Efficacy of Neoadjuvant PD-1 Blockade Plus Chemotherapy for Esophageal Squamous Cell Carcinoma

Study Overview
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Brief Summary
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This study aims to evaluate the efficacy of Camrelizumab plus concurrent chemotherapy as neoadjuvant approach for patients with opearble esophageal squamous cell carcinoma. In addition, potential clinical utility of ctDNA in monitoring tumor burden and dynamics of tumor clonality during neoadjuvant immunotherapy will be assessed as well. At the same time, CD8 and PD-L1 will also be used as monitoring indicators.

Detailed Description
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Immunotherapy improves clinical outcome of patients with advanced stage or metastatic esophageal squamous cell carcinoma (ESCC). In addition, superior effect of immunotherapy for esophageal squamous cell carcinoma was also reported recently. While, clinical application of ctDNA, PD-L1 and CD8 T cell monitoring in neoadjuvant immunotherapy for patients with esophageal squamous cell carcinoma is largely unknown. This trial will evaluate firstly the efficacy and the safety of Camrelizumab plus chemotherapy （albumin-bound paclitaxel plus cisplatin）as neoadjuvant approach. The evaluation indicators include pathological complete response rate (pCR) and objective imaging response rate after neoadjuvant therapy (ORR). ), 2-year progression-free survival (2y-PFS), postoperative progression-free survival (PFS), and overall survival (OS) after treatment. Objective response rate (ORR) based upon immune-Response Evaluation Criteria in Solid Tumors Version (RECIST v1.1). Major pathological response assessed by post-operational pathological review ctDNA efficacy will also be evaluated along with clinical management. Monitoring tumor burden, clonality as well as tumor heterogeneity evaluation will be correlated to radiological assessment and pathological findings.

Official Title
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The Efficacy of Neoadjuvant PD-1 Plus Concurrent Chemotherapy for Stage II-IVA Operable Esophageal Squamous Cell Carcinoma：A Single Armed, Open-label, Multicentre, Clinical Trial

Conditions
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Esophageal Squamous Cell Carcinoma, Immunotherapy

Intervention / Treatment
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* Drug: camrelizumab
* Drug: Paclitaxel for injection (albumin-bound)
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged ≥18 years, ≤70 years. Gastroscope/ultrasound gastroscopy biopsy, Histologically or cytologically confirmed esophageal squamous cell carcinoma. Clinically diagnosed as II-IVA esophageal squamous cell carcinoma (cT2N1-3M0/cT3N0-3M0/cT4N0-3M0). Non-Cervical Esophageal Cancer Previously received no systemic or topical treatment for esophageal cancer, at least one measurable lesion for neoadjuvant treatment imaging evaluation according to RECIST 1.1; Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Estimated survival time ≥ 12 months; Subjects had no major organ dysfunction, and the investigators assessed thyroid, lung, liver, kidney function, and cardiac function as normal. Women of childbearing age must have taken reliable Contraception or have the negative predictive value of urine/ serum pregnancy test within 7 days prior to enrollment. They are also willing to use appropriate methods of contraception during the trial and 8 weeks after the last administration of the test drugs. For men, They must agree to use contraception or surgical sterilization during the trial and 8 weeks after the last administration of the test drug. Subjects voluntarily joined the study and signed informed consent. patients who accept blood sample collection at multiple time points. Able to comply with the required protocol and follow-up procedures, and able to receive oral medications. Exclusion Criteria: Have a history of gastrectomy or have surgical contraindications The investigator assessed that the patient had other serious illnesses that may affect follow-up and short-term survival; There are any active autoimmune diseases or a medical history of autoimmune (including, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, thyroid function Decreased. Subjects with vitiligo or adults who have had childhood asthma but have fully relieved without any intervention may be included. However, subjects who require bronchodilators for medical intervention cannot be included.) Cardiac clinical symptoms or diseases that are not well controlled, such as: a. Heart Failure NYHA > Class Ⅱ, b. unstable angina, c. myocardial infarction within 1 year; d. Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention. Subjects with congenital or acquired immunodeficiency (such as HIV-infected), or active hepatitis (hepatitis B reference: HBsAg-positive, HBV DNA ≥ 2000 IU/ml or copy number ≥ 104/ml; hepatitis C reference: HCV antibody-positive.) Uncontrollable history of diabetes; Patients who have used other clinical trial study drugs within 4 weeks prior to the first dose. Severe allergic reactions to monoclonal antibodies or allergy to paclitaxel or human albumin. Peripheral blood neutrophil count is less than 1500/mm3 Patients who have received or are undergoing other chemotherapy, radiation therapy or targeted therapy. According to the investigator's assessment, there are other factors that may lead to the termination of the study, such as other serious diseases (including mental illness) requiring combined treatment. Any other condition and social/psychological problems, etc., the investigator judged that the patient was not suitable for participation in the study.

Ages Eligible for Study
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Minimum Age: 17 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
Intervention Model: Single Group Assignment
Interventional Model Description: Patients with II-IVA stage with pathologically diagnosed squamous cell lung carcinoma will be enrolled in this study. Camrelizumab plus chemotherapy will be administrated intravenously per 3 weeks at the dosage of 200mg. Contrast-CT evaluation and peripheral blood collected will be performed at pre-neoadjuvant therapy and pre-operation. 6 weeks after neoadjuvant therapy, participants who meet the indication will be assigned to operation. Another peripheral blood sample will be harvested 3-4 weeks after operation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: camrelizumab plus concurrent chemotherapy<br>Neoadjuvant immunotherapy, PD-1, plus concurrent chemotherapy（albumin-bound paclitaxel + Cisplatin） will be applied to patients with operable esophageal squamous cell carcinoma before surgery. | Drug: camrelizumab<br>* Participants will receive camrelizumab, 200mg, intravenously over 30 - 60 minutes, day 1 of every 3 weeks for 6 weeks. Discontinuation will be considered due to toxicity, withdrawal of consent, or end of study. Every 3-week treatment period was considered to be a cycle.<br>* Other names: SHR-1210;Drug: Paclitaxel for injection (albumin-bound)<br>* Paclitaxel for injection (albumin-bound): 260mg/m2(in total), ivgtt d1, d8, q3w，for 2 cycle<br>* Other names: paclitaxel;Drug: Cisplatin<br>* 75mg/m2(in total), ivgtt d1-d3, q3w, for 2 cycles<br>* Other names: CDDP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete remission (PCR) | Primary tumor or lymph node surgery specimen pathological examination without residual tumor cell | 4 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate Determine the tumor shrinkage rate, tumor boundary and the adhesion of tumor | At the end of Cycle 2 (each cycle is 21 days) | 
| 2-year progression-free survival (PFS) | From date of surgery until the date of first documented progression or date of death from any cause | every 2 months (up to 24 months) | 
| Progression-free survival (PFS) | From date of surgery until the date of first documented progression or date of death from any cause | every 2 months (up to 24 months) | 
| Overall survival (OS) | Defined from date of Signing ICF to date of first documentation of death from any cause or censored at the date of the last follow-up. | every 2 months (up to 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant immunotherapy, Stage II-IVA, esophageal squamous cell carcinoma, ctDNA, neoadjuvant chemotherapy