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

Sponsor

Yu jiren (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05729646

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

11.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Stomach Adenocarcinoma of Esophagogastric Junction Mismatch Repair Deficiency	Drug: Toripalimab Drug: Oxaliplatin Drug: S1	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Feb 28, 2023

Anticipated Primary Completion Date :

Feb 28, 2026

Anticipated Study Completion Date :

Feb 28, 2029

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Overall Survival [From randomization to the last follow-up or death from any cause (up to approximately 72 months)]
The duration of overall survival (OS) was defined as the time interval from randomization to the last follow-up or death from any cause.
Progression-free survival [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)]
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.
The incidences and types of adverse events (AE) and severe adverse events (SAE) [From enrollment to 90-day after the last dose administration (up to approximately 39 months)]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Voluntary participation in the clinical study; fully understands and is informed of the study and has signed the Informed Consent Form (ICF).
Participants were ambulatory male or female. Age: ≥ 18 years and ≤ 80 years old.
Histopathologically confirmed gastric or esophagogastric junction adenocarcinoma.
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.
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).
Participants had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 within 7 days before the first dose of study treatment.
Life expectancy ≥ 6 months.
Agreement of providing baseline and surgical specimens for biomarker analysis.
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.

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:

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.
Prior systemic therapy for treatment of gastric cancer (surgery, chemotherapy, radiotherapy, targeted therapy or immunotherapy).
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).
Participants with gastric outlet obstruction, or unable to oral take, or severe gastrointestinal bleeding.
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).
Existence of chronic diarrhea (watery diarrhea: ≥ 5 times per day).
Participants with active infection within 14 days before the first dose of study treatment which need medical intervention.
Participants with active tuberculosis.
Previous or concurrent diagnosed with interstitial lung disease by imaging or symptoms.
Any of the following test is positive: Human Immunodeficiency Virus (HIV) antibody, Hepatitis B surface Antigen (HBsAg), or Hepatitis C Virus (HCV) antibody.
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.
Concurrent or previous have severe allergic reaction to any antibody- based drugs.
Existence of any concurrent autoimmune disease, excepting participants with diabetes mellitus type I, hypothyroidism requiring only hormone replacement therapy.
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.
Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
Existence of systemic disease that is difficult to control despite treatment with several agents, for example, diabetes mellitus, hypertension, etc.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The First Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310003
2	The Second Affiliated Hospital, College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310003
3	Huzhou Central Hospital	Huzhou	Zhejiang	China	313099
4	Lishui Central Hospital	Lishui	Zhejiang	China	323000
5	Ningbo First Hospital	Ningbo	Zhejiang	China	315010
6	Ningbo Medical Center LiHuiLi Hospital	Ningbo	Zhejiang	China	315048
7	Ningbo Second Hospital	Ningbo	Zhejiang	China	315099
8	Taizhou Hospital	Taizhou	Zhejiang	China	317099