Pembrolizumab Plus Paclitaxel, Cisplatin Followed by Surgery for Locally Advanced ESCC (KEYSTONE-001)

Study Overview
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Brief Summary
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The purpose of this study is to observe and evaluate the efficacy and safety of pembrolizumab plus paclitaxel, cisplatin followed by Da Vinci robot radical surgery for locally advanced esophageal squamous cell carcinoma.

Detailed Description
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The Preoperative chemoradiotherapy with surgery is the standard treatment in NCCN guideline. But many patients refused or abandon radiotherapy because of the intolerable adverse effects. We designed a single-arm, open-label, phase II trial of pembrolizumab plus paclitaxel, cisplatin followed by Da Vinci robot radical surgery for locally advanced (stage III) esophageal squamous cell cancer. The purpose of this study is to observe and evaluate the efficacy and safety.

Official Title
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Efficacy and Safety of Pembrolizumab Plus Paclitaxel, Cisplatin Followed by Surgery in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma (KEYSTONE-001)

Conditions
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Stage III, Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Pembrolizumab Injection [Keytruda]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed esophageal squamous cell carcinoma; Potentially resectable cT3N1M0，cT1-3N2M0(stage III)(AJCC 8 TNM classification); Have a performance status of 0 or 1 on the ECOG Performance Scale; Age 18-70 years old, both men and women; Be willing and able to provide written informed consent/assent for the trial; Demonstrate adequate organ function , all screening labs should be performed within 10 days of treatment initiation; Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required; Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion through repeated biopsies. Newly-obtained is defined as a specimen obtained up to 4 weeks (28 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. Exclusion Criteria: Prior therapy (operation, radiotherapy, immunotherapy, or chemotherapy) for esophageal cancer; Ineligibility or contraindication for esophagectomy; Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug; Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); Has severe hypersensitivity and adverse events (≥Grade 3) to nivolumab and/or any PD-1/PD-L1 inhibitors.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+ Paclitaxel+Cisplatin<br>Pembrolizumab 200mg D1; Paclitaxel 135mg/m2 D2; Cisplatin 20mg/m2 D2-D4; repeated every 3 weeks | Drug: Pembrolizumab Injection [Keytruda]<br>* Neoadjuvant period:preoperative therapy with three cycles: Pembrolizumab 200mg D1; Paclitaxel 135mg/m2 D2; Cisplatin 20mg/m2 D2-D4; repeated every 3 weeks. Da Vinci robot radical surgery: Before surgery, head/abdomen/chest CT scan, type B ultrasonic, upper gastrointestinal contrast, endoscopic ultrasound (EUS), and gastroscopy with biopsy will be done. Surgery should be done within 4-6 weeks after last neoadjuvant treatment finished. Adjuvant period: Adjuvant treatment with pembrolizumab 200mg every 3 weeks (6 cycles) should be performed within 3-6 weeks after surgery if the surgical pathology result is not pCR. abdomen/chest CT scan will be performed every 3 month after surgery.<br>* Other names: Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathologic response | Viable tumor comprised ≤ 10% of resected tumor specimens | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Partial response is defined as a decrease by 30% or more in sums of longest diameter of measurable target lesions | 3 months | 
| Disease-free survival (DFS) | DFS is defined as the time interval between the date of enrollment and the date of the first documented evidence of relapse after radical resection at any site or death related to cancer (including toxicity), whichever occurred first. | 24 months | 
| Overall survival (OS) | Time from the enrollment to death of any cause | 24 months | 
| Lymph node derating rate | Lymph node derating rate | At time of surgery | 
| R0 resection rate | R0 resection rate | At time of surgery |