A Multicenter, Phase III, Open-Label, Randomized Study in Previously Untreated Patients With Advanced Indolent Non-Hodgkin's Lymphoma Evaluating the Benefit of GA101 (RO5072759) Plus Chemotherapy Compared With Rituximab Plus Chemotherapy Followed by GA101 or Rituximab Maintenance Therapy in Responders
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,401
- 试验地点
- 183
- 主要终点
- Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed
研究概览
简要总结
This open-label, randomized study will assess the efficacy and safety of obinutuzumab (RO5072759) in combination with chemotherapy compared to rituximab (MabThera/Rituxan) with chemotherapy followed by obinutuzumab or rituximab maintenance in participants with untreated advanced indolent non-Hodgkin's lymphoma. After the end of the induction period, participants achieving response (Complete response [CR] or partial response [PR]) will undergo a maintenance period continuing on the randomized antibody treatment alone every 2 months until disease progression for a total of 2 years. Anticipated time on study treatment is up to approximately 2.5 years. After maintenance or observation, participants will be followed for 5 years until progression. After progression, participants will be followed for new anti-lymphoma therapy and overall survival until the end of the study.
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
- •Cluster of differentiation 20 (CD20)-positive indolent B-cell non-Hodgkin's lymphoma (follicular lymphoma or splenic, nodal or extranodal marginal zone lymphoma)
- •Stage III or IV disease, or Stage II bulky disease (defined as tumor diameter greater than or equal to [>/=] 7 centimeters [cm])
- •For participants with follicular lymphoma: requirement for treatment according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria
- •For participants with symptomatic splenic, nodal, or non-gastric extranodal marginal zone lymphoma: disease that is de novo or has relapsed following local therapy (i.e. surgery or radiotherapy) and requires therapy as assessed by the investigator
- •At least one bi-dimensionally measurable lesion (greater than [>] 2 cm in its largest dimension by computed tomography [CT] scan or magnetic resonance imaging [MRI])
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- •Adequate hematologic function
排除标准
- •Central nervous system lymphoma, leptomeningeal lymphoma, or histological evidence of transformation to a high-grade or diffuse large B-cell lymphoma
- •Grade 3b follicular lymphoma, small lymphocytic lymphoma or Waldenström's macroglobulinaemia
- •Ann Arbor Stage I disease
- •History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
- •Known hypersensitivity to any of the study drugs or sensitivity to murine products, or history of sensitivity to mannitol
- •For participants with follicular lymphoma: prior treatment for non-Hodgkin's lymphoma with chemotherapy, immunotherapy, or radiotherapy
- •For participants with non-follicular lymphoma: prior treatment with chemotherapy or immunotherapy
- •Regular treatment with corticosteroids during the 4 weeks prior to the start of Cycle 1
- •Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results
- •For participants who will be receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP): left ventricular ejection fraction (LVEF) less than (<) 50% by multiple-gated acquisition (MUGA) scan or echocardiogram
- •History of prior other malignancy with the exception of curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study
- •Known active infection, or major episode of infection within 4 week prior to the start of Cycle 1
- •Vaccination with a live vaccine within 28 days prior to randomization
- •Recent major surgery (within 4 weeks prior to start of Cycle 1), other than for diagnosis
- •Abnormal laboratory values as defined by protocol for creatinine, creatinine clearance, aspartate transaminase (AST) or alanine transaminase (ALT), total bilirubin, international normalized ration (INR), partial thromboplastin time (PTT) or activated partial thromboplastin time (aPPT), unless these abnormalities are due to underlying lymphoma
- •Positive test results for human immunodeficiency virus (HIV), human T-lymphotropic virus 1 (HTLV1), hepatitis C or chronic hepatitis B
- •Pregnant or lactating women
- •Life expectancy <12 months
- •Participation in another clinical trial with drug intervention within 28 days prior to start of Cycle 1 and during study
研究组 & 干预措施
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Cyclophosphamide (Drug)
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Doxorubicin (Drug)
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Vincristine (Drug)
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Prednisone (Drug)
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Bendamustine (Drug)
Rituximab+Chemotherapy
Participants will receive either 8 cycles of rituximab along with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (21-day cycle) or 8 cycles of rituximab along with 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) (21-day cycles) or 6 cycles of rituximab along with 6 cycles of bendamustine (28-day cycle) during the induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive rituximab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Rituximab (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Obinutuzumab (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Cyclophosphamide (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Doxorubicin (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Vincristine (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Prednisone (Drug)
Obinutuzumab+Chemotherapy
Participants will receive either 8 cycles of obinutuzumab along with 6 cycles of CHOP (21-day cycle) or 8 cycles of obinutuzumab along with 8 cycles of CVP (21-day cycles) or 6 cycles of obinutuzumab along with 6 cycles of bendamustine (28-day cycle) during induction period. The induction period will be followed by either a maintenance or observation period for responders or non-responders, respectively. Responders will receive obinutuzumab monotherapy every 2 months for 2 years during the maintenance period. Non-responders will receive no protocol specified treatment during the 2-year observation period. Finally, participants will be followed during a 5-year follow-up period. The chemotherapy regimen (CHOP or CVP or bendamustine) for individual participant will be chosen by the site prior to initiation of the study.
干预措施: Bendamustine (Drug)
结局指标
主要结局
Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed
时间窗: Baseline up to data cut-off (up to approximately 4 years and 7 months)
Progression-free survival in participants with follicular lymphoma was defined as the time from randomization until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or \>/=50% increase in any node \> 1 centimeter (cm) or \>/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion \> 1.5 cm or \>/= 50% increase in any previously involved node with a diameter \</= 1 cm such that it is now \>1.5 cm. Tumor measurements were obtained by computed tomography (CT) or magnetic resonance imaging (MRI).
次要结局
- Progression-Free Survival in the Follicular Lymphoma Population, Investigator-Assessed(Baseline up to final analysis (up to 10 years))
- Progression-Free Survival in the Overall Study Population, Investigator-Assessed(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Progression-Free Survival (Follicular Lymphoma Population), IRC-Assessed(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Progression-Free Survival (Overall Study Population), Assessed by Independent Review Committee (IRC)(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Overall Survival (Overall Study Population)(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Overall Response (Follicular Lymphoma Population), Investigator-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Overall Response (Overall Study Population), Investigator-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Complete Response (Follicular Lymphoma Population), Investigator-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Complete Response (Overall Study Population), Investigator-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Overall Response (Follicular Lymphoma Population), IRC-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Overall Response (Overall Study Population), IRC-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Complete Response (Follicular Lymphoma Population), IRC-Assessed(Baseline up to end of induction period (up to approximately 7 months))
- Complete Response (Overall Study Population), IRC-Assessed(Baseline up to end of induction period (up to approximately 7 months)])
- Overall Survival (Follicular Lymphoma Population)(Baseline up to 10 years)
- Event-Free Survival (Follicular Lymphoma Population)(Baseline up to 10 years)
- Event-Free Survival (Overall Study Population)(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Disease-Free Survival (Follicular Lymphoma Population)(From first occurrence of documented CR to data cut-off (up to approximately 5 years and 2 months))
- Disease-Free Survival (Overall Study Population)(From first occurrence of documented CR to data cut-off (up to approximately 5 years and 2 months))
- Duration of Response (DOR) (Follicular Lymphoma Population), Investigator-Assessed(From first occurrence of documented CR or PR to data cut-off (up to approximately 5 years and 2 months))
- Duration of Response (DOR) (Overall Study Population), Investigator-Assessed(From first occurrence of documented CR or PR to data cut-off (up to approximately 4 years and 7 months))
- Time to Next Anti-Lymphoma Treatment (Follicular Lymphoma Population)(Baseline up to 10 years)
- Time to Next Anti-Lymphoma Treatment (Overall Study Population)(Baseline up to data cut-off (up to approximately 5 years and 2 months))
- Percentage of Participants With Adverse Events(Baseline up to 10 years)
- Change From Baseline in All Domains of FACT-G (Follicular Lymphoma Population)(Baseline (Induction Cycle 1, Day 1), data cut-off (up to approximately 5 years and 2 months))
- Change From Baseline in FACT-Lym Total Outcome Index (TOI) Score (Follicular Lymphoma Population)(Baseline (Induction Cycle 1, Day 1), data cut-off (up to approximately 5 years and 2 months))
- Change From Baseline in FACT-Lym Individual Subscale Lymphoma Score (Follicular Population)(Baseline (Induction Cycle 1, Day 1), data cut-off (up to approximately 5 years and 2 months))
- Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Total Score (Follicular Population)(Baseline (Induction Cycle 1, Day 1), data cut-off (up to approximately 5 years and 2 months))
- Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Induction Phase(Induction: Cycle 1 Day 1 (Baseline), Cycle 3 Day 1, End of Induction (up to 7 months); Maintenance: 2, 12 months after Day 1 of last induction cycle, Follow-up: every year up to data cut-off (up to 5 years and 2 months))
- Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Maintenance/Observation Phase(Induction: Cycle 1 Day 1 (Baseline), Cycle 3 Day 1, End of Induction (up to 7 months); Maintenance: 2, 12 months after Day 1 of last induction cycle, Follow-up: every year up to data cut-off (up to 5 years and 2 months))
- Change From Baseline in Euro-Quality of Life-5 Dimensions (EQ-5D) Questionnaire Summary Score (Follicular Lymphoma Population) During Follow Up Phase(Induction: Cycle 1 Day 1 (Baseline), Cycle 3 Day 1, End of Induction (up to 7 months); Maintenance: 2, 12 after Day 1 of last induction cycle, Follow-up: every year for up to data cut-off (up to 5 years and 2 months))