Ipilimumab (N01) Plus Sintilimab and Modified XELOX as Conversion Therapy in Unresectable Locally Advanced Gastric Cancer

This study was a prospective, single-arm, multi-center, phase Ⅱ clinical study to investigate the efficacy and safety of ipilimumab injection N01 combined with sintilimab and modified XELOX conversion therapy in patients with unresectable locally advanced gastric cancer who had not received systemic treatment.

After informed consent, 30 patients were selected and met the inclusion and exclusion criteria. Ipilimumab injection N01 was administered every 6 weeks (up to 4 cycles, according to the investigator's safety evaluation), sintilimab every 21 days, modified (60% standard dose) XELOX (oxaliplatin 78mg/m2, d1; Capecitabine 600mg/m2, bid, d1-14, q3w). Tumor assessments were performed every 8 weeks, and radical surgery was performed within 2-4 weeks after the last dose of study drug if the investigator assessed that it was feasible to perform radical surgery. If the evaluation showed that radical surgery could not be performed, the conversion therapy was continued until the evaluation was operable. Non-pd patients who were still inoperable continued to receive sintilimab combined with XELOX treatment, and PD patients were excluded from the group. Combination therapy was administered until disease progression or intolerable toxicity. After surgery, patients were treated with sintilimab combined with XELOX adjuvant therapy (the total number of chemotherapy cycles in the perioperative period was not more than 8 cycles, and the total treatment of sintilimab was 1 year according to the evaluation of the specific conditions of the patients), and ipilimumab injection N01 was treated with up to 4 cycles before surgery.

According to RECIST v1.1, preoperative imaging (CT/ enhanced CT) was performed to evaluate the efficacy and surgical evaluation. Postoperative imaging was assessed every three months until disease recurrence, and survival follow-up was performed every three months after recurrence. No more than 2 years. Safety visits were from the time of the first dose of dose until 60 days after the last dose or the initiation of a new antitumor therapy.

Biomarker blood and tumor samples, including tumor biopsies that may be performed at baseline or provided from other hospitals, will also be obtained at baseline and during the trial for participants who have signed up for biomarker sample collection.

Inclusion criteria

• Provided written informed consent before performing any trial-related procedures;
• Age ≥18 years old and ≤80 years old, regardless of gender;
• Histologically confirmed gastric or gastroesophageal junction adenocarcinoma, PDL1 CPS≥1, and unresectable locally advanced gastric cancer confirmed by MDT or investigator assessment (based on imaging and EUS assessment). Conclusions: The main reasons for unresectable locally advanced gastric cancer at initial diagnosis include: severe invasion of the primary tumor, inability to separate from surrounding organs or wrap around important blood vessels, or metastasis and fixation of regional lymph nodes, and inability to achieve R0 resection according to MDT discussion or investigator evaluation. R0 resection was considered unresectable if a Whipple's operation was performed in conjunction with it.
• At least one radiographic measurable lesion according to response evaluation Criteria in Solid Tumors (RECIST, version 1.1);
• No previous gastric cancer surgery, anti-tumor chemoradiotherapy/immunotherapy;
• ECOG score 0-1;
• Expected survival time > 6 months;
• Adequate organ function, subject must meet the following laboratory indicators:

• absolute neutrophil count (ANC) ≥1.5x109/L without using granulocyte colony-stimulating factor for the past 14 days.

• platelet count ≥75×109/L without blood transfusion in the past 14 days. 3) hemoglobin ≥75g/L without blood transfusion or erythropoietin use in the past 14 days; 4) Total bilirubin ≤3× upper limit of normal value (ULN); 5) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN; 6) serum creatinine ≤1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥50 ml/min (exclusion due to height); 7) good coagulation function, defined as INR or PT ≤1.5 times ULN; 8) Euthyroid, defined as thyroid stimulating hormone (TSH) within the normal range. If the baseline TSH was beyond the normal range, the subjects could be included if the total T3 (or FT3) and FT4 were within the normal range.

• Myocardial enzymes within the normal range (simple laboratory abnormalities without clinical significance judged by the investigators were also allowed to be enrolled); 10. For women of childbearing age, a negative urine or serum pregnancy test should be performed within 3 days before receiving the first dose of study drug (day 1 of cycle 1). If a urine pregnancy test result could not be confirmed as negative, a blood pregnancy test was requested. Women who were not of reproductive age were defined as those who had been postmenopausal for at least 1 year or had undergone surgical sterilization or hysterectomy.

• If there was a risk of pregnancy, all subjects (male or female) were required to use contraception with an annual failure rate of less than 1% throughout the treatment period until 120 days after the last dose of study drug on treatment (or 180 days after the last dose of chemotherapy drug).

Exclusion criteria

• Known HER2 positivity;
• Malignant diseases other than gastric cancer (excluding radical skin basal cell carcinoma, skin squamous cell carcinoma, and/or radical resection in situ carcinoma) diagnosed within 5 years before the first dose;
• Are currently participating in an interventional clinical study treatment, or have received another study drug or investigational device within 4 weeks before the first dose;
• Previous therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent targeting another T-cell receptor that stimulates or coinhibits it (e.g., CTLA-4, OX-40, CD137);
• Active autoimmune disease leading to systemic therapy (e.g., disease-modifying agents, glucocorticoids, or immunosuppressive agents) occurred within 1 year before the first dose. Alternative therapies (e.g., thyroxine, insulin, or physiological glucocorticoids for adrenal or pituitary insufficiency) were not considered systemic therapy;
• Receiving systemic glucocorticoids (excluding topical glucocorticoids by nasal spray, inhalation, or other route) or any other form of immunosuppressive therapy within 7 days before the first study dose; Note: Physiologic doses of glucocorticoids (≤10 mg per day of prednisone or equivalent) were allowed.
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Patients with known allergy to sintilimab, ipilimumab injection N01, chemotherapy active ingredients or excipients;
• Has not fully recovered from any intervention-related toxicity and/or complications before starting treatment (i.e., grade ≤1 or baseline, excluding fatigue or alopecia);
• Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive);
• Known signs of active bleeding on endoscopy and a history of gastrointestinal perforation and/or fistula within 6 months;
• Received anti-tumor Chinese patent medicine or immunomodulatory drugs (including thymosin, interferon and interleukin, except for local use to control ascites) with systemic treatment within 2 weeks before the first dose;
• Uncontrolled active hepatitis B (defined as both HBsAg positivity and HBV-DNA copies greater than the upper limit of normal range in the laboratory of the research center);

Note: Subjects with hepatitis B who met the following criteria were also eligible for inclusion:

• HBV viral load &lt before the first administration; 1000 copies /ml (200 IU/ml), subjects should receive anti-HBV therapy throughout the study drug treatment to avoid viral reactivation
• For subjects with anti-HBc (+), HBsAg (-), anti-hbs (-) and HBV viral load (-), prophylactic anti-HBV therapy is not required, but viral reactivation should be closely monitored 14. Active HCV-infected subjects (HCV-antibody positive and HCV-RNA level above the lower limit of detection); 15. Received a live vaccine within 30 days before the first dose (cycle 1, day 1); Note: Administration of injectable inactivated virus vaccine against seasonal influenza within 30 days before the first dose is allowed; Live, attenuated, intranasal influenza vaccine was not allowed.

• Pregnant or lactating women; 17. The presence of any serious or uncontrolled systemic illness, such as:

• significant rhythm, conduction or morphological abnormalities in resting ECG, such as complete left bundle branch block, ≥ Ⅱ degree heart block, ventricular arrhythmia or atrial fibrillation;
• unstable angina, congestive heart failure, New York Heart Association (NYHA) grade ≥ 2 chronic heart failure;
• any arterial thrombosis, embolism, or ischemia, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, etc. within 6 months before enrollment;
• poor blood pressure control (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg);
• patients had a history of noninfectious pneumonia requiring glucocorticoid treatment within 1 year before the first dose of glucocorticoid, or current clinically active interstitial lung disease;
• active pulmonary tuberculosis;
• presence of active or uncontrolled infection requiring systemic therapy;
• presence of clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction;
• liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
• poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);
• Urine routine test showed urinary protein ≥++ and confirmed 24-hour urinary protein quantitation > 2.0 g;
• those with mental disorders who are unable to cooperate with treatment; 18. Medical history or evidence of disease, abnormal treatment or laboratory test results, or other conditions deemed by the investigator to be inappropriate for enrollment, or other potential risks considered by the investigator to be inappropriate for participation in the study that may interfere with the trial results or prevent the participant from participating in the study.