An Open-Label, Multi-Center, Phase IB/II Study of Glofitamab and Atezolizumab or Polatuzumab Vedotin (Plus a Single Pre-Treatment Dose of Obinutuzumab) in Adult Patients With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 211
- 试验地点
- 29
- 主要终点
- Best Objective Response Rate (ORR) as Measured by Independent Review Committee (IRC)
研究概览
简要总结
This is an open-label, single arm, multicenter, dose finding, Phase Ib study in order to assess the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) for this combination treatment and to evaluate the general safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and preliminary anti-tumor activity of this combination treatment in adult patients.
This study includes an additional open-label imaging feasibility sub-study using a tracer in adult participants with relpased/refractory B-cell non-Hodgkin's lymphoma to image CD8+T-cells at baseline and after treatment with glofitamab, including pre-treatment with obinutuzumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Main Inclusion Criteria
- •Histologically-confirmed hematologic malignancy that is expected to express CD20 (Relapsed after or refractory to respond to at least one prior treatment regimen; no available treatment options that are expected to prolong survival or patients refusing chemotherapy or autologous stem cell transplant (SCT))
- •Dose-escalation: Grades 1-3b relapsed or refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL) (nodal; extra-nodal; or splenic), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma), HGBCL not otherwise specified (NOS), DLBCL arising from FL (transformed FL)
- •Dose-expansion: R/R LBCL, including DLBCL NOS, DLBCL arising from FL (transformed FL), PMBCL, HGBCL with MYC and BCL2 and/or BCL6 rearrangements (i.e., double-hit and triple-hit lymphomas), and HGBCL NOS
- •At least one measurable target lesion
- •Fresh pre-treatment biopsy, but if this cannot be taken, a previous archived biopsy from metastatic lesion can be taken as replacement if it is not older than 6 months and not confounded by major events (progression, treatment)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Adequate organ function (liver, hematological, renal)
- •Negative test results for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)
- •Inclusion Criteria Specific to Imaging Substudy
- •At least two measurable target lesions
- •Able to provide two fresh tumor biopsies (baseline and on-treatment)
排除标准
- •* Participants with Chronic Lymphocytic Leukemia (CLL), acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, Richter's transformation, CD20-positive ALL, Burkitt lymphoma, or lymphoplasmacytic lymphoma
- •* Current \> Grade 1 peripheral neuropathy (only for participants being treated in the polatuzumab vedotin arm)
- •* Patients with known active infection, or reactivation of a latent infection within 4 weeks prior to Obinutuzumab (Gpt) infusion
- •* Patient with history of confirmed progressive multifocal leukoencephalopathy (PML)
- •* History of leptomeningeal disease
- •* Current or past history of central nervous system (CNS) lymphoma
- •* Current or past history of CNS disease
- •* Major surgery or significant traumatic injury \/= Grade 3 adverse events (AE) with the exception of endocrinopathy managed with replacement therapy
- •* Ongoing corticosteroid use \>25 milligrams/day of prednisone or equivalent within 4 weeks prior to and during study treatment
- •* Treatment with systemic immunosuppressive medication
- •* Administration of a live, attenuated vaccine within 4 weeks prior to Gpt infusion or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last dose of study treatment
- •Exclusion Criteria Specific to Imaging Substudy
- •* Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count and/or the presence of abnormal/malignant cells in the peripheral blood differential signifying circulating lymphoma cell
- •* Participants who have had splenectomy or functional asplenia that could compromise protocol objectives
研究组 & 干预措施
Atezolizumab
Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).
干预措施: Glofitamab (Drug)
Atezolizumab
Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).
干预措施: Obinutuzumab (Drug)
Atezolizumab
Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).
干预措施: Tocilizumab (Drug)
Polatuzumab Vedotin
Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.
干预措施: Glofitamab (Drug)
Polatuzumab Vedotin
Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.
干预措施: Tocilizumab (Drug)
Polatuzumab Vedotin
Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.
干预措施: Polatuzumab Vedotin (Drug)
Imaging Sub-study
Participants will undergo positive-emission tomography/computed tomography (PET/CT) at screening, followed by an "Imaging Cycle," to replace Cycle 1 of the main study. Eligible participants will have the option roll-over to the atezolizumab arm of the main study from Cycle 2 onwards.
干预措施: Glofitamab (Drug)
Imaging Sub-study
Participants will undergo positive-emission tomography/computed tomography (PET/CT) at screening, followed by an "Imaging Cycle," to replace Cycle 1 of the main study. Eligible participants will have the option roll-over to the atezolizumab arm of the main study from Cycle 2 onwards.
干预措施: 89Zr-Df-IAB22M2C (Drug)
Atezolizumab
Participants will receive Glofitamab in combination with Atezolizumab up to the maximum tolerated dose (MTD).
干预措施: Atezolizumab (Drug)
Polatuzumab Vedotin
Participants will receive Glofitamab in combination with polatuzumab vedotin up to the MTD.
干预措施: Obinutuzumab (Drug)
Imaging Sub-study
Participants will undergo positive-emission tomography/computed tomography (PET/CT) at screening, followed by an "Imaging Cycle," to replace Cycle 1 of the main study. Eligible participants will have the option roll-over to the atezolizumab arm of the main study from Cycle 2 onwards.
干预措施: Obinutuzumab (Drug)
结局指标
主要结局
Best Objective Response Rate (ORR) as Measured by Independent Review Committee (IRC)
时间窗: Baseline until the end of treatment (13 to 14 months), then ever 3 months until end of study visit (to occur within 4 weeks of disease progression)
Dose Limiting Toxicities (DLTs)
时间窗: Atezolizumab Arm: During DLT period of 21 days (or up to 42 days in the case of cycle delay), starting on Day 1, Cycle 2; Polatuzumab Vedotin Arm: During 5-week DLT period starting Cycle 1, Day 8
次要结局
- SUVpeak of 89Zr-Df-IAB22M2C (Imaging Sub-study(From baseline to Day 13)
- Best ORR as Measured by Investigator(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Best Complete Response (CR) Rate, as Assessed by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) Scan(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Duration of Complete Response (DOCR)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Duration of Response (DOR)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Progression-Free Survival (PFS)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Event-Free Survival (EFS)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Time to First Complete Response (TFCR)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Time to First Overall Response (TFOR)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Overall Survival (OS)(Baseline through end of survival follow-up phase (survival follow-up is every 3 months until death, lost to follow-up, withdrawal of consent, or study termination))
- Percentage of Participants with Adverse Events (AEs)(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Incidence and Severity of Cytokine Release Syndrome (CRS) Following Glofitamab Administration(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Anti-Drug Antibody (ADA) Formation(Baseline until end of treatment (13 to 14 months), then every 3 months until end of study visit (to occur within 4 weeks of disease progression))
- Elimination Half-Life (T1/2) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Area Under the Concentration-Time Curve (AUC) for Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Time to Maximum Observed Serum Concentration (Tmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Maximum Observed Serum Concentration (Cmax) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Minimum Serum Concentration (Cmin) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Clearance (CL) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- Volume of Distribution at Steady-State (Vss) of Glofitamab Administered in Combination with Atezolizumab or Polatuzumab Vedotin(At pre-defined intervals through the end of study (EoS) visit (to occur within 4 weeks of disease progression))
- CD8-Positive T Cell Proliferation(At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days))
- CD20-Positive B-Cell Reduction(At pre-defined intervals during the study treatment period (up to 17 cycles; Cycle = 21 days))
- SUVmax of 89Zr-Df-IAB22M2C (Imaging Sub-study)(From baseline to Day 13)
- SUVmean of 89Zr-Df-IAB22M2C (Imaging Sub-study)(From baseline to Day 13)
- Tumor Volume Based on 89Zr-Df-IAB22M2C PET-uptake (Imaging Sub-study)(From baseline to Day 13)
- Quantitation of CD8+ Cells on Biopsy Samples (Imaging Sub-study)(From baseline to Day 13)