A Study to Investigate the Efficacy and Safety of Bendamustine Compared With Bendamustine+Obinutuzumab (GA101) in Participants With Rituximab-Refractory, Indolent Non-Hodgkin's Lymphoma (GADOLIN)

Genentech, Inc.413 enrolled

Overview

This open-label, multicenter, randomized Phase III study will investigate the efficacy, safety, pharmacokinetics and pharmacoeconomics of obinutuzumab (RO5072759, GA101) combined with bendamustine followed by continued obinutuzumab treatment (maintenance monotherapy) compared with bendamustine alone treatment in participants with rituximab-refractory indolent Non-Hodgkin's lymphoma (iNHL). The end of study was defined to when safety follow-up for all patients had been completed (2 years' safety follow-up from last dose).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

413

Conditions

Non-Hodgkin's Lymphoma

Interventions

Obinutuzumab

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * History of histologically documented, B-lymphocyte antigen cluster of differentiation 20 plus (CD20+), iNHL * Refractory to any previous regimen containing rituximab (defined by participants who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen) * Previously treated with a maximum of four unique chemotherapy containing treatment regimens * All participants must have at least one bi-dimensionally measurable lesion (greater than \[\>\]1.5 centimeters (cm) in its largest dimension by computed tomography \[CT\] scan) Exclusion Criteria: * Prior use of any monoclonal antibody (other than anti-CD20) within 3 months prior to the start of Cycle 1, prior treatment with obinutuzumab was not allowed * Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1 * Prior treatment with bendamustine (within 2 years of the start of Cycle 1) * Prior allogeneic stem cell transplant * History of severe allergic or anaphylactic reactions to monoclonal antibody therapy * History of sensitivity to mannitol * Central nervous system lymphoma or prior diffuse large B-cell lymphoma (DLBCL), histological evidence of transformation to high grade or diffuse large B-cell lymphoma * 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 * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 4 weeks * Participants with a history of confirmed progressive multifocal leukoencephalopathy (PML) * Vaccination with a live vaccine a minimum of 28 days prior to randomization * Recent major surgery (within 4 weeks), other than for diagnosis * Presence of positive test results for Hepatitis B surface antigen (HBsAg); antibody to hepatitis B core antigen \[anti-HBc\]) with detectable viral load (positive hepatitis B virus \[HBV\] deoxyribo-nucleic acid \[DNA\]) or Hepatitis C * Participants with chronic hepatitis B or seropositive occult (HBV) infection * Participants with seronegative occult HBV infection or past HBV infection (defined as anti-HBc positive and HBV DNA negative) could be eligible if they were willing to be followed according to the protocol for HBV DNA testing * Participants positive for Hepatitis C virus (HCV) antibody were eligible only if polymerase chain reaction(PCR) was negative for HCV Ribonucleic acid (RNA) * Known history of human immunodeficiency virus (HIV) seropositive status * Positive test results for human T-lymphotropic virus type I (HTLV 1) virus in endemic countries * Women who are pregnant or lactating * Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly * Ongoing corticosteroid use \>30 milligrams per day (mg/day) prednisone or equivalent

Locations (121)

Southern Cancer Center, PC

Mobile, Alabama, United States

Dr. Donald W. Hill, MD, FACP

Casa Grande, Arizona, United States

Highlands Oncology Group

Rogers, Arkansas, United States

Kaiser Permanente - Bellflower

Bellflower, California, United States

Bay Area Cancer Research Group, LLC

Pleasant Hill, California, United States

Outcomes

Primary Outcomes

Number of Participants With Progressive Disease (PD) as Assessed by Independent Review Committee (IRC) or Death

PD was assessed by an IRC according to the modified response criteria for indolent Non-Hodgkin's Lymphoma (iNHL) (Modified Cheson et al, 2007). PD was defined as appearance of any new lesion more than 1.5 centimeters (cm) in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50 percent (%) increase from nadir in the sum of product diameter (SPD) of any previously involved nodes, or in a single involved node, or the size of other lesions (example: splenic or hepatic nodules). To be considered PD, a lymph node with a diameter of the short axis of less than (\<) 1.0 cm must increase by greater than or equal to (≥) 50% and to a size of 1.5 multiplied by 1.5 cm or more than 1.5 cm in the long axis; at least a 50% increase in the longest diameter of any single previously identified node greater than (\>) 1 cm in its short axis.

Time frame: Baseline until PD or death, whichever occurred first (assessed at baseline, 14 days prior to Cycle [Cy] 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1, then every 3 months up to 2 years and every 6 months for next 2 years [up to 4.5 years overall])

Progression-Free Survival (PFS) as Assessed by IRC

PFS was defined as the time from randomization to the first occurrence of PD or death as assessed by an IRC according to the modified response criteria for iNHL (Modified Cheson et al, 2007). PD was defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be PD, a lymph node with a diameter of the short axis of \<1.0 cm must increase by ≥ 50% and to a size of 1.5 multiplied by 1.5 cm or more than 1.5 cm in the long axis; at least a 50% increase in the longest diameter of any single previously identified node \>1 cm in its short axis. PFS was estimated using Kaplan-Meier method and 95% confidence interval (CI) for median was computed using the method of Brookmeyer and Crowley.

Time frame: Baseline until PD or death, whichever occurred first (assessed at baseline, 14 days prior to Cy 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1, then every 3 months up to 2 years and every 6 months for next 2 years [up to 4.5 years overall])

Secondary Outcomes

Number of Participants With PD or Death as Assessed by Investigator

PD was assessed by an investigator according to the modified response criteria for iNHL (Modified Cheson et al, 2007). PD was defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be considered PD, a lymph node with a diameter of the short axis of \<1.0 cm must increase by ≥ 50% and to a size of 1.5 multiplied by 1.5 cm or more than 1.5 cm in the long axis; at least a 50% increase in the longest diameter of any single previously identified node \>1 cm in its short axis.

Time frame: Baseline until PD or death, whichever occurred first (up to 8.5 years overall))

PFS as Assessed by Investigator

PFS was defined as the time from randomization to the first occurrence of PD as assessed by an investigator according to the modified response criteria for iNHL (Modified Cheson et al, 2007), or death from any cause on study. PD was defined as appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be considered PD, a lymph node with a diameter of the short axis of \<1.0 cm must increase by ≥ 50% and to a size of 1.5 multiplied by 1.5 cm or more than 1.5 cm in the long axis; at least a 50% increase in the longest diameter of any single previously identified node \>1 cm in its short axis. PFS was estimated using Kaplan-Meier method and 95% CI for median was computed using the method of Brookmeyer and Crowley.

Time frame: Baseline until PD or death, whichever occurred first (up to 8.5 years overall)

Percentage of Participants With Objective Response as Assessed by IRC

Objective response was defined as having CR or PR as assessed according to the modified response criteria for iNHL (Modified Cheson et al, 2007). CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in the size of the other nodes, liver, or spleen; with the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. IRC review was performed up clinical cutoff date of to 1 May 2015.

Percentage of Participants With Objective Response as Assessed by Investigator

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 8.5 years)

Percentage of Participants With Best Overall Response (BOR) as Assessed by IRC

BOR observed during assessment period according to modified response criteria for iNHL (Modified Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease \& disease-related symptoms if present prior to therapy, PR: at least 50% regression of measurable disease compared to tumors measured by baseline scan \& no new sites; no increase in size of other nodes, liver, or spleen; with exception of splenic \& hepatic nodules, involvement of other organs is usually assessable \& no measurable disease should be present, SD: Failing to attain criteria needed for a CR/PR, but not fulfilling those for PD, PD: appearance of any new lesion \>1.5 cm in any axis during or at end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in SPD of any previously involved nodes, or in single involved node, or size of other lesions (e.g., splenic or hepatic nodules). IRC review was performed up clinical cutoff date of to 1 May 2015.

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 5 years)

Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator

BOR: best response for a participant, observed during assessment period according to modified response criteria for iNHL (Modified Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, PR: at least 50% regression of measurable disease compared to tumors measured by baseline scan and no new sites; no increase in size of other nodes, liver, or spleen; with exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present, SD: Failing to attain the criteria needed for a CR or PR, but not fulfilling those for PD, PD: appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 8.5 years)

Percentage of Participants With BOR at the End of Induction Treatment as Assessed by IRC

BOR observed during assessment period according to modified response criteria for iNHL (Modified Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease \& disease-related symptoms if present prior to therapy, PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan \& no new sites; no increase in size of other nodes, liver or spleen; with exception of splenic \& hepatic nodules, involvement of other organs is usually assessable \& no measurable disease should be present, SD: Failing to attain criteria needed for a CR/PR, but not fulfilling those for PD, PD: appearance of any new lesion \>1.5 cm in any axis during or at end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or size of other lesions (e.g., splenic/hepatic nodules). IRC review was performed up clinical cutoff date of to 1 May 2015.

Time frame: Baseline until end of induction treatment (assessed at baseline, 14 days prior to Cy 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1)

Percentage of Participants With BOR at the End of Induction Treatment as Assessed by Investigator

BOR: best response for a participant, observed during assessment period according to modified response criteria for iNHL (Modified Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites; no increase in size of other nodes, liver, or spleen; with exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present, SD: Failing to attain criteria needed for a CR or PR, but not fulfilling those for PD, PD: appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic nodules).

Time frame: Baseline until end of induction treatment (assessed at baseline, 14 days prior to Cy 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1)

Percentage of Participants With Objective Response at the End of Induction Treatment as Assessed by IRC

Time frame: Baseline until end of induction treatment (assessed at baseline, 14 days prior to Cy 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1)

Percentage of Participants With Objective Response at the End of Induction Treatment as Assessed by Investigator

Time frame: Baseline until end of induction treatment (assessed at baseline, 14 days prior to Cy 4 Day 1 [1 Cy=28days], 28-42 days after Cy 6 Day 1)

Duration of Response (DoR) as Assessed by IRC

DoR: time from first objective response of CR/PR to first occurrence of PD/relapse/death from any cause. CR: Complete disappearance of all detectable evidence of disease \& disease-related symptoms if present before therapy; liver, spleen returned to normal size; if bone marrow involved by lymphoma before treatment, infiltrate must be cleared on repeat bone marrow biopsy. PR: at least 50% measurable disease regressed vs. to baseline scan and no new sites; no increase in size of other nodes/liver/spleen, exception: splenic, hepatic nodules; other organs involved is usually assessable; no measurable disease present. PD: any new lesion \>1.5 cm in any axis appear during or at end of therapy, even if other lesions are decreasing in size; at least 50% increase from nadir in SPD of any previously involved nodes, or in single involved node, or size of other lesions. DoR estimated using Kaplan-Meier method. IRC review performed up to clinical cutoff date 1 May 2015.

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 5 years)

Duration of Response (DoR) as Assessed by Investigator

DoR: time from first objective response of CR/PR to first occurrence of PD/relapse/death from any cause. CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy; liver, spleen returned to normal size (if enlarged at baseline); if bone marrow was involved by lymphoma prior to treatment, infiltrate must have cleared on repeat bone marrow biopsy. PR: at least 50% regression of measurable disease compared to baseline scan and no new sites; no increase in size of other nodes, liver, or spleen; with exception of splenic, hepatic nodules; involvement of other organs is usually assessable; no presence of measurable disease. PD: appearance of any new lesion \>1.5 cm in any axis during or at end of therapy, even if other lesions are decreasing in size; at least 50% increase from nadir in SPD of any previously involved nodes, or in single involved node, or size of other lesions. DoR was estimated using Kaplan-Meier method.

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 8.5 years)

Disease-Free Survival (DFS) in Participants With CR as Assessed by IRC

DFS was defined as the time from the first occurrence of a documented CR until progression on the basis of the IRC assessments (as per modified response criteria for iNHL \[Modified Cheson et al, 2007\]) or death from any cause on study. CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present prior to therapy, liver and spleen have returned to normal size (if enlarged at baseline), If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PD: appearance of any new lesion \>1.5 cm in any axis during or at end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in SPD of any previously involved nodes, or in a single involved node, or size of other lesions. DFS was estimated using Kaplan-Meier method. IRC review was performed up clinical cutoff date of to 1 May 2015.

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 5 years)

Disease-Free Survival (DFS) in Participants With CR as Assessed by Investigator

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 8.5 years)

Event-free Survival (EFS) as Assessed by IRC

EFS was defined as the time between the date of randomization and the date of PD/relapse based on IRC assessments (as per modified response criteria for iNHL \[Modified Cheson et al, 2007\]), death from any cause on study, or start of a new anti-lymphoma therapy. PD: appearance of any new lesion \>1.5 cm in any axis during or at end of therapy, even if other lesions are decreasing in size; at least a 50% increase from nadir in SPD of any previously involved nodes, or in a single involved node, or size of other lesions. EFS was estimated using Kaplan-Meier method. IRC review was performed up clinical cutoff date of to 1 May 2015.

Time frame: Baseline until PD or death, whichever occurred first (up to approximately 5 years)

Change From Baseline (CFB) in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)-Physical Well Being Sub-scale Score

The FACT-Lym measures 5 sub-scales which includes 42 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Physical Well-being sub-scale includes 7 items measured on 0-4 point scale. The total score for physical well-being sub-scale is sum of each 7 items (range: 0-28). Higher scores indicate a better participant-reported outcome (PRO)/quality of life (QoL). In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

Time frame: Baseline, Day 1 of Cycles 3, 4, 5, End of induction treatment (up to Month 6); Follow-up Months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, Final Follow-up (up to 2 years after end of induction); Extension follow-up Months 6, 18 and 24

CFB in FACT-Lym-Social/Family Well-being Sub-scale Score

The FACT-Lym measures 5 sub-scales which includes 42 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Social/family Well-being sub-scale includes 7 items measured on 0-4 point scale. The total score for social/family well-being sub-scale is sum of each 7 items (range: 0-28). Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in FACT-Lym-Emotional Well-Being Sub-scale Score

The FACT-Lym measures 5 sub-scales which includes 42 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Emotional Well-being sub-scale includes 6 items measured on 0-4 point scale. The total score for emotional well-being sub-scale is sum of each 6 items (range: 0-24). Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in FACT-Lym-Functional Well-Being Sub-scale Score

The FACT-Lym measures 5 sub-scales which includes 42 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Functional Well-being sub-scale includes 7 items measured on 0-4 point scale. The total score for functional well-being sub-scale is sum of each 7 items (range: 0-28). Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in FACT-Lym-Lymphoma Sub-scale Score

The FACT-Lym measures 5 sub-scales which includes 42 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Lymphoma scale includes 15 items measured on 0-4 point scale. The total score for lymphoma sub-scale is sum of each 15 items (range: 0-60). Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in Euro Quality of Life 5 Dimension (EuroQoL-5D/EQ-5D) - Health State Profile Utility Score During Induction Phase

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state ("confined to bed"). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction). For 'Obinutuzumab + Bendamustine' arm, participants who had their follow-up Month 2 and 4 visits before start of maintenance treatment were reported in induction phase results under "CFB at Follow-up Month 2" and "CFB at Follow-up Month 4" categories.

Time frame: Baseline, Day 1 of Cycles 3, 4, 5, End of induction treatment (up to Month 6); Follow-up Months 2, 4 and 14

CFB in EuroQol 5D (EQ-5D) - Health State Profile Utility Score During Maintenance Phase

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state ("confined to bed"). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. Data for this outcome was planned to be reported only for 'Obinutuzumab + Bendamustine' arm. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction). Follow-up months were during maintenance phase.

Time frame: Baseline, Follow-up Months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, Final follow-up (up to 2 years after end of induction) (End of induction = up to Month 6)

CFB in EQ-5D Visual Analogue Scale (VAS) Score During Induction Phase

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 millimeter (mm) (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction). For 'Obinutuzumab + Bendamustine' arm, participants who had their follow-up Month 2 and 4 visits before start of maintenance treatment were reported in induction phase results under "CFB at Follow-up Month 2" and "CFB at Follow-up Month 4" categories.

Time frame: Baseline, Day 1 of Cycles 3, 4, 5, End of induction treatment (up to Month 6); Follow-up Months 2, 4 and 14

CFB in EQ-5D VAS Score During Maintenance Phase

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. Data for this outcome was planned to be reported only for 'Obinutuzumab + Bendamustine' arm. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction). Follow-up months were during maintenance phase.

Time frame: Baseline, Follow-up Months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, Final Follow-up (up to 2 years after end of induction) (end of induction = up to Month 6)

CFB in Functional Assessment of Cancer Therapy - Generic (FACT-G) Score

The FACT-G is the sum of 4 sub-scales (physical, social, emotional and functional well-being) of FACT-Lym which includes total 27 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-108. Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in FACT-Lym Trial Outcome Index (TOI)

TOI is the sum of 3 sub-scales (physical well-being, functional well-being, and Lymphoma sub-scale) of FACT-Lym which includes total 29 items; responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-116. Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

CFB in FACT-Lym Total Score

FACT-Lym total score is the sum of physical well-being score (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and Lymphoma sub-scale (15 items); responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-168. Higher scores indicate a better PRO/QoL. In timeframe, follow-up months represents months after end of induction (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

Time to Deterioration of FACT-Lym TOI

The median time, in month, from date of randomization until a clinically meaningful decline from baseline in TOI or death, whichever occurred first. TOI: sum of physical well-being score,functional well-being score, and Lymphoma sub-scale of FACT-Lym; total 29 items, responses to each item range from 0, "Not at all" to 4, "Very much". Total score ranges from 0-116. Higher scores indicate a better PRO/QoL. A clinically meaningful decline in TOI score was defined as at least a 6 point decline from baseline. Time to deterioration was estimated using Kaplan-Meier method and 95% CI for median was computed using the method of Brookmeyer and Crowley. In timeframe, follow-up months represents months after end of induction (EOI) (e.g. Follow-up Month 2 is 2 months after end of induction) and extension follow-up months represents months after end of 2 years normal follow-up (e.g. extension follow-up Month 6 is 6 months after end of normal 2 year follow-up).

Time frame: Baseline up to approximately 8.5 years

Percentage of Participants With Definitive Improvement (DI) From Baseline in FACT-Lym Instrument Scores

FACT-Lym: 42-items in 5 subscales. Responses to each item range from 0 (Not at all) to 4 (Very much). FACT-Lym Lymphoma subscale includes 15 items (total score range = 0-60). FACT-Lym TOI is sum of 3 subscales (physical well-being, functional well-being, lymphoma subscale) and includes 29 items (total score range = 0-116). FACT-Lym total score is sum of 42 items (total score ranges from 0-168). For all above, higher scores indicate a better PRO/QoL. DI from baseline: at least 3 point increase from baseline in FACT-Lym Lymphoma subscale; at least 6 point increase from baseline in FACT Lym TOI; at least 7 point increase from baseline in FACT Lym total scores. In timeframe, follow-up months represents months after EOI (e.g. Follow-up Month 2 is 2 months after EOI; EOI = up to Month 6).

Time frame: Baseline, Cycle 5 Day 1 (C5D1) (Cycle length = 28 days), Follow-up Months 6 (FUM6), 12 (FUM12), 18 (FUM18), 24 (FUM24), Extension Follow Up Month 6 (Extension FUM6)