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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pembrolizumab | Drug | Arm1：Pre-operative Pembrolizumab+chemoradiotherapy |
|
| 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 |
| 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 |
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Inclusion Criteria:
A patient will be eligible for inclusion in this study only if ALL of the following criteria apply:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hecheng Li, MD PHD | Ruijin Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ruijin Hospital, Shanghai JiaoTong University School of Medicine | Shanghai | Shanghai Municipality | 200025 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33373868 | Derived | Li C, Zhao S, Zheng Y, Han Y, Chen X, Cheng Z, Wu Y, Feng X, Qi W, Chen K, Xiang J, Li J, Lerut T, Li H. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer. 2021 Feb;144:232-241. doi: 10.1016/j.ejca.2020.11.039. Epub 2020 Dec 26. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 4-6 weeks after completion of preoperative therapy described above. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 4-6 weeks after completion of preoperative therapy described above. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Count of Participants | Participants | From date of treatment allocation until surgery was applied during study period or up to at least 90 days after last dose |
|
From date of treatment allocation until surgery was applied during study period or up to at least 90 days after last dose.
Adverse events were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) 4.0.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 4-6 weeks after completion of preoperative therapy described above. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 and higher-grade adverse events based on CTCAE 4.0. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
This was a single arm study. The sample size was small. Patients were highly selected and from a single center. These may strict the generalizability of the results.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Hecheng Li, Chair of Thoracic Surgery | Ruijin Hospital, Shanghai JiaoTong University School of Medicine | (86)13917113402 | lihecheng2000@hotmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 8, 2019 | Jul 29, 2020 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 8, 2019 | Jul 29, 2020 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000077277 | Esophageal Squamous Cell Carcinoma |
| ID | Term |
|---|---|
| D002294 | Carcinoma, Squamous Cell |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C582435 | pembrolizumab |
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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
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| 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 |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Median | Full Range | kg/m^2 |
|
| Eastern Cooperative Oncology Group (ECOG) Performance Status | Brief description of the criteria of Eastern Cooperative Oncology Group (ECOG) Performance Status: grade 0, normal activity; grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; grade 2, capable of all selfcare but unable to carry out any work activities, ambulatory for more than 50% of time; grade 3, ambulatory for less than 50% of time, capable of only limited selfcare; grade 4, completely disabled, can not carry on any selfcare, totally confined to bed or chair; grade 5, dead. | Count of Participants | Participants |
|
| Smoking History | Count of Participants | Participants |
|
| Tumor Length | Median | Full Range | cm |
|
| Tumor Location | Count of Participants | Participants |
|
| Clinical T Stage | Clinical T stage was measured according to the American Joint Committee on Cancer criteria for esophageal carcinoma, eighth edition, and was evaluated based on pretreatment examinations, including physical examination, contrast-enhanced chest computed tomography, PET-CT, upper gastrointestinal endoscopy, etc. cT3 refers to tumor which invades the adventitia. cT4a refers to tumor which invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum. | Count of Participants | Participants |
|
| Clinical N Stage | Clinical N stage was measured according to the American Joint Committee on Cancer criteria for esophageal carcinoma, eighth edition, and was evaluated based on pretreatment examinations, including physical examination, contrast-enhanced chest computed tomography, PET-CT, upper gastrointestinal endoscopy, etc. Brief description of the criteria: cN0, no regional lymph node metastasis; cN1, metastasis in 1-2 regional lymph nodes; cN2, metastasis in 3-6 regional lymph nodes; cN3, metastasis in ≥7 regional lymph nodes. | Count of Participants | Participants |
|
| Clinical Stage | Clinical stage refers to cTNM stage, which was measured based on the American Joint Committee on Cancer criteria for esophageal carcinoma, eighth edition. cT2N0-1M0 and cT3N0M0 are grouped into stage II. cT1-3N2M0 and cT3N1 are grouped into stage III. cT4a-4bN0-3M0 and cT1-3N3 are grouped into stage IVA. As the clinical stage increases, the severity of the esophageal cancer increases. | Count of Participants | Participants |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | From date of treatment allocation until surgery or definitive chemoradiotherapy was applied, whichever came first, assessed up to 5 months |
|
|
|
| Secondary | 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. | Twenty patients were assigned to this group, while, 18 patients received esophagectomy. Two patients did not receive surgery due to the following reasons: one was determined progression disease due to liver metastasis after completion of preoperative therapy; another patient died while awaiting surgery due to severe esophageal hemorrhage. | Posted | Count of Participants | Participants | Two weeks after surgery |
|
|
|
| Secondary | 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. | Twenty patients were enrolled, and seventeen patients out of them received PET-CT before and after the completion of preoperative treatment. | Posted | Count of Participants | Participants | From date of treatment allocation and during treatment period up to 3 months |
|
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| 1 |
| 20 |
| 13 |
| 20 |
| 20 |
| 20 |
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| Decreased neutrophil count | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 and higher-grade adverse events based on CTCAE 4.0. |
|
| Lymphopenia | Blood and lymphatic system disorders | Systematic Assessment | Grade 3 and higher-grade adverse events based on CTCAE 4.0. |
|
| Esophageal hemorrhage | Gastrointestinal disorders | Non-systematic Assessment | Grade 3 and higher-grade adverse events based on CTCAE 4.0. |
|
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| Decreased neutrophil count | Blood and lymphatic system disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Lymphopenia | Blood and lymphatic system disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Anemia | Blood and lymphatic system disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Pneumonitis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Alopecia | General disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Anorexia | General disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Constipation | Gastrointestinal disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Fatigue | General disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Nausea | Gastrointestinal disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Vomiting | Gastrointestinal disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Esophagitis | Gastrointestinal disorders | Systematic Assessment | Adverse events during neoadjuvant therapy. |
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| Postoperative Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Atelectasis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Anastomotic leakage | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Gastrointestinal fistula | Gastrointestinal disorders | Non-systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
|
| Wound infection | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Hoarseness | Injury, poisoning and procedural complications | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| Dysphagia | Gastrointestinal disorders | Systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
|
| Postoperative intrathoracic hemorrhage | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Postoperative adverse events, which were assessed for 18 participants who underwent surgery. |
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| D009369 | Neoplasms |
| D018307 | Neoplasms, Squamous Cell |
| D004938 | Esophageal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D006258 | Head and Neck Neoplasms |
| D004066 | Digestive System Diseases |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |