Preoperative Anti-PD-1 Antibody Combined With Chemoradiotherapy for Locally Advanced Squamous Cell Carcinoma of Esophagus

Study Overview
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Brief Summary
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This study will evaluate the safety and feasibility of preoperative immune checkpoint therapy with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma. And this study will provide valuable information for further clinical trials of preoperative pembrolizumab and other immune checkpoint therapy in esophageal cancer treatment.

Detailed Description
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Esophageal cancer ranks the eighth most common cancer (the fifth most common cancer in China), while ESCC is the most common subtype in Asia (more than 90 % in china). Radical resection is thought to be the mainstay of esophageal cancer treatment and preoperative CRT is well applied in treating locally advanced esophageal cancer. In a multicohort, phase IB study, pembrolizumab was used in 23 unresectable esophageal cancer patients. In this clinical trial, the incidence of grade 3 treatment-related adverse events was 39 % without the appearance of grade 4 and higher-grade adverse event, while the overall response rate reached 30 %. The safety of immune checkpoint therapy for unresected esophageal cancers using nivolumab, a different PD-1 monoclonal antibody, has also been confirmed by high quality clinical trials. This study will evaluate the safety and feasibility of preoperative immune checkpoint therapy using pembrolizumab with concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma. And this study will provide valuable information for further clinical trials of preoperative pembrolizumab and other immune checkpoint therapy in esophageal cancer.

Official Title
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A Phase Ib Study of Pre-Operative Pembrolizumab + Chemoradiation in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma

Conditions
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Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient will be eligible for inclusion in this study only if ALL of the following criteria apply: Histologically confirmed cT2-T4a,N0-N+,M0 resectable esophageal squamous cell carcinoma Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Patients approve and sign the informed consent Exclusion Criteria: 1. Patients with active autoimmune disease or history of autoimmune disease 2. Patients who have a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications 3. Subjects with a history of symptomatic interstitial lung disease 4. History of allergy to study drug components 5. Women must not be pregnant or breast-feeding 6. Men with female partners (WOCBP) that are not willing to use contraception 7. Patient has received prior chemotherapy, radiotherapy, target therapy and immune therapy for this malignancy or for any other past malignancy 8. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events

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
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will receive carboplatin (AUC=2) IV and paclitaxel (50mg/m²) IV on day 1,8,15,22,29. And radiotherapy will start on day 1 of chemotherapy. A total of 41.4 Gy, 23 fractions of 1.8 Gy, 5 fractions a week. Participants will also receive pembrolizumab (2mg/kg) IV on days 1 and 22. Surgery will be performed within 6 weeks after completion of preoperative therapy described above
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Arm 1:preoperative pembrolizumab with chemoradiotherapy group Participants will receive carboplatin (AUC=2) IV and paclitaxel (50mg/m²) IV on day 1,8,15,22,29. And radiotherapy will start on day 1 of chemotherapy. A total of 41.4 Gy, 23 fractions of 1.8 Gy, 5 fractions a week. Participants will also receive pembrolizumab (2mg/kg) IV on days 1 and 22. Surgery will be performed within 6 weeks after completion of preoperative therapy described above. | Drug: Pembrolizumab<br>* Arm1：Pre-operative Pembrolizumab+chemoradiotherapy<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Number of Participants With Grade 3 and Higher-grade Treatment-related Adverse Events) | The number of participants with grade 3 and higher-grade treatment-related adverse events. Adverse events were evaluated using CTCAE 4.0, grade 3 treatment-related adverse events and higher-grade adverse events were reported. | From date of treatment allocation until surgery was applied during study period or up to at least 90 days after last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility (Number of Participants Who Finished Pembrolizumab With Chemoradiotherapy and Receive Surgery Within 4-6 Weeks After Preoperative Therapies) | The number of participants who finished pembrolizumab with chemoradiotherapy and receive surgery within 4-6 weeks after preoperative therapies. | From date of treatment allocation until surgery or definitive chemoradiotherapy was applied, whichever came first, assessed up to 5 months | 
| Pathologic Complete Response | Pathologic complete response was defined as the lack of all signs of cancer in tissue samples removed during surgery after treatment with pembrolizumab and chemoradiotherapy. | Two weeks after surgery | 
| Radiographic Response | To assess radiographic response to neoadjuvant pembrolizumab with concurrent chemoradiotherapy using RECIST 1.1. Complete metabolic response (cMR), defined as a physiological distribution of FDG uptake on PET-CT with a SUVmax value of less than 4 with no nodal uptake. | From date of treatment allocation and during treatment period up to 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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esophageal squamous cell carcinoma, neoadjuvant chemoradiotherapy, pembrolizumab, immune therapy, checkpoint inhibitor