SHR-1701 + Rivoceranib (± SHR-2554) in Advanced GC After First-Line Immunotherapy Failure

This is a prospective, open-label, dual-cohort, Phase II clinical study designed to observe and evaluate the efficacy and safety of SHR-1701 combined with Rivoceranib, with or without SHR-2554, in patients with advanced gastric cancer who have failed first-line immunotherapy. The study targets patients with gastric or gastroesophageal junction adenocarcinoma who have progressed on or are intolerant to first-line immunotherapy-containing regimens. Eligible subjects who provide informed consent and pass screening will be randomized in a 1:1 ratio to receive the study treatment.

Cohort 1: SHR-1701+ Rivoceranib+ SHR-2554；Cohort 2: SHR-1701 + Rivoceranib. Primary Endpoint (based on RECIST v1.1): Progression Free Survival (PFS); Secondary Endpoints (based on RECIST v1.1): Objective Response Rate (ORR); Duration of Response (DoR); Overall Survival (OS); Safety; Exploratory Endpoint: Multi-omics analysis of the tumor microenvironment (including, but not limited to, ctDNA and TMB).

Official Title：A Prospective, Dual-Cohort, Phase II Clinical Study of SHR-1701 Combined with Rivoceranib With or Without SHR-2554 in Patients with Advanced Gastric Cancer Who Failed First-Line Immunotherapy

Inclusion criteria

• Age ≥ 18 years, male or female.
• Histologically or pathologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.
• Disease progression on or intolerance to a prior treatment regimen that contained an immune checkpoint inhibitor (ICI).
• HER2-negative expression.
• Willingness to provide tumor tissue samples from prior to the first systemic therapy for biomarker analysis (e.g., PD-L1). Freshly obtained biopsies are preferred; if unavailable, archived formalin-fixed paraffin-embedded (FFPE) tissue blocks or 5-8 slides of 3-5μm thickness are acceptable.
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥ 12 weeks.
• Adequate organ and bone marrow function, defined as:

• Hemoglobin ≥ 90 g/L (no blood transfusion within 14 days);
• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L;
• Platelet count ≥ 90 × 10^9/L;
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; for patients with liver metastases, ALT and AST ≤ 5 × ULN;
• Serum creatinine ≤ 1.5 × ULN;
• Left ventricular ejection fraction (LVEF) ≥ 50%; QTc interval < 450 ms for males and < 470 ms for females.
• For patients not on therapeutic anticoagulation: International Normalized Ratio (INR) ≤ 1.5 and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN. Patients receiving full-dose or parenteral anticoagulants are eligible provided the dose has been stable for at least 2 weeks prior to study entry and relevant coagulation parameters are within the therapeutic range.
• For women of childbearing potential: a negative serum or urine pregnancy test within 14 days prior to enrollment, and agreement to use highly effective contraception during the study and for 3 months after the last dose of the study drug. For male patients: surgical sterilization or agreement to use highly effective contraception during the study and for 3 months after the last dose.
• Recovery from toxicities of prior therapies to ≤ Grade 1 (per NCI CTCAE). For prior surgeries, the wound must have healed completely.
• Voluntary participation, provision of signed informed consent, expected good compliance, and ability to comply with the study protocol requirements.

Exclusion criteria

• Gastrointestinal perforation and/or fistula within 6 months prior to treatment, or active gastrointestinal bleeding within 3 months.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage.
• Known history of allergy to any component of the investigational drugs or their excipients.
• Prior treatments as follows:

• Treatment with any other investigational agent within 4 weeks prior to the first dose of the study drug, or within 5 half-lives of the previous investigational agent (whichever is longer).
• Concurrent enrollment in another interventional clinical study. (Observation studies or follow-up phases of interventional studies are permitted).
• Any antitumor therapy (including radiotherapy, chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biotherapy, or tumor embolization) within 2 weeks prior to the first dose of the study drug.
• Requirement for systemic corticosteroids (>10 mg prednisone equivalent daily) within 2 weeks prior to the first dose. The use of corticosteroids for premedication with certain chemotherapy regimens, inhaled or topical steroids, and adrenal replacement therapy at doses ≤10 mg/day prednisone equivalent is permitted. Other cases require discussion with the Investigator.
• Prior administration of an anti-tumor vaccine or live vaccine within 4 weeks prior to the first dose.
• Major surgery or significant trauma within 4 weeks prior to the first dose.
• History of leptomeningeal metastasis, or current evidence of leptomeningeal metastasis or active brain metastases. (Patients with stable, treated brain metastases may be discussed for eligibility).
• Active autoimmune disease or history of autoimmune disease requiring systemic treatment in the past 2 years. Exceptions include vitiligo, resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, or Type I diabetes stable on insulin regimen.
• Immunodeficiency history, including positive HIV test, other acquired/congenital immunodeficiency disorders, history of organ transplant or allogeneic bone marrow transplantation, or active hepatitis.
• Poorly controlled cardiovascular diseases, including but not limited to: (1) Heart failure of NYHA Class II or higher; (2) Unstable angina; (3) Myocardial infarction within the past year; (4) Clinically significant supraventricular or ventricular arrhythmia without effective medical control.
• Severe infection within 4 weeks prior to the first dose. Active pulmonary inflammation on baseline imaging, or signs/symptoms of active infection within 2 weeks prior to the first dose.
• History of interstitial lung disease.
• Active tuberculosis infection based on history/CT findings, or history of active TB within one year prior to enrollment, or prior active TB over one year ago without appropriate treatment.
• Diagnosis of another malignancy within 5 years prior to the first dose. Exceptions include malignancies with low risk of metastasis/death.
• Pregnancy or lactation.
• Any other condition deemed by the investigator to potentially compromise patient safety or study compliance. -