An Open-Label, Multicenter, Dose-Escalation Phase I Study of RO6874813, Administered Intravenously in Patients With Locally Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 120
- 试验地点
- 8
- 主要终点
- Part 1: Percentage of Participants With Dose-Limiting Toxicity (DLT)
研究概览
简要总结
This first-in-human study consists of three parts. The primary purpose of Part 1 is to characterize the safety and tolerability of RO6874813 in participants with locally advanced and/or metastatic solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists. In addition, the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) will be determined. In Part 2 the safety and tolerability of RO6874813 will continue to be characterized in participants with locally advanced and/or metastatic solid tumors known to be fibroblast activation protein-alpha positive (FAP+). In addition, treatment-induced efficacy of RO6874813 will be assessed by functional imaging and paired tumor biopsies. The primary purpose of Part 3 is to demonstrate anti-tumor activity of RO6874813 in participants with recurrent or metastatic FAP+ sarcomas.
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
- •Part 1: Participants with histologically/cytologically confirmed locally advanced or metastatic, non-resectable solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists
- •Part 2: Participants with histologically/ cytologically confirmed locally advanced or metastatic, non-resectable solid tumors known to be FAP+ whose disease has progressed despite standard therapy or for whom no standard therapy exists
- •Part 3: Participants with histologically confirmed recurrent or metastatic, non-resectable confirmed FAP+ sarcoma with two or fewer prior regimens for advanced disease
- •All participants must have tumor tissue that can be imaged for pharmacodynamic assessments and from which a pre- and on-treatment biopsy can be safely obtained
- •An archival tumor sample must be available for retrospective FAP expression analysis
- •Measurable disease as determined by RECIST v1.1
- •World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1
- •Recovery from all reversible AEs of previous anti-cancer therapies to baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade 1, except for alopecia (any grade) and Grade <=2 sensory peripheral neuropathy
- •Negative pregnancy test
排除标准
- •Primary central nervous (CNS) tumors or CNS tumor involvement
- •Major surgery or any other prior anti-cancer treatment within 4 weeks prior to study Day
- •Received wide-field radiotherapy <= 4 weeks or limited-field radiotherapy <=2 weeks prior to starting study drug
- •Known hypersensitivity to any of the components of RO6874813 or to the contrast agents used in the study
- •Another invasive malignancy in the last 2 years except for those with a minimal risk of metastasis or death
- •Any other conditions or diseases that would contraindicate participation in the clinical study because of safety concerns or compliance with clinical study procedures
研究组 & 干预措施
Part 2: Tumor Biopsy and Imaging
The first 15 participants with fibroblast activation protein-alpha positive (FAP+) tumors will be treated at the RP2D and dosing schedule as determined in Part 1, and will undergo paired tumor biopsies for biomarker assessments. Up to 5 participants with FAP+ tumors will undergo baseline and on-treatment tumor biopsies for biomarker assessments at a dose below the RP2D. The dose for these participants can be escalated to RP2D after 4 weeks of treatment and upon completion of biomarker assessment.
干预措施: RO6874813 (Biological)
Part 3: Preliminary Efficacy Assessment
Participants with locally advanced or metastatic non-resectable FAP+ sarcoma will be treated with RO6874813 at the RP2D and as per schedule determined upon completion of Part 1. Participants continuing treatment with RO6874813 beyond 36 weeks will enter the extension phase of Part 3 and will be monitored for disease status and clinical safety per routine standard of care.
干预措施: RO6874813 (Biological)
Part 1: Dose Escalation
All participants will be given RO6874813 as a single low dose of 0.5 milligrams per kilogram (mg/kg) via intravenous (IV) infusion in a 7-day pharmacokinetic (PK) run-in period (Cycle 0). This is followed by dose escalation (Cycle 1) for which participants will receive escalating doses of RO6874813 (starting dose = 1 mg/kg) via IV infusion every week (qw) or every 2 weeks (Q2W) for 28 to 42 days to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).
干预措施: RO6874813 (Biological)
结局指标
主要结局
Part 1: Percentage of Participants With Dose-Limiting Toxicity (DLT)
时间窗: 28 days
Part 1: Maximum Tolerated Dose (MTD) of RO6874813
时间窗: 28 days
Part 1: Recommended Phase 2 Dose (RP2D) of RO6874813
时间窗: 28 days
Parts 1 and 2: Percentage of Participants With Anti-Drug Antibodies (ADAs)
时间窗: Predose (Hour [Hr] 0) on Day 1 up to approximately 12 months; please see outcome measure description for detailed time frame
Q2W (1 cycle=14 days): Predose (Hr 0) on Day 1 of Run-in period (Part 1 only), Cycles 1, 3, 5, then every 2 cycles (up to approximately 12 months); QW (1 cycle=7 days): Predose on Day 1 of Run-in period (Part 1 only), Cycles 1, 2, 5, then every 2 cycles (up to approximately 12 months)
Part 3: Percentage of Participants With Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
时间窗: Baseline until disease progression (up to approximately 12 months)
Parts 1 and 2: Percentage of Participants With Adverse Events (AEs)
时间窗: Baseline up to approximately 24 months
Part 3: Percentage of Participants With Disease Control as Determined by the Investigator Using RECIST v1.1
时间窗: Baseline up to approximately 12 months
Part 3: Duration of Response (DoR) as Determined by the Investigator Using RECIST v1.1
时间窗: Baseline up to approximately 12 months
Part 3: Median Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1
时间窗: Baseline up to approximately 12 months
Part 3: Percentage of Participants Who are Progression-Free at Months 3 as Determined by the Investigator Using RECIST v1.1
时间窗: Month 3
Part 3: Percentage of Participants Who are Progression-Free at Month 6 as Determined by the Investigator Using RECIST v1.1
时间窗: Month 6
Part 3: Median Overall Survival (OS)
时间窗: Baseline until death (up to approximately 24 months)
Part 3: Percentage of Participants Who are Alive at Month 12
时间窗: Month 12
次要结局
- Parts 1, 2, and 3: Minimum Observed Serum Concentration (Cmin) of RO6874813(QW or Q2W: Predose (Hr 0) on Day 1 in Cycles 0, 1, 2, 3, 4, 5, 6, 7, and every 2 cycles thereafter (up to approximately 12 months))
- Parts 1, 2, and 3: Clearance (CL) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Volume at Steady State (Vss) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Observed Steady-State Concentration at the End of a Dosing Interval (Ctrough) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Change from Baseline in Body Weight Corrected Maximum Standardized Uptake Volume (SUVmax) as Measured by 2-[18F]Fluoro-2-Deoxyglucose Positron Emission Tomography ([18F]-FDG PET)(Baseline and 12 months)
- Part 1 and 2: Percentage of Participants With Objective Response as Determined by the Investigator Using RECIST v1.1(Baseline up to approximately 12 months)
- Part 3: Percentage of Participants With AEs(Baseline up to approximately 24 months)
- Parts 1, 2, and 3: Maximum Observed Serum Concentration (Cmax) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Half-Life (t1/2) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: AUC During One Dose Interval (AUCtau) of RO6874813(Q2W (1 cycle=14 days): Predose, EoI, 2, 6, 24, 72, 96, 168, and 240 hrs after EoI in Cycle 1 and QW (1 cycle=7 days): Predose, EoI, 2, 6, 24, 48, 72, and 96 hrs after EoI in Cycle 1)
- Parts 1, 2, and 3: Accumulation Ratio (RA) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Part 1 and 2: Percentage of Participants With Disease Control as Determined by the Investigator Using RECIST v1.1(Baseline up to approximately 12 months)
- Part 1 and 2: DOR as Determined by the Investigator Using RECIST v1.1(Baseline up to approximately 12 months)
- Part 1 and 2: Median PFS as Determined by the Investigator Using RECIST v1.1(Baseline up to approximately 12 months)
- Part 1 and 2: Percentage of Participants Who are Progression-Free at Month 6 as Determined by the Investigator Using RECIST v1.1(Month 6)
- Part 3: Percentage of Participants With ADAs(Predose (Hr 0) on Day 1 up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Time to Reach Cmax (Tmax) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)
- Parts 1, 2, and 3: Area Under the Concentration-Time Curve (AUC) of RO6874813(Predose (Hr 0) up to approximately 12 months; please see outcome measure description for detailed time frame)