Neo-adjuvant Immunochemotheray Versus Neo-adjuvant Chemotherapy for Resectable Esophageal Carcinoma

Study Overview
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Brief Summary
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The effect of neo-adjuvant immunochemotherapy on survival of patients with thoracic esophageal squamous cell carcinomas remains unknown. One of our objectives is to evaluate whether the neo-adjuvant immunochemotherapy Toripalimab (JS001) with cisplatin and paclitaxel followed by right thoracic approach esophagectomy with total 2-field lymph node dissection improves the overall survival of thoracic esophageal cancer patients versus neo-adjuvant chemotherapy.

Detailed Description
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The effect of immunochemotherapy in second line treatment of esophageal cancer got a positive results in the world. We tried to apply the immunotheray in resectable esophageal cancer and have planed this phase III clinical trials. The optimal management of resectable esophageal squamous cell carcinomas may have a new chapter in the era of immunotherapy.

Official Title
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A Phase III, Randomized Controlled Study of Neo-adjuvant Toripalimab (JS001) in Combination With Chemotherapy Versus Neo-adjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma

Conditions
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Survival, Esophageal Cancer, Surgery, Neoadjuvant Treatment

Intervention / Treatment
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* Drug: Neoadjuvant immunochemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of local advance squamous cell thoracic esophageal carcinoma of Stage (T1N1-3 or T2-3N0-3 M0), (8th Union for International Cancer Control, UICC-TNM). No metastatic lymph node in cervical by color doppler sonography. Patients must not have received any prior anticancer therapy of esophageal carcinoma. Age ranges from 18 to 75 years. Without operative contraindication. Absolute white blood cells count ≥4.0×109/L, neutrophil ≥1.5×109/L, platelets ≥100.0×109/L, hemoglobin ≥90g/L, and normal functions of liver and kidney, total bilirubin（TBIL）≤1.5N, aspartate aminotransferase (AST)≤2.5N, alanine aminotransferase(ALT)≤2.5N, prothrombin time(PT)≤1.5N, and activated partial thromboplastin time(APTT) is in normal range, endogenous creatinine clearance rate(CRE)≤1.5N. Patients must not have diagnosed with other cancer and must not received any prior anticancer therapy except prostatic cancer with more than 5 years disease-free survival(DFS). expected R0 resection. ECOG 0～1. Patients should agree to use contraceptive measures during the study period and within 6 months of the end of the study. Women must be non-lactation. Signed informed consent document on file. 10. . Exclusion Criteria: 1. Multiple primary cancer. 2.Patients with infections disease that require treatment 3.Patients who need continuous hormone treatment 4.unstable angina within 3 months, myocardial infarction within 6 months 5.psychopath 6.Patients with concomitant hemorrhagic disease. 7.Any unexpected reason for patients can't get operation 8.Inability to use gastric conduit after esophagectomy because of a prior surgery. 9.Pregnant or breast feeding 10.Patients are diagnosed or suspected to be allergic to cisplatin or Paclitaxel. 11.Bronchial asthma who requires intermittent use of bronchodilators or medical interventions 12.Due to co-existing diseases, the immunosuppressant was used. And the dosage of immunosuppressant was more than 10mg/ day orally and more than 2 weeks before enrollment 13.Abnormal coagulation function (PT>16s, APTT>53s, TT>21s, Fib<1.5g/L), tendency of bleeding or receiving thrombolysis or anticoagulant therapy 14.Previous or present pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, lung function severely impaired 15.Autoimmune diseases, immune deficiency, organ transplantation； 16.Hepatitis b/c patients。

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant immunochemotherapy<br>Neo-adjuvant chemotherapy(cisplatin and paclitaxel): Paclitaxel, 175mg/m2, d1, Cisplatin, 75mg/m2, d1, 3 week, 2 cycles. JS001, 240mg ivgtt, d3, >30min, 3week, 2 cycles Surgery: 2-3weeks after Neo-adjuvant chemotherapy Surgeons: the operation shall be performed by senior thoracic surgeons. Try to achieve the consistency of operation quality. Operation: the thoracic esophagectomy must be through right thoracic cavity. (open and minimally invasive McKeown or Ivor Lewis). Total two-field lymphadenectomy (right and left recurrent laryngeal nerve lymph nodes must be included). After surgery/ maintain period: JS001, 240mg ivgtt, d3, >30min, 3week (8 cycles at most) | Drug: Neoadjuvant immunochemotherapy<br>* Neo-adjuvant chemotherapy(cisplatin and paclitaxel): Paclitaxel, 175mg/m2, d1, Cisplatin, 75mg/m2, d1, 3 week, 2 cycles. JS001, 240mg ivgtt, d3, >30min, 3week, 2 cycles Surgery: 2-3weeks after Neo-adjuvant chemotherapy Surgeons: the operation shall be performed by senior thoracic surgeons. Try to achieve the consistency of operation quality. Operation: the thoracic esophagectomy must be through right thoracic cavity. (open and minimally invasive McKeown or Ivor Lewis). Total two-field lymphadenectomy (right and left recurrent laryngeal nerve lymph nodes must be included). After surgery/ maintain period: JS001, 240mg ivgtt, d3, >30min, 3week (8 cycles at most)<br>|
| Active Comparator: Neoadjuvant chemotherapy<br>Neo-adjuvant chemotherapy(cisplatin and paclitaxel): Paclitaxel, 175mg/m2, d1, Cisplatin, 75mg/m2, d1, 3 week, 2 cycles. Surgery: 2-3weeks after Neo-adjuvant chemotherapy Surgeons: the operation shall be performed by senior thoracic surgeons. Try to achieve the consistency of operation quality. Operation: the thoracic esophagectomy must be through right thoracic cavity. (open and minimally invasive McKeown or Ivor Lewis). Total two-field lymphadenectomy (right and left recurrent laryngeal nerve lymph nodes must be included). | Drug: Neoadjuvant immunochemotherapy<br>* Neo-adjuvant chemotherapy(cisplatin and paclitaxel): Paclitaxel, 175mg/m2, d1, Cisplatin, 75mg/m2, d1, 3 week, 2 cycles. JS001, 240mg ivgtt, d3, >30min, 3week, 2 cycles Surgery: 2-3weeks after Neo-adjuvant chemotherapy Surgeons: the operation shall be performed by senior thoracic surgeons. Try to achieve the consistency of operation quality. Operation: the thoracic esophagectomy must be through right thoracic cavity. (open and minimally invasive McKeown or Ivor Lewis). Total two-field lymphadenectomy (right and left recurrent laryngeal nerve lymph nodes must be included). After surgery/ maintain period: JS001, 240mg ivgtt, d3, >30min, 3week (8 cycles at most)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | The date from the beginning of randomization to the date of first record of unresectable disease, distant metastases, local recurrences of any causes, and death of any cause. | The date from the beginning of randomization to the date of first record. 3 years EFS | 
| Event-free survival (EFS) | The date from the beginning of randomization to the date of first record of unresectable disease, distant metastases, local recurrences of any causes, and death of any cause. | The date from the beginning of randomization to the date of first record. 5 years EFS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR | pathological complete response rate | within 14 working days after operation | 
| DFS | Disease free survival | 3 years DFS | 
| DFS | Disease free survival | 5 years DFS | 
| OS | Overall survival rate | 3 years OS | 
| OS | Overall survival rate | 5 years OS | 
| ORR | The Overall Response Rate. ORR=CR+PR. Criteria: Response Evaluation Criteria in Solid Tumors, RECIST. | 3-4 weeks after the last cycle of neoadjuvant treatment | 
| R0 resection rate | the complete resection rate of all tumor under microscope | within 14 working days after operation | 
| MPR | MPR rate was defined as the percentage of patients who achieved a major pathological response (residual tumor ≤10%) | within 14 working days after operation | 
| EORTC QLQ-C30 | EORTC QLQ-C30 repeated measurement model | before surgery, 1month, 3 months, 6 months, 9 months, 1 year after operation | 
| EORTC QLQ-OES18 | EORTC QLQ-OES18 repeated measurement model | before surgery, 1month, 3 months, 6 months, 9 months, 1 year after operation | 
| NRS-2002 | NRS-2002 repeated measurement model | before surgery, 1month, 3 months, 6 months, 9 months, 1 year after operation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant chemotherapy, Neoadjuvant immunochemotherapy