A Prospective, Single-Arm Phase II Clinical Study of Neoadjuvant Chemoradiotherapy Combined With CTLA-4 Monoclonal Antibody Plus PD-1 Monoclonal Antibody for Locally Advanced Esophageal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Pathologic complete response rate
研究概览
简要总结
This is a prospective, single-arm phase II clinical trial intended to investigate the efficacy of neoadjuvant CTLA-4 monoclonal antibody combined with PD-1 monoclonal antibody plus preoperative chemoradiotherapy for locally advanced esophageal cancer. A total of 44 patients with resectable esophageal squamous cell carcinoma (ESCC) will be enrolled.All enrolled subjects will receive induction therapy with the combination of a CTLA-4 inhibitor and a PD-1 inhibitor. Three weeks afterwards, patients will transition to concurrent chemoradiotherapy combined with PD-1 inhibitor. Intensity-modulated radiotherapy (IMRT) will be delivered at a total dose of 40 Gy in 20 fractions. Radical esophagectomy with two-field thoracic and abdominal lymph node dissection will be performed 6-8 weeks after completion of chemoradiotherapy.The primary objective of this trial is to evaluate the efficacy and safety of the triplet regimen consisting of CTLA-4 inhibitor plus PD-1 inhibitor combined with preoperative chemoradiotherapy in locally advanced esophageal cancer, so as to further optimize the multimodal therapeutic strategy for esophageal cancer.
详细描述
This is a single-arm, phase II, single-center clinical trial enrolling patients with resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC) staged as T1-4aN1-3M0 or T3-4aN0M0 per the 8th edition of the UICC TNM staging system. A total of 51 subjects are planned for enrollment. Patients will receive neoadjuvant concurrent chemoradiotherapy combined with dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1 monoclonal antibodies) to evaluate the efficacy and safety of this regimen.
Treatment Regimens Chemotherapy and dual immunotherapy agents Anti-CTLA-4 monoclonal antibody (IBI310): 1 mg/kg via intravenous infusion on Day 1 (D1);Anti-PD-1 monoclonal antibody (sintilimab): 200 mg per administration via intravenous infusion on D1, D22 and D43;Nab-paclitaxel: 75 mg/m² via intravenous infusion on D22, D29, D36 and D43;Cisplatin: 25 mg/m² via intravenous infusion on D22, D29, D36 and D43.
Radiotherapy Intensity-modulated radiotherapy (IMRT) is delivered at a total dose of 40 Gy in 20 fractions (40 Gy/20 f), initiated on D22 with 5 fractions per week to be completed within 4 weeks.
Surgery Preoperative re-evaluation is scheduled at 6-8 weeks after completion of neoadjuvant chemoradiotherapy plus dual immunotherapy. Patients without surgical contraindications will undergo radical esophagectomy plus two-field (thoracoabdominal) lymph node dissection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Histologically confirmed resectable thoracic esophageal squamous cell carcinoma (ESCC); pretreatment clinical stage of T1-4aN1-3M0 or T3-4aN0M0 per the 8th edition of UICC staging system.
- •Treatment-naive patients without prior anti-tumor therapy.
- •Expected survival duration > 6 months.
- •Aged between 18 and 75 years, either male or female.
- •Adequate function of major vital organs meeting the following laboratory criteria:
- •White blood cell (WBC) ≥4.0×10⁹/L; absolute neutrophil count (ANC) ≥1.5×10⁹/L;
- •Platelet count ≥100×10⁹/L;
- •Hemoglobin ≥9 g/dL;
- •Serum albumin ≥2.8 g/dL;
- •Total bilirubin ≤1.5 × ULN; ALT, AST and/or ALP ≤2.5 × ULN;
- •Serum creatinine ≤1.5 × ULN, or creatinine clearance >60 mL/min.
- •Eastern Cooperative Oncology Group (ECOG) PS score: 0-
- •Capable of understanding the study protocol and signing written informed consent.
- •Absence of severe complications including active massive gastrointestinal hemorrhage, perforation, jaundice, bowel obstruction, or non-malignant fever >38℃.
- •Female and male patients of childbearing potential must use effective contraception throughout relevant study period.
- •Good treatment compliance and availability for scheduled follow-up of efficacy and adverse events per study protocol.
排除标准
- •Patients who have received prior anti-tumor therapies including chemotherapy, radiotherapy, surgery, immunotherapy, etc.
- •Patients with known or suspected hypersensitivity to any components of CTLA-4 inhibitors, sintilimab or other monoclonal antibodies, as well as chemotherapeutic agents (nab-paclitaxel and cisplatin).
- •Patients with pre-existing hemorrhagic disorders.
- •Patients with unresectable disease due to other uncontrollable conditions.
- •Female patients who are pregnant or breastfeeding.
- •Patients lacking capacity to provide informed consent due to psychological, familial or social reasons.
- •Patients with peripheral neuropathy graded ≥ Grade 2 per CTCAE criteria.
- •Patients with a prior history of other malignancies besides esophageal cancer, except for non-melanoma skin cancer, cervical carcinoma in situ, or previously cured early-stage prostate cancer.
- •Patients with more than 10 years of diabetes mellitus and poorly controlled blood glucose.
- •Patients with severe impairment of cardiac, pulmonary, hepatic or renal function, hematological diseases or cachexia that preclude tolerance to chemotherapy, radiotherapy or surgery.
- •Patients with active or past history of autoimmune diseases (including but not limited to colitis, hepatitis, hyperthyroidism), or history of immunodeficiency diseases (HIV positive, other acquired or congenital immunodeficiency disorders), or previous history of solid organ or allogeneic hematopoietic stem cell transplantation.
- •Patients with prior history of interstitial lung disease or non-infectious pneumonia.
- •Subjects with active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL) or active hepatitis C (HCV antibody positive with HCV-RNA above the lower limit of quantification of the assay).
研究组 & 干预措施
Single-Arm
neoadjuvant CTLA-4 monoclonal antibody combined with PD-1 monoclonal antibody plus preoperative chemoradiotherapy
干预措施: Ipilimumab (1mg/kg) (Drug)
Single-Arm
neoadjuvant CTLA-4 monoclonal antibody combined with PD-1 monoclonal antibody plus preoperative chemoradiotherapy
干预措施: Sinitilimab (Drug)
Single-Arm
neoadjuvant CTLA-4 monoclonal antibody combined with PD-1 monoclonal antibody plus preoperative chemoradiotherapy
干预措施: IMRT combine with cisplatin concurrent chemotherapy (Radiation)
Single-Arm
neoadjuvant CTLA-4 monoclonal antibody combined with PD-1 monoclonal antibody plus preoperative chemoradiotherapy
干预措施: Nab-paclitaxel + Cisplatin (Drug)
结局指标
主要结局
Pathologic complete response rate
时间窗: Two weeks after surgery
No malignant tumor cells were detected in the removed specimens including primary tumor and lymph nodes
次要结局
- R0 resection rate(Two weeks after surgery)
- Tumor Regression Grade(Two weeks after surgery)
- Progression free survival(At end of enrollment-up to 5 years in follow up)
- Overall survival(At the end of enrollment-up to 5 years in follow up)
- Incidence of perioperative complications(Ninety days after surgery)
研究者
Yang Hong
Prof
Sun Yat-sen University