A Multicenter, Open-label, Phase I/II Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of Escalating Doses of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab Administered After a Fixed, Single Dose Pre-treatment of Obinutuzumab (Gazyva®/Gazyvaro™) in 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
- 940
- 试验地点
- 93
- 主要终点
- Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is a Phase I/II, multicenter, open-label, dose-escalation study designed to evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of a novel T-Cell bispecific (TCB), glofitamab, administered by intravenous (IV) infusion as a single agent and in combination with obinutuzumab, following pre-treatment with a one-time, fixed dose of obinutuzumab. This entry-into-human (EIH) study is divided in 3 parts: dose escalation (Parts I and II) and dose expansion (Part III). Single-participant dose-escalation cohorts will be used in Part I, followed by conversion to multiple participant dose-escalation cohorts (Part II), in order to define a tentative maximum tolerated dose (MTD) or optimal biological dose (OBD). The expansion cohorts (Part III) will be initiated when the tentative MTD/OBD is defined, to further evaluate the safety, PK and therapeutic activity of glofitamab.
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
- •Depending upon study part, a history or status of: 1) a histologically-confirmed hematological malignancy that is expected to express cluster of differentiation (CD)20; 2) relapse after or failure to respond to at least one prior treatment regimen; and 3) no available treatment options that are expected to prolong survival (e.g., standard chemotherapy or autologous stem cell transplant [ASCT])
- •Measurable disease, defined as at least one bi-dimensionally measurable nodal lesion, defined as > 1.5 cm in its longest dimension, or at least one bi-dimensionally measurable extranodal lesion, defined as > 1.0 cm in its longest dimension
- •Able to provide a tumor tissue pretreatment biopsy at last relapse or during screening from a safely accessible site, per investigator determination, providing the patient has more than one measurable target lesion
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy of >/=12 weeks
- •AEs from prior anti-cancer therapy must have resolved to Grade less than or equal to (</=) 1
- •Adequate liver, hematological and renal function
- •Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic Hepatitis B virus (HBV) infection
- •Negative test results for Hepatitis C virus (HCV) and human immunodeficiency virus (HIV)
- •Negative serum pregnancy test within 7 days prior to study treatment in women of childbearing potential. Women who are not of childbearing potential who are considered to be post-menopausal (at least 12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test
排除标准
- •Inability to comply with protocol mandated hospitalizations and restrictions
- •Participants with chronic lymphocytic leukemia (CLL), Burkitt lymphoma and lymphoplasmacytic lymphoma
- •Participants with a known or suspected history of hemophagocytic lymphohistiocytosis (HLH)
- •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 or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of dosing
- •Prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (e.g., anti-cytotoxic T-lymphocyte-associated protein 4 [anti-CTLA4], anti-programmed death 1 [anti-PD1] and anti-programmed death ligand 1 [anti-PDL1]) within 4 weeks or five half-lives of the drug, whichever is shorter, before obinutuzumab infusion on Cycle 1 Day -7
- •History of treatment-emergent immune-related AEs associated with prior immunotherapeutic agents
- •Documented refractoriness to an obinutuzumab-containing regimen
- •Treatment with standard radiotherapy, any chemotherapeutic agent, or treatment with any other investigational anti-cancer agent, including chimeric antigen receptor therapy (CAR-T) within 4 weeks prior to obinutuzumab infusion
- •Prior solid organ transplantation
- •Prior allogeneic stem cell transplantation (SCT)
- •Autologous SCT within 100 days prior to obinutuzumab infusion
- •Participant with history of confirmed progressive multifocal leukoencephalopathy (PML)
- •Current or past history of central nervous system (CNS) lymphoma
- •Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participants with a past history of stroke that have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits are allowed
- •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
- •Participants with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood for recurrence)
- •Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV or Objective Class C or D cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina
- •Administration of a live, attenuated vaccine within 4 weeks before obinutuzumab infusion or anticipation that such a live attenuated vaccine will be required during the study
- •Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within two weeks prior to obinutuzumab infusion. Treatment with corticosteroid </= 25 mg/day prednisone or equivalent is allowed. Inhaled and topical steroids are permitted
- •Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
- •History of autoimmune disease, including but not limited to myocarditis, pneumonitis, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus, erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Participants with a remote history of, or well controlled autoimmune disease, may be eligible to enroll after consultation with the Medical Monitor
- •In Part III diffuse large B-cell lymphoma (DLBCL) dexamethasone cohort, participants with a history of hypersensitivity to dexamethasone or systemic corticosteroids will be excluded
研究组 & 干预措施
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered.
Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined.
Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
干预措施: Glofitamab (Drug)
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
干预措施: Tocilizumab (Drug)
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
干预措施: Obinutuzumab (Drug)
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered.
Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined.
Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
干预措施: Obinutuzumab (Drug)
Part II: Dose Escalation
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered.
Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined.
Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
干预措施: Tocilizumab (Drug)
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
干预措施: Glofitamab (Drug)
Part I: Dose Escalation
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
干预措施: Glofitamab (Drug)
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
干预措施: Obinutuzumab (Drug)
Part III: Dose Expansion
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Part I and II: Percentage of Participants With Dose Limiting Toxicities (DLTs)
时间窗: From Baseline up to 4 weeks
Part I, II and III: Percentage of Participants With Adverse Events (AEs)
时间窗: From Baseline up to 90 days after last dose of study drug or until study completion or participant withdrawal (up to 5 years)
Part II: MTD or OBD of Glofitamab
时间窗: From Baseline up to 4 weeks
Part II: Recommended Phase II Dose (RP2D) of Glofitamab
时间窗: From Baseline up to 5 years
Part I, II and III: Area Under the Serum Concentration Versus Time Curve (AUC) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 to Day 71
Part III: Complete Response (CR) Rate as Assessed by Independent Review Committee (IRC) According to Standard Non-hodgkin's Lymphoma (NHL) Response Criteria (Lugano Classification)
时间窗: From treatment start up to 5 years
Part I, II and III: Maximum Serum Concentration (Cmax) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 to Day 198
Part I, II and III: Minimum Serum Concentration (Cmin) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 up to Day 198
Part I, II and III: Clearance (CL) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 to Day 71
Part I, II and III: Volume of Distribution at Steady-state (Vss) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 to Day 71
Part I, II and III: Half-life (t1/2) of Glofitamab
时间窗: At pre-defined intervals from Cycle 1 Day 1 to Day 71
次要结局
- Parts I and II: Percentage of Participants With Overall Response (Partial Response [PR] or Complete Response [CR]) as Determined by the Lugano Classification(From Baseline up to end of study or discontinuation due to disease progression (up to 5 years))
- Part I, II and III: Cmin of Obinutuzumab(Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1)
- Part I, II and III: Cmax of Obinutuzumab(Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of Cycle 1)
- Overall Survival (OS)(From the time of first study treatment to death from any cause (up to 5 years))
- Part I, II and III: Anti-drug Antibodies (ADA) to Glofitamab(Pre-dose of obinutuzumab on Day -7; pre-dose (Hr 0) of glofitamab on Day 1 of each cycle from Cycle 2 onwards for a maximum of 8-12 cycles, and at EOT/follow-up visit (up to 5 years))
- Part I, II and III: Percentage of Participants With PR or CR (Overall Response Rate [ORR]) as Determined by the Lugano Classifications(From Baseline up to end of study or discontinuation due to disease progression (up to 5 years))
- Part I, II and III: Duration of Response (DOR) as Determined by the Lugano Classification(From first occurrence of documented objective response until disease progression, relapse or death due to any cause (up to 5 years))
- Part I, II and III: Duration of Complete Response (DOCR) as Determined by the Lugano Classification(From the first occurrence of a documented, complete response, until the time of relapse or death from any cause (up to 5 years))
- Part I, II and III: Progression-Free Survival (PFS) as Determined by the Lugano Classification(From first study treatment to the first occurrence of disease progression or death due to any cause (up to 5 years))
- Time to First Overall Response (TFOR)(From time of treatment start to first documented response (up to 5 years))
- Time to First Complete Response (TFCR)(From treatment start to first documented complete response (up to 5 years))
- Part III: Health Related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)(From baseline through follow-up or until disease progression (up to 5 years))
- Part III: HRQoL as Assessed by the Functional Assessment of Cancer Therapy-lymphoma (FACT-lym) Scale(From baseline through follow-up or until disease progression (up to 5 years))