Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC (iCROSS)
Primary Purpose
Esophageal Squamous Cell Carcinoma Stage II, Esophageal Squamous Cell Carcinoma Stage III
Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Neoadjuvant Chemoradiotherapy
Tislelizumab
Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)
Sponsored by
About this trial
This is an interventional treatment trial for Esophageal Squamous Cell Carcinoma Stage II focused on measuring Esophageal Squamous Cell Carcinoma
Eligibility Criteria
Inclusion Criteria:
- Histologically-confirmed esophageal squamous cell carcinoma and whose tissue samples were taken before treatment;
- Tumors of the esophagus are located in the thoracic cavity;
- Pre-treatment stage as clinical II-III (AJCC/UICC 8th Edition)
- Age is between 18 years and 75 years;
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and expected survival time ≥12 months;
- Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %;
- Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests ;
- Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L);
- Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase(AST) and Alanine transaminase (ALT) <1.5x ULN);
- Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 µmol/L);
- The patient has provided written informed consent and is able to understand and comply with the study;
Exclusion Criteria:
Exclusion Criteria associated with Cancer:
- Patients with histological non-squamous cell carcinoma;
- Patients with advanced non-operable or metastatic esophageal cancer;
- Pre-treatment stage as cM+, cN3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 8th Edition) or cTis-1a, cT1bN0;
- Patients with another previous or current malignant disease which is likely to interfere with treatment or the assessment of response in the judgement of the local surgical investigator;
Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy;
Other Exclusion Criteria:
- Patients with autoimmune diseases history;
- Recently or currently taking Glucocorticoids or Immunosuppressants;
- Patients who underwent immunotherapy in the past;
- Allergy to any antibody drugs or allergy to Paclitaxel and Carboplatin.
- Past or currently suffering from chronic or recurrent autoimmune diseases;
- Patients with active infection of immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); HIV seropositivity; HBV DNA or HCV RNA positive;
- Patients with organ transplantation (including autologous bone marrow transplantation and peripheral stem cell transplantation);
- Patients with severe systematic intercurrent disease, such as active infection or poorly controlled diabetes; coagulation disorders; hemorrhagic tendency or under treatment of thrombolysis or anticoagulant therapy;
- Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder;
- Pregnant or lactating women and fertile women who will not be using contraception during the trial;
- Participation in another intervention clinical trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention during this study or during the last 30 days prior to informed consent;
- Expected lack of compliance with the protocol.
Sites / Locations
- Shanghai Zhongshan HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Neoadjuvant chemoradiotherapy combined with anti-PD-1 antibody
Neoadjuvant chemoradiotherapy
Arm Description
Neoadjuvant chemoradiotherapy (NCRT) combined with tislelizumab is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Neoadjuvant chemoradiotherapy (NCRT) is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Outcomes
Primary Outcome Measures
Pathological response rate(pCR)
The resected specimen following neo-adjuvant treatment are assessed by using standardized work up of the resection specimen in the pathology department and standardized histological criteria for tumor regression grading. The degree of histomorphologic regression is clarified into four categories as follows: grade 1, no evidence of vital residual tumor cells (pathological complete response); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; and grade 4, more than 50%.
Overall survival(OS)
Secondary Outcome Measures
Treatment related complications
Number and severity of adverse events that are related to treatment of each patients (including adverse events associated with neoadjuvant chemoradiotherapy, immunotherapy(irAE) and surgery), and hospital re-admission. Treatment-related adverse events as assessed by CTCAE v5.0
Progression-free survival(PFS)
Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs)
R0 resection rate
No vital tumor is presented at the proximal, distal, or circumferential resection margin, it is considered to be R0 resection. If a vital tumor is shown at 1 mm or less from the proximal, distal, or circumferential resection margin, it is considered to be microscopically positive (R1).
Number and Location of positive lymph nodes
According to pathological reports, record the number and location of positive lymph nodes
Overall Quality of life
Overall Quality of life is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 Scale (EORTC QLQ-C30)
Quality of life in eating and swallowing function
Quality of life in eating and swallowing function is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the EORTC QLQ-OES18 Scale
Recurrence-free survival (RFS)
RFS is defined in resected patients who achieved an R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whichever comes first.
Correlation between genetic profile and tumor response
Genetic profile (assessed by whole exome sequencing, T-cell receptor sequencing, RNA sequencing) .illumina HiSeq and Nanostring platforms will be used to evaluate the patient's genetic profile. The tumor response will be evaluated by an experienced thoracic tumor pathologist in our center through Tumor regression grading (TRG) systems.
Full Information
NCT ID
NCT04973306
First Posted
June 28, 2021
Last Updated
June 26, 2022
Sponsor
Shanghai Zhongshan Hospital
Collaborators
Peking University Cancer Hospital & Institute, Shanghai Chest Hospital, First Affiliated Hospital of Wenzhou Medical University, Tianjin Medical University Cancer Institute and Hospital, Ningbo Medical Center Lihuili Hospital, The First People's Hospital of Changzhou, Zhongshan Hospital (Xiamen), Fudan University, Xuhui Central Hospital, Shanghai, Shanghai Minhang Central Hospital, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Zhejiang Cancer Hospital, Sichuan Cancer Hospital and Research Institute, Tongji Hospital, Sun Yat-sen University, Shanghai Fifth People's Hospital
1. Study Identification
Unique Protocol Identification Number
NCT04973306
Brief Title
Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC
Acronym
iCROSS
Official Title
Neoadjuvant Immunotherapy Combined With Chemoradiotherapy Versus Neoadjuvant Chemoradiotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma (cII-III Stage): A Multi-center Prospective Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 2, 2022 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shanghai Zhongshan Hospital
Collaborators
Peking University Cancer Hospital & Institute, Shanghai Chest Hospital, First Affiliated Hospital of Wenzhou Medical University, Tianjin Medical University Cancer Institute and Hospital, Ningbo Medical Center Lihuili Hospital, The First People's Hospital of Changzhou, Zhongshan Hospital (Xiamen), Fudan University, Xuhui Central Hospital, Shanghai, Shanghai Minhang Central Hospital, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Zhejiang Cancer Hospital, Sichuan Cancer Hospital and Research Institute, Tongji Hospital, Sun Yat-sen University, Shanghai Fifth People's Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study was to evaluate the safety, feasibility and outcome of anti-PD-1 antibody (Tislelizumab, BeiGene) combined with neoadjuvant chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by minimally invasive esophagectomy for locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) patient.
Detailed Description
It is a prospective randomized phase II&III clinical trial sponsored by Shanghai Zhongshan Hospital with other twelve hospitals in China participating in. 476 patients with locally advanced resectable esophageal squamous cell carcinoma (cII-III Stage) are recruited and randomly assigned into the neoadjuvant chemoradiotherapy combined with immunotherapy group (nCRT plus anti-PD-1 Group) and the neoadjuvant chemoradiotherapy group (nCRT Group) according to the proportion of 1:1. The safety, efficacy of protocols and prognosis of patients are compared between the two regimens.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Esophageal Squamous Cell Carcinoma Stage II, Esophageal Squamous Cell Carcinoma Stage III
Keywords
Esophageal Squamous Cell Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
176 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Neoadjuvant chemoradiotherapy combined with anti-PD-1 antibody
Arm Type
Experimental
Arm Description
Neoadjuvant chemoradiotherapy (NCRT) combined with tislelizumab is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Arm Title
Neoadjuvant chemoradiotherapy
Arm Type
Active Comparator
Arm Description
Neoadjuvant chemoradiotherapy (NCRT) is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Intervention Type
Procedure
Intervention Name(s)
Neoadjuvant Chemoradiotherapy
Intervention Description
Chemotherapy: carboplatin (AUC 2 mg/mL per min) and paclitaxel (50 mg/m2 of body-surface area) were administered intravenously for five cycles, starting on days 1, 8, 15, 22, and 29. For each cycle, Carboplatin and paclitaxel were administered 30 minutes apart.
Radiotherapy: A total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy, 5 days per week (Radiotherapy was performed on the 2nd, 3rd, 4th, 5th, and 6th day in each cycle, and only 3 times in the 5th cycle)
Intervention Type
Drug
Intervention Name(s)
Tislelizumab
Other Intervention Name(s)
anti-PD-1 antibody
Intervention Description
Tislelizumab (200mg/time) was administered intravenously on the 1st and 22nd day.
The intravenous injection lasts about 30 minutes (micropump is recommended, intravenous bolus is prohibited, duration should be not less than 20 minutes and not more than 60 minutes);
Intervention Type
Procedure
Intervention Name(s)
Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)
Intervention Description
After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)
Primary Outcome Measure Information:
Title
Pathological response rate(pCR)
Description
The resected specimen following neo-adjuvant treatment are assessed by using standardized work up of the resection specimen in the pathology department and standardized histological criteria for tumor regression grading. The degree of histomorphologic regression is clarified into four categories as follows: grade 1, no evidence of vital residual tumor cells (pathological complete response); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; and grade 4, more than 50%.
Time Frame
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
Title
Overall survival(OS)
Time Frame
Up to the date of death of any causes since the date of randomization, up to 36 months
Secondary Outcome Measure Information:
Title
Treatment related complications
Description
Number and severity of adverse events that are related to treatment of each patients (including adverse events associated with neoadjuvant chemoradiotherapy, immunotherapy(irAE) and surgery), and hospital re-admission. Treatment-related adverse events as assessed by CTCAE v5.0
Time Frame
Up to 1 month after surgery since the data of randomization, up to 13 months
Title
Progression-free survival(PFS)
Description
Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs)
Time Frame
Up to the date of disease recurrence since the date of randomization, up to 36 months
Title
R0 resection rate
Description
No vital tumor is presented at the proximal, distal, or circumferential resection margin, it is considered to be R0 resection. If a vital tumor is shown at 1 mm or less from the proximal, distal, or circumferential resection margin, it is considered to be microscopically positive (R1).
Time Frame
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
Title
Number and Location of positive lymph nodes
Description
According to pathological reports, record the number and location of positive lymph nodes
Time Frame
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
Title
Overall Quality of life
Description
Overall Quality of life is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 Scale (EORTC QLQ-C30)
Time Frame
Up to the end of follow-up since the data of surgery, up to 36 months
Title
Quality of life in eating and swallowing function
Description
Quality of life in eating and swallowing function is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the EORTC QLQ-OES18 Scale
Time Frame
Up to the end of follow-up since the data of surgery, up to 36 months
Title
Recurrence-free survival (RFS)
Description
RFS is defined in resected patients who achieved an R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whichever comes first.
Time Frame
Up to the date of disease recurrence since the date of surgery, up to 36 months
Title
Correlation between genetic profile and tumor response
Description
Genetic profile (assessed by whole exome sequencing, T-cell receptor sequencing, RNA sequencing) .illumina HiSeq and Nanostring platforms will be used to evaluate the patient's genetic profile. The tumor response will be evaluated by an experienced thoracic tumor pathologist in our center through Tumor regression grading (TRG) systems.
Time Frame
Up to the end of follow-up since the data of surgery, up to 36 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically-confirmed esophageal squamous cell carcinoma and whose tissue samples were taken before treatment;
Tumors of the esophagus are located in the thoracic cavity;
Pre-treatment stage as clinical II-III (AJCC/UICC 8th Edition)
Age is between 18 years and 75 years;
Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and expected survival time ≥12 months;
Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %;
Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests ;
Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L);
Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase(AST) and Alanine transaminase (ALT) <1.5x ULN);
Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 µmol/L);
The patient has provided written informed consent and is able to understand and comply with the study;
Exclusion Criteria:
Exclusion Criteria associated with Cancer:
Patients with histological non-squamous cell carcinoma;
Patients with advanced non-operable or metastatic esophageal cancer;
Pre-treatment stage as cM+, cN3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 8th Edition) or cTis-1a, cT1bN0;
Patients with another previous or current malignant disease which is likely to interfere with treatment or the assessment of response in the judgement of the local surgical investigator;
Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy;
Other Exclusion Criteria:
Patients with autoimmune diseases history;
Recently or currently taking Glucocorticoids or Immunosuppressants;
Patients who underwent immunotherapy in the past;
Allergy to any antibody drugs or allergy to Paclitaxel and Carboplatin.
Past or currently suffering from chronic or recurrent autoimmune diseases;
Patients with active infection of immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); HIV seropositivity; HBV DNA or HCV RNA positive;
Patients with organ transplantation (including autologous bone marrow transplantation and peripheral stem cell transplantation);
Patients with severe systematic intercurrent disease, such as active infection or poorly controlled diabetes; coagulation disorders; hemorrhagic tendency or under treatment of thrombolysis or anticoagulant therapy;
Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder;
Pregnant or lactating women and fertile women who will not be using contraception during the trial;
Participation in another intervention clinical trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention during this study or during the last 30 days prior to informed consent;
Expected lack of compliance with the protocol.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lijie Tan, MD
Organizational Affiliation
Shanghai Zhongshan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shanghai Zhongshan Hospital
City
Shanghai
ZIP/Postal Code
200032
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lijie Tan, MD
Phone
+8621-64041990-692017
Email
tan.lijie@zs-hospital.sh.cn
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
According to the regulations on the management of human genetic resources of the People's Republic of China, we will not be able to share Individual Participant Data
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Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC
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