A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab Plus Tiragolumab in Combination With Paclitaxel and Cisplatin Compared With Paclitaxel and Cisplatin as First-Line Treatment in Patients With Unresectable Locally Advanced, Unresectable Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 461
- 试验地点
- 130
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of atezolizumab plus tiragolumab in combination with paclitaxel and cisplatin (PC) compared with atezolizumab matching placebo plus tiragolumab matching placebo plus PC as first-line treatment in participants with unresectable locally advanced, unresectable recurrent, or metastatic esophageal carcinoma (EC). Participants will be randomized in a 1:1 ratio to receive one of the following treatment regimens during induction phase:
Arm A: Atezolizumab plus Tiragolumab and PC Arm B: Atezolizumab placebo plus Tiragolumab placebo and PC Following the induction phase, participants will continue maintenance therapy with either atezolizumab plus tiragolumab (Arm A) or atezolizumab matching placebo plus tiragolumab matching placebo (Arm B).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Histologically confirmed EC
- •Unresectable locally advanced, unresectable recurrent, or metastatic disease
- •Measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Adequate hematologic and end-organ function
- •Female participants must be willing to avoid pregnancy and refrain from donating eggs during the treatment period and for 90 days after the final dose
- •Male participants with partners of childbearing potential must commit to the use of two methods of contraception and must not donate sperm for the study duration and 90 days after the final dose
排除标准
- •Palliative radiation treatment for EC within 4 weeks prior to initiation of study treatment
- •Evidence of complete esophageal obstruction not amenable to treatment
- •Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
- •Uncontrolled tumor-related pain, uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- •Active or history of autoimmune disease or immune deficiency or leptomeningeal disease
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
- •Malignancies other than EC within 2 years prior to screening with a negligible risk of metastasis or death adequately treated with expected curative outcome
- •Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety
- •Positive test result for human immunodeficiency virus (HIV)
- •Active hepatitis B or hepatitis C
- •Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-CTLA-4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •Treatment with any investigational therapy prior to initiation of study treatment
- •Poor peripheral venous access
- •Prior allogeneic stem cell or solid organ transplantation
- •Concurrent participation in another therapeutic clinical trial
研究组 & 干预措施
Atezolizumab + Tiragolumab + PC
Participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Atezolizumab (Drug)
Atezolizumab + Tiragolumab + PC
Participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Tiragolumab (Drug)
Atezolizumab + Tiragolumab + PC
Participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Paclitaxel (Drug)
Atezolizumab + Tiragolumab + PC
Participants will receive atezolizumab and tiragolumab on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Cisplatin (Drug)
Placebo + PC
Participants will receive atezolizumab matching placebo and tiragolumab matching placebo on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Paclitaxel (Drug)
Placebo + PC
Participants will receive atezolizumab matching placebo and tiragolumab matching placebo on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Cisplatin (Drug)
Placebo + PC
Participants will receive atezolizumab matching placebo and tiragolumab matching placebo on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Atezolizumab Matching Placebo (Drug)
Placebo + PC
Participants will receive atezolizumab matching placebo and tiragolumab matching placebo on Day 1 of each 21-day cycle during the study followed by paclitaxel and cisplatin on Day 1 of each 21-day cycle until disease progression, loss of clinical benefit or unacceptable toxicity, during the induction treatment phase.
干预措施: Tiragolumab Matching Placebo (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: From randomization to death from any cause (up to approximately 35 months)
Independent Review Facility (IRF)-Assessed Progression-Free Survival (PFS)
时间窗: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 35 months)
Independent Review Facility (IRF)-Assessed Progression-free Survival (PFS)
时间窗: From randomization to the first occurrence of PD or death from any cause, whichever occurred first (up to approximately 19 months)
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause (whichever occurred first), as determined by an IRF according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm) or unequivocal progression of existing non-target lesions. Kaplan-Meier (KM) method was used to estimate median PFS.
Overall Survival (OS)
时间窗: From randomization to death from any cause (up to approximately 27.5 months)
OS was defined as the time from randomization to death from any cause. K-M method was used to estimate median OS.
次要结局
- Investigator-Assessed Confirmed ORR(From randomization up to approximately 35 months)
- Investigator-Assessed DOR(From the first occurrence of a documented confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 35 months))
- IRF-Assessed Duration of Objective Response (DOR)(From the first occurrence of a documented confirmed objective response to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 35 months))
- Investigator-Assessed PFS(From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to approximately 35 months))
- IRF-Assessed Confirmed Objective Response Rate (ORR)(From randomization up to approximately 35 months)
- Time to Confirmed Deterioration (TTCD) in Participant-Reported Physical Functioning, Role Functioning and Global Health Status (GHS)/Quality of Life (QoL) as Measured by EORTC QLQ-C30(From randomization until the first confirmed clinically meaningful deterioration (up to approximately 35 months))
- TTCD in Participant-Reported Dysphagia as Measured by EORTC QLQ-OES18(From randomization until the first confirmed clinically meaningful deterioration (up to approximately 35 months))
- Percentage of Participants With Adverse Events (AEs)(Up to approximately 35 months)
- Minimum Serum Concentration (Cmin) of Tiragolumab(Cycle 1 (cycle=21 days), Day 1: predose, 0.5 hour (h) postdose; Cycles 2, 3, 4, 8, 12, 16, Day 1: predose and at treatment discontinuation (TD) visit (up to approximately 35 months))
- Maximum Serum Concentration (Cmax) of Tiragolumab(Cycle 1 (cycle=21 days), Day 1: predose, 0.5h postdose; Cycles 2, 3, 4, 8, 12, 16: Day 1: predose and at TD visit (up to approximately 35 months))
- Cmin of Atezolizumab(Cycle 1 (cycle=21 days): Day 1 (predose, 0.5 h postdose); Cycles 2, 3, 4, 8, 12, 16: Day 1 (predose) and at TD visit (up to approximately 35 months))
- Cmax of Atezolizumab(Cycle 1 (cycle=21 days): Day 1 (predose, 0.5 h postdose); Cycles 2, 3, 4, 8, 12, 16: Day 1 (predose) and at TD visit (up to approximately 35 months))
- Percentage of Participants With Anti-drug Antibodies (ADAs) to Tiragolumab(Predose on Day 1 of Cycles (cycle=21 days) 1, 2, 3, 4, 8, 12 and 16 and at TD visit (up to approximately 35 months))
- Percentage of Participants With ADAs to Atezolizumab(Predose on Day 1 of Cycles (cycle=21 days) 1, 2, 3, 4, 8, 12 and 16 and at TD visit (up to approximately 35 months))
- Cmax of Atezolizumab(30 minutes post-dose on Day 1 of Cycle 1 (1 Cycle=21 days))
- Investigator-assessed PFS(From randomization to the first occurrence of PD or death from any cause, whichever occurs first (up to approximately 19 months))
- IRF-assessed Confirmed Objective Response Rate (ORR)(Up to approximately 19 months)
- Investigator-assessed Confirmed ORR(Up to approximately 19 months)
- IRF-assessed Duration of Objective Response (DOR)(From the first occurrence of a of a confirmed OR to PD or death from any cause, whichever occurred first (up to approximately 19 months))
- Investigator-assessed DOR(From the first occurrence of a of a confirmed OR to PD or death from any cause, whichever occurred first (up to approximately 19 months))
- Time to Confirmed Deterioration (TTCD) in Participant-reported Physical Functioning, as Measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)(Up to approximately 27 months)
- TTCD in Participant-reported Role Functioning (RF), as Measured by EORTC QLQ-C30(Up to approximately 27 months)
- TTCD in Participant-Reported GHS/QoL, as Measured by EORTC QLQ-C30(Up to approximately 27 months)
- TTCD in Participant-reported Dysphagia, as Measured by European Organisation for Research and Treatment of Cancer Quality-of-life Esophageal Cancer, Module 18 Questionnaire (EORTC QLQ-OES18)(Up to approximately 27 months)
- Number of Participants With Adverse Events (AEs)(Up to approximately 49.6 months)
- Number of Participants With Cytokine-release Syndrome (CRS), With Severity Determined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading Scale(Up to approximately 49.6 months)
- Minimum Serum Concentration (Cmin) of Tiragolumab(Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, and 16 (1 Cycle=21 days))
- Maximum Serum Concentration (Cmax) of Tiragolumab(30 minutes post-dose on Day 1 of Cycle 1 (1 Cycle=21 days))
- Cmin of Atezolizumab(Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12, and 16 (1 Cycle=21 days))
- Number of Participants With Anti-drug Antibodies (ADAs) to Tiragolumab(Up to approximately 27.5 months)
- Number of Participants With ADAs to Atezolizumab(Up to approximately 27.5 months)