A Randomised, Multi-centre, Open-label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients With HER2/ErbB2 Positive Primary Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 8,381
- 试验地点
- 1
- 主要终点
- Disease-Free Survival (DFS) at the Primary Analysis
研究概览
简要总结
This was a four-arm (parallel group) randomized, open-label, multicenter Phase 3 study to investigate the use of a combination of Lapatinib and Trastuzumab, a sequence of Trastuzumab followed by Lapatinib, and Lapatinib alone, compared to Trastuzumab alone in the adjuvant treatment of Human Epidermal Growth Factor Receptor 2 (HER2) positive early breast cancer.
详细描述
Treatment allocation was stratified by blocked randomization, with three stratification factors:
- Hormone receptor status: Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) positive versus both negative.
- Axillary lymph node involvement: not assessed because of neoadjuvant chemotherapy versus node negative versus 1-3 positive nodes versus 4 or more positive nodes.
- Timing of adjuvant chemotherapy: concurrently with taxanes and targeted therapy (Design 2) and concurrently with non-anthracycline-based platinum chemotherapy and targeted therapy (Design 2B) versus all other chemotherapy completed before randomization (Design 1). Treatments delivered differed according to the timing and type of adjuvant chemotherapy.
The primary objective of this study was to compare disease-free survival (DFS) in subjects with HER2 overexpressing and/or amplified breast cancer randomized to trastuzumab for one year versus lapatinib for one year versus trastuzumab (12 or 18 weeks, according to assigned design) followed by a six week treatment-free interval followed by lapatinib (28 or 34 weeks, according to assigned design) versus trastuzumab in combination with lapatinib for one year (52 weeks).
Secondary objectives included treatment comparisons with respect to overall survival, time to recurrence, time to distant recurrence, safety and tolerability, and incidence of brain metastasis.
Based on the recommendation of the Independent Data Monitoring Committee (IDMC) at the first interim analysis (18-Aug-2011), the Lapatinib alone arm was discontinued prior to primary analysis due to futility. The IDMC also stated that the other three arms (trastuzumab alone, sequential trastuzumab/lapatinib arm and the combination arm) could continued as planned with no changes.
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
- •Patients >= 18 years of age with histologically confirmed, non-metastatic, operable and over expression/amplification of HER2 (3+ by IHC and/or FISH positive) primary breast cancer, treated with definitive surgery, with baseline LVEF >= 50%, known hormone receptor status (ER/PgR or ER alone) and ECOG performance status =< 1, were included.
- •For Designs 1 and 2: Patients must have had received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen or a protocol specified exception.
- •Approved, signed written informed consent obtained prior to any study specific screening procedures.
排除标准
- •History of any prior (ipsi- and/or contralateral) invasive breast carcinoma, past (less than 10 years) or current history of malignant neoplasms, any clinically staged T4 tumor, or bilateral tumors.
- •Concurrent anti-cancer treatment, except hormonal therapy or radiotherapy for the present breast cancer;
- •Patients with positive or suspicious internal mammary nodes identified by sentinel node technique, which had not been irradiated or would not be irradiated, or patients with supraclavicular lymph node involvement.
- •Any prior anti-HER therapy, which includes agents that target other members of the HER family of receptors, e.g. gefitinib (Iressa)
- •(Neo-) or adjuvant chemotherapy using peripheral stem cell or bone marrow stem cell support;
- •Serious cardiac illness or medical conditions.
- •Any of the following abnormal laboratory tests immediately prior to randomization:
- •Serum total bilirubin >1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (<2 x ULN) was allowed;
- •Alanine amino transferase (ALT) or aspartate amino transferase (AST) >2.5 x ULN;
- •Alkaline phosphatase (ALP) >2.5 x ULN;
- •Serum creatinine >2.0 x ULN;
- •Total white blood cell count (WBC) <2.5 x 10^9/L;
- •Absolute neutrophil count <1.5 x 10^9/L;
- •Platelets <100 x 10^9/L.
- •Women of childbearing potential and male patients with partners of childbearing potential, who are unable or unwilling to use adequate contraceptive measures during study treatment, and pregnant or lactating women.
- •Concomitant use of CYP3A4 inhibitors or inducers.
研究组 & 干预措施
Lapatinib plus Trastuzumab
Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).
干预措施: Lapatinib (Drug)
Lapatinib plus Trastuzumab
Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).
干预措施: Trastuzumab (Biological)
Trastuzumab followed by Lapatinib
Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).
干预措施: Lapatinib (Drug)
Trastuzumab followed by Lapatinib
Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).
干预措施: Trastuzumab (Biological)
Lapatinib
Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).
干预措施: Lapatinib (Drug)
Trastuzumab
Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks.
Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total).
Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).
干预措施: Trastuzumab (Biological)
结局指标
主要结局
Disease-Free Survival (DFS) at the Primary Analysis
时间窗: From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.
次要结局
- Disease-Free Survival (DFS) at the 10-Year Follow-Up(From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause, assessed up to approximately 10 years)
- Overall Survival (OS) at the Primary Analysis(From randomization until death due to any cause (median follow-up of 4.5 years))
- Overall Survival (OS) at the 10-Year Follow-Up(From randomization until death due to any cause, assessed up to approximately 10 years)
- Analysis of Time to Recurrence (TTR)(From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years)
- Analysis of Time to Distant Recurrence (TTDR)(From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years)
- Analysis of Time to Central Nervous System (CNS) Recurrence(From randomization until the first central nervous system recurrence, assessed up to approximately 10 years)
- Cumulative Incidence of Brain Metastases(From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years)