Perioperative Chemotherapy Plus Toripalimab for dMMR Locally Advanced Gastric or Esophagogastric Junction Adenocarcinoma

Perioperative S-1 Plus Oxaliplatin Combined With Toripalimab or Toripalimab Monotherapy Versus S-1 Plus Oxaliplatin for Treatment of dMMR Locally Advanced Gastric or Esophagogastric Junction Adenocarcinoma: a Prospective, Multi-center, Randomized Controlled Study

This study is a prospective, multi-center, randomized controlled phase II trial to compare the efficacy of perioperative SOX plus toripalimab, toripalimab monotherapy with SOX regimen in participants with dMMR locally advanced gastric or esophagogastric junction adenocarcinoma

Study Overview

• Status: Recruiting
• Conditions: Adenocarcinoma of the Stomach; Mismatch Repair Deficiency; Adenocarcinoma of Esophagogastric Junction
• Intervention / Treatment: Drug: Toripalimab; Drug: Oxaliplatin; Drug: S1

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jiren Yu; Phone Number: 0086-0571-87237931; Email: yujr0909@zju.edu.cn
• Study Contact Backup: Name: Kankai Zhu; Email: zhukankai0401@163.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital, College of Medicine, Zhejiang University
      • Contact: Jiren Yu
    • Hangzhou, Zhejiang, China, 310003
      • Not yet recruiting
      • The Second Affiliated Hospital, College of Medicine, Zhejiang University
      • Contact: Jian Chen
    • Huzhou, Zhejiang, China, 313099
      • Not yet recruiting
      • Huzhou Central Hospital
      • Contact: Yunhai Wei
    • Lishui, Zhejiang, China, 323000
      • Not yet recruiting
      • Lishui Central Hospital
      • Contact: Hongtao Xu
    • Ningbo, Zhejiang, China, 315010
      • Not yet recruiting
      • Ningbo First Hospital
      • Contact: Zhilong Yan
    • Ningbo, Zhejiang, China, 315048
      • Not yet recruiting
      • Ningbo Medical Center Lihuili Hospital
      • Contact: Weiming Yu
    • Ningbo, Zhejiang, China, 315099
      • Not yet recruiting
      • Ningbo Second Hospital
      • Contact: Ping Chen
    • Taizhou, Zhejiang, China, 317099
      • Not yet recruiting
      • Taizhou Hospital
      • Contact: Shenkang Zhou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntary participation in the clinical study; fully understands and is informed of the study and has signed the Informed Consent Form (ICF).
2. Participants were ambulatory male or female. Age: ≥ 18 years and ≤ 80 years old.
3. Histopathologically confirmed gastric or esophagogastric junction adenocarcinoma.
4. Mismatch repair deficient (dMMR) adenocarcinoma, which was determined by immunohistochemistry (ICH) test of endoscopic biopsy specimen. dMMR was defined as loss of nuclear expression of one or more MMR proteins.
5. cT2-4bN+/-, M0 according to the American Joint Committee on Cancer and Union for International Cancer Control (AJCC-UICC) TNM classification for carcinoma of the stomach (8th edition).
6. Participants had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 within 7 days before the first dose of study treatment.
7. Life expectancy ≥ 6 months.
8. Agreement of providing baseline and surgical specimens for biomarker analysis.
9. The functions of the vital organs meet requirements as follows (within 14 days before the first dose of study treatment, meanwhile, participants had not received treatment of recombinant human thrombopoietin or granulocyte stimulating factor):

1). Hematological function#

-White blood cell count (WBC): 3.5 × 10^9/L ~12.0 × 10^9/L

-Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

-Platelet count (PLT) ≥ 100 × 10^9/L

• Hemoglobin (Hb) ≥ 90g/L. 2). Hepatic function
• Total bilirubin (TBIL) ≤ 1.5 × ULN (upper limit of normal); -Aspartate aminotransferase (AST) ≤ 2.5 × ULN;
• Alanine aminotransferase (ALT) ≤ 2.5 × ULN;
• Albumin (ALB) ≥ 30g/L. 3). Renal function

• Creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 60 ml / min for those with creatinine level > 1.5 × ULN.

  4). Coagulation function#

  • International normalized ratio (INR) ≤ 1.5;

  • Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

    10. Female participants of childbearing age must meet requirements: urine or serum pregnancy test must be negative within 7 days before the first dose of study treatment, and she must agree to use adequate contraception methods or keep abstinence (starting with the ICF is signed through 120 days after the last dose of toriplimab, or 180 days after the last dose of chemotherapy, whichever is longer, and should not be breastfeeding. Male participants must meet requirements: agree to use adequate contraception methods or keep abstinence (starting with the ICF is signed through 120 days after the last dose of toriplimab, or 180 days after the last dose of chemotherapy, whichever is longer).

Exclusion Criteria:

1. HER2-positive status defined as either IHC score of 3+ or IHC 2+ with amplification proven by fluorescent in situ hybridization (FISH) based on pretreatment endoscopic biopsies.
2. Prior systemic therapy for treatment of gastric cancer (surgery, chemotherapy, radiotherapy, targeted therapy or immunotherapy).
3. Previous or concurrent have other active malignant tumors within the past 5 years (except for basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate cancer or cervical cancer or breast cancer in situ that has undergone curative therapy).
4. Participants with gastric outlet obstruction, or unable to oral take, or severe gastrointestinal bleeding.
5. Myocardial infarction within 6 months before the first dose of study treatment, uncontrolled angina, arrhythmia which need medical intervention (including but not limited to cardiac pacemaker), congestive heart failure (New York Heart Association (NYHA) class III or IV).
6. Existence of chronic diarrhea (watery diarrhea: ≥ 5 times per day).
7. Participants with active infection within 14 days before the first dose of study treatment which need medical intervention.
8. Participants with active tuberculosis.
9. Previous or concurrent diagnosed with interstitial lung disease by imaging or symptoms.
10. Any of the following test is positive: Human Immunodeficiency Virus (HIV) antibody, Hepatitis B surface Antigen (HBsAg), or Hepatitis C Virus (HCV) antibody.
11. Participants who need long-term systemic steroid therapy (> 10 mg/d prednisone equivalent) or any other form of immunosuppressive therapy within 14 days before the first dose of study treatment or during the study period.
12. Concurrent or previous have severe allergic reaction to any antibody- based drugs.
13. Existence of any concurrent autoimmune disease, excepting participants with diabetes mellitus type I, hypothyroidism requiring only hormone replacement therapy.
14. Receive live vaccines within 28 days before the first dose of study treatment or during the study period, excepting inactivated viral vaccines for seasonal influenza.
15. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
16. Existence of systemic disease that is difficult to control despite treatment with several agents, for example, diabetes mellitus, hypertension, etc.
17. Existence of other serious physical or mental diseases or serious laboratory abnormalities that may increase the risk of participating in the study. Participants who were judged unsuitable as subjects of this trial by investigator.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (Chemotherapy+Toripalimab); Toripalimab, 240 mg IV infusion on Day 1 of each 21 day cycle for 3 cycles prior to surgery and 3 cycles after surgery. Chemotherapy: SOX(S-1+Oxaliplatin) Oxaliplatin, administered as a 2-hour intravenous infusion (130 mg/m2) S-1, orally twice daily for 2 weeks followed by a 7-day rest period. The dose of S-1 was 80 mg/day for body surface area less than 1.25 m2, 100 mg/day for body surface area greater than or equal to 1.25 to less than 1.5 m2, and 120 mg/day for body surface area greater than or equal to 1.5 m2 Chemotherapy will be repeated each 21 day for 3 cycles prior to surgery and 3 cycles after surgery.	Drug: Toripalimab; Perioperative Toripalimab, 240 mg IV infusion; Drug: Oxaliplatin; Oxaliplatin (130 mg/m2) infusion as perioperative chemotherapy; Drug: S1; S-1 orally intake as perioperative chemotherapy
Experimental: Arm B (Toripalimab monotherapy); Toripalimab, 240 mg IV infusion on Day 1 of each 21 day cycle for 3 cycles prior to surgery and 3 cycles after surgery.	Drug: Toripalimab; Perioperative Toripalimab, 240 mg IV infusion
Active Comparator: Arm C (Chemotherapy); Chemotherapy: SOX(S-1+Oxaliplatin) Oxaliplatin, administered as a 2-hour intravenous infusion (130 mg/m2) S-1, orally twice daily for 2 weeks followed by a 7-day rest period. The dose of S-1 was 80 mg/day for body surface area less than 1.25 m2, 100 mg/day for body surface area greater than or equal to 1.25 to less than 1.5 m2, and 120 mg/day for body surface area greater than or equal to 1.5 m2 Chemotherapy will be repeated each 21 day for 3 cycles prior to surgery and 3 cycles after surgery.	Drug: Oxaliplatin; Oxaliplatin (130 mg/m2) infusion as perioperative chemotherapy; Drug: S1; S-1 orally intake as perioperative chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of major pathological response (MPR)	Percentage of patients with MPR referring to the total number of patients with surgery, as evaluated centrally by a reference pathologist.	From enrollment to surgery after pre-operative treatment (up to approximately 36 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The duration of overall survival (OS) was defined as the time interval from randomization to the last follow-up or death from any cause.	From randomization to the last follow-up or death from any cause (up to approximately 72 months)
Progression-free survival	Progression-free survival (PFS) was defined as the time from randomization to the last follow-up or the time of disease progression or relapse or death from any cause.	From randomization to the last follow-up or the time of disease progression or relapse or death from any cause (up to approximately 72 months)
The incidences and types of adverse events (AE) and severe adverse events (SAE)	The incidences and severity of adverse events that occur during treatment will be evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3	From enrollment to 90-day after the last dose administration (up to approximately 39 months)

Collaborators and Investigators

• Sponsor: Yu jiren
• Investigators: Principal Investigator: Jiren Yu, First Affiliated Hospital of Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2023
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): February 28, 2029

Study Registration Dates

• First Submitted: February 7, 2023
• First Submitted That Met QC Criteria: February 7, 2023
• First Posted (Actual): February 15, 2023

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: July 24, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Toripalimab; Gastric Adenocarcinoma; Perioperative Chemotherapy; Esophagogastric Junction Adenocarcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Antineoplastic Agents; Oxaliplatin
• Other Study ID Numbers: IIT20220083C-R1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No