A Randomized, Multicenter, Double Blind, Phase II Study of Neoadjuvant Nivolumab or Placebo Plus Chemotherapy Followed by Surgery and Adjuvant Treatment in Subjects With Resectable Esophageal Squamous Cell Carcinoma
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Pathological Complete Response (pCR) rate
研究概览
简要总结
Esophageal cancer, the 7th most common cancer globally, accounts for more than half a million deaths each year. The incidence of ESCC, the most common histologic type, has been stable, whereas the incidences of esophageal and gastroesophageal junction adenocarcinomas continue to increase in Western countries.
Neoadjuvant chemoradiotherapy followed by surgery has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer, especially in western countries. In Asia, nCT is considered as the standard of care for Stage II/III ESCC based on JCOG9204 and JCOG9907 trials. The superiority of nCRT/nCT, in terms of long-term survival, remains to be elucidated. For Stage II/III ESCC patients with multiple stations of lymph nodes involvement, nCT might be more appropriate for the inaccessibility of radiotherapy.
There are only limited studies on preoperative immune checkpoint inhibitor in combination with chemotherapy followed by surgery for the locally advanced ESCC. Therefore, this study intends to use Nivolumab 360 mg Q3W combined with standard chemotherapy as the neoadjuvant therapy regimen.
详细描述
- Background Esophageal cancer, the 7th most common cancer globally, accounts for more than half a million deaths each year. The incidence of ESCC, the most common histologic type, has been stable, whereas the incidences of esophageal and gastroesophageal junction adenocarcinomas continue to increase in Western countries.
Neoadjuvant chemoradiotherapy followed by surgery has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer, especially in western countries. In Asia (especially Japan), nCT is considered as the standard of care for Stage II/III ESCC based on JCOG9204 and JCOG9907 trials. The superiority of nCRT/nCT, in terms of long-term survival, remains to be elucidated. For Stage II/III ESCC patients with multiple stations of lymph nodes involvement, nCT might be more appropriate for the inaccessibility of radiotherapy.
There are only limited studies on preoperative immune checkpoint inhibitor in combination with chemotherapy followed by surgery for the locally advanced ESCC. Therefore, this study intends to use Nivolumab 360 mg Q3W combined with standard chemotherapy as the neoadjuvant therapy regimen. 2. Sample Size The planned sample size is approximately 81 subjects. The sample size calculations are based on the results of neoadjuvant therapy clinical research in our center (Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University).
In the past two years, about 85% of patients can undergo surgery and complete the entire treatment plan, combining with the results of neoadjuvant immunotherapy in lung cancer. As calculated based on an asymptotic method, 81 patients will be 2:1 randomized to Nivolumab/Chemo and Chemo group, with 80% power to detect a 21% difference in the proportion of patients achieving a pCR at a one-sided α of 0.05, assuming a pCR rate of 25% in the Nivolumab/Chemo group and 4% in the Chemo group. Considering a 10% drop rate, 90 patients will be enrolled.
10-20 more subjects may be added to each group after the evaluation of feasibility and safety as the justification. 3. Research Process 3.1 Screening period 1) Tumor evaluation, including CT/MRI, PET/CT, endoscopy and pathological evaluation should be performed within 14 days before enrollment.
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
- Double (Participant, Investigator)
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
- •Patients enrolled in the study must meet all of the following conditions:
- •The patient volunteers to participate in the study, signs a consent form, has good compliance, and obeys the follow-up, and is willing and able to follow the protocol during the study.
- •Male or female, aged ≥18 years and ≤75 years.
- •The ECOG PS score is 0-
- •Histologically-confirmed squamous cell carcinoma of the esophagus. Tumors of the esophagus are located in the thoracic cavity.
- •Pre-treatment stage as Stage II-III (cT2N0-1M0, cT3N0-1M0, cT1-3N2M0, AJCC/UICC 8th Edition);
- •Expected lifetime > 1 year.
- •Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %.
- •Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests.
- •Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L). AST, ALT ≤ 3 x ULN (If liver metastases exist, AST and ALT allow ≤ 5 x ULN).
- •Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) and Alanine transaminase (ALT) <1.5x ULN).
- •Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 μmol/L).
- •All acute toxic effects of previous anti-cancer treatment or surgery were all relieved by NCI-CTCAE version 5.0 ≤ 1 (except for hair loss or other toxic effects that the investigator judges to have no risk to the patient's safety).
- •Have the ability to act autonomously, have the ability to swallow pills, and have no gastrointestinal diseases that affect oral drug absorption.
- •Agree to provide hematology and histology samples.
排除标准
- •Patients who meet any of the following conditions will be excluded:
- •Patients have previously received an anti-PD-1, PD-L1 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- •Related to cancer:
- •Patients with non-squamous cell carcinoma histology.
- •Patients with advanced inoperable or metastatic esophageal cancer (M1).
- •Patients without qualified Pre-treatment stage.
- •Patients with another previous or current malignant disease.
- •Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder.
- •Patients who have autoimmune diseases.
- •Pregnant or lactating women and fertile women who will not be using contraception during the trial.
- •Allergy to any drugs.
- •Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy.
- •Patients who recently or currently taking hormones or immunosuppressive agents.
- •Immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) active infection or known HIV seropositivity; including HBV or HCV surface antigen positive (RNA).
研究组 & 干预措施
NIT+NCT Group (Arm A)
- Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Nivolumab (Drug)
NIT+NCT Group (Arm A)
- Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Cisplatin (Drug)
NIT+NCT Group (Arm A)
- Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Paclitaxel (Drug)
NIT+NCT Group (Arm A)
- Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: 5Fluorouracil (Drug)
NIT+NCT Group (Arm A)
- Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Esophagectomy (minimally invasive) (Procedure)
NCT Group (Arm B)
- Placebo: NS ivgtt (dose, frequency and duration same as the Nivolumab);
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Cisplatin (Drug)
NCT Group (Arm B)
- Placebo: NS ivgtt (dose, frequency and duration same as the Nivolumab);
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Paclitaxel (Drug)
NCT Group (Arm B)
- Placebo: NS ivgtt (dose, frequency and duration same as the Nivolumab);
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: 5Fluorouracil (Drug)
NCT Group (Arm B)
- Placebo: NS ivgtt (dose, frequency and duration same as the Nivolumab);
- Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously.
- MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy.
- Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.
干预措施: Esophagectomy (minimally invasive) (Procedure)
结局指标
主要结局
Pathological Complete Response (pCR) rate
时间窗: Up to the date of pathological reports obtained since the date of randomization, up to 12 months
pCR rate is defined as the proportion of the subjects in the analysis population who have a complete response in postoperative pathology. It is assessed in the resected specimen following neoadjuvant therapy using standardized work up of the resection specimen in the pathology department and standardized histological criteria for tumor regression grading. The Tumor Regression Grade (TRG) is categorized as follow: grade 1, no evidence of vital residual tumor cells (pCR); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; grade 4, more than 50%.
次要结局
- R0 resection rate(Up to the date of pathological reports obtained since the date of randomization, up to 12 months)
- Events-free Survival (EFS)(Up to the date of death of any causes since the date of randomization, up to 36 months)
- Incidence of Treatment-Emergent Adverse Events(Up to the date of death of any causes since the date of randomization, up to 36 months)
- Overall survival (OS)(Up to the date of death of any causes since the date of randomization, up to 36 months)