PD-1 Inhibitor Combined With Neoadjuvant Chemoradiotherapy Plus Surgery for Locally Advanced ESCC

Study Overview
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Brief Summary
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The primary objective is to compare PD-1 inhibitor combined with preoperative chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery, in terms of the overall survival time (OS) in patients with Stage T1-4aN1-3M0 or T3-4aN0M0 squamous cell esophageal carcinoma.

Official Title
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Phase III Multicenter Randomized Controlled Trial of PD-1 Inhibitor Combined With Preoperative Concurrent Chemoradiotherapy and Surgery for Locally Advanced Esophageal Squamous Cell Carcinoma

Conditions
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Squamous Cell Esophageal Carcinoma, Esophageal Cancer, Oesophageal Cancer

Intervention / Treatment
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* Drug: Sintilimab
* Radiation: Preoperative radiotherapy
* Drug: Paclitaxel
* Drug: Cisplatin
* Procedure: esophagectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of squamous cell thoracic esophageal carcinoma of Stage T1-4aN1-3M0 or T3-4aN0M0,which is potentially resectable. Patients must not have received any prior anticancer therapy. More than 6 months of expected survival. Age ranges from 18 to 70 years. 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. WHO PS score 0-1 Signed informed consent document on file. Exclusion Criteria: Patients have received any prior anticancer therapy. Patients are diagnosed or suspected to be allergic to sintilimab,toxal or cisplatin. Patients with concomitant hemorrhagic disease. Patients who cannot tolerate surgery. Pregnant or breast feeding. Patients without informed consent because of psychological, family, social or any other factors. Patients with concomitant peripheral neuropathy, whose CTC status is 2 or even more. Patients with malignant tumors other than esophageal cancer,except for non-melanoma skin cancer, in situ cervical cancer, or cured early prostate cancer. Patients with history of diabetes over 10 years and unsatisfactory glycemic control. Patients with severe heart,lung,liver,renal dysfunction, hematopoietic system diseases, immune system diseases, cachexia or other diseases that lead to intolerance of chemoradiotherapy or surgery. Patients with history of autoimmune diseases, immunodeficiency, or organ and allogeneic bone marrow transplantation. Patients with history of interstitial lung disease or noninfectious pneumonia. Patients with active pulmonary tuberculosis infection, or a history of active pulmonary tuberculosis infection within one year before enrollment, or a history of active pulmonary tuberculosis infection more than one year ago without regular treatment. Patients with active hepatitis B ( HBV DNA ≥ 2000 IU / mL or 104 copies / mL ) or hepatitis C ( HCV antibody positive ).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: NCRT+IO group<br>• NCRT+IO group consists of the PD-1 inhibitor combined with concurrent chemoradiotherapy prior to surgery. The patient will receive 4 weeks of radiation therapy. The radiation will generally commence on the 1st day of treatment and will run for 4 weeks.PD-1 inhibitor is given by intravenous infusion on days 1 and 22. Chemotherapy is given by intravenous infusion on days 1, 8, 15, and 22. Interventions: Radiation: (40 or 45 Gy/20 fractions) Drug: Sintilimab Drug: Paclitaxel Drug: Cisplatin | Drug: Sintilimab<br>* Sintilimab 200mg, IV (in the vein) on day 1 and day 22<br>Radiation: Preoperative radiotherapy<br>* External radiation with a total dose of 40.0 or 45.0 Gy is given in 20 fractions,5 fractions a week.<br>Drug: Paclitaxel<br>* 50mg/m2, IV (in the vein) on day 1,day 8,day 15 and day 22<br>* Other names: Taxol;Drug: Cisplatin<br>* 25mg/m2,IV DRIP on day 1,day 8,day 15 and day 22<br>* Other names: DDP;Procedure: esophagectomy<br>* McKeown esophagectomy, Ivor Lewis esophagectomy or minimally invasive esophagectomy will be performed 6-8 weeks after chemoradiotherapy. Two-field lymphadenectomy with total mediastinal lymph node dissection is performed during surgery.<br>|
| Active Comparator: NCRT group<br>• NCRT group consists of the concurrent chemoradiotherapy prior to surgery. The patient will receive 4 weeks of radiation therapy. The radiation will generally commence on the 1st day of treatment and will run for 4 weeks. Chemotherapy is given by intravenous infusion on days 1, 8, 15, and 22. Interventions: Radiation: (40 or 45 Gy/20 fractions) Drug: Paclitaxel Drug: Cisplatin | Radiation: Preoperative radiotherapy<br>* External radiation with a total dose of 40.0 or 45.0 Gy is given in 20 fractions,5 fractions a week.<br>Drug: Paclitaxel<br>* 50mg/m2, IV (in the vein) on day 1,day 8,day 15 and day 22<br>* Other names: Taxol;Drug: Cisplatin<br>* 25mg/m2,IV DRIP on day 1,day 8,day 15 and day 22<br>* Other names: DDP;Procedure: esophagectomy<br>* McKeown esophagectomy, Ivor Lewis esophagectomy or minimally invasive esophagectomy will be performed 6-8 weeks after chemoradiotherapy. Two-field lymphadenectomy with total mediastinal lymph node dissection is performed during surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be calculated from the date of randomization and an event registered on the date of death from any cause. Patients lost to follow up, or those with no death recorded on the day the database is frozen, will be censored on the date of last follow up. | At end of enrollment- up to 5 years in follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival is defined as the time from randomization until objective tumor progression or death. | At end of enrollment- up to 5 years in follow up | 
| Pathologic complete response rate | No malignant tumor cells were detected in the removed specimens including primary tumor and lymph nodes | Two weeks after surgery | 
| R0 resection rate | The percentage of patients who undergo complete resection | Two weeks after surgery | 
| Incidence of perioperative complications | Incidence of complications | Ninety days after surgery | 
| Perioperative mortality | Incidence of death postoperatively | Ninety after surgery |