An Open-Label, Multi-Center, Randomized, Dose-Escalation, Phase 1b Study to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6874281 in Combination With Atezolizumab ± Bevacizumab in Patients With Unresectable Advanced and/or Metastatic Renal Cell Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 69
- 试验地点
- 23
- 主要终点
- Percentage of Participants with Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is an open-label, multi-center, randomized, Phase 1b, adaptive, clinical study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic activity of RO6874281 in combination with atezolizumab with/without bevacizumab in participants with unresectable advanced and/or metastatic RCC. The study will consist of a dose-escalation part and an extension part.
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
- 未提供
排除标准
- •Symptomatic or untreated central nervous system (CNS) metastases
- •Participants with asymptomatic CNS metastases with previous or concomitant brain deficiencies, as defined in the protocol
- •Participants with confirmed bilateral pleural effusion
- •Episode of significant cardiovascular/cerebrovascular acute disease within 6 months prior to Cycle 1 Day 1
- •Active or uncontrolled infections
- •Human immunodeficiency virus (HIV) or active Hepatitis A, B, C, D and E virus (HAV, HBV, HCV, HDV and HEV) infection.
- •Major surgery or significant traumatic injury <28 days prior to Cycle 1 Day 1 (excluding fine needle biopsies) or anticipation of the need for major surgery during study treatment
- •Serious, non-healing wound; active ulcer; or untreated bone fracture
- •Proteinuria as demonstrated by a urine protein to creatinine ratio (UPCR) of >=1.0 at screening
- •History of, active or suspicion of autoimmune disease
- •Concurrent use of high dose of systemic steroids. The use of inhaled, topical and ophthalmic steroids is allowed.
研究组 & 干预措施
Escalation Part (Arm A): Atezolizumab, RO6874281
Participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has complete response (CR), treatment may be discontinued and reintroduced if progressive disease (PD), for a maximum duration of 24 months.
干预措施: Atezolizumab (Drug)
Escalation Part (Arm A): Atezolizumab, RO6874281
Participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has complete response (CR), treatment may be discontinued and reintroduced if progressive disease (PD), for a maximum duration of 24 months.
干预措施: RO6874281 (Drug)
Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Participants will receive RO6874281 in combination with atezolizumab and bevacizumab until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
干预措施: Atezolizumab (Drug)
Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Participants will receive RO6874281 in combination with atezolizumab and bevacizumab until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
干预措施: Bevacizumab (Drug)
Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Participants will receive RO6874281 in combination with atezolizumab and bevacizumab until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
干预措施: RO6874281 (Drug)
Extension Part (Arm A): Atezolizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: Atezolizumab (Drug)
Extension Part (Arm A): Atezolizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: RO6874281 (Drug)
Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: Atezolizumab (Drug)
Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: Bevacizumab (Drug)
Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: RO6874281 (Drug)
Extension Part (Arm C): Atezolizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: Atezolizumab (Drug)
Extension Part (Arm C): Atezolizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
干预措施: RO6874281 (Drug)
Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: Arm D is closed for future enrollment
干预措施: Atezolizumab (Drug)
Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: Arm D is closed for future enrollment
干预措施: Bevacizumab (Drug)
Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: Arm D is closed for future enrollment
干预措施: RO6874281 (Drug)
结局指标
主要结局
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
时间窗: Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
The first patient in each cohort and regimen will be observed for safety for one week after the administration of RO6874281and atezolizumab +-bevacizumab, prior to enrollment of additional patients in a cohort. The DLT will be counted for each dose separately and each patient will contribute one single representative data point.
Recommended Dose of RO6874281
时间窗: Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
The recommended dose is defined as the lowest safe dose with the best likelihood for clinical benefit.
Maximum Tolerated Dose (MTD) of RO6874281
时间窗: Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
The MTD is defined as the highest dose with less than 33% probability of dose limiting toxicity (DLT).
Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
时间窗: Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Objective response rate (ORR) defined as the number of patients who achieved an objective response (partial response (PR) plus complete response (CR)) confirmed 28 or more days later, as determined by the Investigator using RECIST v1.1 and modified RECIST criteria at any time during the study divided by the number of response-evaluable patients.
次要结局
- Area Under the Serum Concentration-Time Curve (AUC) for RO6874281(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Cmax of Atezolizumab(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- AUC of Bevacizumab(Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Serum Atezolizumab Concentration(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Serum RO6874281 Concentration(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Maximum Observed Serum Concentration (Cmax) of RO6874281(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Cmax of Bevacizumab(Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- AUC of Atezolizumab(Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Serum Bevacizumab Concentration(Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description))
- Density of Lymphocytes in Tumor Samples(Archival biopsy: Baseline; Fresh biopsies: Baseline, Day 8 of Cycle 4; Optional biopsies: Any time during the study conduct (1 cycle = 15 days) (up to 60 months))
- Percentage of Participants with Programmed Death-Ligand 1 (PD-L1) Status in Tumor Samples(Archival biopsy: Baseline; Fresh biopsies: Baseline, Day 8 of Cycle 4; Optional biopsies: Any time during the study conduct (1 cycle = 15 days) (up to 60 months))
- Percentage of Participants with CR as Determined by the Investigator Using RECIST v1.1(Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months))
- Percentage of Participants with Disease Control as Determined by the Investigator Using RECIST v1.1(Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months))
- Absolute Lymphocytes Count in Peripheral Blood(Screening until 120 days post last dose of study treatment (up to 60 months))
- Percentage of Participants with Anti-Drug Antibodies (ADA) to RO6874281(Baseline until 3 months post last dose of study treatment (detailed timeframe is provided in outcome measure description))
- Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1(Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months))
- Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1(From randomization until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months))
- Overall Survival (OS)(From randomization until death (up to 60 months))