Zanidatamab Combined With Chemotherapy as Neoadjuvant/Conversion Therapy for HER2-Positive (IHC 3+ or IHC 2+) Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a Phase II Open-Label Study
Zanidatamab: Zanidatamab injection, 300 mg/vial (manufacturer: Wuxi WuXi Biologics). Administered 30 mg/kg IV Q3W. Premedication (corticosteroids, antihistamines, antipyretics) 30-60 min before infusion. First two infusions over 120-150 min; subsequent may be shortened to 60-90 min if tolerated.
Oxaliplatin: Oxaliplatin 130 mg/m2 IV infusion over \> 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.
Capecitabine: Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.
S-1: S-1 (Tegafur, Gimeracil, Oteracil) 40 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to capecitabine as part of SOX backbone.
Tislelizumab: Tislelizumab 200 mg Q3W IV. Alternatively, sintilimab 200 mg Q3W may be used at investigator's discretion. Conversion cohort only, for patients without immunotherapy contraindication.
Study summary
This is a phase II open-label study to evaluate the efficacy and safety of zanidatamab combined with chemotherapy as neoadjuvant/conversion therapy in patients with HER2-positive (IHC 3+ or IHC 2+) locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma. The study consists of two cohorts: a neoadjuvant cohort (Simon's two-stage design, n=46) for treatment-naive stage III locally advanced disease, and an exploratory conversion cohort for oligometastatic disease. Patients receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, with or without PD-1 inhibitor (tislelizumab or sintilimab). The primary endpoint is pathological complete response (pCR).
Eligibility
Sex
ALL
Min age
18 Years
Max age
75 Years
Healthy volunteers
No
Inclusion Criteria:
1. Willing and able to provide written informed consent (ICF).
2. Histologically and radiologically (CT/MRI) confirmed gastric or gastroesophageal junction adenocarcinoma.
* Neoadjuvant cohort: Clinical stage III (cT3-4aN+M0) or locally advanced unresectable (cT4bNany M0) assessed by MDT as not amenable to R0 resection, or technically resectable but with high-risk factors (e.g., bulky nodal fusion, invasion of critical structures).
* Conversion cohort: Not amenable to direct surgery (e.g., invasion of adjacent organs or vessels) or with distant metastases, including liver metastases (C-GCLM type I and II), confirmed retroperitoneal lymph node metastases, or other single-organ metastases.
3. HER2-positive by IHC (3+; or 2+ with FISH testing). No time window restriction on FISH.
4. Age 18-75 years, male or female.
5. ECOG performance status 0-1; no contraindication to surgery.
6. Adequate organ function for successful abdominal surgery.
7. Life expectancy \>= 3 months.
8. Laboratory parameters within 7 days before enrollment:
1. WBC \> 4.0 x 10\^9/L and \< 15 x 10\^9/L; ANC \> 1.5 x 10\^9/L; Hb \>= 90 g/L; PLT \>= 100 x 10\^9/L.
2. Total bilirubin \<= 1.5 x ULN; AST and ALT \<= 2.5 x ULN.
3. Creatinine \<= 1.5 x ULN, or CrCl \> 60 mL/min (Cockcroft-Gault).
4. No anticoagulation: INR and aPTT \<= 1.5 x ULN. On stable anticoagulation: maintain stable dose.
9. Good compliance; able to complete protocol-specified examinations and specimen collection.
10. Female patients of childbearing potential must agree to contraception from ICF signing through at least 5 months after last dose and refrain from breastfeeding. Male patients must agree to contraception from first dose through at least 7 months after last dose.
Exclusion Criteria:
1. Synchronous or metachronous malignancies of other organs, or recurrent disease.
2. Prior systemic therapy for gastric cancer (neoadjuvant cohort).
3. History of malignancy within 5 years before screening, except those with \> 90% 5-year overall survival.
4. Significant cardiopulmonary dysfunction.
5. Major surgery within 4 weeks before study treatment initiation, or anticipated major surgery during study period (excluding diagnostic procedures).
6. Severe infection within 4 weeks before study treatment initiation.
7. Prior chemotherapy or molecular targeted therapy (neoadjuvant cohort).
8. Known hypersensitivity to study drugs or excipients, or history of severe allergic reactions to monoclonal antibodies.
9. Factors affecting oral medication intake (e.g., dysphagia \>= grade 2, chronic diarrhea).
10. Significant uncontrolled comorbidities that may affect protocol compliance or interpretation of outcomes.
11. Pregnancy or breastfeeding, or planning pregnancy during the study.
12. Diagnosis of immunodeficiency or receiving systemic corticosteroid (\> 10 mg/day prednisone equivalent) or other immunosuppressive therapy within 2 weeks before first dose.
13. Active hepatitis B (HBV DNA \>= 1 x 10\^3 copies/mL or \>= 200 IU/mL), positive anti-HCV, or positive HIV.
14. Participation in another anti-tumor clinical trial within 28 days before first dose.
15. Any condition that in the investigator's judgment may lead to premature study termination (e.g., serious illness including psychiatric disorders requiring concomitant treatment, severe laboratory abnormalities, family/social factors affecting subject safety or data collection).
16. Patient or family refusal to sign informed consent.
Primary outcome measure(s)
Pathological Complete Response (pCR) — At the time of surgery, approximately 4-6 weeks after completion of 3 cycles of neoadjuvant treatment (each cycle is 21 days) pCR is defined as the absence of residual tumor cells in the primary tumor and all resected lymph nodes (ypT0N0) after neoadjuvant treatment, assessed by histopathological evaluation of surgical specimens.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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