Gastric Adenocarcinoma, Gastroesophageal Adenocarcinoma, Mismatch Repair Deficient or MSI-High Solid Tumors, Immunotherapy
Conditions
Brief summary
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.
Interventions
DRUGAdebrelimab
Participants in both arms will receive neoadjuvant adebrelimab 1200mg intravenously on day 1 of a 21-day cycle for four cycles.
DRUGXELOX
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.
DRUGSHR-8068
Participants assigned to arm 2 will receive SHR-8068 280 mg administered intravenously on day 1 for one cycle.
PROCEDURED2 radical gastrectomy
Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle.
Sponsors
Shanghai Zhongshan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological complete response (pCR) rate | From randomization to the date of surgery, an average of 14 weeks. | The proportion of participants in whom no viable tumor cells remain in the primary tumor bed and regional lymph nodes (ypT0N0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major pathological response (MPR) rate | From randomization to the date of surgery, an average of 14 weeks. | The proportion of participants in whom residual viable tumor cells constitute \<10 % of the primary tumor bed in the resected surgical specimen. |
| ypN stage | From randomization to the date of surgery, an average of 14 weeks. | Lymph-node status after neoadjuvant therapy (ypN stage) will be assessed according to the American Joint Committee on Cancer (AJCC) 8th edition staging system. |
| R0 resection rate | From randomization to the date of surgery, an average of 14 weeks. | The proportion of patients who undergo surgery with microscopically negative resection margins. |
| Event-free survival (EFS) | 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) | The time from randomization to death from any cause, assessed up to 5 years. | — |
Contacts
CONTACTZhaoqing Tang, PhD, MD
Outcome results
None listed