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

NCT07685704 | Not Yet Recruiting Phase 2

• 1 other identifier: KY20252609-F-1
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Gastric Cancer; Gastroesophageal Junction Adenocarcinoma; HER2-positive Gastric Cancer

Keywords

zanidatamab; HER2; neoadjuvant therapy; conversion therapy; gastric cancer; gastroesophageal junction adenocarcinoma; bispecific antibody

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response (pCR)

  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.

  At the time of surgery, approximately 4-6 weeks after completion of 3 cycles of neoadjuvant treatment (each cycle is 21 days)

Secondary Outcomes (11)

• Major Pathological Response (MPR)

  At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment

• R0 Resection Rate

  At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment

• Down-Staging Rate

  At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment

• Tumor Regression Grade 0/1 Rate (NCCN TRG)

  At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment

• Recurrence-Free Survival (RFS)

  From date of complete response after treatment until date of recurrence or death, assessed up to 60 months

Study Arms (2)

Neoadjuvant Cohort: Zanidatamab + Chemotherapy

EXPERIMENTAL

Patients with previously untreated stage III locally advanced gastric/gastroesophageal junction adenocarcinoma (cT3-4aN+M0, or cT4bNany M0 not amenable to R0 resection per MDT assessment) receive 3 cycles of zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy (SOX: oxaliplatin 130 mg/m2 IV D1 + S-1 40 mg/m2 PO BID D1-14, Q3W; or CAPOX: oxaliplatin 130 mg/m2 IV D1 + capecitabine 1000 mg/m2 PO BID D1-14, Q3W), followed by D2 radical gastrectomy 4-6 weeks after treatment. Simon's two-stage design: n=46, H0 pCR \<= 9.6%, H1 pCR \>= 25%, one-sided alpha=0.05, power=80%.

Drug: Zanidatamab; Drug: Oxaliplatin; Drug: Capecitabine; Drug: S-1

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor

EXPERIMENTAL

Patients with oligometastatic disease (M1, \<=2 organs, \<=5 total lesions, including liver metastases C-GCLM type I/II, retroperitoneal lymph node metastases, or other single-organ metastases) deemed potentially resectable by MDT receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, plus tislelizumab (200 mg Q3W) or sintilimab (200 mg Q3W) if no immunotherapy contraindication. Up to 8 cycles, tumor assessment every 3 cycles. Exploratory cohort; no sample size calculation.

Drug: Zanidatamab; Drug: Oxaliplatin; Drug: Capecitabine; Drug: S-1; Drug: Tislelizumab

Interventions

Zanidatamab DRUG

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.

Also known as: ZIIHERA

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor; Neoadjuvant Cohort: Zanidatamab + Chemotherapy

Oxaliplatin DRUG

Oxaliplatin 130 mg/m2 IV infusion over \> 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.

Also known as: Eloxatin

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor; Neoadjuvant Cohort: Zanidatamab + Chemotherapy

Capecitabine DRUG

Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.

Also known as: Xeloda

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor; Neoadjuvant Cohort: Zanidatamab + Chemotherapy

S-1 DRUG

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.

Also known as: Teysuno

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor; Neoadjuvant Cohort: Zanidatamab + Chemotherapy

Tislelizumab DRUG

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.

Also known as: BGB-A317

Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent (ICF).
• 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.
• HER2-positive by IHC (3+; or 2+ with FISH testing). No time window restriction on FISH.
• Age 18-75 years, male or female.
• ECOG performance status 0-1; no contraindication to surgery.
• Adequate organ function for successful abdominal surgery.
• Life expectancy \>= 3 months.
• Laboratory parameters within 7 days before enrollment:
• 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.
• Total bilirubin \<= 1.5 x ULN; AST and ALT \<= 2.5 x ULN.
• Creatinine \<= 1.5 x ULN, or CrCl \> 60 mL/min (Cockcroft-Gault).
• No anticoagulation: INR and aPTT \<= 1.5 x ULN. On stable anticoagulation: maintain stable dose.
• Good compliance; able to complete protocol-specified examinations and specimen collection.

You may not qualify if:

• Synchronous or metachronous malignancies of other organs, or recurrent disease.
• Prior systemic therapy for gastric cancer (neoadjuvant cohort).
• History of malignancy within 5 years before screening, except those with \> 90% 5-year overall survival.
• Significant cardiopulmonary dysfunction.
• Major surgery within 4 weeks before study treatment initiation, or anticipated major surgery during study period (excluding diagnostic procedures).
• Severe infection within 4 weeks before study treatment initiation.
• Prior chemotherapy or molecular targeted therapy (neoadjuvant cohort).
• Known hypersensitivity to study drugs or excipients, or history of severe allergic reactions to monoclonal antibodies.
• Factors affecting oral medication intake (e.g., dysphagia \>= grade 2, chronic diarrhea).
• Significant uncontrolled comorbidities that may affect protocol compliance or interpretation of outcomes.
• Pregnancy or breastfeeding, or planning pregnancy during the study.
• Diagnosis of immunodeficiency or receiving systemic corticosteroid (\> 10 mg/day prednisone equivalent) or other immunosuppressive therapy within 2 weeks before first dose.
• Active hepatitis B (HBV DNA \>= 1 x 10\^3 copies/mL or \>= 200 IU/mL), positive anti-HCV, or positive HIV.
• Participation in another anti-tumor clinical trial within 28 days before first dose.
• 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).

Sponsors & Collaborators

• Zhifeng Zhao, PhD: lead

Study Sites (1)

Xijing Hospital, Air Force Medical University

Xi'an, Shaanxi, China

Location

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

zanidatamab; Oxaliplatin; Capecitabine; S 1 (combination); tegafur-gimeracil-oteracil; tislelizumab

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Jianjun Yang, Prof.

  Department of Digestive Surgery, Xijing Hospital, Air Force Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jianjun Yang, Prof.

CONTACT

+86-029-84775507; yangjj@fmmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Study Coordinator

Study Record Dates

• First Submitted: June 29, 2026
• First Posted: July 6, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: July 6, 2026

Record last verified: 2026-06

Locations

CN (1)