Nab-PTX Plus S-1 and Sintilimab as Adjuvant Therapy in Patients With Stage IIIC Gastric Cancer

In this study, we combine Nab-PTX, S-1 and sintilimab as adjuvant regimen to patients with stage IIIC GC. We are aiming to investigate the recommended dose of this regimen in a phase I study and estimate the toxicity and efficacy of this regimen in a phase II study.

The phase I study is a dose-escalation study using a standard 3+3 design. The regimen involves 3-week cycles with escalated doses of nab-paclitaxel (80-120 mg/m2 on days 1 and 8) and fixed doses of sintilimab (200 mg on day 1) and S-1 (based on body-surface area on day 1 to 14). The primary endpoints are safety and determination the recommended dose in the subsequent phase II study. In the phase II trial, the primary endpoint is 3-year relapse-free survival (RFS). Secondary endpoints are 5-year overall survival (OS), 3-year OS, 5-year RFS, and quality of life. Exploratory endpoint is time to peritoneal metastasis. Adverse events are monitored and graded according to the Common Terminology Criteria for Adverse Events version 4.0.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years to 80 years;
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
3. Primary gastric cancer or gastroesophageal junction cancer that is pathologically diagnosed as adenocarcinoma;
4. Patients who have underwent radical resection with D2 lymphadenectomy and histologically proven to be stage IIIC gastric cancer according to the 8th edition of the UICC/AJCC TNM staging system for gastric cancer\[29\];
5. Patients who have received no prior chemotherapy or radiotherapy or immunotherapy for gastric cancer or gastroesophageal junction cancer;
6. No peritoneal metastasis by laparoscopy and no tumor cells in peritoneal fluid on cytologic analysis;
7. Adequate organ function for chemotherapy as follows:

   * absolute neutrophil count of ≥1.5×109/L;
   * platelet count of ≥100×109/L;
   * hemoglobin ≥90g/L;
   * bilirubin of \<1.5×upper limit of normal \[ULN\];
   * alanine aminotransferase and aspartate aminotransferase of \<2.5×ULN;
   * serum creatinine of ≤1.5×ULN;
   * creatinine clearance of \>50 mL/min;
   * TSH ≤1×ULN (if abnormal, T3 and T4 levels should be inspected at the same time, if T3 and T4 levels are normal, they can be included in the group);
   * APTT ≤1.5×ULN and INR ≤1.5×ULN;
   * myocardial enzymogram ≤1×ULN.
8. Written (signed) informed consent;
9. Good compliance with the study procedures, including examination and treatment;
10. Surgeons should have experience doing this type of surgery (\>50 procedures per year);
11. Patients have recovered from the operation and have no unresolved postoperative complications (such as postoperative infection, anastomotic leakage, gastrointestinal bleeding, pancreatic leakage) during baseline evaluation;
12. Start first treatment between 4 weeks and 12 weeks after surgery and there is no potential disease recurrence at the baseline evaluation;
13. The serum or urine HCG test of the female patients of non-surgical sterilization must be negative within 72 hours before the study group for the female patients of non-surgical sterilization or childbearing age;
14. During the study treatment period and within 3 months after the end of the study treatment period, a medically recognized contraceptive measure (such as IUD, contraceptive pill or condom) should be used for the enrolled patients.

Exclusion Criteria:

1. Distant metastatic disease evaluated by Chest-abdomen-pelvis CT, bone scan and head MR when with central nervous system symptoms or PET-CT;
2. R1 or R2 surgical margins;
3. Hospital stays exceeding 60 days;
4. Patients with history of prior or concurrent malignant tumors. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, are eligible;
5. Patients who received study drug treatment within 4 weeks before enrollment (participate in other clinical trials);
6. Patients with serious complications such as:

   * Uncontrolled cardiovascular disease, angina and arrhythmia;
   * Myocardial infarction in past six months;
   * Uncontrolled diabetes mellitus.
7. History of receiving anti-PD-1, anti-PD-L1, anti-PD-L2 or any other T cell co-simulation or checkpoint inhibitor therapy (eg. CTLA-4, OX-40, CD137);
8. Received any anti-cancer for this disease, including chemotherapy or radiotherapy or immunotherapy or Chinese traditional herb therapy;
9. Refuse to provide blood/tissue sample;
10. Female patients who are pregnant or lactating, or planning to become pregnant or lactating;
11. Active autoimmune disease or history of refractory autoimmune disease; Subjects with hypothyroidism requiring only hormone replacement therapy and skin diseases without systemic treatment (such as vitiligo, psoriasis or alopecia) can be selected;
12. Steroid or other systemic immunosuppressive therapy was used 14 days before admission, excluding local or physiological doses of systemic glucocorticoids (eg. no more than 10mg/day of prednisone or other glucocorticoids of equivalent dose) by nasal spray, inhalation or other routes, or hormones used to prevent allergy of contrast agents;
13. Uncontrollable pleural effusion, pericardial effusion or ascites;
14. History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;
15. Patients with history of hypersensitivity to any drugs in this study;
16. It may affect the absorption of S-1 in patients with upper gastrointestinal obstruction /bleeding, abnormal digestive function or malabsorption syndrome;
17. Have not fully recovered from toxicity or complications caused by any intervention before starting treatment;
18. HIV antibody positive, active hepatitis B or C (hepatitis B: HBsAg positive and HBV DNA ≥10 copies/ml; hepatitis C: HCV antibody and HCV-RNA positive, requiring antiviral treatment at the same time).
19. Receive live attenuated vaccine within 4 weeks before the first dose of study treatment or during the study period;
20. Severe or uncontrolled systemic disease:

    * severe cardiovascular diseases such as symptomatic coronary heart disease, congestive heart failure ≥ level II, uncontrolled arrhythmia and myocardial infarction within 12 months before admission;
    * active infection which requires systemic treatment;
    * active tuberculosis;
    * central nervous system (CNS) disorder or peripheral nervous system disorder or psychiatric disease;
    * history of primary immunodeficiency;
    * complicated with severe uncontrolled concurrent infection or other serious uncontrolled concomitant diseases, moderate or severe renal injury.
21. Other factors that may affect the safety or test compliance of the subjects according to the judgment of the researchers.