Neoadjuvant Anti-PD-1 Plus Chemotherapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

March 17, 2023 updated by: Shanghai Zhongshan Hospital

A Single-center, Prospective Cohort Study of Neoadjuvant Anti-PD-1 Plus Chemotherapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

The purpose of this study is to evaluate the outcomes and identify predictors of neoadjuvant anti-PD-1 plus chemotherapy in locally advanced resectable esophageal squamous cell carcinoma (ESCC). In this single-center cohort study, we are aiming to (1) evaluate the therapeutic efficacy and survival benefits on patients with locally advanced resectable ESCC (cT3-4aN0-1M0); (2) evaluate the value of genomic indicators including MMR alternation status in predicting therapeutic responses and prognosis; (3) evaluate the value of transcriptomic indicators including B cell lineage features in predicting therapeutic responses and prognosis; (4) evaluate the value of microbial and metabolite indicators in predicting therapeutic responses and prognosis. Whole exome sequencing, RNA sequencing, 16S rRNA sequencing and Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) of samples of patients to neoadjuvant chemoimmunotherapy before and after treatment are performed to explore the mechanisms of drug resistance and identification of predictive and prognosis biomarkers.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Multiple clinical trials investigated the safety and feasibility of neoadjuvant anti-PD-1 plus chemotherapy in esophageal squamous cell carcinoma (ESCC). However, the efficacy of neoadjuvant chemoimmunotherapy was undetermined and existing biomarkers failed to provide stable prediction of therapeutic responses. This study seek to further evaluate the clinical outcomes and identify biological predictors of neoadjuvant anti-PD-1 plus chemotherapy in locally advanced resectable esophageal squamous cell carcinoma (ESCC). In this single-center cohort study, our aims include:

  1. evaluate the therapeutic efficacy and survival benefits on patients with locally advanced resectable ESCC (cT3-4aN0-1M0);
  2. evaluate the value of genomic indicators in predicting therapeutic responses and prognosis;
  3. evaluate the value of transcriptomic indicators in predicting therapeutic responses and prognosis;
  4. evaluate the value of microbial and metabolite indicators in predicting therapeutic responses and prognosis. Whole exome sequencing, RNA sequencing, 16S rRNA sequencing and Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) of samples of responders and non-responders to neoadjuvant chemoimmunotherapy before and after treatment are performed to explore the mechanisms of drug resistance and identification of predictive and prognosis biomarkers, providing guidance to clinical decisions.

Study Type

Observational

Enrollment (Anticipated)

40

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

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

Sampling Method

Probability Sample

Study Population

Patients with locally advanced resectable ESCC (cT3-4aN0-1M0)

Description

Inclusion Criteria:

  1. Histologically-confirmed squamous cell carcinoma of the esophagus;
  2. Tumors of the esophagus are located in the thoracic cavity;
  3. Pre-treatment stage as cT3-4aN0-1M0 (AJCC/UICC 7th Edition) (In case of stage cT4a, curative resectability has to be explicitly verified by the local surgical investigator prior to randomization).
  4. Age is between 18 years and 75 years,
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
  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:

  1. Patients with non-squamous cell carcinoma histology;
  2. Patients with advanced inoperable or metastatic esophageal cancer;
  3. Pre-treatment stage as cT1-2N0-1M0 (AJCC/UICC 7th Edition);
  4. Pre-treatment stage as cN2-3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 7th Edition);
  5. 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.
  6. 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;
  7. Pregnant or lactating women and fertile women who will not be using contraception during the trial;
  8. Allergy to any drugs;
  9. Participation in another intervention clinical trial with interference to the therapeutic intervention during this study or during the last 30 days prior to informed consent;
  10. 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

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Neoadjuvant Anti-PD-1 Plus Chemotherapy Group
Patients with locally advanced resectable ESCC (cT3-4aN0-1M0) who receive neoadjuvant anti-PD-1 plus chemotherapy and donate biological samples
Drug: neoadjuvant anti-PD-1 plus chemotherapy

Patients will be given preoperative treatment as below once recruited:

  1. Chemotherapy is delivered and composed of two cycles of Nab-paclitaxel 135mg per square meter of body-surface area and cisplatin 75mg per square meter of body-surface area every 3 weeks;
  2. PD-1 antibody is delivered 200 mg (iv, in 30 minutes) every 3 weeks;
  3. After neoadjuvant therapy of 3-4 cycles, esophagectomy is performed. We advise starting 4 cycles of identical chemoimmunotherapy in 6w after surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major pathological regression (MPR) rate
Time Frame: Up to the date of pathological reports obtained since the date of enrollment, up to 6 months
The resected specimen following neo-adjuvant treatment are assessed by using standardised work up of the resection specimen in the pathology department and standardised histological criteria for tumour regression grading. MPR was defined as ≤10% residual viable tumor.
Up to the date of pathological reports obtained since the date of enrollment, up to 6 months

Secondary 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 enrollment, up to 6 months
The resected specimen following neo-adjuvant treatment are assessed by using standardised work up of the resection specimen in the pathology department and standardised histological criteria for tumour regression grading. PCR was defined as no evidence of vital residual tumor cells.
Up to the date of pathological reports obtained since the date of enrollment, up to 6 months
objective response rate (ORR)
Time Frame: 36 months after the last subject participating in
ORR is evaluated by chest, abdominal & pelvic CT/MRI based on RESIST 1.1. Evaluation will be conducted every 6 weeks during neoadjuvant therapy and every 6 months after surgery.
36 months after the last subject participating in
overall survival (OS)
Time Frame: 36 months after the last subject participating in
OS is defined as time interval from recruitment to all-caused death or censoring.
36 months after the last subject participating in
Progression-free survival(PFS)
Time Frame: 36 months after the last subject participating in
Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs).
36 months after the last subject participating in
The correlation between detection of genomic, immune, microbial and metabolite features and the rate of therapeutic responses.
Time Frame: 36 months after the last subject participating in
The detection of genomic, immune, microbial and metabolite features from biological samples before and after neoadjuvant chemoimmunotherapy is performed to analyze the correlation to treatment vulnerability.
36 months after the last subject participating in

Collaborators and Investigators

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

Sponsor

Shanghai Zhongshan Hospital

Investigators

  • Study Director: Di Ge, MD, Fudan University

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)

December 1, 2020

Primary Completion (Anticipated)

December 1, 2023

Study Completion (Anticipated)

December 1, 2028

Study Registration Dates

First Submitted

February 14, 2023

First Submitted That Met QC Criteria

February 14, 2023

First Posted (Actual)

February 23, 2023

Study Record Updates

Last Update Posted (Actual)

March 21, 2023

Last Update Submitted That Met QC Criteria

March 17, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • B2021-129

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The IPD will not be shared with other researchers in order to protect patients' privacy.

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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