A Randomized Phase III Double-Blind Placebo-Controlled Trial of First-Line Chemotherapy and Trastuzumab With or Without Bevacizumab for Patients With HER-2/NEU Over-Expressing Metastatic Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 96
- 试验地点
- 746
- 主要终点
- Progression-free Survival
研究概览
简要总结
This randomized phase III trial studies first-line chemotherapy and trastuzumab to compare how well they work when given with or without bevacizumab in treating patients with breast cancer that overexpresses human epidermal growth factor receptor 2 (HER-2/NEU) and has spread to other areas of the body. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether giving first-line chemotherapy together with trastuzumab is more effective with or without bevacizumab in treating patients with metastatic breast cancer that overexpresses HER-2/NEU.
详细描述
PRIMARY OBJECTIVES:
I. Evaluate efficacy of the addition of bevacizumab in patients eligible for first-line trastuzumab with chemotherapy for HER-2/NEU overexpressing metastatic breast cancer, by assessing the progression-free survival (PFS) after initiation of combination therapy.
SECONDARY OBJECTIVES:
I. Evaluate response rates (RR) in patients with measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST]), when applicable.
II. Evaluate overall survival (OS).
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, Care Provider, 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
- •Histologically confirmed breast cancer that overexpresses HER-2/NEU with evidence of metastatic disease and/or chest wall recurrence prior to randomization
- •HER-2/NEU overexpression is defined as 3+ HER-2 positivity as measured by immunohistochemistry OR HER-2 gene amplification as measured by fluorescent in situ hybridization (FISH, e.g. Vysis), per American Society of Clinical Oncology guidelines
- •NOTE: representative diagnostic tissue must be submitted for central diagnostic review for confirmation of HER-2/NEU overexpression within two weeks following patient randomization
- •Evaluable (measurable or non-measurable) disease is allowed if confirmed within 4 weeks prior to randomization
- •Prior endocrine treatment in the adjuvant or metastatic setting is allowed, provided last dose given >= 2 weeks prior to randomization
- •Radiation therapy is allowed provided last dose is given >= 3 weeks prior to randomization
- •Adjuvant trastuzumab therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
- •Adjuvant or neoadjuvant taxane therapy for breast cancer is allowed provided last dose was given >= 12 months prior to diagnosis of recurrence
- •Adjuvant or neoadjuvant therapy with lapatinib is allowed provided last dose is given >= 4 weeks prior to diagnosis of recurrence
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Absolute neutrophil count >= 1,000/mm^3
- •Platelet count >= 100,000/mm^3
- •Total bilirubin =< 1.5 mg/dL
- •Aspartate aminotransferase (AST) =< 2 times upper limit of normal (ULN) (=< 5 times normal in patients with known liver involvement)
- •Serum creatinine =< 1.5 mg/dL
- •Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1000 mg
- •International normalized ratio (INR) =< 1.5 X ULN
- •Partial thromboplastin time (PTT) =< 1.5 X ULN
- •Multi gated acquisition scan (MUGA) scan or echocardiogram (ECHO) within 6 weeks prior to randomization with an left ventricular ejection fraction (LVEF) above the institutional lower limit of normal
- •Patients must be able to understand and provide signed and dated written informed consent
- •Major surgical procedure within 4 weeks prior to randomization is not allowed (except for non-operative biopsy, which would not be considered major surgery); treatment can not begin until seven (7) days after placement of a vascular access device
- •Women must not be pregnant or breastfeeding; all females of childbearing potential must have a blood or urine test within 2 weeks prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must use an accepted and effective method of contraception
- •Patients on full-dose anticoagulants (e.g., warfarin) with PT/INR > 1.5 may be eligible provided that both of the following criteria are met:
- •The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
- •The patient has not active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
- •Patients with a concurrent active malignancy except carcinoma in situ of the cervix or non-melanoma skin cancers (unless disease-free for at least 5 years at study entry) are not allowed
排除标准
- •Prior chemotherapy, trastuzumab, or bevacizumab for metastatic breast cancer
- •Patients who have had a cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2 in the adjuvant or neo-adjuvant setting at any time
- •Patients with grade 2-4 neuropathy
- •Patients with a history or radiologic evidence of central nervous system (CNS) disease
- •Patients have a current non-healing wound or fracture
- •Patients have a hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
- •Patients have a serious medical or psychiatric illness that would prevent ability to safely participate or provide informed consent
- •Patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal)
- •Clinically significant cardiovascular disease, including:
- •History of cerebrovascular (CVA) within 6 months
- •Uncontrolled hypertension
- •Myocardial infarction or unstable angina within 6 months
- •New York Heart Association class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
- •Clinically significant peripheral vascular disease
研究组 & 干预措施
Arm B (chemotherapy and bevacizumab)
INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Carboplatin (Drug)
Arm B (chemotherapy and bevacizumab)
INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
Arm A (chemotherapy and placebo)
INDUCTION THERAPY: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Placebo (Other)
Arm A (chemotherapy and placebo)
INDUCTION THERAPY: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Trastuzumab (Biological)
Arm B (chemotherapy and bevacizumab)
INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Bevacizumab (Biological)
Arm B (chemotherapy and bevacizumab)
INDUCTION THERAPY: Patients receive trastuzumab and paclitaxel with or without carboplatin as in Arm A. Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Trastuzumab (Biological)
Arm A (chemotherapy and placebo)
INDUCTION THERAPY: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Carboplatin (Drug)
Arm A (chemotherapy and placebo)
INDUCTION THERAPY: Patients receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, and 22 and paclitaxel IV over 60 minutes with or without carboplatin IV over 60 minutes on days 1, 8, and 15. Patients also receive placebo IV over 30-90 minutes on day 1 and 15. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Beginning 1 week after the last dose of induction trastuzumab, patients receive trastuzumab IV over 30-90 minutes and placebo IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Progression-free Survival
时间窗: assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years
Progression-free survival (PFS) was defined as time from date of randomization to first disease progression, new second breast primaries, or to death from any cause, whichever occurred first, otherwise cases were censored at date last documented to be free of progression. Disease progression was defined using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Kaplan-Meier method was used to estimate the median PFS.
次要结局
- Overall Survival(assessed every 3 months for patients within 2 years of registration, every 6 months for patients 3-5 years from registration and then yearly for up to10 years)
- Proportion of Progression-free at 6 Months(assessed at baseline, at 3 and 6 months after study entry)
- Overall Response Rate(assessed at baseline, every 12 weeks while on treatment, then very 3 months if patient is <2 years from study entry, every 6 months if 2-5 years from study entry, and annually if 6-10 years from study entry until disease progression)
- Number of Patients Experiencing Congestive Heart Failure(assessed every 3 months while on treatment and at 3 months post treatment)