A Phase Ia/Ib Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Tiragolumab as a Single Agent and in Combination With Atezolizumab and/or Other Anti-Cancer Therapies in Patients With Locally Advanced or Metastatic Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 518
- 试验地点
- 28
- 主要终点
- Percentage of Participants with Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This first-in-human open-label, multicenter, dose-escalation and expansion study is designed to evaluate the safety, tolerability, and PK of tiragolumab alone or in combination with atezolizumab and/or other anti-cancer therapies in participants with locally advanced, recurrent, or metastatic incurable tumors for whom standard therapy does not exist, has proven to be ineffective or intolerable, or is considered inappropriate, or for whom a clinical trial of an investigational agent is a recognized standard of care.
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
- •Adults 18 years of age or older
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy at least 12 weeks
- •Adequate hematologic and end organ function
- •Histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for which standard therapy has proven ineffective, intolerable, or considered inappropriate; or for which a clinical trial of an investigational agent is a recognized standard of care
- •Confirmed availability of representative tumor specimens
- •Measurable disease according to RECIST Version 1.1
排除标准
- •Any anti-cancer therapy, whether investigational or approved, including chemotherapy, hormonal therapy, or radiotherapy, within 3 weeks prior to initiation of study treatment
- •Malignancies other than disease under study within 5 years prior to Day 1 of Cycle 1
- •Primary central nervous system (CNS) malignancy, or untreated/active CNS metastases
- •Leptomeningeal disease
- •History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on Screening chest computed tomograph (CT) scan
- •History of autoimmune disease
- •Positive human immunodeficiency virus (HIV) test
- •Active hepatitis B or C, or tuberculosis
- •Severe infection within 4 weeks prior to randomization
- •Prior allogeneic bone marrow or solid organ transplant
- •Significant cardiovascular disease
- •Known clinically significant liver disease
研究组 & 干预措施
Phase Ia Dose-Escalation Stage: Tiragolumab
Cohorts of at least 3 participants each will be treated with escalating doses of tiragolumab.
干预措施: Tiragolumab (Drug)
Phase Ia Dose-Expansion Stage: Tiragolumab
Participants will be treated with tiragolumab at or below the maximum tolerated dose (MTD) or maximum administered dose (MAD) in the study.
干预措施: Tiragolumab (Drug)
Phase Ib Q3W Dose-Escalation Stage: Tiragolumab+Atezolizumab
A minimum of 3 participants will be treated for each dose level of tiragolumab in combination with a fixed dose of atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Atezolizumab (Drug)
Phase Ib Q3W Dose-Escalation Stage: Tiragolumab+Atezolizumab
A minimum of 3 participants will be treated for each dose level of tiragolumab in combination with a fixed dose of atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Tiragolumab (Drug)
Phase Ib Q3W Dose-Expansion Stage: Tiragolumab+Atezolizumab
Participants will be treated every 3 weeks (Q3W) with tiragolumab at or below the MTD or MAD in combination with a fixed dose of atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Atezolizumab (Drug)
Phase Ib Q3W Dose-Expansion Stage: Tiragolumab+Atezolizumab
Participants will be treated every 3 weeks (Q3W) with tiragolumab at or below the MTD or MAD in combination with a fixed dose of atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Tiragolumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort A
In Cohort A, carboplatin or cisplatin and pemetrexed chemotherapy will be administered after atezolizumab and tiragolumab intravenous (IV) infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin and pemetrexed on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab in combination with pemetrexed on Day 1 of each 21-day cycle.
干预措施: Atezolizumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort A
In Cohort A, carboplatin or cisplatin and pemetrexed chemotherapy will be administered after atezolizumab and tiragolumab intravenous (IV) infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin and pemetrexed on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab in combination with pemetrexed on Day 1 of each 21-day cycle.
干预措施: Tiragolumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort A
In Cohort A, carboplatin or cisplatin and pemetrexed chemotherapy will be administered after atezolizumab and tiragolumab intravenous (IV) infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin and pemetrexed on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab in combination with pemetrexed on Day 1 of each 21-day cycle.
干预措施: Carboplatin (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort A
In Cohort A, carboplatin or cisplatin and pemetrexed chemotherapy will be administered after atezolizumab and tiragolumab intravenous (IV) infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin and pemetrexed on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab in combination with pemetrexed on Day 1 of each 21-day cycle.
干预措施: Cisplatin (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort A
In Cohort A, carboplatin or cisplatin and pemetrexed chemotherapy will be administered after atezolizumab and tiragolumab intravenous (IV) infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin and pemetrexed on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab in combination with pemetrexed on Day 1 of each 21-day cycle.
干预措施: Pemetrexed (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort B
In Cohort B, carboplatin and paclitaxel chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin and paclitaxel on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle (participants enrolled under protocol version 4) or Day 1 of each 28-day cycle (participants enrolled under protocol version 5).
干预措施: Atezolizumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort B
In Cohort B, carboplatin and paclitaxel chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin and paclitaxel on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle (participants enrolled under protocol version 4) or Day 1 of each 28-day cycle (participants enrolled under protocol version 5).
干预措施: Tiragolumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort B
In Cohort B, carboplatin and paclitaxel chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin and paclitaxel on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle (participants enrolled under protocol version 4) or Day 1 of each 28-day cycle (participants enrolled under protocol version 5).
干预措施: Carboplatin (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort B
In Cohort B, carboplatin and paclitaxel chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin and paclitaxel on Day 1 of each 21-day cycle for 4 to 6 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle (participants enrolled under protocol version 4) or Day 1 of each 28-day cycle (participants enrolled under protocol version 5).
干预措施: Paclitaxel (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort C
In Cohort C, carboplatin or cisplatin and etoposide chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin on Day 1 of each 21-day cycle and etoposide on Day 1 to 3 of each 21-day cycle for 4 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 28-day cycle.
干预措施: Atezolizumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort C
In Cohort C, carboplatin or cisplatin and etoposide chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin on Day 1 of each 21-day cycle and etoposide on Day 1 to 3 of each 21-day cycle for 4 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 28-day cycle.
干预措施: Tiragolumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort C
In Cohort C, carboplatin or cisplatin and etoposide chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin on Day 1 of each 21-day cycle and etoposide on Day 1 to 3 of each 21-day cycle for 4 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 28-day cycle.
干预措施: Carboplatin (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort C
In Cohort C, carboplatin or cisplatin and etoposide chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin on Day 1 of each 21-day cycle and etoposide on Day 1 to 3 of each 21-day cycle for 4 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 28-day cycle.
干预措施: Cisplatin (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort C
In Cohort C, carboplatin or cisplatin and etoposide chemotherapy will be administered after atezolizumab and tiragolumab IV infusion. During induction phase, participants will receive atezolizumab and tiragolumab in combination with carboplatin or cisplatin on Day 1 of each 21-day cycle and etoposide on Day 1 to 3 of each 21-day cycle for 4 cycles. During maintenance phase, participants will receive atezolizumab and tiragolumab on Day 1 of each 28-day cycle.
干预措施: Etoposide (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort D
In Cohort D, participants will receive atezolizumab and tiragolumab on Day 1 and capecitabine on Day 1-14 of each 21-day cycle.
干预措施: Atezolizumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort D
In Cohort D, participants will receive atezolizumab and tiragolumab on Day 1 and capecitabine on Day 1-14 of each 21-day cycle.
干预措施: Tiragolumab (Drug)
Phase Ib Chemotherapy Dose-Expansion Stage: Cohort D
In Cohort D, participants will receive atezolizumab and tiragolumab on Day 1 and capecitabine on Day 1-14 of each 21-day cycle.
干预措施: Capecitabine (Drug)
Phase Ib Q4W Sequential Dose-Expansion Stage: Tiragolumab+Atezolizumab
Participants will be treated every 4 weeks (Q4W) with fixed doses of tiragolumab and atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Atezolizumab (Drug)
Phase Ib Q4W Sequential Dose-Expansion Stage: Tiragolumab+Atezolizumab
Participants will be treated every 4 weeks (Q4W) with fixed doses of tiragolumab and atezolizumab with tiragolumab being administered prior to atezolizumab.
干预措施: Tiragolumab (Drug)
Phase Ib Q4W Coinfusion Expansion Cohort Tiragolumab+Atezolizumab
Participants will be treated Q4W with fixed doses of tiragolumab and atezolizumab mixed and administered in one IV bag.
干预措施: Atezolizumab (Drug)
Phase Ib Q4W Coinfusion Expansion Cohort Tiragolumab+Atezolizumab
Participants will be treated Q4W with fixed doses of tiragolumab and atezolizumab mixed and administered in one IV bag.
干预措施: Tiragolumab (Drug)
Phase Ib Non-Chemotherapy Dose-Expansion Stage: Cohort NC1
In Cohort NC1, participants will receive atezolizumab and tiragolumab in combination with bevacizumab on Day 1 of each 21-day cycle.
干预措施: Atezolizumab (Drug)
Phase Ib Non-Chemotherapy Dose-Expansion Stage: Cohort NC1
In Cohort NC1, participants will receive atezolizumab and tiragolumab in combination with bevacizumab on Day 1 of each 21-day cycle.
干预措施: Tiragolumab (Drug)
Phase Ib Non-Chemotherapy Dose-Expansion Stage: Cohort NC1
In Cohort NC1, participants will receive atezolizumab and tiragolumab in combination with bevacizumab on Day 1 of each 21-day cycle.
干预措施: Bevacizumab (Drug)
Phase Ib Non-Chemotherapy Dose-Expansion Stage: Cohort NC2
In Cohort NC2, participants will receive tiragolumab in combination with pembrolizumab on Day 1 of each 21-day cycle.
干预措施: Tiragolumab (Drug)
Phase Ib Non-Chemotherapy Dose-Expansion Stage: Cohort NC2
In Cohort NC2, participants will receive tiragolumab in combination with pembrolizumab on Day 1 of each 21-day cycle.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
时间窗: From Baseline to the end of Cycle 1 (up to 21 days)
Number of Cycles with Tiragolumab
时间窗: From Baseline to last dose (up to approximately 8 years)
Percentage of Participants with Adverse Events (AEs) Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0
时间窗: From Baseline up to 90 days after last dose of study treatment or until initiation of another systemic anti-cancer therapy (up to approximately 8 years)
Phase Ib: Percentage of Participants with ADAs to Atezolizumab
时间窗: Day 1 up to 8 years
Phase 1b (without Chemotherapy): Pre-dose on Day 1, Cycles 1-4, 8, then Q8C, at DC, every 30 days up to 120 days (cycle length 21 days); Phase 1b (Chemotherapy Cohorts and Q4W): Pre-dose on Day 1, Cycles 1-4, 8, 12 and 16, then DC (cycle length 21/28 days).
Phase Ia and Ib: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Tiragolumab
时间窗: Day 1 up to 8 years
Phase (Ph) 1a: Pre-dose on Day 1, Cycles 1-4, 8, 16, every eight cycles (Q8C), at discontinuation (DC), every 30 days up to 120 days (cycle length 21 days); Phase 1b without Chemotherapy: Pre-dose on Day 1, Cycles 1-4, 8, then Q8C, DC (cycle length 21 days); Phase 1b (Chemotherapy Cohorts and Q4W): Pre-dose on Day 1, Cycles 1-4, 8, 12 and 16, then DC (cycle length 21/28 days).
次要结局
- Maximum Serum Concentration (Cmax) of Tiragolumab(Day 1 up to 8 years)
- Plasma Concentration of Cisplatin(Pre-dose (5 min) and post-dose (1 hour) on Day 1 of Cycles 1 and 3 (cycle length 21 days))
- Plasma Concentration of Capecitabine(Pre-dose (5 min) on Day 1 of Cycle 1 and post-dose (2 hours) on Day 1 of Cycle 3 (cycle length 21 days))
- Progression-Free Survival (PFS) According to RECIST Version 1.1(From Baseline until disease progression (up to 8 years))
- Cmin of Atezolizumab(Day 1 up to 8 years)
- Plasma Concentration of Etoposide(Pre-dose (5 min) and post-dose (1 hour) on Day 1 of Cycles 1 and 3 (cycle length 21 days))
- Duration of Objective Response (DOR) According to RECIST Version 1.1(From Baseline until disease progression (up to 8 years))
- Overall survival (OS) According to RECIST Version 1.1(Baseline until death from any cause (up to approximately 8 years))
- Area Under the Concentration-Time Curve (AUC) of Tiragolumab(Day 1 up to 8 years)
- Minimum Serum Concentration (Cmin) of Tiragolumab(Day 1 up to 8 years)
- Plasma Concentration of Carboplatin(Pre-dose (5 min) and post-dose (1 hour) on Day 1 of Cycles 1 and 3 (cycle length 21 days))
- Plasma Concentration of Pemetrexed(Pre-dose (5 min) and post-dose (1 hour) on Day 1 of Cycles 1 and 3 (cycle length 21 days))
- Volume of Distribution at Steady State (Vss) of Tiragolumab(Day 1 up to 8 years)
- Cmax of Atezolizumab(Day 1 up to 8 years)
- Plasma Concentration of Paclitaxel(Pre-dose (5 min) and post-dose (1 hour) on Day 1 of Cycles 1 and 3 (cycle length 21 days))
- Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(From Baseline until disease progression (up to 8 years))
- Clearance (CL) of Tiragolumab(Day 1 up to 8 years)