Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety, feasibility and outcome of anti-PD-1 antibody (Tislelizumab, BeiGene) combined with neoadjuvant chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by minimally invasive esophagectomy for locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) patient.

Detailed Description
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It is a prospective randomized phase II&III clinical trial sponsored by Shanghai Zhongshan Hospital with other twelve hospitals in China participating in. 476 patients with locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) are recruited and randomly assigned into the neoadjuvant chemoradiotherapy combined with immunotherapy group (nCRT plus anti-PD-1 Group) and the neoadjuvant chemoradiotherapy group (nCRT Group) according to the proportion of 1:1. The safety, efficacy of protocols and prognosis of patients are compared between the two regimens.

Official Title
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Neoadjuvant Immunotherapy Combined With Chemoradiotherapy Versus Neoadjuvant Chemoradiotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma (cII-III Stage): A Multi-center Prospective Randomized Clinical Trial

Conditions
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Esophageal Squamous Cell Carcinoma Stage II, Esophageal Squamous Cell Carcinoma Stage III

Intervention / Treatment
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* Procedure: Neoadjuvant Chemoradiotherapy
* Drug: Tislelizumab
* Procedure: Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed esophageal squamous cell carcinoma and whose tissue samples were taken before treatment; Tumors of the esophagus are located in the thoracic cavity; Pre-treatment stage as clinical II-III (AJCC/UICC 8th Edition) Age is between 18 years and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and expected survival time ≥12 months; 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); 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); The patient has provided written informed consent and is able to understand and comply with the study; Exclusion Criteria: Exclusion Criteria associated with Cancer: Patients with histological non-squamous cell carcinoma; Patients with advanced non-operable or metastatic esophageal cancer; Pre-treatment stage as cM+, cN3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 8th Edition) or cTis-1a, cT1bN0; Patients with another previous or current malignant disease which is likely to interfere with treatment or the assessment of response in the judgement of the local surgical investigator; Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy; Other Exclusion Criteria: Patients with autoimmune diseases history; Recently or currently taking Glucocorticoids or Immunosuppressants; Patients who underwent immunotherapy in the past; Allergy to any antibody drugs or allergy to Paclitaxel and Carboplatin. Past or currently suffering from chronic or recurrent autoimmune diseases; Patients with active infection of immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); HIV seropositivity; HBV DNA or HCV RNA positive; Patients with organ transplantation (including autologous bone marrow transplantation and peripheral stem cell transplantation); Patients with severe systematic intercurrent disease, such as active infection or poorly controlled diabetes; coagulation disorders; hemorrhagic tendency or under treatment of thrombolysis or anticoagulant therapy; 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; Pregnant or lactating women and fertile women who will not be using contraception during the trial; Participation in another intervention clinical trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention during this study or during the last 30 days prior to informed consent; Expected lack of compliance with the protocol.

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 chemoradiotherapy combined with anti-PD-1 antibody<br>Neoadjuvant chemoradiotherapy (NCRT) combined with tislelizumab is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients. | Procedure: Neoadjuvant Chemoradiotherapy<br>* Chemotherapy: carboplatin (AUC 2 mg/mL per min) and paclitaxel (50 mg/m2 of body-surface area) were administered intravenously for five cycles, starting on days 1, 8, 15, 22, and 29. For each cycle, Carboplatin and paclitaxel were administered 30 minutes apart. Radiotherapy: A total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy, 5 days per week (Radiotherapy was performed on the 2nd, 3rd, 4th, 5th, and 6th day in each cycle, and only 3 times in the 5th cycle)<br>Drug: Tislelizumab<br>* Tislelizumab (200mg/time) was administered intravenously on the 1st and 22nd day. The intravenous injection lasts about 30 minutes (micropump is recommended, intravenous bolus is prohibited, duration should be not less than 20 minutes and not more than 60 minutes);<br>* Other names: anti-PD-1 antibody;Procedure: Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)<br>* After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)<br>|
| Active Comparator: Neoadjuvant chemoradiotherapy<br>Neoadjuvant chemoradiotherapy (NCRT) is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients. | Procedure: Neoadjuvant Chemoradiotherapy<br>* Chemotherapy: carboplatin (AUC 2 mg/mL per min) and paclitaxel (50 mg/m2 of body-surface area) were administered intravenously for five cycles, starting on days 1, 8, 15, 22, and 29. For each cycle, Carboplatin and paclitaxel were administered 30 minutes apart. Radiotherapy: A total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy, 5 days per week (Radiotherapy was performed on the 2nd, 3rd, 4th, 5th, and 6th day in each cycle, and only 3 times in the 5th cycle)<br>Procedure: Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)<br>* After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological response rate(pCR) | The resected specimen following neo-adjuvant treatment are assessed by using standardized work up of the resection specimen in the pathology department and standardized histological criteria for tumor regression grading. The degree of histomorphologic regression is clarified into four categories as follows: grade 1, no evidence of vital residual tumor cells (pathological complete response); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; and grade 4, more than 50%. | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| Overall survival(OS) |  | Up to the date of death of any causes since the date of randomization, up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related complications | Number and severity of adverse events that are related to treatment of each patients (including adverse events associated with neoadjuvant chemoradiotherapy, immunotherapy(irAE) and surgery), and hospital re-admission. Treatment-related adverse events as assessed by CTCAE v5.0 | Up to 1 month after surgery since the data of randomization, up to 13 months | 
| Progression-free survival(PFS) | Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs) | Up to the date of disease recurrence since the date of randomization, up to 36 months | 
| R0 resection rate | No vital tumor is presented at the proximal, distal, or circumferential resection margin, it is considered to be R0 resection. If a vital tumor is shown at 1 mm or less from the proximal, distal, or circumferential resection margin, it is considered to be microscopically positive (R1). | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| Number and Location of positive lymph nodes | According to pathological reports, record the number and location of positive lymph nodes | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| Overall Quality of life | Overall Quality of life is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 Scale (EORTC QLQ-C30) | Up to the end of follow-up since the data of surgery, up to 36 months | 
| Quality of life in eating and swallowing function | Quality of life in eating and swallowing function is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the EORTC QLQ-OES18 Scale | Up to the end of follow-up since the data of surgery, up to 36 months | 
| Recurrence-free survival (RFS) | RFS is defined in resected patients who achieved an R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whichever comes first. | Up to the date of disease recurrence since the date of surgery, up to 36 months | 
| Correlation between genetic profile and tumor response | Genetic profile (assessed by whole exome sequencing, T-cell receptor sequencing, RNA sequencing) .illumina HiSeq and Nanostring platforms will be used to evaluate the patient's genetic profile. The tumor response will be evaluated by an experienced thoracic tumor pathologist in our center through Tumor regression grading (TRG) systems. | Up to the end of follow-up since the data of surgery, up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal Squamous Cell Carcinoma