A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination With Polatuzumab Vedotin and Lenalidomide in Patients With Relapsed or Refractory Follicular Lymphoma and Rituximab in Combination With Polatuzumab Vedotin and Lenalidomide in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 114
- 试验地点
- 28
- 主要终点
- Percentage of Participants With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This study will evaluate the safety, efficacy, and pharmacokinetics of induction treatment with obinutuzumab, polatuzumab vedotin, and lenalidomide in participants with relapsed or refractory (R/R) follicular lymphoma (FL) and rituximab in combination with polatuzumab vedotin and lenalidomide in participants with R/R diffuse large B-cell lymphoma (DLBCL), followed by post-induction treatment with obinutuzumab in combination with lenalidomide in participants with FL who achieve a complete response (CR), partial response (PR), or stable disease (SD) at end of induction (EOI) and post-induction treatment with rituximab plus lenalidomide in participants with DLBCL who achieve a CR or PR at EOI.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Age greater than or equal to (>/=) 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •For obinutuzumab in combination with polatuzumab vedotin and lenalidomide (G + Pola + Len) treatment group: R/R FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and for which no other more appropriate treatment option exists as determined by the investigator
- •For rituximab in combination with polatuzumab vedotin and lenalidomide (R + Pola + Len) treatment group: R/R DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in patients who are not eligible for autologous stem-cell transplantation or who have experienced disease progression following treatment with high-dose chemotherapy plus autologous stem-cell transplantation
- •Histologically documented CD20-positive B-cell lymphoma as determined by the local laboratory
- •fluorodeoxyglucose (FDG)-avid lymphoma (i.e., positron emission tomography (PET)-positive lymphoma)
- •At least one bi-dimensionally measurable lesion
- •Agreement to remain abstinent or use adequate contraception, among women or men of childbearing potential
排除标准
- •Grade 3b follicular lymphoma
- •History of transformation of indolent disease to diffuse large B-cell lymphoma (DLBCL)
- •Known CD20-negative status at relapse or progression
- •Central nervous system (CNS) lymphoma or leptomeningeal infiltration
- •Prior allogeneic stem-cell transplantation (SCT), or autologous SCT within 100 days prior to Day 1 of Cycle 1
- •Current use of systemic immunosuppressant(s), or prior anti-cancer therapy to include: lenalidomide, fludarabine, or alemtuzumab within 12 months; radioimmunoconjugate within 12 weeks; mAb or antibody-drug conjugate within 4 weeks; or radiotherapy/chemotherapy/hormone therapy/targeted small-molecule therapy within 2 weeks prior to Day 1 of Cycle 1
- •Active infection
- •Positive for human immunodeficiency virus (HIV) or hepatitis B or C
- •Receipt of a live virus vaccine within 28 days prior to Day 1 of Cycle 1
- •Poor hematologic, renal, or hepatic function
- •Pregnant or lactating women
- •Life expectancy less than (<) 3 months
研究组 & 干预措施
Dose-escalation Cohort: FL
Participants with R/R FL will receive 6 months of induction treatment with polatuzumab vedotin and lenalidomide at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and lenalidomide when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 24-month maintenance regimen consisting of lenalidomide and obinutuzumab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Lenalidomide (Drug)
Dose-escalation Cohort: FL
Participants with R/R FL will receive 6 months of induction treatment with polatuzumab vedotin and lenalidomide at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and lenalidomide when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 24-month maintenance regimen consisting of lenalidomide and obinutuzumab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Obinutuzumab (Drug)
Dose-escalation Cohort: FL
Participants with R/R FL will receive 6 months of induction treatment with polatuzumab vedotin and lenalidomide at escalating doses to identify the recommended Phase 2 dose (RP2D) for polatuzumab vedotin and lenalidomide when combined with a fixed dose of obinutuzumab. Those who achieve CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 24-month maintenance regimen consisting of lenalidomide and obinutuzumab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Polatuzumab Vedotin (Drug)
Dose-escalation Cohort: DLBCL
Participants with R/R DLBCL will receive 6 months of induction treatment with fixed dose of polatuzumab vedotin and rituximab along with dose escalating lenalidomide. Lenalidomide will be administered at escalating doses to identify the recommended Phase 2 dose (RP2D) for lenalidomide. Those who achieve CR and PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 6-month consolidation regimen consisting of lenalidomide and rituximab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Lenalidomide (Drug)
Dose-escalation Cohort: DLBCL
Participants with R/R DLBCL will receive 6 months of induction treatment with fixed dose of polatuzumab vedotin and rituximab along with dose escalating lenalidomide. Lenalidomide will be administered at escalating doses to identify the recommended Phase 2 dose (RP2D) for lenalidomide. Those who achieve CR and PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 6-month consolidation regimen consisting of lenalidomide and rituximab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Polatuzumab Vedotin (Drug)
Dose-escalation Cohort: DLBCL
Participants with R/R DLBCL will receive 6 months of induction treatment with fixed dose of polatuzumab vedotin and rituximab along with dose escalating lenalidomide. Lenalidomide will be administered at escalating doses to identify the recommended Phase 2 dose (RP2D) for lenalidomide. Those who achieve CR and PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will be eligible to receive a 6-month consolidation regimen consisting of lenalidomide and rituximab, to be initiated 8 weeks after Day 1 of Cycle 6 (induction cycle).
干预措施: Rituximab (Drug)
Expansion Cohort: FL
Participants with R/R FL who received induction treatment with polatuzumab vedotin and lenalidomide, in addition to obinutuzumab and achieved CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 24-months maintenance regimen consisting of lenalidomide and obinutuzumab for first 12 months followed by obinutuzumab treatment for next 12 months. Post-induction therapy will start 8 weeks after Cycle 6 Day 1.
干预措施: Lenalidomide (Drug)
Expansion Cohort: FL
Participants with R/R FL who received induction treatment with polatuzumab vedotin and lenalidomide, in addition to obinutuzumab and achieved CR, PR, or SD at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 24-months maintenance regimen consisting of lenalidomide and obinutuzumab for first 12 months followed by obinutuzumab treatment for next 12 months. Post-induction therapy will start 8 weeks after Cycle 6 Day 1.
干预措施: Obinutuzumab (Drug)
Expansion Cohort: DLBCL
Participants with R/R DLBCL who received induction treatment with polatuzumab vedotin and lenalidomide in addition to rituximab and achieved CR or PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 6-month consolidation regimen consisting of lenalidomide and rituximab. Post-induction therapy will start 8 weeks after Cycle 6 Day 1.
干预措施: Lenalidomide (Drug)
Expansion Cohort: DLBCL
Participants with R/R DLBCL who received induction treatment with polatuzumab vedotin and lenalidomide in addition to rituximab and achieved CR or PR at the EOI (6-8 weeks after Day 1 of Cycle 6) will receive a 6-month consolidation regimen consisting of lenalidomide and rituximab. Post-induction therapy will start 8 weeks after Cycle 6 Day 1.
干预措施: Rituximab (Drug)
结局指标
主要结局
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Day 1 of Cycle 1 to Day 1 of Cycle 2 (1 cycle = 28 days) in dose-escalation phase
A DLT was defined as any one of the following toxicities occurring during the first cycle of treatment and assessed by the investigator as related to study treatment: Any adverse event of any grade that lead to a delay of \> 14 days in the start of the next treatment cycle, Grade 3 or 4 non-hematologic adverse events with few exceptions; increase in hepatic transaminase \> 3 x baseline and an increase in direct bilirubin \> 2 x upper limits of normal (ULN), without any findings of cholestasis or jaundice, or signs of hepatic dysfunction, and in the absence of other contributory factors; hematologic adverse events that met a few protocol specified criteria. DLTs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Percentages have been rounded off to the first decimal point.
Percentage of Participants With Adverse Events (AEs)
时间窗: From study start up to end of study (Up to a maximum of 69 months)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Percentages have been rounded off to the first decimal point.
Percentage of Participants With Complete Response (CR) at End of Induction (EOI), Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography (PET) and Computed Tomography (CT) Scans
时间窗: 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks)
CR at EOI was assessed by IRC according to Modified Lugano Response Criteria (MLRC). Per MLRC, CR based on PET-CT was defined as complete metabolic response (MR) in lymph nodes and extralymphatic sites (ELS) with a score of 1, 2, or 3 with or without residual mass, on 5-point scale (5PS) where 1=no uptake above background; 2=uptake ≤ mediastinum; 3=uptake \> mediastinum but ≤ liver; 4=uptake moderately \> liver; 5=uptake markedly higher than liver and/or new lesions no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. Bone marrow is normal by morphology; if indeterminate, immunohistochemistry (IHC) negative. Analysis was done 6-8 weeks after Cycle 6, Day 1 (cycle=28 days). Percentages have been rounded off to the first decimal point.
次要结局
- Percentage of Participants With CR at EOI, Determined by the IRC on the Basis of CT Scans Alone(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Percentage of Participants With Objective Response (OR) at EOI, Determined by the IRC on the Basis of PET-CT Scans(6 to 8 weeks after Day 1 of Cycle 6 (cycle=28 days) (up to approximately 28 weeks))
- Percentage of Participants With CR at EOI, Determined by the Investigator on the Basis of PET-CT Scans(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Percentage of Participants With CR at EOI, Determined by Investigator on the Basis of CT Scans Alone(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Percentage of Participants With Objective Response at EOI, Determined by Investigator on the Basis of PET-CT Scans(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Percentage of Participants With Objective Response at EOI, Determined by the IRC on the Basis of CT Scans Alone(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Percentage of Participants With Best Response of CR or PR, Determined by the Investigator on the Basis of CT Scans Alone(Up to every 6 months until disease progression, unacceptable toxicity or study completion (up to approximately 69 months))
- Serum Concentration of Polatuzumab Vedotin Analyte: Total Antibody(Day 1 of Cycles 1, 2, 4: predose (1 cycle = 28 days), Day 120 post last dose; one year post last dose; study drug discontinuation; unscheduled visit: predose (up to approximately 69 months))
- Observed Plasma Lenalidomide Concentration(Day 1 Cycle 1: predose and 2 hours (hr) post-dose; Day 15 Cycle 1: predose, 0.5hr, 1hr, 2hr, 4hr, 8hr post-dose; Day 1 Cycle 6: 2hr post-dose; unscheduled visits: 2hr post-dose (1 cycle = 28 days) (up to approximately 69 months))
- Percentage of Participants With Objective Response, Determined by the Investigator on the Basis of CT Scans Alone(6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks))
- Observed Serum Rituximab Concentration(Day 1 of Cycles 1, 2, 4, 6: predose and 30 mins post-dose (1 cycle = 28 days) (up to approximately 69 months))
- Plasma Concentration of Polatuzumab Vedotin Analyte: Antibody-conjugated MMAE (acMMAE)(Day 1 of Cycles 1, 2, 4: predose and 30 mins post-dose; Days 8 and 15 of Cycle 1; Day 1 of Cycle 6: predose, study drug discontinuation; unscheduled visit: predose (1 cycle = 28 days) (up to approximately 69 months))
- Observed Serum Obinutuzumab Concentration(Day 1 of Cycles 1, 2, 4 & 6: predose & 30 mins postdose; EOI: predose; Day 1 of Maintenance Months 1,7, 13, 19;Day 120 post last dose; one year post last dose; study drug discontinuation; unscheduled visit: predose (up to approximately 69 months))
- Number of Participants With Human Anti-human Antibodies (HAHAs) to Obinutuzumab(Baseline up to approximately 2 years after last dose (up to approximately 69 months))
- Number of Participants With Human Anti-chimeric Antibodies (HACAs) to Rituximab(Baseline up to approximately 2 years after last dose (up to approximately 69 months))
- Number of Participants With Anti-therapeutic Antibodies (ATAs) to Polatuzumab Vedotin(Baseline up to approx. 2 years after the last dose of polatuzumab vedotin (up to approximately 30 months))
- Plasma Concentration of Polatuzumab Vedotin Analyte: Unconjugated MMAE(Day 1 of Cycles 1, 2, 4: predose and 30 mins post-dose; Days 8 and 15 of Cycle 1 and Day 1 of Cycle 6: predose, study drug discontinuation; unscheduled visit: predose (1 cycle = 28 days) (up to approximately 69 months))