Denmark, 4000

Sygehus Lillebælt, Vejle

Vejle, Denmark, 7100

France

Hôpital Morvan

Brest, France, 29609

Centre Hospitalier Départemental Les Oudairies

La Roche sur Yon, France, 85925

Hopital Claude Huriez - CHU Lille

Lille, France, 59037

Hopital Saint Eloi

Montpellier, France, 34295

CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation

Nantes, France, 44093

Hopital Robert Debre

Paris, France, 75019

Centre Hospitalier Lyon Sud

Pierre Benite, France, 69495

CHU Poitiers - Hopital La Miletrie

Poitiers, France, 86000

CHU de Rennes - Hopital de Pontchaillo

Rennes, France, 35033

Centre Henri Becquerel

Rouen, France, 76038

Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)

Toulouse, France, 31059

CHU Tours - Hôpital Bretonneau

Tours, France, 37044

Hôpital de Brabois Adultes

Vandoeuvre-les-nancy, France, 54511

Germany

Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden

Dresden, Germany, 01307

Universitaetsklinikum Freiburg

Freiburg, Germany, 79106

Universitätsklinikum Tübingen

Tübingen, Germany, 72076

Hungary

Semmelweis Egyetem

Budapest, Hungary, 1088

Orszagos Onkologiai Intezet

Budapest, Hungary, 1122

Debreceni Egyetem Klinikai Központ; B?rgyógyászati Klinika

Debrecen, Hungary, 4012

Somogy Megyei Kaposi Mor Oktato Korhaz

Pecs, Hungary, 7624

Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.

Szeged, Hungary, 6720

Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino; Radiology

Torino, Abruzzo, Italy, 10126

Azienda Ospedaliero Universitaria San Martino

Genova, Liguria, Italy, 16132

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)

Bergamo, Lombardia, Italy, 24127

Ospedale San Raffaele

Milano, Lombardia, Italy, 20132

Asst Grande Ospedale Metropolitano Niguarda; SC Farmacia Ospedale

Milano, Lombardia, Italy, 20162

Azienda Ospedaliero Universitaria Ospedali Riuniti

Torrette Di Ancona, Marche, Italy, 60126

Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari

Bari, Puglia, Italy, 70124

Azienda Ospedaliera Universitaria Careggi

Florence, Toscana, Italy, 50134

Azienda Ospedaliera Di Padova

Padova, Veneto, Italy, 35128

Korea, Republic of

Seoul National University Bundang Hospital

Seongnam-si, Korea, Republic of, 463-707

Severance Hospital, Yonsei University Health System

Seoul, Korea, Republic of, 03722

Konkuk University Medical Center

Seoul, Korea, Republic of, 05030

The Catholic University of Korea Seoul St. Mary?s Hospital

Seoul, Korea, Republic of, 6591

Netherlands

Amsterdam UMC, Locatie VUMC; Neurology

Amsterdam, Netherlands, 1081 HV

Amsterdam UMC Location AMC

Amsterdam, Netherlands, 1105 AZ

Albert Schweitzer Ziekenhuis, Dordwijk; Internal Medicine, Hemato-Oncology

Dordrecht, Netherlands, 3318 AT

Medisch Spectrum Twente

Enschede, Netherlands, 7512 KZ

Leids Universitair Medisch Centrum; Cardiology

Leiden, Netherlands, 2333 ZA

Erasmus Medisch Centrum

Rotterdam, Netherlands, 3000 CA

UMC Utrecht

Utrecht, Netherlands, 3508

New Zealand

North Shore Hospital; Haematolgy

Auckland, New Zealand, 1309

Middlemore Hospital

Auckland, New Zealand

Christchurch Hospital NZ

Christchurch, New Zealand, 8011

Baxter Healthcare

Mount Wellington, New Zealand, 1060

Poland

SP ZOZ Zespol Szpitali Miejskich w Chorzowie

Chorzow, Poland, 41-500

Uniwersyteckie Centrum Kliniczne

Gdansk, Poland

Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

Lodz, Poland, 93-513

Szpital Wojewodzki w Opolu

Opole, Poland, 45-061

MTZ Clinical Research Sp. z o.o.

Warszawa, Poland, 02-106

Samodzielny Publiczny Szpital Kliniczny nr 1

Zabrze, Poland, 44803

Russian Federation

FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"

Moscow, Moskovskaja Oblast, Russian Federation, 115478

SRI of Hematology and Transfusiology

Sankt-peterburg, Sankt Petersburg, Russian Federation, 191024

North-West Federal Medical Research Center n.a. V.A. Almazov

St. Petersburg, Sankt Petersburg, Russian Federation, 197341

Kemerovo Regional Clinical Hospital

Kemerovo, Russian Federation, 650066

BHI of Omsk region Clinical Oncology Dispensary

Omsk, Russian Federation, 644013

Spain

Complejo Hospitalario de Navarra

Pamplona, Navarra, Spain, 31008

Hospital Universitari Vall d'Hebron

Barcelona, Spain, 08035

Hospital Clinic i Provincial de Barcelona; Hematology

Barcelona, Spain, 08036

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

Hospital Clinico Universitario de Salamanca

Salamanca, Spain, 37007

Sweden

Skånes Universitetssjukhus

Lund, Sweden, 221 85

Akademiska Sjukhuset

Uppsala, Sweden, 751 85

Taiwan

National Taiwan University Hospital

Taipei, Taiwan, 10002

United Kingdom

Bristol Haematology and Oncology centre

Bristol, United Kingdom, BS2 8ED

The Christie

Manchester, United Kingdom, M20 4BX

Southampton General Hospital

Southampton, United Kingdom, SO16 6YD

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)

Documents provided by Hoffmann-La Roche:

Study Protocol  [PDF] March 30, 2018

Statistical Analysis Plan  [PDF] May 18, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.

Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. doi: 10.1182/blood.2021015014.

Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. doi: 10.1200/JCO.20.00948. Epub 2020 Sep 28.

Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol. 2019 Feb 1;37(4):269-277. doi: 10.1200/JCO.18.01580. Epub 2018 Dec 3.

Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. doi: 10.1056/NEJMoa1713976.

Jones AK, Freise KJ, Agarwal SK, Humerickhouse RA, Wong SL, Salem AH. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AAPS J. 2016 Sep;18(5):1192-1202. doi: 10.1208/s12248-016-9927-9. Epub 2016 May 27.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02005471
• Other Study ID Numbers: GO28667; 2013-002110-12 ( EudraCT Number )
• First Posted: December 9, 2013
• Results First Posted: October 1, 2018
• Last Update Posted: October 17, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Rituximab; Venetoclax; Bendamustine Hydrochloride; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action