A Phase Ib/II Study Evaluating the Safety and Efficacy of Obinutuzumab in Combination With Idasanutlin in Patients With Relapsed or Refractory Follicular Lymphoma and Obinutuzumab or Rituximab in Combination With Idasanutlin in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 25
- 试验地点
- 24
- 主要终点
- Percentage of Participants With Complete Response at the End of Induction, Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography and Computed Tomography (PET-CT) Scans Using Modified Lugano 2014 Criteria
研究概览
简要总结
This is a open-label, multicenter, non-randomized, study to evaluate the safety, efficacy, and pharmacokinetics of idasanutlin in combination with obinutuzumab in participants with R/R FL and rituximab in combination with idasanutlin in R/R DLBCL. The study will include an initial dose-escalation phase followed by an expansion phase. The dose-escalation phase is designed to determine the recommended phase 2 dose (RP2D) for idasanutlin in combination with obinutuzumab for FL and in combination with rituximab for DLBCL. The expansion phase is designed to further assess the safety and efficacy of obinutuzumab in combination with idasanutlin at the RP2D with the selected regimen in participants with R/R FL and of rituximab in combination with idasanutlin at the RP2D in participants with R/R DLBCL.
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
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Histologically documented cluster of differentiation (CD) 20-positive B-cell lymphoma classified as relapsed or refractory FL or DLBCL after treatment with at least two prior chemoimmunotherapy regimens that included an anti-CD20 monoclonal antibody (mAb) and for which no other more appropriate treatment option exists
- •At least one bidimensionally measurable lesion
- •Agreement to remain abstinent or use adequate contraception, among women or men of childbearing potential
排除标准
- •Known CD20-negative status at relapse or progression
- •Prior allogeneic stem cell transplantation (SCT), or autologous SCT within 100 days prior to Day 1 of Cycle 1
- •Current use of systemic corticosteroids greater than (>) 20 mg prednisone per day (or equivalent), or prior anti-cancer therapy to include: 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
- •Requirement for chronic anticoagulation
- •Central nervous system (CNS) disease
- •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
- •History of progressive multifocal leukoencephalopathy (PML)
研究组 & 干预措施
DLBCL Non-Bridging: Idasanutlin 100 mg + Obinutuzumab 1000 mg
Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 100 milligrams (mg) orally in combination with a fixed dose of obinutuzumab 1000 mg intravenously (IV) for 6 cycles (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
DLBCL Non-Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
DLBCL Non-Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
DLBCL Non-Bridging: Idasanutlin 200 mg + Obinutuzumab 1000 mg
Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 200 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
DLBCL Non-Bridging: Idasanutlin 200 mg + Obinutuzumab 1000 mg
Participants with diffuse large B-cell lymphoma (DLBCL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 200 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
DLBCL Bridging: Idasanutlin 150 mg + Rituximab 375 mg/m^2
Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 150 mg orally in combination with rituximab 375 milligrams per square meter of body surface area (mg/m^2) IV for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
DLBCL Bridging: Idasanutlin 150 mg + Rituximab 375 mg/m^2
Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 150 mg orally in combination with rituximab 375 milligrams per square meter of body surface area (mg/m^2) IV for 6 cycles (1 cycle = 28 days).
干预措施: Rituximab (Drug)
DLBCL Bridging: Idasanutlin 200 mg + Rituximab 375 mg/m^2
Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 200 mg orally in combination with rituximab 375 mg/m^2 IV for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
DLBCL Bridging: Idasanutlin 200 mg + Rituximab 375 mg/m^2
Participants with diffuse large B-cell lymphoma (DLBCL) in this bridging cohort received induction treatment with idasanutlin 200 mg orally in combination with rituximab 375 mg/m^2 IV for 6 cycles (1 cycle = 28 days).
干预措施: Rituximab (Drug)
FL Non-Bridging: Idasanutlin 100 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 100 milligrams (mg) orally in combination with a fixed dose of obinutuzumab 1000 mg intravenously (IV) for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
FL Non-Bridging: Idasanutlin 100 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 100 milligrams (mg) orally in combination with a fixed dose of obinutuzumab 1000 mg intravenously (IV) for 6 cycles (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
FL Non-Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
FL Non-Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this non-bridging dose-escalation cohort received induction treatment with idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for 6 cycles (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
FL Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this bridging cohort received induction treatment with single-agent obinutuzumab 1000 mg IV for Cycle 1 and then idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for Cycles 2-6 (1 cycle = 28 days).
干预措施: Idasanutlin (Drug)
FL Bridging: Idasanutlin 150 mg + Obinutuzumab 1000 mg
Participants with follicular lymphoma (FL) in this bridging cohort received induction treatment with single-agent obinutuzumab 1000 mg IV for Cycle 1 and then idasanutlin 150 mg orally in combination with a fixed dose of obinutuzumab 1000 mg IV for Cycles 2-6 (1 cycle = 28 days).
干预措施: Obinutuzumab (Drug)
结局指标
主要结局
Percentage of Participants With Complete Response at the End of Induction, Determined by an Independent Review Committee (IRC) on the Basis of Positron Emission Tomography and Computed Tomography (PET-CT) Scans Using Modified Lugano 2014 Criteria
时间窗: Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days)
The plan was for the IRC to evaluate responses at the end of induction treatment in participants from the expansion phase using Lugano 2014 criteria for malignant lymphoma for a PET-CT-based complete response (CR), which required a complete metabolic response with a score of 1, 2, or 3 with or without a residual mass in lymph nodes and extralymphatic sites on the PET 5-point scale for 18-fluorodeoxyglucose (FDG) uptake (1 = no uptake above background; 2 = uptake less than or equal to \[≤\] mediastinum; 3 = uptake greater than \[\>\] mediastinum and ≤ liver; 4 = uptake moderately \> liver; 5 = uptake markedly \> liver and/or new lesions). The CR criteria were slightly modified to require normal bone marrow by morphology (if indeterminate, immunohistochemistry negative). PET-CT scans were performed at end of induction only on participants who had received at least 2 cycles of induction treatment; those without a post-baseline tumor assessment were to be considered non-responders.
次要结局
- Number of Participants With a Dose-Limiting Toxicity(Cycles 1, 2 (1 cycle is 28 days))
- Percentage of Participants With Complete Response at the End of Induction, Determined by the IRC on the Basis of CT Scans Alone Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Percentage of Participants With Complete Response at the End of Induction, Determined by the Investigator on the Basis of PET-CT Scans Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Percentage of Participants With Complete Response at the End of Induction, Determined by the Investigator on the Basis of CT Scans Alone Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Baseline Value and Change From Baseline Values of Pulse Rate at Specified Timepoints(Baseline, Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6 (up to 6 cycles; 1 cycle is 28 days), and then every 2 months (FL) or every month (DLBCL) until end of maintenance or consolidation treatment, respectively (up to 29 months))
- Baseline Value and Change From Baseline Values of Respiratory Rate at Specified Timepoints(Baseline, Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6 (up to 6 cycles; 1 cycle is 28 days), and then every 2 months (FL) or every month (DLBCL) until end of maintenance or consolidation treatment, respectively (up to 29 months))
- Percentage of Participants With Complete Response at the End of Induction, Determined by the Investigator on the Basis of PET-CT Scans Using Modified Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Percentage of Participants With Objective Response at the End of Induction, Determined by an IRC on the Basis of CT Scans Alone Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Percentage of Participants With Objective Response at the End of Induction, Determined by the Investigator on the Basis of CT Scans Alone Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Percentage of Participants With Best Response of Complete Response or Partial Response During the Study, Determined by the Investigator on the Basis of CT Scans Alone Using Lugano 2014 Criteria(Baseline, Cycle 2, end of induction (up to 6 cycles; 1 cycle is 28 days), every 2 months (FL) until end of maintenance or at 4 months (DLBCL) of consolidation treatment, and then every 6 months during follow-up until disease progression (up to 3.5 years))
- Serum Obinutuzumab Concentrations in DLBCL and FL Participants at Nominal Sampling Timepoints(Pre-infusion (0 hour) and 0.5 hours after end of obinutuzumab infusion on Day 1 of Cycles 1, 2, 4, and 6)
- Percentage of Participants With Objective Response at the End of Induction, Determined by the IRC on the Basis of PET-CT Scans Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Plasma Idasanutlin Concentrations in DLBCL and FL Participants at Nominal Sampling Timepoints Grouped by Idasanutlin Dose and Combination Partner (Obinutuzumab or Rituximab)(Predose (0 hours) and 6 hours postdose on Day 1 of Cycles 1, 2, and 4; Predose (0 hours) and 2, 4, 6, and 24 hours postdose on Day 5 of Cycles 1 and 2; Predose (0 hours) and 6 and 24 hours postdose on Cycle 4, Day 5 (1 cycle is 28 days))
- Baseline Value and Change From Baseline Values of Body Temperature at Specified Timepoints(Baseline, Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6 (up to 6 cycles; 1 cycle is 28 days), and then every 2 months (FL) or every month (DLBCL) until end of maintenance or consolidation treatment, respectively (up to 29 months))
- Hematology Laboratory Test Results Shift Table: Number of Participants by Highest NCI-CTCAE v4.0 Grade at Baseline to Highest Grade Post-Baseline(From Baseline until 35 days after the last dose of study drug (up to 29 months))
- Blood Chemistry Laboratory Test Results Shift Table: Number of Participants by Highest NCI-CTCAE v4.0 Grade at Baseline to Highest Grade Post-Baseline(From Baseline until 35 days after the last dose of study drug (up to 29 months))
- Percentage of Participants With Objective Response at the End of Induction, Determined by the Investigator on the Basis of PET-CT Scans Using Lugano 2014 Criteria(Within 6 to 8 weeks after Day 1 of Cycle 6 (up to approximately 28 weeks; 1 cycle is 28 days))
- Serum Rituximab Concentrations in DLBCL Participants at Nominal Sampling Timepoints(Pre-infusion (0 hours) at Cycle 1, Day 1 and Cycle 2, Day 1; Post-infusion 0.5 hours at Cycle 1, Day 1 (1 cycle is 28 days))
- Safety Summary of the Number of Participants With at Least One Adverse Event by Type and Severity According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)(From first dose until 90 days after the last dose of study drug treatment (up to 31 months))
- Baseline Value and Change From Baseline Values of Systolic Blood Pressure at Specified Timepoints(Baseline, Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6 (up to 6 cycles; 1 cycle is 28 days), and then every 2 months (FL) or every month (DLBCL) until end of maintenance or consolidation treatment, respectively (up to 29 months))
- Baseline Value and Change From Baseline Values of Diastolic Blood Pressure at Specified Timepoints(Baseline, Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2-6 (up to 6 cycles; 1 cycle is 28 days), and then every 2 months (FL) or every month (DLBCL) until end of maintenance or consolidation treatment, respectively (up to 29 months))
- Number of Participants by Electrocardiogram (ECG) Results Assessment Shift From Baseline to Specified Post-Baseline Timepoints(Baseline, Induction Cycle 1 Day 1 and Cycle 4 Day 1, End of Induction (up to 6 cycles; 1 cycle is 28 days); Every 2 months during maintenance treatment from Months 1-23; End of Maintenance (up to 24 months); Unscheduled Visits (as clinically indicated))