A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study of Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Paclitaxel Compared With Placebo With Paclitaxel for Patients With Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 653
- 试验地点
- 161
- 主要终点
- Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population
研究概览
简要总结
This Phase 3, multicenter, randomized, double-blind, placebo controlled study is designed to evaluate the efficacy and safety of atezolizumab (MPDL3280A, an anti-programmed death-ligand 1 [PD-L1] antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in participants with previously untreated, inoperable locally advanced or metastatic, centrally confirmed TNBC. Participants will be randomized in a 2:1 ratio to receive atezolizumab or placebo plus paclitaxel until disease progression or unacceptable toxicity or end of study, whichever occurs first (maximum up to approximately 40 months). In addition, the Sponsor may decide to terminate the study at any time.
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)
盲法说明
The Sponsor and its agents; the study site personnel, including the investigator; and the participant will be blinded to treatment assignment.
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
- •Participants with locally advanced or metastatic, histologically documented TNBC (absence of human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PR] expression), not amenable to surgical therapy
- •Participants eligible for taxane monotherapy
- •No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable locally advanced or metastatic TNBC
- •Availability of formalin-fixed paraffin-embedded (FFPE) tumor block (preferred) or at least 17 unstained slides, collected ≤3 months prior to randomization, with an associated pathology report, if available. If a tumour sample taken within 3 months before randomisation is not available and a tumour biopsy is not clinically feasible, the primary surgical resection sample or the most recent FFPE tumour biopsy sample may be used. Of these additional options, the most recent sample should be used.
- •Eastern Cooperative Oncology Group performance status of 0 or 1
- •Life expectancy at least 12 weeks
- •Measurable disease, as defined by RECIST v1.1
- •Adequate hematologic and end-organ function
- •Negative human immunodeficiency virus (HIV) test at screening.
- •Negative hepatitis B surface antigen (HBsAg) test at screening
- •Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be performed only for patients who have a positive HBcAb test.
- •Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
- •Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug
- •For men and women of child bearing potential: agreement to remain abstinent or use protocol defined contraceptive measures during the treatment period and for at least 5 months after the last dose of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel
排除标准
- •Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 2 weeks prior to randomization
- •Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases
- •Leptomeningeal disease
- •Uncontrolled pleural effusion, pericardial effusion, or ascites
- •Uncontrolled tumor-related pain, or uncontrolled hypercalcemia or clinically significant (symptomatic) hypercalcemia
- •Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer)
- •Pregnant or breast-feeding women, or intending to become pregnant during the study
- •Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease, cardiovascular disease, and presence of an abnormal electrocardiogram (ECG)
- •Serious infection requiring antibiotics within 2 weeks prior to randomization, including but not limited to infections requiring hospitalization or IV antibiotics, such as bacteremia, or severe pneumonia
- •Major surgical procedure within 4 weeks prior to randomization or anticipation of the need for a major surgical procedure during the study other than for diagnosis
- •Treatment with investigational therapy within 30 days prior to initiation of study treatment
- •History of hypersensitivity reactions to study drug or any component of the study drug formulation
研究组 & 干预措施
Atezolizumab and Paclitaxel
Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
干预措施: Atezolizumab Placebo (Drug)
Placebo and Paclitaxel
Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
干预措施: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody (Drug)
Placebo and Paclitaxel
Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Atezolizumab and Paclitaxel
Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population
时间窗: From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months)
PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
时间窗: From Day 1 to disease progression (PD) or death from any cause, assessed up to primary completion date (approximately 26 months)
PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
次要结局
- Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Unconfirmed, Investigator-Assessed)(From Day 1 to PD, assessed up to primary completion date (approximately 26 months))
- Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed, Investigator-Assessed )(From Day 1 to PD, assessed up to primary completion date (approximately 26 months))
- Overall Survival (OS) in the ITT Population(From Day 1 to death from any cause, assessed up to end of study (up to approximately 36 months))
- Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Confirmed, Investigator-Assessed )(From Day 1 to PD, assessed up to primary completion date (approximately 26 months))
- Progression Free Survival by PD-L1 Status, Intent to Treat Population(From Day 1 up to primary completion date (approximately 26 months))
- Duration of Confirmed Response (C-DoR) in (C-DoR)-Evaluable Population(From objective response to PD, assessed up to primary completion date (approximately 26 months))
- Overall Survival (OS) in the PD-L1-Positive Subpopulation(From Day 1 to death from any cause, assessed up 36 months)
- Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1-Positive Population (Confirmed, Investigator-Assessed )(From Day 1 to PD, assessed up to primary completion date (approximately 26 months))
- Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in DOR-evaluable Population (Unconfirmed)(From objective response to PD, assessed up to primary completion date (approximately 26 months))
- Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response-evaluable Population(From Day 1 to PD, assessed up to primary completion date (approximately 26 months))
- Maximum Observed Serum Concentration (Cmax) of Atezolizumab in PK-evaluable Population(C1D1 30 min postdose)
- Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)(From Day 1 From baseline up to 64 months)
- Percentage of Participants Who Are Alive at 12 and 18 Months(From Day 1 to death from any cause, assessed up to 12 and 18 months)
- Time to Deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population(From Day 1 to deterioration, assessed up 64 months)
- Percentage of Participants Who Are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1(From Day 1 to PD or death from any cause, assessed up to 12 months)
- Minimum Observed Plasma Concentration (Cmin) of Paclitaxel(Pre-dose (0 hours) on Day 1 of Cycle 3 (1 Cycle = 28 days))
- Maximum Observed Plasma Concentration (Cmax) of Paclitaxel(Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3 (paclitaxel infusion duration= 60 min) (1 Cycle = 28 days))
- Percentage of Participants With Anti-Drug Antibodies' (ADAs) Against Atezolizumab in ADA Evaluable Population(Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at every 8 cycles thereafter until TD, at TD, and at 90-150 days after TD (maximum up to 45 months) (1 Cycle = 28 days))
- Overall Survival by PD-L1 Status, Intent to Treat Population(From Day 1 up to 66 months)
- Minimum Observed Serum Concentration (Cmin) of Atezolizumab in PK Evaluable Population(Pre-dose (0 hours) on Day 1 of Cycles 2-4 and at treatment discontinuation (TD), (approximately 9 months).)