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
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Shanghai Zhongshan Hospital
- Enrollment
- 30
- Primary Endpoint
- Pathological complete response (pCR) rate
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts 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)
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)
Arms & Interventions
Arm 1
Participants assigned to arm 1 will receive neoadjuvant adebrelimab 1200 mg intravenously on day 1 combined with XELOX (capecitabine 1000 mg/m² orally twice daily on days 1-14 plus oxaliplatin 130 mg/m² intravenously on day 1) for one cycle, followed by adebrelimab monotherapy at the same dose and schedule for three additional cycles. Within 4-6 weeks after completion of the fourth cycle, curative-intent D2 radical gastrectomy will be performed. Post-operative adjuvant systemic therapy-regimen, duration, and number of cycles-will be left to the discretion of the treating investigator, guided by institutional standards and the patient's pathological and clinical status.
Intervention: Adebrelimab (Drug)
Arm 1
Participants assigned to arm 1 will receive neoadjuvant adebrelimab 1200 mg intravenously on day 1 combined with XELOX (capecitabine 1000 mg/m² orally twice daily on days 1-14 plus oxaliplatin 130 mg/m² intravenously on day 1) for one cycle, followed by adebrelimab monotherapy at the same dose and schedule for three additional cycles. Within 4-6 weeks after completion of the fourth cycle, curative-intent D2 radical gastrectomy will be performed. Post-operative adjuvant systemic therapy-regimen, duration, and number of cycles-will be left to the discretion of the treating investigator, guided by institutional standards and the patient's pathological and clinical status.
Intervention: XELOX (Drug)
Arm 1
Participants assigned to arm 1 will receive neoadjuvant adebrelimab 1200 mg intravenously on day 1 combined with XELOX (capecitabine 1000 mg/m² orally twice daily on days 1-14 plus oxaliplatin 130 mg/m² intravenously on day 1) for one cycle, followed by adebrelimab monotherapy at the same dose and schedule for three additional cycles. Within 4-6 weeks after completion of the fourth cycle, curative-intent D2 radical gastrectomy will be performed. Post-operative adjuvant systemic therapy-regimen, duration, and number of cycles-will be left to the discretion of the treating investigator, guided by institutional standards and the patient's pathological and clinical status.
Intervention: D2 radical gastrectomy (Procedure)
Arm 2
Participants in arm 2 will receive neoadjuvant adebrelimab 1200 mg plus SHR-8068 280 mg administered intravenously on day 1 of a 21-day cycle for one cycle, followed by adebrelimab 1200 mg monotherapy on day 1 every 3 weeks for three additional cycles. Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle. Any post-operative adjuvant systemic treatment-including regimen, duration, and number of cycles-will be determined at the investigator's discretion according to institutional guidelines and the patient's pathological and clinical status.
Intervention: Adebrelimab (Drug)
Arm 2
Participants in arm 2 will receive neoadjuvant adebrelimab 1200 mg plus SHR-8068 280 mg administered intravenously on day 1 of a 21-day cycle for one cycle, followed by adebrelimab 1200 mg monotherapy on day 1 every 3 weeks for three additional cycles. Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle. Any post-operative adjuvant systemic treatment-including regimen, duration, and number of cycles-will be determined at the investigator's discretion according to institutional guidelines and the patient's pathological and clinical status.
Intervention: SHR-8068 (Drug)
Arm 2
Participants in arm 2 will receive neoadjuvant adebrelimab 1200 mg plus SHR-8068 280 mg administered intravenously on day 1 of a 21-day cycle for one cycle, followed by adebrelimab 1200 mg monotherapy on day 1 every 3 weeks for three additional cycles. Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle. Any post-operative adjuvant systemic treatment-including regimen, duration, and number of cycles-will be determined at the investigator's discretion according to institutional guidelines and the patient's pathological and clinical status.
Intervention: D2 radical gastrectomy (Procedure)
Outcomes
Primary Outcomes
Pathological complete response (pCR) rate
Time Frame: 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 Outcomes
- Major pathological response (MPR) rate(From randomization to the date of surgery, an average of 14 weeks.)
- ypN stage(From randomization to the date of surgery, an average of 14 weeks.)
- 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.)
- R0 resection rate(From randomization to the date of surgery, an average of 14 weeks.)
- Overall survival (OS)(The time from randomization to death from any cause, assessed up to 5 years.)
Investigators
Xuefei.Wang
Chief of Department of Gastrointestinal Surgery
Shanghai Zhongshan Hospital