A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 808
- 试验地点
- 315
- 主要终点
- Progression-Free Survival (PFS) Determined by an Independent Review Facility
研究概览
简要总结
This study was a Phase III, randomized, double-blind, placebo-controlled, multicenter international clinical trial conducted to investigate the use of pertuzumab in combination with trastuzumab and docetaxel as first-line treatment for participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Participants could have received one prior hormonal treatment for MBC. Participants may have received systemic breast cancer treatment in the neo-adjuvant or adjuvant setting, provided that the participant had experienced a disease-free interval (DFI) of greater than or equal to (≥)12 months from completion of adjuvant systemic treatment (excluding hormonal therapy) to metastatic diagnosis. Participants may have received trastuzumab and/or a taxane during the neo-adjuvant or adjuvant treatment.
Participants were randomized in 1:1 ratio to receive either pertuzumab or placebo, along with trastuzumab and docetaxel once every 3 weeks (q3w), during the treatment phase of the study until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. Participants in the Placebo arm were not allowed to receive open-label pertuzumab after discontinuation from study treatment. However, if any analysis of overall survival had met the predefined criteria for statistical significance, participants in the Placebo arm still on treatment were offered the option to receive open-label pertuzumab in addition to other study medications.
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
- Triple (Participant, 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 or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Participants with measurable and non-measurable disease are eligible (locally recurrent disease must not be amenable to resection with curative intent; participants with de novo Stage IV disease are eligible)
- •Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC)
- •Left ventricular ejection fraction (LVEF) ≥50 percent (%) at baseline (within 42 days of randomization)
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- •For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective form of contraception and to continue its use for the duration of study treatment and for at least 7 months after the last dose of study treatment
排除标准
- •History of anti-cancer therapy for MBC (with the exception of one prior hormonal regimen for MBC, which must be stopped prior to randomization)
- •History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting
- •History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of less than (<)12 months
- •History of persistent Grade ≥2 hematologic toxicity resulting from previous adjuvant therapy
- •Current peripheral neuropathy of National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0, Grade ≥3 at randomization
- •History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent
- •Current clinical or radiographic evidence of central nervous system (CNS) metastases
- •Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is mandatory in cases of clinical suspicion of brain metastases
- •History of exposure to cumulative doses of anthracyclines
- •Current uncontrolled hypertension or unstable angina
- •History of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception: atrial fibrillation or paroxysmal supraventricular tachycardia)
- •History of myocardial infarction within 6 months of randomization
- •History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy
- •Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
- •Inadequate organ function, as defined in the protocol, within 28 days prior to randomization
- •Current severe, uncontrolled systemic disease
- •Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
- •Pregnant or lactating women
- •History of receiving any investigational treatment within 28 days of randomization
- •Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
- •Receipt of IV antibiotics for infection within 14 days of randomization
- •Current chronic daily treatment with corticosteroids (excluding inhaled steroids)
- •Known hypersensitivity to any of the study drugs
- •Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
研究组 & 干预措施
Pertuzumab + Trastuzumab + Docetaxel
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Pertuzumab (Drug)
Pertuzumab + Trastuzumab + Docetaxel
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Trastuzumab (Drug)
Pertuzumab + Trastuzumab + Docetaxel
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Docetaxel (Drug)
Placebo + Trastuzumab + Docetaxel
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Placebo (Drug)
Placebo + Trastuzumab + Docetaxel
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Trastuzumab (Drug)
Placebo + Trastuzumab + Docetaxel
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
干预措施: Docetaxel (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) Determined by an Independent Review Facility
时间窗: Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)
PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
次要结局
- Progression-Free Survival (PFS) Determined by the Investigator(Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in pertuzumab vs. placebo arms: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks))
- Duration of Objective Response Determined by an Independent Review Facility(From initial IRF-confirmed objective response until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months))
- Time to Symptom Progression(Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months))
- Objective Response Determined by an Independent Review Facility(Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months))
- Overall Number of Participants Who Experienced at Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period(Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm))
- Overall Survival(From randomization to death from any cause, up to each respective analysis data cut-off date (see the Description field for the median time on study per treatment arm))
- Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3 to 5) Per 100 Patient-Years of Exposure During the Treatment Period(From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo vs. Pertuzumab arms: 526.81 vs. 989.88 patient-years))
- Cardiac-Related AEs to Monitor: Number of Participants Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious AE Suggestive of Congestive Heart Failure by Severity During the Treatment Period(Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm))
- Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period(From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years))
- Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period(Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks))
- Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period(On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm))
- Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period(Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm))
- Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication(Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm))
- Overall Number of Participants Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication(Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm))
- Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period(Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm))
- Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period(On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm))