Efficacy of Perioperative Chemotherapy Plus PD-1 Antibody in the Locally Advanced Gastric Cancer

• ClinicalTrials.gov Identifier: NCT04250948
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2020
• Last Update Posted: August 1, 2023
• Sponsor: Sun Yat-sen University
• Collaborator: Shanghai Junshi Bioscience Co., Ltd.
• Information provided by (Responsible Party): Rui-hua Xu, MD, PhD, Sun Yat-sen University

Tracking Information

• First Submitted Date: November 10, 2019
• First Posted Date: January 31, 2020
• Last Update Posted Date: August 1, 2023
• Actual Study Start Date: October 12, 2019
• Actual Primary Completion Date: June 27, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2020)

TRG0/1 [ Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 12 weeks. ]

Pathological tumor regression grade 0/1

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 5, 2020)

• pCR [ Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 12 weeks. ]
  Pathological complete response
• 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 12 weeks. ]
  Rate of microscopically margin-negative resection
• Recurrence free survival (RFS) [ 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
• Objective response rate (ORR) [ 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 ]
  Defined as the proportion of patients whose tumors shrink for a certain period of time
• Disease control rate (DCR) [ 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] ]
  Defined as the proportion of patients whose tumors shrink or remain stable for a certain period of time
• Overall survival (OS) [ 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 death from any cause or the last follow-up date.

Original Secondary Outcome Measures (submitted: January 30, 2020)

• pCR [ Time Frame: From the initiation date of first cycle (each cycle is 21 days) to the date of operation, an average of 12 weeks. ]
  Pathological complete response
• 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 12 weeks. ]
  Rate of microscopically margin-negative resection
• Recurrence free survival (RFS) [ 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
• Objective response rate (ORR) [ 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 ]
  Defined as the proportion of patients whose tumors shrink for a certain period of time, including CR and PR.
• Disease control rate (DCR) [ 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] ]
  Defined as the proportion of patients whose tumors shrink or remain stable for a certain period of time, including CR, PR and SD.
• Overall survival (OS) [ 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 death from any cause or the last follow-up date.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of Perioperative Chemotherapy Plus PD-1 Antibody in the Locally Advanced Gastric Cancer
• Official Title: Perioperative Chemotherapy Plus PD-1 Antibody Compared With Perioperative Chemotherapy in the Locally Advanced Gastric Cancer: a Open-label, Phase 2 Randomised Controlled Trial
• Brief Summary: For locally advanced gastric cancer (cT3-4aN+M0), neoadjuvant chemotherapy can downstage T and N stage, increase the resectability of tumor, and finally improve the long-term survival. Combination of perioperative PD-1 antibody and chemotherapy for locally advanced gastric cancer could be a novel therapy to increase response rate and resectability 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 tolerability, safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced gastric cancer.
• Detailed Description: Gastric cancer is one of the most common malignancies in China with incidence and mortality both ranking the 2nd among malignancies in China. Surgery is the only possible way to cure gastric cancer, however, over 80-90% of gastric cancer patients in China are in advanced stage. Locally advanced gastric cancer (cT3-4aN+M0) could be cured by multi-disciplinary therapies including surgery, chemotherapy and radiotherapy. Neoadjuvant chemotherapy can downstage T and N stage, increase the resectability of tumor, 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 gastric cancer could be a novel therapy to increase response rate and resectability 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 tolerability, safety and efficacy of JS001 in combination with perioperative chemotherapy in locally advanced gastric cancer.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Gastric Cancer
• Locally Advanced Solid Tumor

Intervention

• 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

Study Arms

• Active Comparator: 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 3 cycles, adjuvant chemotherapy for 5 cycles.

  Interventions:

  • Drug: Oxaliplatin
  • Drug: S1
  • Drug: Capecitabine
• Experimental: 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 3 cycles, adjuvant chemotherapy for 5 cycles.

  Interventions:

  • Drug: JS001
  • Drug: Oxaliplatin
  • Drug: S1
  • Drug: Capecitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 30, 2020): 108
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 5, 2024
• Actual Primary Completion Date: June 27, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Written (signed) informed consent;
2. Histologically CT/MRI confirmed cT3-4aN+M0 gastric adenocarcinoma;
3. Consent to send tumor tissue from biopsy or resection for PD-L1, EBV, MSI detection;
4. Female or male, 18-75 years;
5. ECOG 0-1, no surgery contraindications;
6. Physical condition and adequate organ function to ensure the success of abdominal surgery;
7. Expected survival ≥3 months;
8. Adequate hematological, liver, renal and coagulation function;

1) Platelet (PLT) count ≥100,000 /mm3; 2) Neutrophil count (ANC) ≥1,500 /mm3; 3) Hemoglobin (Hb) level ≥9.0 g/dl; 4) International normalized ratio (INR) ≤1.5; 5) Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5×ULN; 6) Glycosylated hemoglobin (HbA1c) <7.5%; 7) Total bilirubin (TBIL) level ≤1.5×ULN; 8) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN (≤5×ULN in case of liver metastasis); 9) Alkaline phosphatase level ≤2.5×ULN (≤5×ULN in case of liver metastasis); 10) Serum creatinine (Cr) level ≤1.5×ULN and creatinine clearance ≥60 ml/min; 11) Thyroid stimulating hormone (TSH) ≤ULN; 12) Normal serum free thyroid hormone (T4); 13) Normal serum free triiodothyronine (T3); 14) Serum amylase ≤1.5×ULN; 15) Lipase ≤1.5×ULN.

9.Females of child bearing age must have a negative pregnancy test, and have to take contraception measures and avoid breast feeding during the study and for 3 months after the last dose; male subjects must agree to taken contraception measures during the study and for 3 months after the last dose.

Exclusion Criteria:

1. Known allergy to study drug or excipients, or allergy to similar drugs;
2. Patients with active malignant tumor in recent 2 years, except the tumor studied in this research or cured localized tumor like resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ;
3. Uncontrollable pleural effusion, pericardial effusion, or ascites in 2 weeks before recruitment;
4. Weight loss >20% within 2 weeks before recruitment;
5. Unable to swallow study drug;
6. Prior chemotherapy, radiotherapy, surgery for gastric cancer;
7. Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1) or CTLA-4 agent;
8. Prior therapy with tyrosine kinase inhibitor within 2 weeks.
9. 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;
10. Have vaccination with attenuated live vaccines within 4 weeks prior to initiation of the study treatment or plan to vaccinate during the study;
11. Poorly controlled hypertension or diabetes;
12. With bleeding tendency, or evident hemoptysis or other hemorrhagic events (e.g. gastrointestinal hemorrhage, hemorrhagic gastric ulcer) within 2 months prior to initiation of study treatment, or presence of hereditary or acquired bleeding or thrombotic tendency (e.g. hemophilia, coagulopathy, thrombocytopenia, etc.), or current/long-term thrombolytic or anticoagulant therapy (except aspirin ≤100 mg/day);
13. Present or history of any autoimmune disease;
14. With active tuberculosis or receiving previous anti-tuberculosis therapy within one year;
15. Diagnosed with interstitial pneumonia, non-infectious pneumonia, pulmonary fibrosis, acute lung disease;
16. Pregnancy or breast feeding;
17. Human immunodeficiency virus (HIV) infection (HIV antibody positive), or active hepatitis C virus (HCV) infection (HCV antibody positive), or active hepatitis B virus (HBV) infection (HBsAg or HBcAb positive, and HBV-DNA ≥2000 IU/ml (copies/ml)), or other severe infection requiring systemic antibiotic treatment, or unexplained body temperature >38.5℃ during screening period/before study treatment;
18. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04250948
• Other Study ID Numbers: Neoadjuvant PD-1/LAGC
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Rui-hua Xu, MD, PhD, Sun Yat-sen University
• Original Responsible Party: Ruihua Xu, Sun Yat-sen University, President, Professor
• Current Study Sponsor: Sun Yat-sen University
• Original Study Sponsor: Same as current
• Collaborators: Shanghai Junshi Bioscience Co., Ltd.

Investigators

• Principal Investigator: Rui-hua Xu, MD,PhD; Sun Yat-sen University

• PRS Account: Sun Yat-sen University
• Verification Date: July 2023