A Phase Ib Study of Pre-Operative Pembrolizumab + Chemoradiation in Patients With Locally Advanced Esophageal Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Esophageal Squamous Cell Carcinoma
Sponsor: Hecheng Li M.D., Ph.D

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A Phase Ib Study of Pre-Operative Pembrolizumab + 
Chemoradiation in Patients With Locally Advanced 
Esophageal Squamous Cell Carcinoma 
 
Department of Thoracic Surgery  
Ruijin Hospital Shanghai JiaoTong University School of Medicine 
 
Registration Number: NCT03792347 (www.clinicaltrials.gov)  
Date: April 08, 2019 
 
 

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Objectives 
Neoadjuvant chemoradiotherapy followed by esophagectomy has been recommended 
the standard of care for locally advanced esophageal cancer, although, with limited 
outcomes. Pembrolizumab, an immune checkpoint inhibitor targeting PD-1, has been 
verified to be safe and effective for patients with advanced esophageal cancer.  
This single center, single arm study will evaluate the safety and feasibility of 
preoperative 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 treatment. 
 
Research Strategy 
We propose to conduct a prospective, single-center, single arm clinical trial. 
 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Histologically confirmed cT2-T4a, N0-N+, M0 resectable esophageal squamous cell 
carcinoma; 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 
3. 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 that are not willing to use contraception; 

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7. Patients who have 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. 
 
Case Load 
Considering the exploratory nature of this study, a sample size of 20 participants was 
decided. 
 
Treatment Plan 
Participants will receive carboplatin (AUC=2) IV and paclitaxel (50mg/m²) IV on day 
1,8,15,22,29. Radiotherapy will start on day 1 of chemotherapy. A total of 41.4 Gy, 23 
fractions of 1.8 Gy, 5 fractions a week will be provided. Participants will also receive 
pembrolizumab (2mg/kg) IV on days 1 and 22. Surgery will be performed within 4-6 
weeks after completion of preoperative therapy described above. 
 
Rules for Dose Modification 
1. Serious adverse events that need dose modification for chemotherapy or radiotherapy 
in the investigator’s opinion; 
2. When facing serious pembrolizumab related adverse events, suspension of 
pembrolizumab should be applied rather than dose modification. 
 
Reasons for Early Cessation of Trial Therapy 
1. Serious adverse events that do not improve after short term suspension of 
preoperative treatment, for example, leukopenia, lymphopenia and anemia; 
2. Allergy to study drug components which occurred during preoperative treatment; 
3. Intolerance to preoperative treatment or surgery due to non-treatment related reasons; 
4. Unresectable disease observed before esophagectomy; 
5. Patients who meet newly identified exclusion criteria. 

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Primary Outcome Measure 
Safety (The rates of grade 3 and higher-grade treatment-related adverse events): 
Incidence of adverse events will be evaluated using CTCAE 4.0, grade 3 treatment-
related adverse events and higher-grade adverse events will be reported. 
 
Secondary Outcome Measures 
1. Feasibility (The rates of patients who finished pembrolizumab with 
chemoradiotherapy and receive surgery within 4-6 weeks after preoperative therapies); 
2. Pathologic complete response: Pathologic complete response was defined as 
pT0N0M0; 
3. Radiographic response: To assess radiographic response to neoadjuvant 
pembrolizumab with concurrent chemoradiotherapy using RECIST 1.1. 
 
Statistical Analysis 
All statistical analyses were performed under STATA version 1.51 (StataCorp, College 
Station, TX). Continuous variables were presented as mean with standard deviation or 
median with range. Frequency with percentage was used for presenting categorical 
variables. Student’s t test was conducted for comparing continuous variables. And chi-
squared test or Fisher’s exact test were performed for categorical variables.