A Translational Randomized Phase III Study Exploring the Effect of the Addition of Capecitabine to Carboplatine Based Chemotherapy in Early "Triple Negative" Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 920
- 试验地点
- 24
- 主要终点
- Pathological complete response rate.
研究概览
简要总结
Primary aim: To compare the effect on pathologic complete response (pCR) rate of adding capecitabine to carboplatin based preoperative chemotherapy in early ER-negative and HER2-negative breast cancer. Pembrolizumab is allowed in both arms after approval for TNBC 2022.
详细描述
Primary aim: Pathological complete response rate after preoperative chemotherapy is the primary end-point of the study, which will be evaluated by comparing the effects of neoadjuvant administration of a carboplatin-based treatment and treatment adding capecitabine on pCR. After the approval of pembrolizumab in the preoperative treatment of early TNBC in 2022 the study will consist of two cohorts, one (cohort 1) without the addition of pembrolizumab, and one (cohort 2) with the addition of pembrolizumab to both study arms. The primary evaluation will be performed on the entire study population including both cohorts.
Primary translational aim: To investigate if the effects of the treatments depend on homologous repair deficiency (HRD)-status. More specifically, the aim is to test for differential effect of the two treatments on pCR for HRD-negative (HRD low and intermediate by oncoscan) and HRD-positive (HRD high by oncoscan) patients.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed written informed consent approved by the Ethical Review Board (IRB).
- •Age ≥ 18 to < 76 years.
- •Histologically confirmed unilateral adenocarcinoma of the breast where neoadjuvant chemotherapy followed by definitive surgery is planned.
- •Node positive disease (N1-3) or if clinically N0 Tumor size >20 mm. When deciding T-stage the following hierarchy applies,
- •Mammography
- •Clinical examination
- •ER negative tumor defined by at least one the following:
- •ER < 1% cells positive by immunohistochemistry (IHC) or ER ≤ 10% cells positive by IHC and basal-like subtype using gene expression analysis
- •ER < 10% cells positive by IHC and PgR < 10% cells positive by IHC
- •HER2-normal tumor defined according to applicable national guidelines
- •Consent for germline mutation screening for BRCA1, BRCA2 and other inherited breast cancer associated genes.
- •WHO performance status 0 or
- •Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization).
- •Willingness of female patients of childbearing potential, male patients, and their sexual partners to use an effective means of contraception during the treatment period and at least 6 months thereafter.
- •Willingness by the patient to undergo treatment and study related procedures according to the protocol.
排除标准
- •Clinical or radiological signs of metastatic disease.
- •History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer.
- •Previous chemotherapy for cancer or other malignant disease.
- •Charlson comorbidity index, excluding score for malignancy: (CCI) > 2, Comment: In patients 70-75 a CCI = 3 is allowed, see appendix B.
- •Inadequate organ function, suggested by the following laboratory results:
- •a Absolute neutrophil count < 1,5 x 109/L
- •b Platelet count < 100 x 109/L
- •c Hemoglobin < 90 g/L
- •d Total bilirubin greater than the upper limit of normal (ULN) unless the patient has documented Gilbert´s syndrome
- •e ASAT (SGOT) and/or ALAT (SGPT) > 2,5 x ULN
- •f ASAT (SGOT) and/or ALAT (SGPT) > 1,5 x ULN with concurrent serum alkaline phosphatase (ALP) > 2,5 x ULN
- •g Serum creatinine clearance < 50 ml/min
- •Concurrent peripheral neuropathy of grade 3 or greater (NCI-CTCAE, Version 5.0).
- •Patient who is actively breast feeding.
- •Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
- •Patients with known deficiency of the DPD-enzyme who completely lack DPD.
研究组 & 干预措施
Arm A (Platinum-based dose dense EC):
ddEC x 4 + pembrolizumab→ PK x 4 + pembrolizumab, Two-weekly epirubicin/cyclophosphamide (EC) x 4 (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2), followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2). Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.*
干预措施: epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab (Drug)
Arm B (Platinum-based with capecitabine):
CEX x 4→ PK x 4, Three-weekly cyclophosphamide/epirubicin/capecitabine (CEX) (epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2 and capecitabine 900 mg/m2) x 4, followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2).Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.*
*The addition of pembrolizumab is strongly recommended to all participating patients. However, patients with a documented contraindication, or unwilling to receive immunotherapy may be included in the study without the administration of pembrolizumab.
干预措施: epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab (Drug)
结局指标
主要结局
Pathological complete response rate.
时间窗: Immediately after surgery
Rate of pathological complete response, allowing residual dcis, at surgery after preoperative chemotherapy.
Primary translational outcome.
时间窗: Immediately after surgery
Pathological complete response rate, allowing residual dcis, stratified for homologous repair deficiency.
次要结局
- Invasive Disease Free Survival (IDFS)(Throughout the study, an average of 3 years)
- Overall Survival (OS)(Throughout the study, an average of 5 years)
- Breast Cancer Specific Survival (BCSS)(Throughout the study, an average of 3 years)
- Toxicity according to CTCAE version 5.0(Immediately after surgery)
- Distant Recurrence Free Survival (DRFS)(Throughout the study, an average of 3 years)
- Dose intensity(Immediately after surgery)