Follicular Lymphoma
Conditions
Brief summary
This open-label, international, multicenter study will investigate the safety and efficacy of venetoclax (GDC-0199) in combination with bendamustine plus rituximab (venetoclax + BR) compared with BR alone in participants with relapsed and refractory fNHL, comparing two chemotherapy-containing regimens (Chemotherapy-Containing Cohort). In addition, an exploratory analysis of the safety and efficacy of venetoclax in combination with rituximab (venetoclax + rituximab), a chemotherapy-free regimen, will be performed (Chemotherapy-Free Cohort). Assignment to the Chemotherapy-Containing or Chemotherapy-Free Cohort will be decided at the discretion of the Investigator, unless one of the cohorts is not open to enrollment; in which case, participants may be enrolled only to the open cohort. The first 6 participants enrolled in the Chemotherapy-Containing Cohort (or more if required) will comprise the Safety Run-In group for Treatment Arm B, dosing venetoclax at 600 milligrams (mg) in combination with BR. Once a dose has been chosen from the Safety Run-In Period, randomization to the two treatment arms of the Chemotherapy-Containing Cohort (Arms B and C) will begin.
Interventions
DRUGVenetoclax
Venetoclax will be administered as per the schedule specified under arm description.
DRUGBendamustine
Bendamustine will be administered as per the schedule specified under arm description.
DRUGRituximab
Rituximab will be administered as per the schedule specified under arm description.
Sponsors
AbbVie
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have histologically confirmed follicular lymphoma (FL) of Grade 1, 2, or 3a * Participants must have received at least one prior therapy for FL * For participants potentially receiving chemotherapy: if the participant has received prior bendamustine, response duration must have been greater than (\>) 1 year * At least one bi-dimensionally measurable lesion on imaging scan defined as \>1.5 centimeters (cm) in its longest dimension * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 * Adequate hematologic function * For female participants of childbearing potential and male participants with female partners of childbearing potential, agreement to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception throughout the course of study treatment and for at least 30 days after the last dose of venetoclax and 12 months after the last dose of rituximab, whichever is longer * Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined specifications prior to study enrollment
Exclusion criteria
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products * Contraindication to potential treatment agents * Ongoing corticosteroid use \>30 milligrams per day (mg/day) of prednisone or equivalent. Participants receiving corticosteroid treatment with less than equal to (\</=) 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to randomization (Cycle 1 Day 1) * Primary central nervous system (CNS) lymphoma * Vaccination with live vaccines within 28 days prior to treatment * Chemotherapy or other investigational therapy within five half-lives of a biologic agent with a minimum of 28 days prior to the start of Cycle 1 * History of other malignancy that could affect compliance with the protocol or interpretation of results * Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the participant * Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm) * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1 * Requires the use of warfarin * Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis * Presence of positive test results for hepatitis B surface antigen or hepatitis C virus (HCV) antibody * Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * Participants with occult or prior hepatitis B virus (HBV) infection may be included if HBV deoxyribonucleic acid (DNA) is undetectable at screening. These participants must be willing to undergo monthly HBV DNA test until at least 12 months after the last treatment cycle * Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1) * Pregnant or lactating * Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1), other than for diagnosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA) | 6-8 weeks after Cycle 6 Day 1 (PRA) (Cycle length = 28 days) | CMR: a score 1 (no uptake above background), 2 (uptake less than or equal to \[\<=\] mediastinum), or 3 (uptake less than \[\<\] mediastinum but \<=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites with no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1 | 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (uptake \<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1 | 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | CR: defined as reduction of longest transverse diameter of lesion (LDi) of target nodes/nodal masses to \<=1.5 centimeters (cm), and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/immunohistochemistry (IHC)-negative bone marrow morphology. Assessment was performed by an IRC according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | CR: defined as reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. Assessment was performed by Investigator according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | OR was defined as CMR or Partial Metabolic Response (PMR). CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. PMR: a score 4 (uptake moderately greater than \[\>\] liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites with no new lesions and reduced residual uptake in bone marrow compared with baseline. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | OR was defined as CMR or PMR. CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. PMR: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites with no new lesions and reduced residual uptake in bone marrow compared with baseline. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | OR was defined as CR or Partial Response (PR). CR: reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. PR: greater than or equal to (\>=) 50 percent (%) decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen at least \>50% beyond normal; and no new lesions. Assessment was performed by an IRC according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days) | OR was defined as CR or PR. CR: reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. PR: \>=50% decrease in SPD of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen at least \>50% beyond normal; and no new lesions. Assessment was performed by Investigator according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan | Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years) | OR was defined as CMR/CR or PMR/PR. CMR, CR, PMR, and PR have been defined in previous endpoints, and are not repeated here due to space constraint. Assessment was performed by Investigator according to Lugano classification using PET scan or CT scan (if PET is missing). |
| Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan | From CMR or PMR until disease progression or death due to any cause (assessed up to approximately 2.5 years) | DOR was defined as time from CMR/CR or PMR/PR until progressive disease (PD) or death due to any cause. CMR, CR, PMR, and PR have been defined in previous endpoints, and are not repeated here due to space constraint. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan or CT scan (if PET is missing). DOR was calculated using Kaplan-Meier method. |
| Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death | Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years) | PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. |
| Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA | 4-10 weeks after Cycle 6 Day 1 (Cycle length = 28 days) | CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method. |
| Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy | Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years) | PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. |
| Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years) | EFS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) to the date of disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. EFS was calculated using Kaplan-Meier method. |
| Percentage of Participants Who Died Due to Any Cause | Baseline until death due to any cause (assessed up to approximately 2.5 years | — |
| Overall Survival (OS) | Baseline until death due to any cause (assessed up to approximately 2.5 years) | OS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) to death due to any cause. For participants who are alive, OS was censored at the last contact. OS was calculated using Kaplan-Meier method. |
| Apparent Clearance (CL) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. |
| Apparent Volume of Distribution (Vd) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | Vd was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Time to Maximum Plasma Concentration (Tmax) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | — |
| Maximum Plasma Concentration (Cmax) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | — |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | Area under the plasma concentration versus time curve from zero to the last measured concentration (AUClast). |
| Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax | Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days) | Area under the plasma concentration versus time curve from time 0 (pre-dose) to 8 hours post dose (AUC0-8h). |
| Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years) | PFS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) until the date of disease progression, or death due to any cause. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. PFS was calculated using Kaplan-Meier method. |
Countries
Australia, Belgium, Canada, France, Germany, Italy, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) Participants received venetoclax no more than 600 milligrams (mg) orally once daily continuously along with rituximab 375 milligrams per square meter (mg/m\^2) intravenous (IV) infusion on Day 1 of 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of the 28-day cycle. Safety run-in continued until first 9 participants completed the safety observation window of 28 days. After first 28 days of safety observation (Cycle 1), participants continued to receive venetoclax 600 mg orally once daily up to 1 year along with rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. | 9 |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) Participants received venetoclax 800 mg orally once daily for 1 year along with rituximab 375 mg/m\^2 IV infusion on Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 4, 6, 8, 10, and 12. Each cycle was of 28 days. | 52 |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) Participants received venetoclax 800 mg orally once daily continuously for 1 year along with rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. | 51 |
| Chemotherapy-Containing Cohort: Arm C (BR) Participants received rituximab 375 mg/m\^2 IV infusion on Day 1 of each 28-day cycle and bendamustine 90 mg/m\^2 IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles. | 51 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 | 1 |
| Overall Study | Death | 0 | 3 | 1 | 2 |
| Overall Study | Other | 0 | 1 | 7 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 3 |
| Overall Study | Progressive Disease | 4 | 42 | 19 | 22 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 3 | 3 |
Baseline characteristics
| Characteristic | Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Chemotherapy-Containing Cohort: Arm C (BR) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 12.7 | 61.9 years STANDARD_DEVIATION 12 | 64.9 years STANDARD_DEVIATION 9.8 | 61.0 years STANDARD_DEVIATION 11.6 | 62.3 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 5 Participants | 25 Participants | 16 Participants | 21 Participants | 67 Participants |
| Sex: Female, Male Male | 4 Participants | 27 Participants | 35 Participants | 30 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 49 / 52 | 49 / 49 | 48 / 50 |
| serious Total, serious adverse events | 4 / 9 | 16 / 52 | 26 / 49 | 12 / 50 |
Outcome results
Primary
Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA)
CMR: a score 1 (no uptake above background), 2 (uptake less than or equal to \[\<=\] mediastinum), or 3 (uptake less than \[\<\] mediastinum but \<=liver) with or without a residual mass on PET 5-point scale (5-PS), for lymph nodes and extralymphatic sites with no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% confidence interval (CI) for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 6-8 weeks after Cycle 6 Day 1 (PRA) (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA) | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA) | 11.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA) | 74.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Complete Metabolic Response (CMR) According to Independent Review Committee (IRC) as Per Lugano Classification, Using Positron Emission Tomography (PET) Scan at Primary Response Assessment (PRA) | 70.6 percentage of participants |
95% CI: [-13.38, 21.23]
Secondary
Apparent Clearance (CL) of Venetoclax
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: The data could not be collected as the timepoints for pharmacokinetics collection and the daily dosing of venetoclax did not permit an assessment of CL.
Secondary
Apparent Volume of Distribution (Vd) of Venetoclax
Vd was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: The data could not be collected as the timepoints for pharmacokinetics collection and the daily dosing of venetoclax did not permit an assessment of Vd.
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax
Area under the plasma concentration versus time curve from time 0 (pre-dose) to 8 hours post dose (AUC0-8h).
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: Pharmacokinetic-evaluable population. 'Overall number of participants analyzed'=those evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax | 5240 hours*ng/mL | Standard Deviation 1860 |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax | 4820 hours*ng/mL | Standard Deviation 1980 |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Area Under the Plasma Concentration-Time Curve From Time 0 to 8 Hours Post Dose (AUC0-8h) of Venetoclax | 5330 hours*ng/mL | Standard Deviation 2270 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax
Area under the plasma concentration versus time curve from zero to the last measured concentration (AUClast).
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: Pharmacokinetic-evaluable population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax | 5310 hours*ng/mL | Standard Deviation 1730 |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax | 4950 hours*ng/mL | Standard Deviation 1950 |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Area Under the Plasma Concentration-Time Curve From Time 0 to Last Observed Concentration (AUClast) of Venetoclax | 5500 hours*ng/mL | Standard Deviation 2270 |
Secondary
Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan
DOR was defined as time from CMR/CR or PMR/PR until progressive disease (PD) or death due to any cause. CMR, CR, PMR, and PR have been defined in previous endpoints, and are not repeated here due to space constraint. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan or CT scan (if PET is missing). DOR was calculated using Kaplan-Meier method.
Time frame: From CMR or PMR until disease progression or death due to any cause (assessed up to approximately 2.5 years)
Population: ITT population. 'Overall number of participants analyzed'=those evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 32.46 months |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 15.79 months |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 24.87 months |
| Chemotherapy-Containing Cohort: Arm C (BR) | Duration of Response (DOR) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 15.64 months |
Comparison: Stratified Analysis: Strata were disease burden and DOR of prior cancer therapy.95% CI: [0.38, 1.27]
Comparison: Unstratified Analysis95% CI: [0.43, 1.4]
Secondary
Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan
EFS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) to the date of disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. EFS was calculated using Kaplan-Meier method.
Time frame: Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 35.09 months |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 6.57 months |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 27.63 months |
| Chemotherapy-Containing Cohort: Arm C (BR) | Event-Free Survival (EFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 18.43 months |
Comparison: Stratified Analysis: Strata were disease burden and EFS of prior cancer therapy.95% CI: [0.38, 1.24]
Comparison: Unstratified Analysis95% CI: [0.43, 1.36]
Secondary
Maximum Plasma Concentration (Cmax) of Venetoclax
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: Pharmacokinetic-evaluable population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Maximum Plasma Concentration (Cmax) of Venetoclax | 1350 nanograms per milliliter (ng/mL) | Standard Deviation 427 |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Maximum Plasma Concentration (Cmax) of Venetoclax | 1220 nanograms per milliliter (ng/mL) | Standard Deviation 478 |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Maximum Plasma Concentration (Cmax) of Venetoclax | 1340 nanograms per milliliter (ng/mL) | Standard Deviation 460 |
Secondary
Overall Survival (OS)
OS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) to death due to any cause. For participants who are alive, OS was censored at the last contact. OS was calculated using Kaplan-Meier method.
Time frame: Baseline until death due to any cause (assessed up to approximately 2.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Overall Survival (OS) | NA months |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Overall Survival (OS) | NA months |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Overall Survival (OS) | NA months |
| Chemotherapy-Containing Cohort: Arm C (BR) | Overall Survival (OS) | NA months |
Comparison: Stratified Analysis: Strata were disease burden and OS of prior cancer therapy.95% CI: [0.04, 5.37]
Comparison: Unstratified Analysis95% CI: [0.05, 5.63]
Secondary
Percentage of Participants Who Died Due to Any Cause
Time frame: Baseline until death due to any cause (assessed up to approximately 2.5 years
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants Who Died Due to Any Cause | 0 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants Who Died Due to Any Cause | 5.8 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants Who Died Due to Any Cause | 2.0 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants Who Died Due to Any Cause | 3.9 percentage of participants |
Secondary
Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA
CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 4-10 weeks after Cycle 6 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA | 15.4 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA | 70.6 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at PRA | 68.6 percentage of participants |
95% CI: [-15.89, 19.81]
Secondary
Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1
CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1 | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1 | 17.3 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1 | 39.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With CMR According to Investigator as Per Lugano Classification, Using PET Scan at Year 1 | 47.1 percentage of participants |
95% CI: [-27.01, 11.32]
Secondary
Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1
CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (uptake \<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1 | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1 | 21.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1 | 41.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With CMR According to IRC as Per Lugano Classification, Using PET Scan at Year 1 | 39.2 percentage of participants |
95% CI: [-17.07, 20.99]
Secondary
Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan
CR: defined as reduction of longest transverse diameter of lesion (LDi) of target nodes/nodal masses to \<=1.5 centimeters (cm), and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/immunohistochemistry (IHC)-negative bone marrow morphology. Assessment was performed by an IRC according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | 6-8 weeks after Cycle 6 Day 1 | 44.4 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | Year 1 | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | Year 1 | 13.2 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | 6-8 weeks after Cycle 6 Day 1 | 5.7 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | 6-8 weeks after Cycle 6 Day 1 | 39.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | Year 1 | 27.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | 6-8 weeks after Cycle 6 Day 1 | 25.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Complete Response (CR) According to IRC as Per Lugano Classification, Using Computed Tomography (CT) Scan | Year 1 | 23.5 percentage of participants |
Comparison: At 6-8 weeks after Cycle 6 Day 195% CI: [-4.24, 31.69]
Comparison: At Year 195% CI: [-12.98, 20.82]
Secondary
Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan
CR: defined as reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. Assessment was performed by Investigator according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 22.2 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 33.3 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 5.7 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 5.7 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 15.7 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 13.7 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 31.4 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With CR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 21.6 percentage of participants |
Comparison: At 4-10 weeks after Cycle 6 Day 195% CI: [-31.87, 0.49]
Comparison: At Year 195% CI: [-22.56, 6.87]
Secondary
Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy
PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan.
Time frame: Baseline until disease progression, death, or start of a new anti-lymphoma therapy whichever occurred first (assessed up to approximately 2.5 years)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy | 44.4 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy | 86.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy | 41.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan), Death, or Start of a New Anti-lymphoma Therapy | 52.9 percentage of participants |
Secondary
Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death
PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan.
Time frame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death | 44.4 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death | 86.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death | 41.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Disease Progression (According to Investigator as Per Lugano Classification, Using PET or CT Scan) or Death | 52.9 percentage of participants |
Secondary
Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan
OR was defined as CMR or Partial Metabolic Response (PMR). CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. PMR: a score 4 (uptake moderately greater than \[\>\] liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites with no new lesions and reduced residual uptake in bone marrow compared with baseline. Assessment was performed by an IRC according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | 6-8 weeks after Cycle 6 Day 1 | 55.6 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | Year 1 | 66.7 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | Year 1 | 32.7 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | 6-8 weeks after Cycle 6 Day 1 | 21.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | 6-8 weeks after Cycle 6 Day 1 | 76.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | Year 1 | 45.1 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | 6-8 weeks after Cycle 6 Day 1 | 74.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With Objective Response (OR) According to IRC as Per Lugano Classification, Using PET Scan | Year 1 | 51.0 percentage of participants |
Secondary
Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan
OR was defined as CR or PR. CR: reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. PR: \>=50% decrease in SPD of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen at least \>50% beyond normal; and no new lesions. Assessment was performed by Investigator according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 55.6 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 28.3 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 32.1 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 74.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 47.1 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | 4-10 weeks after Cycle 6 Day 1 | 78.4 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using CT Scan | Year 1 | 49.0 percentage of participants |
Secondary
Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan
OR was defined as CMR/CR or PMR/PR. CMR, CR, PMR, and PR have been defined in previous endpoints, and are not repeated here due to space constraint. Assessment was performed by Investigator according to Lugano classification using PET scan or CT scan (if PET is missing).
Time frame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
Population: ITT population. 'Overall number of participants analyzed'=those evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan | 66.7 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan | 36.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan | 80.4 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET or CT Scan | 80.4 percentage of participants |
Secondary
Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan
OR was defined as CMR or PMR. CMR: a score 1 (no uptake above background), 2 (uptake \<=mediastinum), or 3 (\<mediastinum but \<=liver) with or without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites with no new lesions and no evidence of FDG-avid disease in bone marrow. PMR: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites with no new lesions and reduced residual uptake in bone marrow compared with baseline. Assessment was performed by Investigator according to Lugano classification using PET scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 4-10 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | Year 1 | 55.6 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | 4-10 weeks after Cycle 6 Day 1 | 55.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | Year 1 | 21.2 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | 4-10 weeks after Cycle 6 Day 1 | 28.8 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | 4-10 weeks after Cycle 6 Day 1 | 76.5 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | Year 1 | 39.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | Year 1 | 49.0 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to Investigator as Per Lugano Classification, Using PET Scan | 4-10 weeks after Cycle 6 Day 1 | 76.5 percentage of participants |
Secondary
Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan
OR was defined as CR or Partial Response (PR). CR: reduction of LDi of target nodes/nodal masses to \<=1.5 cm, and no extralymphatic sites of disease; absence of non-measured lesions and new lesions; reduction of enlarged organs to normal; and normal/IHC-negative bone marrow morphology. PR: greater than or equal to (\>=) 50 percent (%) decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 target measurable nodes and extra-nodal sites; absence/reduction/no increase in size of non-measured lesions; reduction in length of spleen at least \>50% beyond normal; and no new lesions. Assessment was performed by an IRC according to Lugano classification using CT scan. 95% CI for percentage of responders was calculated using Clopper-Pearson method.
Time frame: 6-8 weeks after Cycle 6 Day 1 and 48-56 weeks after Cycle 1 Day 1 (Cycle length = 28 days)
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | 6-8 weeks after Cycle 6 Day 1 | 66.7 percentage of participants |
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | Year 1 | 66.7 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | Year 1 | 22.6 percentage of participants |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | 6-8 weeks after Cycle 6 Day 1 | 30.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | 6-8 weeks after Cycle 6 Day 1 | 80.4 percentage of participants |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | Year 1 | 41.2 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | 6-8 weeks after Cycle 6 Day 1 | 84.3 percentage of participants |
| Chemotherapy-Containing Cohort: Arm C (BR) | Percentage of Participants With OR According to IRC as Per Lugano Classification, Using CT Scan | Year 1 | 60.8 percentage of participants |
Secondary
Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan
PFS was defined as the period from the date of treatment initiation (Safety Run-in and Arm A) or randomization date (Arms B and C) until the date of disease progression, or death due to any cause. PD: a score 4 (uptake moderately \>liver) or 5 (uptake markedly \>liver and/or new lesions) with increase in intensity of uptake from baseline on PET 5-PS for individual target nodes/nodal lesions; new FDG-avid foci for extranodal lesions; new FDG-avid foci consistent with lymphoma for new lesions; or new or recurrent FDG-avid foci for bone marrow. Assessment was performed by Investigator according to Lugano classification using PET or CT scan. PFS was calculated using Kaplan-Meier method.
Time frame: Baseline until disease progression or death due to any cause (assessed up to approximately 2.5 years)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 35.09 months |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 6.57 months |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 27.63 months |
| Chemotherapy-Containing Cohort: Arm C (BR) | Progression-Free Survival (PFS) According to Investigator as Per Lugano Classification, Using PET or CT Scan | 18.43 months |
Comparison: Stratified Analysis: Strata were disease burden and PFS of prior cancer therapy.95% CI: [0.38, 1.24]
Comparison: Unstratified Analysis95% CI: [0.43, 1.36]
Secondary
Time to Maximum Plasma Concentration (Tmax) of Venetoclax
Time frame: Pre-dose (within 30 minutes), and 2, 4, 6, 8 hours post-dose on Cycle 1 Day 1; pre-dose (within 30 minutes) on Cycle 1 Days 8, 15, 22; pre-dose (within 30 minutes) and 4 hours post-dose on Day 1 of Cycles 4 and 6 (Cycle length = 28 days)
Population: Pharmacokinetic-evaluable population included all enrolled participants with available pharmacokinetic data for venetoclax.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-Containing Cohort:Safety Run-In (Venetoclax + BR) | Time to Maximum Plasma Concentration (Tmax) of Venetoclax | 8.00 hours |
| Chemotherapy-Free Cohort: Arm A (Venetoclax + Rituximab) | Time to Maximum Plasma Concentration (Tmax) of Venetoclax | 6.00 hours |
| Chemotherapy-Containing Cohort: Arm B (Venetoclax + BR) | Time to Maximum Plasma Concentration (Tmax) of Venetoclax | 6.21 hours |