Adebrelimab Combined With Induction Chemotherapy or SHR-8068 for Mismatch Repair-Deficient/Microsatellite Instability-High (dMMR/MSI-H) Locally Advanced Gastric/Gastroesophageal Junction Adenocarcinoma：A Randomized, Non-comparative Phase 2 Study

Обзор

This is a randomized, non-comparative, open-label, two-arm phase II clinical trial designed to evaluate the efficacy and safety of neoadjuvant therapy with adebrelimab plus induction chemotherapy versus adebrelimab plus SHR-8086 in patients with dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma.

Вмешательства

• Препарат Adebrelimab
  Participants in both arms will receive neoadjuvant adebrelimab 1200mg intravenously on day 1 of a 21-day cycle for four cycles.
• Препарат XELOX
  Participants assigned to arm 1 will receive neoadjuvant XELOX (capecitabine 1000 mg/m² orally twice daily on days 1-14 plus oxaliplatin 130 mg/m² intravenously on day 1) for one cycle.
• Препарат SHR-8068
  Participants assigned to arm 2 will receive SHR-8068 280 mg administered intravenously on day 1 for one cycle.
• Процедура D2 radical gastrectomy
  Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle.

Первичные конечные точки

• Pathological complete response (pCR) rate [Срок оценки: From randomization to the date of surgery, an average of 14 weeks.]

Вторичные конечные точки (5)

• Major pathological response (MPR) rate [Срок оценки: From randomization to the date of surgery, an average of 14 weeks.]
• ypN stage [Срок оценки: From randomization to the date of surgery, an average of 14 weeks.]
• R0 resection rate [Срок оценки: From randomization to the date of surgery, an average of 14 weeks.]
• Event-free survival (EFS) [Срок оценки: The time from randomization to documented disease progression, disease recurrence, or death from any cause, whichever occurs first, assessed up to 5 years.]
• Overall survival (OS) [Срок оценки: The time from randomization to death from any cause, assessed up to 5 years.]

Критерии участия

Критерии включения

• Male or female, age ≥ 18 years
• Pathologically confirmed gastric or gastro-oesophageal-junction adenocarcinoma (Siewert II and III only)
• dMMR confirmed by IHC or MSI-H confirmed by PCR
• Investigator-assessed potentially curative resection feasible before study entry
• CT or MRI clinical stage cT ≥ 2 N any M0 per AJCC 8th edition; laparoscopy with peritoneal washing cytology (and peritoneal biopsy if indicated) recommended to exclude peritoneal metastasis
• ECOG performance status 0-2
• Able to swallow tablets
• Expected survival ≥ 6 months
• Laboratory values within 7 days before randomisation:

ANC > 1.5 × 10⁹/L, Hb ≥ 80 g/L, PLT ≥ 75 × 10⁹/L Serum creatinine ≤ 1.5 × ULN or eGFR ≥ 60 mL/min/1.73 m² ALT and AST ≤ 2.5 × ULN; total bilirubin ≤ 1.5 × ULN (or TBIL > 1.5 × ULN with direct bilirubin ≤ ULN); albumin ≥ 25 g/L INR or PT ≤ 1.5 × ULN and aPTT ≤ 1.5 × ULN (or on anticoagulation within therapeutic range)

• Signed written informed consent; able to comply with protocol visits, treatment, labs, biospecimen collection
• WOCBP must have negative serum pregnancy test within 72 h before randomisation, not breastfeeding, and use highly effective contraception from screening until 2 months after last adebrelimab/SHR-8068 or 6 months after last chemotherapy, whichever is longer
• Men with pregnant partners or WOCBP partners must be surgically sterile or use highly effective contraception during study and for same post-treatment periods; no sperm donation allowed

Критерии исключения

• Tumour histology squamous-cell, neuro-endocrine, or other non-adenocarcinoma types
• Unresectable disease (tumour-related or surgical contraindication) or subject refuses surgery
• Tumour requiring transthoracic surgical approach
• CNS metastases and/or carcinomatous meningitis
• Prior anti-gastric-cancer therapy (surgery, radiotherapy, chemotherapy, targeted, immunotherapy) except bypass for obstruction
• Previous malignancy or concurrent malignancy except completely excised basal/squamous skin cancer, superficial bladder cancer, or in-situ prostate/cervix/breast cancer disease-free ≥ 5 years
• Cardiac conditions:

NYHA class > II or LVEF < 50 % on echo Unstable angina MI within 1 year Resting QTc > 450 ms (M) or > 470 ms (F) Clinically significant ECG abnormalities, complete LBBB, 3rd-degree AV block, 2nd-degree AV block, PR > 250 ms Risk factors for QT prolongation (HF, hypokalaemia, congenital long-QT syndrome, family history of long QT or sudden death < 40 y, concomitant QT-prolonging drugs)

• History of GI perforation, intra-abdominal abscess, or bowel obstruction within 3 months or imaging/clinical signs of obstruction
• Clinically significant bleeding or bleeding diathesis within 3 months (e.g. GI bleeding, haemorrhagic gastritis, vasculitis); positive faecal occult blood must be endoscopically cleared if still positive on repeat testing (unless gastroscopy within 3 months shows no lesion)
• Arterial or venous thrombo-embolic event within 6 months (stroke, TIA, intracranial haemorrhage, cerebral infarction)
• Hypersensitivity to any study-drug component
• Severe hypersensitivity history to any monoclonal antibody
• Pregnant or lactating women
• Positive HIV antibody
• Active hepatitis (HBsAg positive with HBV DNA ≥ 500 IU/mL; HCV antibody positive with HCV RNA > ULN)
• Prior therapy targeting CTLA-4/PD-1/PD-L1 or other T-cell co-stimulatory/immune-checkpoint pathways (including therapeutic vaccines)
• Active autoimmune disease or autoimmune disease with relapse risk within 2 years (except stable hypothyroidism on replacement or well-controlled type 1 diabetes on insulin)
• History of idiopathic pulmonary fibrosis, drug-related pneumonia, organising pneumonia (BOOP/COP), or CT evidence of active pneumonia at screening
• Live attenuated vaccine within 4 weeks before first study dose or expected need during study
• Immunodeficiency disorder or chronic systemic corticosteroids or other immunosuppressive therapy within 7 days before first dose (includes prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-TNF agents)
• Any condition that, in the investigator's opinion, increases study risk, interferes with protocol conduct, or compromises informed consent or compliance

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07266025 · KY2025379

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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