Neoadjuvant Immunotherapy and Chemotherapy for Locally Advanced Esophagogastric Junction and Gastric Cancer Trial (NICE)

November 13, 2022 updated by: Guoxin Li, Nanfang Hospital of Southern Medical University

Efficacy and Safety of Neoadjuvant Immunotherapy and Chemotherapy for Locally Advanced Esophagogastric Junction and Gastric Cancer : a Open-label, Phase 2 Randomised Controlled Trial (NICE Trial)

For locally advanced esophagogastric junction and gastric cancer (cT3-4aNxM0 or cT2N+M0), neoadjuvant chemotherapy can downstage T and N stage,treated distant micrometastases early before local therapy has begun, and finally improve the long-term survival. Combination of perioperative PD-1 antibody and chemotherapy for locally advanced esophagogastric junction and gastric cancer could be a novel therapy to increase response rate and reduce recurrence rate. JS001 in this study is a Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is a multi-center, open-label, randomized phase II clinical trial to evaluate safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced esophagogastric junction and gastric cancer. Differences in gut microbiome and tumor immune microenvironment were detected to screen people who were more sensitive to immunotherapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide and a substantial global health burden. Surgery is the only possible way to cure gastric cancer, however, more than 80% of the Chinese patients are diagnosed at advanced stages. Locally advanced esophagogastric junction and gastric cancer (cT3-4aNxM0 or cT2N+M0) could be cured by multi-disciplinary therapies including surgery, chemotherapy and radiotherapy. Neoadjuvant chemotherapy can downstage T and N stage, treated distant micrometastases early before local therapy has begun, and finally improve the long-term survival. However, the therapeutic effects remain unsatisfactory. PD-1 antibody has demonstrated its efficacy in metastatic gastric cancer and has been proved to be effective in neoadjuvant setting in lung cancer and melanoma. Combination of perioperative PD-1 antibody and chemotherapy for locally advanced esophagogastric junction and gastric cancer could be a novel therapy to increase response rate and reduce recurrence rate. JS001 in this study is a Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is a multi-center, open-label, randomized phase II clinical trial to evaluate safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced esophagogastric junction and gastric cancer. Differences in gut microbiome and tumor immune microenvironment were detected to screen people who were more sensitive to immunotherapy.

Study Type

Interventional

Enrollment (Anticipated)

110

Phase

  • Phase 2

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

  • China
    • Fujian
      • Fuzhou, Fujian, China
        • Recruiting
        • Fujian Provincial Hospital
        • Contact:
          • Fangqin Xue
          • Phone Number: +8618750162636
      • Xiamen, Fujian, China
        • Not yet recruiting
        • The First Affiliated Hospital of Xiamen University
        • Contact:
          • Jun You
          • Phone Number: +8613906051681
    • Guangdong
      • Guangzhou, Guangdong, China, 510-515
        • Recruiting
        • Nanfang Hospital, Southern Medical University
        • Contact:
        • Sub-Investigator:
          • Liying Zhao, M.D., Ph.D.
      • Guangzhou, Guangdong, China, 510515
        • Recruiting
        • The six affiliated hospital, Sun Yat-sen University
        • Contact:
        • Principal Investigator:
          • Lei Lian, MD
      • Guangzhou, Guangdong, China
        • Recruiting
        • Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine,
        • Contact:
          • Wei Wang
          • Phone Number: +8613922255515
      • Maoming, Guangdong, China
        • Not yet recruiting
        • Mao ming people's hospital
        • Contact:
          • Dingming Li
          • Phone Number: +8613500078234
      • Shenzhen, Guangdong, China
        • Recruiting
        • Peking University Shenzhen Hospital
        • Contact:
          • Guoqing Lv
          • Phone Number: +8613928404691
      • Shenzhen, Guangdong, China
        • Not yet recruiting
        • The Eighth Affiliated Hospital, Sun Yat-Sen University
        • Contact:
          • Xiaobin Wu
          • Phone Number: +8613928800055
      • Zhongshan, Guangdong, China
        • Recruiting
        • Zhongshan People's Hospital
        • Contact:
          • Hong Chen
    • Heilongjiang
      • Harbin, Heilongjiang, China
        • Not yet recruiting
        • Harbin Medical University Cancer Hospital

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. Written (signed) informed consent;
  2. Age ≥ 18 years and ≤75 years.
  3. Confirmed gastric and gastroesophageal junction adenocarcinoma by Gastroscopic biopsy histopathological examination.
  4. Imaging (CT/MRI) and diagnostic laparoscopy confirmed at the stage of cT3/4a Nx or T2 N+, M0(AJCC 8th) before randomization.

  5. confirmed by immunohistochemistry (IHC) staining or genetic and transcriptional profiling detection to meet one of the following conditions:

    1. Combined positive score (CPS) of PD-L1 protein expression ≥5.
    2. Epstein-Barr virus-positive (EBV(+)).
    3. mismatch repair-deficient (dMMR).
    4. Microsatellite instability-high (MSI-H)
  6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1
  7. Expected survival period ≥ 12 weeks

  8. The main organ function meets the following criteria within 7 days before treatment:

    1. Hemoglobin (Hb) level ≥9.0 g/dl
    2. Neutrophil count (ANC)≥1.5×l09/L
    3. Platelet (PLT) ≥100×109/L
    4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN
    5. Alkaline phosphatase(ALP)level ≤2.5×ULN
    6. Serum creatinine (Cr) level ≤1.5×ULN and creatinine clearance ≥60 ml/min
    7. Thyroid stimulating hormone (TSH) level ≤1×ULN (if abnormal, should require normal serum free thyroid hormone (T4) and Normal serum free triiodothyronine (T3))

Exclusion Criteria:

  1. Confirmed at stage IV (AJCC 8th) or unresectable by investigator before randomization.
  2. Prior chemotherapy, radiotherapy, surgery immunotherapy or molecular targeted therapy for gastric cancer;
  3. Patients who have HER2 positive confiemed with IHC3+ or IHC2+ and FISH positive
  4. Patients are allergic to study medication and its ingredients

  5. Patients with a history of following treatments:

    1. Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1) or CTLA-4 agent
    2. Prior therapy with tyrosine kinase inhibitor within 2 weeks.
    3. Patients who have participated in other clinical trials of anti-tumor drugs within four weeks
    4. Have vaccination with attenuated live vaccines within 4 weeks prior to initiation of the study treatment or plan to vaccinate during the study;
    5. Concurrent medical condition requiring the use of cortisol (>10mg/day Prednisone or equivalent dose) or other systematic immunosuppressive medications within 14 days before the study treatment. Except: inhalation or topical corticosteroids. Doses > 10 mg/day prednisone or equivalent for replacement therapy
  6. Patients have experienced or currently has other malignancies within 5 years.
  7. Patients have an active or history of autoimmune disease that may recur or require immunosuppressive drugs within 2 weeks or less or during the study. Or have a history of immunodeficiency, including HIV-positive or other acquired, congenital immunodeficiency disease, or a history of organ transplantation
  8. Patients with other severe acute or chronic conditions that may increase the risk of participation in the study and study treatment, or may interfere with interpretation of study results, and judged by the investigator as not suitable for participation in this clinical trial.
  9. Within 2 weeks or 2 weeks before randomization, patients have an active or uncontrollable infection that requires systemic antibiotic treatment
  10. Diagnosed with interstitial pneumonia, non-infectious pneumonia, pulmonary fibrosis, acute lung disease;
  11. Patients with active tuberculosis or receiving previous anti-tuberculosis therapy within one year
  12. Women who are pregnant, breast-feeding or planning to become pregnant during treatment or within 6 months after treatment ends.
  13. Patients have a history of psychotropic substance abuse and are unable to quit or have a mental disorder

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: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control group

The patients with combined positive score (CPS) of PD-L1 protein expression≥5 were randomised to control group(N=40), will receive the neoadjuvant regime of XELOX or SOX.

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1. Oxaliplatin: 130mg/m2, iv drip for 2h, d1, q3w; S-1:40~60mg Bid, d1~14, q3w; Capecitabine: 1000mg/m2 Bid, d1-14, q3w; Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.
Drug: XELOX or SOX

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1

Oxaliplatin: 130mg/m2, iv drip for 2h, d1, q3w;

S-1:40~60mg Bid, d1~14, q3w;

Capecitabine: 1000mg/m2 Bid, d1-14, q3w;

Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.

Drug: Oxaliplatin Oxaliplatin: 130mg/m2，iv drip for 2h，d1, q3w

Drug: S1 S-1: 40~60mg Bid，d1~14, q3w

Drug: Capecitabine Capecitabine: 1000mg/m2 Bid, d1-14, q3w Other Name: XELODA

JS001: 240mg, ivdrip, d1, q3w;

S-1:40~60mg Bid, d1~14, q3w;

Capecitabine: 1000mg/m2 Bid, d1-14, q3w;

Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.

Drug: JS001 JS001, recombinant humanized anti-PD-1 monoclonal antibody for injection; 240mg ivdrip, d1, q3w.

Other Name: PD-1 antibody

Drug: Oxaliplatin Oxaliplatin: 130mg/m2,iv drip for 2h, d1, q3w

Drug: S1 S-1: 40~60mg Bid,d1~14, q3w

Drug: Capecitabine Capecitabine: 1000mg/m2 Bid, d1-14, q3w Other Name: XELODA

Other Names:
  • Control group
Experimental: Experimental group

The patients with combined positive score (CPS) of PD-L1 protein expression≥5 were randomised to experimental group(N=40), will receive the neoadjuvant regime of JS001+XELOX or SOX.

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1. JS001: 240mg, ivdrip, d1, q3w; S-1:40~60mg Bid, d1~14, q3w; Capecitabine: 1000mg/m2 Bid, d1-14, q3w; Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.
Drug: JS001+XELOX or SOX

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1

JS001: 240mg, ivdrip, d1, q3w;

S-1:40~60mg Bid, d1~14, q3w;

Capecitabine: 1000mg/m2 Bid, d1-14, q3w;

Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.

Drug: JS001 JS001, recombinant humanized anti-PD-1 monoclonal antibody for injection; 240mg ivdrip, d1, q3w.

Other Name: PD-1 antibody

Drug: Oxaliplatin Oxaliplatin: 130mg/m2,iv drip for 2h, d1, q3w

Drug: S1 S-1: 40~60mg Bid,d1~14, q3w

Drug: Capecitabine Capecitabine: 1000mg/m2 Bid, d1-14, q3w Other Name: XELODA

Other Names:
  • Experimental group and Exploratory group
Other: Exploratory group

All the patients of Epstein-Barr virus-positive (EBV(+)) [N=15]or mismatch repair-deficient (dMMR)/ microsatellite instability-high (MSI-H)[N=15] , will be assigned to exploratory group, and will receive the neoadjuvant regime of JS001+XELOX or SOX.

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1. JS001: 240mg, ivdrip, d1, q3w; S-1:40~60mg Bid, d1~14, q3w; Capecitabine: 1000mg/m2 Bid, d1-14, q3w; Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.
Drug: JS001+XELOX or SOX

XELOX: Oxaliplatin+Capecitabine; SOX: Oxaliplatin+S-1

JS001: 240mg, ivdrip, d1, q3w;

S-1:40~60mg Bid, d1~14, q3w;

Capecitabine: 1000mg/m2 Bid, d1-14, q3w;

Neoadjuvant chemotherapy for 4 cycles, adjuvant chemotherapy for 4 cycles.

Drug: JS001 JS001, recombinant humanized anti-PD-1 monoclonal antibody for injection; 240mg ivdrip, d1, q3w.

Other Name: PD-1 antibody

Drug: Oxaliplatin Oxaliplatin: 130mg/m2,iv drip for 2h, d1, q3w

Drug: S1 S-1: 40~60mg Bid,d1~14, q3w

Drug: Capecitabine Capecitabine: 1000mg/m2 Bid, d1-14, q3w Other Name: XELODA

Other Names:
  • Experimental group and Exploratory group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major pathologic response (MPR)
Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks
It is defined as residual tumors less than 10% after neoadjuvant immunotherapy and(or) chemotherapy
From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-free survival (DFS)
Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
The Kaplan-Meier survival from the initiation date of first cycle until the date of first documented recurrence.
From the initiation date of first cycle (each cycle is 21 days) to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Overall survival(OS)
Time Frame: From date of randomization until the date of first documented date of death from any cause, assessed up to 36 months
From date of randomization until the date of first documented date of death from any cause, assessed up to 36 months
pCR
Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks
Pathological complete response after neoadjuvant immunotherapy and(or) chemotherapy
From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks
R0 resection rate
Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks
Rate of microscopically margin-negative resection
From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 14 weeks
Adverse event incidence rate
Time Frame: Patients will be assessed for adverse events throughout the study at every visit during treatment and at 3-month follow-up visit (3 months after treatment ends)
Number of participants with treatment-related adverse events as assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] v4.03
Patients will be assessed for adverse events throughout the study at every visit during treatment and at 3-month follow-up visit (3 months after treatment ends)

Collaborators and Investigators

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

Sponsor

Nanfang Hospital of Southern Medical University

Collaborators

Shanghai Junshi Bioscience Co., Ltd.

Investigators

  • Principal Investigator: Guoxin Li, M.D., PH.D., Nanfang Hospital of Southern Medical University
  • Principal Investigator: Liying Zhao, M.D., Ph.D., Nanfang Hospital of Southern Medical 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)

March 12, 2021

Primary Completion (Anticipated)

December 30, 2023

Study Completion (Anticipated)

December 30, 2024

Study Registration Dates

First Submitted

January 23, 2021

First Submitted That Met QC Criteria

February 8, 2021

First Posted (Actual)

February 9, 2021

Study Record Updates

Last Update Posted (Actual)

November 15, 2022

Last Update Submitted That Met QC Criteria

November 13, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NiCE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

We will share Study Protocol and Statistical Analysis Plan (SAP)

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)

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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