An Open-Label, Multicenter, Dose-Escalation Phase I Study to Evaluate the Safety, Pharmacokinetics, and Therapeutic Activity of RO6958688, A Novel T-cell Bispecific Antibody That Targets the Human Carcinoembryonic Antigen (CEA) on Tumor Cells and CD3 on T Cells, Administered Intravenously in Patients With Locally Advanced and/or Metastatic CEA(+) Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 149
- 试验地点
- 21
- 主要终点
- Percentage of Participants with Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
Study BP29541 is a first-in-human, open-label, multi-center, dose-escalation Phase I clinical study of single-agent RO6958688 in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA) positive solid tumors who have progressed on standard treatment, are intolerant to standard of care (SOC), and/or are non-amenable to SOC. The study will be conducted in two parts. Part I of the study will investigate the safety and pharmacokinetics of a single dose of RO6958688 in single participant cohorts with dosing starting from a minimal anticipated biological effect level dose of 0.05 milligrams (mg) and up to a maximum dose of 2.5 mg. Part II will establish the appropriate therapeutic dose based on safety, pharmacokinetics, and the maximum tolerated dose (MTD) of RO6958688 for the once per week (QW) regimen, every three weeks (Q3W) regimen, and for the step up dosing regimen.
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
- •For dose escalation, locally advanced and/or metastatic gastrointestinal (GI) solid tumor in participants who have progressed on a standard therapy, are intolerant to SOC, and/or are non-amenable to SOC and other solid tumors expressing CEA. Only locally advanced and/or metastatic colorectal cancer participants should be included in the scheduled comparison expansion
- •Radiologically measurable disease according to RECIST v1.1
- •Life expectancy, in the opinion of the investigator of greater than or equal (>/=) to 12 weeks and LDH= 2.5 x ULN
- •Eastern Cooperative Oncology Group Performance Status of 0-1
- •All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade less than or equal to 1 or returned to baseline except alopecia (any grade) and Grade 2 peripheral neuropathy
- •Adequate hematological, liver, and renal function
- •Participants must agree to remain abstinent or be willing to use effective methods of contraception as defined in the protocol
- •Non-GI solid tumors (like non-small cell lung cancer or breast cancer) should have confirmed CEA expression in tumor tissue >/= 20% of tumor cells staining with at least moderate to high intensity of CEA expression are required (immunohistochemistry [IHC]2+ and IHC 3+). For CRC, pancreatic and gastric cancer participants, the CEA assessment will be performed retrospectively and the result is not needed to enroll the participant
排除标准
- •Participants with a history or clinical evidence of central nervous system primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days before screening
- •Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 2 weeks prior to enrollment
- •Leptomeningeal disease
- •Participants with paraspinal, paratracheal and mediastinal pathologic lesions larger than 2 centimeters unless they are previously irradiated. Irradiation of lesions must be completed at least 14 days prior to initiation of study treatment
- •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)
- •Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or contraindicate the use of an investigational drug, including diabetes mellitus, history of relevant cardio-pulmonary disorders, and known autoimmune diseases
- •Participants with bilateral lung lesions and dyspnea and/or with bilateral lung lesions and an oxygen saturation (SaO2) level less than 92% or participants with lobectomy or pneumonectomy with lung metastases in the remaining lung and either dyspnea or SaO2 less than 92% at baseline
- •Uncontrolled hypertension (systolic blood pressure [BP] greater than [>] 150 millimeters of mercury [mmHg] and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure of any New York Heart Association classification, serious cardiac arrhythmia that requires treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia, and history of myocardial infarction within 6 months of enrollment
- •Active or uncontrolled infections
- •Known human immunodeficiency virus (HIV) or known active hepatitis B or hepatitis C infection for participants not receiving obinutuzumab pretreatment
- •Known HIV (HIV testing will be performed at screening if required by local regulations) in participants to be pretreated with obinutuzumab
- •Pregnant or breastfeeding women
- •Known hypersensitivity to any of the components of RO6958688 and/or obinutuzumab
- •Concurrent therapy with any other investigational drug
- •Last dose of any chemotherapy less than 28 days prior to the first RO6958688 infusion
- •Expected need for regular immunosuppressive therapy
- •Regular dose of corticosteroids the 28 days prior to Day 1 of this study or anticipated need for corticosteroids that exceeds prednisone 10 mg/day or equivalent within 28 days prior to the first RO6958688 infusion. Inhaled and topical steroids are permitted
- •Radiotherapy within the last 28 days prior to the first RO6958688 infusion with the exception of limited-field palliative radiotherapy.
- •Additional Exclusion Criteria for Participants to be Pretreated with Obinutuzumab:
- •Positive test results for human T-lymphotropic virus 1 (HTLV-1) or active HIV infection
- •Positive test results for chronic hepatitis B infection or hepatitis C
- •Known active tuberculosis (TB) requiring treatment within 3 years prior to baseline or latent TB that has not been appropriately treated
- •Active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with intravenous (IV) antibiotics within 4 weeks of Cycle 1, Day 1
- •Known hypersensitivity to any of the components of obinutuzumab; hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- •History of progressive multifocal leukoencephalopathy (PML)
研究组 & 干预措施
Part I: RO6958688
Participants will receive single dose of RO6958688 starting from a dose of 0.05, 0.15, 0.45, 1.3, and 2.5 mg in Part I of the study.
干预措施: RO6958688 (Drug)
Part I: RO6958688
Participants will receive single dose of RO6958688 starting from a dose of 0.05, 0.15, 0.45, 1.3, and 2.5 mg in Part I of the study.
干预措施: Tocilizumab (Drug)
Part II: RO6958688 With/Without Obinutuzumab Pretreatment
Participants will receive RO6958688 with or without obinutuzumab pretreatment QW, Q3W, or according to a combined QW/Q3W step up dosing schedule. Doses will start at 40mg and increase with each administration up to the MTD or 1200mg, whichever is lower.
干预措施: RO6958688 (Drug)
Part II: RO6958688 With/Without Obinutuzumab Pretreatment
Participants will receive RO6958688 with or without obinutuzumab pretreatment QW, Q3W, or according to a combined QW/Q3W step up dosing schedule. Doses will start at 40mg and increase with each administration up to the MTD or 1200mg, whichever is lower.
干预措施: Obinutuzumab (Drug)
Part II: RO6958688 With/Without Obinutuzumab Pretreatment
Participants will receive RO6958688 with or without obinutuzumab pretreatment QW, Q3W, or according to a combined QW/Q3W step up dosing schedule. Doses will start at 40mg and increase with each administration up to the MTD or 1200mg, whichever is lower.
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
时间窗: Day 1 up to Day 21
MTD of RO6958688 With/Without Obinutuzumab Pretreatment
时间窗: Day 1 up to Day 21
Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0) on Day 1 of Cycles 1, 2-3; 120 hours after end of infusion (EOI) in Cycle 1. Part II QW: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4. Part II Q3W: pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4; 120 hours and 336 hours after EOI in Cycle 1, and 120 hours after EOI in Cycles 2, 3, 4. For Part I and II (QW and Q3W): pre-dose (Hour 0) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle = 7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Half-Life (t1/2) of RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Clearance (CL) of RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Cmin for Obinutuzumab
时间窗: Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days)
Volume of Distribution at Steady State (Vss) of RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Minimum Drug Concentration (Cmin) for RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Percentage of Participants with Adverse Events (AEs) or Serious Adverse Events (SAEs)
时间窗: Baseline up to 60 months
Late Cycle MTD of RO6958688 Without Obinutuzumab Pretreatment for the Step up Dosing Regimen
时间窗: Day 1 up to Day 7 of each cycle as long as the dose is escalated weekly in Part II QW (up to approximately 60 months; Cycle = 7 days)
Late cycle MTD is defined as the highest dose with less than or equal to DLT having been observed for 6 evaluable participants. If more than 6 participants are evaluable for DLT, late cycle MTD is the highest dose where less than (\<) 33% of participants have DLT.
Maximum Serum Concentration (Cmax) for RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Area Under the Concentration-Time Curve (AUC) for RO6958688
时间窗: Pre-dose (Hour 0) on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome description section)
Part I: Pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2-3; 24, 48, and 120 hours after EOI of Cycle 1. Part II QW: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24 and 120 hours after EOI of Cycles 1 and 2; 48 hours after EOI of Cycle 1. Part II Q3W: pre-dose (Hour 0), EOI, 2 hours after EOI on Day 1 of Cycles 1, 2, 3, and 4; 24, 48, 120, and 336 hours after EOI of Cycle 1; 24 and 120 hours after EOI of Cycles 2, 3, and 4; 48 hours after EOI of Cycle 2. For Part I and II (QW and Q3W): pre-dose (Hour 0), EOI, 2 hours after EOI (only for Part I) on Day 1 of every cycle after Cycle 4 (Cycle 3 for Part I), 2 hours after EOI on Day 1 of Cycles 8 and 12 (only for Part II QW) up to treatment discontinuation (approximately 60 months), 28 days after last dose (approximately 60 months) (Cycle =7 days for Part I and II QW; 21 days for Part II Q3W) (infusion duration = 30 minutes for Part I and 120 minutes for Part II \[QW and Q3W\])
Cmax for Obinutuzumab
时间窗: Screening (pre-obinutuzumab dose [Hour 0] and EOI on Day -13 or Days -13 and -12), pre-RO6958688 dose [Hour 0] on Day 1 of Cycles 1, 2, 4, 8, and 12 in Part II QW (Cycle = 7 days)
次要结局
- Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v)1.1(Baseline up to 60 months (detailed timeframe is provided in outcome description section))
- Duration of Response (DOR) According to RECIST v1.1(Baseline up to 60 months (detailed timeframe is provided in outcome description section))
- Percentage of Participants With Stable Disease (SD) According to RECIST v1.1(Baseline up to 60 months (detailed timeframe is provided in outcome description section))
- Percentage of Participants With Disease Control, Defined as PR+CR+SD, According to RECIST v1.1(Baseline up to 60 months (detailed timeframe is provided in outcome description section))
- Progression-Free Survival (PFS) According to RECIST v1.1(From the first study treatment to the first occurrence of objective disease progression or death from any cause (up to 60 months))
- Change From Baseline in Activated Intra-Tumoral Cells(Baseline, Day 1 of Cycles 2, 3, 4, or 7 in Part II QW and Q3W (Cycle = 7 days for Part II QW and 21 days for Part II Q3W))
- Best Overall Response (BOR)(Baseline up to 60 months (detailed timeframe is provided in outcome description section))