A Randomized Open-label Phase II Study of Letrozole Plus Afatinib Versus Letrozole Alone in First-line Treatment of Advanced ER+, HER2- Postmenopausal Breast Cancer With Low ER Expression
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 44
- 试验地点
- 26
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
The purpose of the study is to compare the efficacy of treatment with afatinib plus letrozole to treatment with letrozole alone in women diagnosed with a specific type of breast cancer.
详细描述
This is an open-label, multicenter, international, randomized, Phase II clinical trial that will assess the efficacy and safety of letrozole in combination with afatinib(oral epidermal growth factor receptor (EGFR ) inhibitor) versus letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, Human Epidermal Growth Factor Receptor 2 (HER2) negative advanced breast cancer with low ER expression.
In order to assess the level of estrogen receptor (ER) expression we will use a semi-quantitative scoring system (McClelland, 1990) defined as :
H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 2x2) + (% of cells stained at intensity category 3x3).
This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells stained strongly (i.e., 3+). Low ER expression will be defined as tumor sample with H-score below 160 (Finn, 2009).
All subjects who consented for the study must submit a tumor sample to the designated central laboratory for central confirmation of ER / Progesterone receptor (PR) and HER2 statuses and determination of the H-score. This will be assessed prior to randomization.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Signed and dated informed consent.
- •Postmenopausal females, 18 years of age or older.
- •Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locally recurrent disease not amenable to resection or radiation therapy with curative intent, or metastatic disease.
- •HER2 negative breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is HER2 negative by FISH or Immunohistochemistry (IHC).
- •ER positive breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score [1-159]).
- •Paraffin-embedded tumor block(s) or 15 to 20 unstained slides available for centralized assessment of ER, PR, and HER
- •Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or bone-only non measurable disease.
- •Eastern Cooperative Oncology Group (ECOG) Performance status 0 or
- •Adequate hematological, hepatic and renal functions.
- •Baseline left ventricular ejection fraction (LVEF) 50%.
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
排除标准
- •Brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease.
- •Prior treatment with any type of systemic therapy for advanced disease.
- •Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval ≤ 12 months from completion of treatment until randomization.
- •Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant setting.
- •Any concurrent or previous malignancy within 5 years prior to randomization, except for adequately and radically treated basal or squamous skin cancer, or carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm.
- •Non-measurable disease according to RECIST 1.1, with the exception of bone-only non-measurable disease.
- •Known pre-existing interstitial lung disease.
- •Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom.
- •History or presence of clinically relevant cardiovascular abnormalities as per investigator assessment.
- •Any other concomitant serious illness or organ system dysfunction as per investigator assessment
- •Any contraindication to oral agents.
- •Active hepatitis B infection, active hepatitis C infection or known HIV carrier.
- •Known or suspected active drug or alcohol abuse.
- •Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial drugs.
- •Concomitant treatment with strong inhibitor of P-gp.
- •Any ongoing acute clinically significant toxic effect of prior anticancer therapy or any persisting complication of prior surgery.
- •Subjects with known history of keratitis, ulcerative keratitis or severe dry eye.
- •Participation in the active phase of other clinical trials of investigational agents in which last study treatment was administered within 2 weeks prior to randomization
研究组 & 干预措施
Arm A
Continuous regimen of oral Letrozole 2.5 mg daily
干预措施: Letrozole (Drug)
Arm B
Continuous regimen of oral Letrozole 2.5 mg daily plus oral Afatinib 30 mg daily
干预措施: Letrozole (Drug)
Arm B
Continuous regimen of oral Letrozole 2.5 mg daily plus oral Afatinib 30 mg daily
干预措施: Afatinib (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.
Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the "start date". If the status at the last assessment date was "Non-complete response/ Non-progressive disease" or "Complete response", then the patient was considered "censored". If the status at the last assessment for any tumor was "Progressive disease", then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.
次要结局
- Overall Survival (OS)(Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months)
- Objective Response Rate (ORR)(Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.)
- Time to Tumor Progression (TTP)(Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.)
- Number of Participants With Adverse Events(Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months)