Neoadjuvant Immunotherapy Plus CRT Versus Neoadjuvant CRT for Locally Advanced Resectable ESCC (iCROSS)

June 26, 2022 updated by: Shanghai Zhongshan Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

176

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
      • Shanghai, China, 200032

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Histologically-confirmed esophageal squamous cell carcinoma and whose tissue samples were taken before treatment;
  2. Tumors of the esophagus are located in the thoracic cavity;
  3. Pre-treatment stage as clinical II-III (AJCC/UICC 8th Edition)
  4. Age is between 18 years and 75 years;
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and expected survival time ≥12 months;
  6. 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 %;
  7. Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests ;
  8. Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L);
  9. Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase(AST) and Alanine transaminase (ALT) <1.5x ULN);
  10. Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 µmol/L);
  11. The patient has provided written informed consent and is able to understand and comply with the study;

Exclusion Criteria:

Exclusion Criteria associated with Cancer:

  1. Patients with histological non-squamous cell carcinoma;
  2. Patients with advanced non-operable or metastatic esophageal cancer;
  3. 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;
  4. 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;

  5. Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy;

    Other Exclusion Criteria:

  6. Patients with autoimmune diseases history;
  7. Recently or currently taking Glucocorticoids or Immunosuppressants;
  8. Patients who underwent immunotherapy in the past;
  9. Allergy to any antibody drugs or allergy to Paclitaxel and Carboplatin.
  10. Past or currently suffering from chronic or recurrent autoimmune diseases;
  11. 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;
  12. Patients with organ transplantation (including autologous bone marrow transplantation and peripheral stem cell transplantation);
  13. 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;
  14. 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;
  15. Pregnant or lactating women and fertile women who will not be using contraception during the trial;
  16. 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;
  17. Expected lack of compliance with the protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neoadjuvant chemoradiotherapy combined with anti-PD-1 antibody
Neoadjuvant chemoradiotherapy (NCRT) combined with tislelizumab is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Procedure: Neoadjuvant Chemoradiotherapy

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)

Drug: Tislelizumab

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);

Other Names:
  • anti-PD-1 antibody
Procedure: Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)
After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)
Active Comparator: Neoadjuvant chemoradiotherapy
Neoadjuvant chemoradiotherapy (NCRT) is performed followed by Ivor-Lewis or Mckeown esophagectomy in enrolled patients.
Procedure: Neoadjuvant Chemoradiotherapy

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)

Procedure: Ivor-Lewis or Mckeown Esophagectomy(Mckeown Esophagectomy recommended)
After neoadjuvant therapy, patients in groups receive Ivor-Lewis or Mckeown Esophagectomy (Mckeown Esophagectomy recommended)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological response rate(pCR)
Time Frame: Up to the date of pathological reports obtained since the date of randomization, up to 12 months
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%.
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
Overall survival(OS)
Time Frame: Up to the date of death of any causes since the date of randomization, up to 36 months
Up to the date of death of any causes since the date of randomization, up to 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment related complications
Time Frame: Up to 1 month after surgery since the data of randomization, up to 13 months
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
Up to 1 month after surgery since the data of randomization, up to 13 months
Progression-free survival(PFS)
Time Frame: Up to the date of disease recurrence since the date of randomization, up to 36 months
Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs)
Up to the date of disease recurrence since the date of randomization, up to 36 months
R0 resection rate
Time Frame: Up to the date of pathological reports obtained since the date of randomization, up to 12 months
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).
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
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
According to pathological reports, record the number and location of positive lymph nodes
Up to the date of pathological reports obtained since the date of randomization, up to 12 months
Overall Quality of life
Time Frame: Up to the end of follow-up since the data of surgery, up to 36 months
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)
Up to the end of follow-up since the data of surgery, up to 36 months
Quality of life in eating and swallowing function
Time Frame: Up to the end of follow-up since the data of surgery, up to 36 months
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
Up to the end of follow-up since the data of surgery, up to 36 months
Recurrence-free survival (RFS)
Time Frame: Up to the date of disease recurrence since the date of surgery, up to 36 months
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.
Up to the date of disease recurrence since the date of surgery, up to 36 months
Correlation between genetic profile and tumor response
Time Frame: Up to the end of follow-up since the data of surgery, up to 36 months
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.
Up to the end of follow-up since the data of surgery, up to 36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shanghai Zhongshan Hospital

Collaborators

Zhejiang Cancer Hospital
Sun Yat-sen University
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Tongji Hospital
Peking University Cancer Hospital & Institute
Ningbo Medical Center Lihuili Hospital
Tianjin Medical University Cancer Institute and Hospital
Shanghai Chest Hospital
First Affiliated Hospital of Wenzhou Medical University
Sichuan Cancer Hospital and Research Institute
Shanghai Minhang Central Hospital
The First People's Hospital of Changzhou
Zhongshan Hospital, Fudan University (Xiamen Branch)
Xuhui Central Hospital, Shanghai
Shanghai Fifth People's Hospital

Investigators

  • Principal Investigator: Lijie Tan, MD, Shanghai Zhongshan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 2, 2022

Primary Completion (Anticipated)

July 1, 2024

Study Completion (Anticipated)

July 1, 2027

Study Registration Dates

First Submitted

June 28, 2021

First Submitted That Met QC Criteria

July 13, 2021

First Posted (Actual)

July 22, 2021

Study Record Updates

Last Update Posted (Actual)

June 30, 2022

Last Update Submitted That Met QC Criteria

June 26, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • B2021-369R

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD 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

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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