A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) as Monotherapy and in Combination With Platinum-Based Chemotherapy in Patients With Untreated Locally Advanced or Metastatic Urothelial Carcinoma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,213
- 试验地点
- 204
- 主要终点
- Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm
研究概览
简要总结
A Phase III, randomised study of atezolizumab alone and in combination with chemotherapy versus chemotherapy alone in participants with untreated advanced urothelial cancer.
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
- Double (Participant, Investigator)
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
- •Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
- •Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to enrolment
- •Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments
- •Participants with treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: * Evaluable or measurable disease outside the CNS * No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm) * No history of intracranial or spinal cord hemorrhage * No ongoing requirement for corticosteroid as therapy for CNS disease; anti-convulsants at a stable dose are allowed * No evidence of significant vasogenic edema * No stereotactic radiation, whole-brain radiation or neurosurgical resection within 4 weeks prior to Cycle 1, Day 1 * Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNS-directed therapy and the screening radiographic study * Screening CNS radiographic study >/=4 weeks since completion of radiotherapy or surgical resection and >/=2 weeks since discontinuation of corticosteroids
- •Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
- •Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1 or anticipated requirement for systemic immunosuppressive medications during the study
- •Leptomeningeal disease
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- •Uncontrolled tumour-related pain or hypercalcemia
- •Significant cardiovascular disease including known left ventricular ejection fraction (LVEF) <40%
- •Severe infections within 4 weeks before randomization or therapeutic oral or IV antibiotics within 2 weeks before randomization
- •Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
- •Malignancies other than urothelial carcinoma within 5 years prior to Cycle 1, Day 1
- •Life expectancy of <12 weeks
- •Pregnant or lactating, or intending to become pregnant during the study
- •Serum albumin <25 gram per liter (g/L)
- •History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- •Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
- •History of autoimmune disease
- •Participants with prior allogeneic stem cell or solid organ transplantation
- •History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
- •Positive test for human immunodeficiency virus (HIV)
- •Active hepatitis B or hepatitis C
- •Active tuberculosis
- •Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
研究组 & 干预措施
Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Atezolizumab (Drug)
Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Carboplatin (Drug)
Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Gemcitabine (Drug)
Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Cisplatin (Drug)
Placebo+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Carboplatin (Drug)
Placebo+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Gemcitabine (Drug)
Placebo+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Placebo (Other)
Placebo+Gemcitabine+Carboplatin/Cisplatin
Participants will receive blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
干预措施: Cisplatin (Drug)
Atezolizumab Monotherapy
Eligible participants will receive open-label atezolizumab as monotherapy.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm
时间窗: Baseline up to first documented disease progression or death, whichever occurs first (up to approximately 35 months)
PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first.
Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
时间窗: Baseline until death due to any cause (up to approximately 73 months)
OS is defined as the time from randomization to death due to any cause.
Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm
时间窗: Baseline until death due to any cause (up to approximately 73 months)
OS is defined as the time from randomization to death due to any cause.
次要结局
- Objective Response Rate (ORR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months))
- Objective Response Rate (ORR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months))
- Duration of Response (DOR) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months))
- Duration of Response (DOR) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months))
- IRF-PFS(Randomization to first documented disease progression or death from any cause (up to 35 months))
- OS Event Free Rate Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(Year 1)
- OS Event Free Rate in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(Year 1)
- PFS Event Free Rate(Year 1)
- Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm(Up to approximately 73 months)
- Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm(Up to approximately 73 months)
- Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm(Up to approximately 73 months)
- Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm(Up to approximately 73 months)
- Maximum Atezolizumab Serum Concentration(Cycle 1 Day 1)
- Minimum Atezolizumab Serum Concentration(Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 32 Day 1, Day 120 post dose of last blinded atezolizumab treatment, and study drug early discontinuation)
- Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs)(Up to approximately 35 months)
- Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated With Atezolizumab Monotherapy Arm Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin Arm(Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (assessed at baseline, every 9 weeks for 54 weeks and every 12 weeks thereafter up to 35 months))
- Percentage of Participants With Grade 3-4 Adverse Events (AEs)(Baseline up to 93 months)
- Percentage of Participants With Grade 5 Adverse Events (AEs)(Baseline up to 93 months)
- Percentage of Participants With Serious Adverse Events (SAEs)(Baseline up to 93 months)
- Percentage of Participants With Adverse Events (AEs) Leading to Withdrawal of Any Study Treatment(Baseline up to 93 months)
- Percentage of Participants With Atezolizumab-Specific Adverse Events of Special Interest (AESIs)(Baseline up to 93 months)