An Open-Label, Multicenter, Randomized, Phase III Study to Investigate the Efficacy and Safety of Bendamustine Compared With Bendamustine+RO5072759 (GA101) in Patients With Rituximab-Refractory, Indolent Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 413
- 试验地点
- 119
- 主要终点
- Number of Participants With Progressive Disease (PD) as Assessed by Independent Review Committee (IRC) or Death
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Bendamustine Alone
Participants will receive bendamustine 120 milligrams per meter square (mg/m^2) Intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for up to six cycles.
干预措施: Bendamustine (Drug)
Obinutuzumab + Bendamustine
Induction phase: Participants will receive bendamustine 90 mg/m^2 IV on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2-6 (28-day cycles) for the first 10 participants and on Days 1 and 2 of each 28-day cycle for Cycles 1-6 for remaining participants. Participants will also receive obinutuzumab 1000 mg IV infusion on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2-6.
Maintenance phase: Participants with complete response (CR), partial response (PR) or stable response (SD) then will receive obinutuzumab 1000 mg IV infusion every 2 months until disease progression or for up to 2 years (whichever occurs first).
干预措施: Obinutuzumab (Drug)
Obinutuzumab + Bendamustine
Induction phase: Participants will receive bendamustine 90 mg/m^2 IV on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2-6 (28-day cycles) for the first 10 participants and on Days 1 and 2 of each 28-day cycle for Cycles 1-6 for remaining participants. Participants will also receive obinutuzumab 1000 mg IV infusion on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2-6.
Maintenance phase: Participants with complete response (CR), partial response (PR) or stable response (SD) then will receive obinutuzumab 1000 mg IV infusion every 2 months until disease progression or for up to 2 years (whichever occurs first).
干预措施: Bendamustine (Drug)
结局指标
主要结局
Number of Participants With Progressive Disease (PD) as Assessed by Independent Review Committee (IRC) or Death
时间窗: 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])
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.
Progression-Free Survival (PFS) as Assessed by IRC
时间窗: 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])
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.
次要结局
- Percentage of Participants With Objective Response as Assessed by Investigator(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(Baseline until PD or death, whichever occurred first (up to approximately 5 years))
- Number of Participants With PD or Death as Assessed by Investigator(Baseline until PD or death, whichever occurred first (up to 8.5 years overall)))
- PFS as Assessed by Investigator(Baseline until PD or death, whichever occurred first (up to 8.5 years overall))
- Percentage of Participants With Objective Response as Assessed by IRC(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(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(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(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(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(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(Baseline until PD or death, whichever occurred first (up to approximately 5 years))
- Duration of Response (DoR) as Assessed by Investigator(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(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(Baseline until PD or death, whichever occurred first (up to approximately 8.5 years))
- Event-free Survival (EFS) as Assessed by IRC(Baseline until PD or death, whichever occurred first (up to approximately 5 years))
- Percentage of Participants Who Died(Baseline until death (up to 8.5 years overall))
- Overall Survival (OS)(Baseline until death (up to 8.5 years overall))
- Percentage of Participants With Definitive Improvement (DI) From Baseline in FACT-Lym Instrument Scores(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))
- Change From Baseline (CFB) in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)-Physical Well Being Sub-scale Score(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(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-Emotional Well-Being Sub-scale Score(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-Functional Well-Being Sub-scale Score(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-Lymphoma Sub-scale Score(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 Euro Quality of Life 5 Dimension (EuroQoL-5D/EQ-5D) - Health State Profile Utility Score During Induction Phase(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(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(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(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(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 Trial Outcome Index (TOI)(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 Total Score(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)
- Time to Deterioration of FACT-Lym TOI(Baseline up to approximately 8.5 years)