A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 558
- 试验地点
- 119
- 主要终点
- Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population
研究概览
简要总结
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who have received no prior systemic treatment.
详细描述
The participants will be randomized in a 2:1 ratio to one of the two treatment arms: Arm A (experimental arm): Atezolizumab +bevacizumab; Arm B (control arm): Sorafenib
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
- 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
- •Locally advanced or metastatic and/or unresectable Hepatocellular Carcinoma (HCC)
- •No prior systemic therapy for HCC. Previous use of herbal therapies/traditional Chinese medicines with anti-cancer activity included in the label is allowed, provided that these medications are discontinued prior to randomization.
- •At least one measurable untreated lesion
- •ECOG Performance Status of 0 or 1
- •Adequate hematologic and end-organ function
- •For women of childbearing potential: agreement to remain abstinent
- •For men: agreement to remain abstinent
- •Child-Pugh class A
排除标准
- •History of leptomeningeal disease
- •Active or history of autoimmune disease or immune deficiency
- •History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
- •Known active tuberculosis
- •History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
- •Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last dose of sorafenib
- •Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
- •Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
- •A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
- •Moderate or severe ascites
- •History of hepatic encephalopathy
- •Co-infection of HBV and HCV
- •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
- •Uncontrolled or symptomatic hypercalcemia
- •Treatment with systemic immunostimulatory agents
- •Inadequately controlled arterial hypertension
- •Prior history of hypertensive crisis or hypertensive encephalopathy
- •Evidence of bleeding diathesis or significant coagulopathy
- •History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
- •Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
- •Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
- •Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
- •Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID)
研究组 & 干预措施
Atezolizumab + Bevacizumab
Participants will receive Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator
干预措施: Atezolizumab (Drug)
Atezolizumab + Bevacizumab
Participants will receive Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator
干预措施: Bevacizumab (Drug)
Sorafenib
Participants will receive Sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator
干预措施: Sorafenib (Drug)
结局指标
主要结局
Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population
时间窗: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Overall Survival (OS) in the Global Population
时间窗: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)
OS was defined as the time from randomization to death from any cause.
PFS-IRF Per RECIST v1.1 in the China Population
时间窗: Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of \>/= 5 millimeters (mm).
Overall Survival (OS) in the China Population
时间窗: From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 months)
OS was defined as the time from randomization to death from any cause.
次要结局
- Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population(Post-dose on Day 1 of Cycle 1 (cycle length = 21 days))
- Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS-IRF Per HCC mRECIST in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS-INV Per RECIST v1.1 by Baseline AFP in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS-IRF Per RECIST v1.1 by Baseline AFP in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- TTP-IRF Per HCC mRECIST in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Objective Response Rate by IRF-Assessment (ORR-IRF) Per RECIST v1.1 in the Global Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Objective Response Rate by IRF-Assessment (ORR-IRF) Per Hepatocellular Carcinoma (HCC) Modified RECIST (mRECIST) in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Duration of Response by IRF-Assessment (DOR-IRF) Per RECIST v1.1 in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- TTP-IRF Per HCC mRECIST in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Overall Survival by Baseline AFP in the Global Population(From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Number of Participants With Adverse Events (AEs) in the Global Population(Up to end of study (up to approximately 56 months))
- Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population(Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 months))
- ORR by Investigator-Assessment (ORR-INV) Per RECIST v1.1 in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS-IRF Per HCC mRECIST in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Time to Deterioration (TTD) in the Global Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population(Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days))
- Duration of Response by Investigator Assessment (DOR-INV) Per RECIST v1.1 in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- PFS by Investigator Assessment (PFS-INV) Per RECIST v1.1 in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Duration of Response by IRF Assessment (DOR-IRF) Per HCC mRECIST in the China Population(Randomization up to CCOD of 29Aug2019 (up to approximately 18 months))
- Time to Progression (TTP) by IRF Assessment (TTP-IRF) Per RECIST v1.1 in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Time to Deterioration (TTD) in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population(Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months))
- TTP by Investigator Assessment (TTP-INV) Per RECIST v1.1 in the China Population(Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months))
- Number of Participants With Adverse Events (AEs) in the China Population(Up to end of study (up to approximately 56 months))
- Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population(Post-dose on Day 1 of Cycle 1 (cycle length = 21 days))
- Trough Serum Concentration (Cmin) of Atezolizumab in the China Population(Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length = 21 days))