An Open-Label, Phase I/II Study to Evaluate the Safety, Pharmacokinetics and Preliminary Anti-Tumor Activity of Englumafusp Alfa (RO7227166, A CD19 Targeted 4-1BB Ligand) in Combination With Obinutuzumab and in Combination With Glofitamab Following a Pre-treatment Dose of Obinutuzumab Administered in Participants 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
- 498
- 试验地点
- 60
- 主要终点
- Nature and frequency of dose-limiting toxicities (DLTs)
研究概览
简要总结
This is a phase I/II, open-label, dose-escalation study designed to evaluate the safety, tolerability, and efficacy of englumafusp alfa (RO7227166) in participants with relapsed/refractory Non-Hodgkin's Lymphoma (r/r NHL). Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab and in combination with glofitamab. A fixed dose of obinutuzumab (Gpt; pre-treatment) will be administered up to seven days prior to the first administration of englumafusp alfa and seven days prior to the first administration of glofitamab. This entry-into-human study is divided into a dose-escalation stage (Part I and Part II) and a dose expansion stage (Part III).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 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 or status of a histologically-confirmed hematological malignancy that is expected to express CD19 and CD20; relapse after or failure to respond to at least one prior treatment regimen; no available treatment options that are expected to prolong survival (Part I and II); relapsed after or failed to respond to only one prior systemic treatment regimen (Part III)
- •* Must have at least one measurable target lesion (\>/= 1.5 cm) in its largest dimension by computed tomography scan
- •* Able and willing to provide a fresh biopsy from a safely accessible site, per Investigator's determination, providing the participant has more than one measurable target lesion
- •* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, or \/= 12 weeks
- •* Adverse events from prior anti-cancer therapy must have resolved to Grade \
排除标准
- •Circulating lymphoma cells, defined by out of range (high) absolute lymphocyte count (ALC) or the presence of abnormal cells in the peripheral blood signifying circulating lymphoma cells (for some participants in Part III, ALC only)
- •Participants with acute bacterial, viral, or fungal infection at baseline, confirmed by a positive blood culture within 72 hours prior to obinutuzumab infusion or by clinical judgment in the absence of a positive blood culture
- •Participants with known active infection, or reactivation of a latent infection, whether bacterial, viral fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics
- •Pregnant or breast-feeding or intending to become pregnant during the study
- •Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines or monoclonal antibodies within 4 weeks or five half-lives of the drug, whichever is shorter, before obinutuzumab infusion
- •History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents and auto-immune disease
- •Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational or approved anti-cancer agent within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to obinutuzumab infusion
- •Prior solid organ transplantation
- •Prior allogeneic stem cell transplant
- •Autologous stem cell transplant within 100 days prior to obinutuzumab infusion
- •History of severe allergic or anaphylactic reactions to monoclonal antibody therapy and confirmed progressive multifocal leukoencephalopathy
- •Current or past history of central nervous system (CNS) lymphoma and CNS disease
- •Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders and known autoimmune diseases
- •Major surgery or significant traumatic injury < 28 days prior to the Gpt infusion or anticipation of the need for major surgery during study treatment
- •Participants with another invasive malignancy in the last 2 years
- •Significant cardiovascular disease
- •Administration of a live, attenuated vaccine within 4 weeks before Gpt infusion or anticipation that such a live attenuated vaccine will be required during the study
- •Received systemic immunosuppressive medications (including but not limited to cyclohosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within two weeks prior to Gpt, with the exception of corticosteroid treatment <=25 mg/day of prednisone or equivalent, however there must be documentation that the participant was on a stable dose of at least a 2-week duration prior to Gpt infusion. Inhaled and topical steroids are permitted
研究组 & 干预措施
Part III
Dose-Expansion Stage: Participants with r/r diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL) will receive englumafusp alfa administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Englumafusp alfa (Drug)
Part I
Combination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab up to seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab in a three-weekly schedule (Q3W).
干预措施: Englumafusp alfa (Drug)
Part II
Combination Dose-Escalation: Mixed r/r participants and participants with mixed r/r mantle cell lymphoma (MCL) and Richters transformation will receive a fixed dose of obinutuzumab seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Englumafusp alfa (Drug)
Part I
Combination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab up to seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab in a three-weekly schedule (Q3W).
干预措施: Obinutuzumab (Drug)
Part I
Combination Dose-Escalation: Mixed r/r NHL participants will receive a fixed dose of obinutuzumab up to seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by intravenous (IV) infusion in combination with obinutuzumab in a three-weekly schedule (Q3W).
干预措施: Tocilizumab (Drug)
Part II
Combination Dose-Escalation: Mixed r/r participants and participants with mixed r/r mantle cell lymphoma (MCL) and Richters transformation will receive a fixed dose of obinutuzumab seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Glofitamab (Drug)
Part II
Combination Dose-Escalation: Mixed r/r participants and participants with mixed r/r mantle cell lymphoma (MCL) and Richters transformation will receive a fixed dose of obinutuzumab seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Obinutuzumab (Drug)
Part II
Combination Dose-Escalation: Mixed r/r participants and participants with mixed r/r mantle cell lymphoma (MCL) and Richters transformation will receive a fixed dose of obinutuzumab seven days prior to first administration of englumafusp alfa. Englumafusp alfa will be administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Tocilizumab (Drug)
Part III
Dose-Expansion Stage: Participants with r/r diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL) will receive englumafusp alfa administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Obinutuzumab (Drug)
Part III
Dose-Expansion Stage: Participants with r/r diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL) will receive englumafusp alfa administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Tocilizumab (Drug)
Part III
Dose-Expansion Stage: Participants with r/r diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), and DLBCL arising from FL (transformed FL) will receive englumafusp alfa administered by IV infusion in combination with glofitamab in a three-weekly schedule (Q3W).
干预措施: Glofitamab (Drug)
结局指标
主要结局
Nature and frequency of dose-limiting toxicities (DLTs)
时间窗: 28 days in Part I and Part II
Duration of Response (DOR)
时间窗: After end of Study approximately every 3 months until death, loss to follow-up or study termination
Proportion of Participants with Adverse Event (AE)
时间窗: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
Incidence, nature, and severity of AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Overall Response Rate (ORR)
时间窗: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
Disease Control Rate (DCR)
时间窗: Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months
Complete Response (CR)
时间窗: Part III: Up to 9 months or up to 18 months
Progression-free Survival (PFS)
时间窗: After end of Study approximately every 3 months until death, loss to follow-up or study termination
Overall Survival (OS)
时间窗: After end of Study approximately every 3 months until death, loss to follow-up or study termination
次要结局
- DCR(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- OS(After end of Study approximately every 3 months until death, loss to follow-up or study termination)
- Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with glofitamab(Part III: Up to 9 months or up to 18 months)
- Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with obinutuzumab and glofitamab(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- Total exposure (area under the concentration time curve [AUC]) of englumafusp alfa in combination with obinutuzumab and glofitamab(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- Volume of distribution of steady state (Vss) and half-life (t1/2) of englumafusp alfa in combination with obinutuzumab and glofitamab(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- ORR(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- T-cell and Natural killer (NK)-cell status in blood, using markers of T and NK-cell lineage, function and activation including, but not limited to, CD3, CD8, 41BB, and Ki67 expression(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- Time to First Complete Response (TFCR)(Up to 18 months)
- Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with obinutuzumab and glofitamab(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- Clearance (CL) of englumafusp alfa in combination with obinutuzumab and glofitamab(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- Proportion of Participants with Adverse Event (AE)(After end of Study approximately every 3 months until death, loss to follow-up or study termination)
- B-cell reduction in blood and tumor tissue(Part I: Up to 24 months; Part II: Up to 18 months; Part III: Up to 9 months or up to 18 months)
- DOR(After end of Study approximately every 3 months until death, loss to follow-up or study termination)
- PFS(After end of Study approximately every 3 months until death, loss to follow-up or study termination)
- Clearance (CL) of englumafusp alfa in combination with glofitamab(Part III: Up to 9 months or up to 18 months)
- Volume of distribution of steady state (Vss) and half-life (t1/2) of englumafusp alfa in combination with glofitamab Part I/II/III(Part III: Up to 9 months or up to 18 months)
- Time to First Overall Response (TFOR)(Up to 18 months)
- Duration of Complete Response (DOCR)(Part III: Up to 9 months or up to 18 months)
- Change from Baseline in Physical Function, Role Function, and Health-Related Quality of Life (HRQoL) Based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)(Part III: Up to 9 months or up to 18 months)
- Change from Baseline in englumafusp alfa Anti-Drug Antibody (ADA) Titer(Part 1: Up to 24 months; Part ll/lll: Up to 18 months)
- Change from Baseline in Physical Function, Role Function, and HRQoL According to the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Lymphoma Scale(Part III: Up to 9 months or up to 18 months)
- Maximum serum concentration (peak concentration, Cmax) of englumafusp alfa in combination with glofitamab(Part III: Up to 9 months or up to 18 months)
- Minimum serum concentration (trough concentration, Cmin) of englumafusp alfa in combination with glofitamab(Part III: Up to 9 months or up to 18 months)