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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

29. juni 2026 opdateret af: Zhifeng Zhao, PhD

A Phase II Open-Label Study Evaluating 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

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).

Studieoversigt

Status

Ikke rekrutterer endnu

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

Background:

HER2 overexpression (IHC 3+ or IHC 2+) occurs in approximately 12-20% of gastric and gastroesophageal junction adenocarcinomas. While perioperative trastuzumab-based regimens have shown promising pathological responses (pCR rates of 9.6% in NEOHX, 21.4% in HER-FLOT, 35% in PETRARCA), there remains an unmet need for more effective HER2-directed therapies in the neoadjuvant/conversion setting, particularly for IHC 2+ patients whose in situ hybridization testing rates are low in real-world practice.

Zanidatamab is a humanized bispecific IgG1-like antibody targeting two distinct HER2 epitopes (ECD4 and ECD2), demonstrating unique mechanisms including enhanced receptor clustering, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and superior in vivo antitumor activity compared to trastuzumab plus pertuzumab. In a phase II study (NCT03929666), zanidatamab combined with chemotherapy as first-line treatment for HER2-positive advanced gastroesophageal adenocarcinoma achieved a confirmed objective response rate of 76.2%, median progression-free survival of 12.5 months, and median overall survival of 36.5 months, with manageable safety.

Study Design:

This is an investigator-initiated, phase II, open-label, two-cohort study. Neoadjuvant Cohort: Treatment-naive patients with stage III locally advanced gastric/gastroesophageal junction adenocarcinoma (cT3-4aN+M0, or cT4bNany M0 not amenable to R0 resection as assessed by MDT, or technically resectable but with high-risk factors such as bulky nodal fusion or invasion of critical structures) receive 3 cycles of zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy (SOX or CAPOX per 2025 CSCO guidelines), followed by D2 radical gastrectomy 4-6 weeks after treatment completion. This cohort uses a Simon's two-stage design with a planned enrollment of 46 patients (H0: pCR <= 9.6%, H1: pCR >= 25%, one-sided alpha=0.05, power=80%). If <=2 pCRs among the first 17 patients, study terminates for futility; if >=7 pCRs among all 46, superiority over historical control is declared.

Conversion Cohort (Exploratory): Patients with oligometastatic disease (M1, <=2 organs, <=5 total metastatic lesions), including liver metastases (C-GCLM type I and II), confirmed retroperitoneal lymph node metastases, or other single-organ metastases, deemed potentially resectable by MDT, receive zanidatamab (30 mg/kg Q3W) plus oxaliplatin-based chemotherapy, with tislelizumab (200 mg Q3W, or sintilimab 200 mg Q3W) for patients without immunotherapy contraindications. Treatment continues up to 8 cycles with tumor assessment every 3 cycles; surgery timing at investigator's discretion.

Adjuvant therapy: For the neoadjuvant cohort, adjuvant therapy (4-5 cycles starting 4-6 weeks post-surgery) may be administered at the investigator's discretion. Total perioperative treatment duration should not exceed 8 cycles. Conversion cohort adjuvant therapy is at the investigator's discretion.

Endpoints: Primary endpoint is pathological complete response (pCR, ypT0N0). Secondary endpoints include MPR, R0 resection rate, down-staging rate, NCCN TRG 0/1, RFS, OS, treatment completion rate, and safety (CTCAE v5.0). Conversion cohort additionally evaluates ORR (RECIST v1.1, with iRECIST for pseudoprogression), PFS, and surgical conversion rate.

Undersøgelsestype

Interventionel

Tilmelding (Anslået)

46

Fase

  • Fase 2

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiekontakt

Studiesteder

  • Kina
    • Shaanxi
      • Xi'an, Shaanxi, Kina
        • Xijing Hospital, Air Force Medical University
        • Kontakt:
          • Jianjun Yang
          • Telefonnummer: +86-13572533693

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

  • Voksen
  • Ældre voksen

Tager imod sunde frivillige

Ingen

Beskrivelse

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.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Ikke-randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Neoadjuvant Cohort: Zanidatamab + Chemotherapy
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%.
Medicin: 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.
Andre navne:
  • ZIIHERA
Medicin: Oxaliplatin
Oxaliplatin 130 mg/m2 IV infusion over > 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.
Andre navne:
  • Eloxatin
Medicin: Capecitabine
Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.
Andre navne:
  • Xeloda
Medicin: 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.
Andre navne:
  • Teysuno
Eksperimentel: Conversion Cohort: Zanidatamab + Chemotherapy +/- PD-1 Inhibitor
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.
Medicin: 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.
Andre navne:
  • ZIIHERA
Medicin: Oxaliplatin
Oxaliplatin 130 mg/m2 IV infusion over > 2 hours, D1 of each 21-day cycle. Administered after zanidatamab. Manufacturer not restricted.
Andre navne:
  • Eloxatin
Medicin: Capecitabine
Capecitabine 1000 mg/m2 PO BID, D1-14 of each 21-day cycle. Alternative to S-1 as part of CAPOX backbone.
Andre navne:
  • Xeloda
Medicin: 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.
Andre navne:
  • Teysuno
Medicin: 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.
Andre navne:
  • BGB-A317

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Pathological Complete Response (pCR)
Tidsramme: 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.
At the time of surgery, approximately 4-6 weeks after completion of 3 cycles of neoadjuvant treatment (each cycle is 21 days)

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Major Pathological Response (MPR)
Tidsramme: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
MPR is defined as residual tumor cells <= 10% in the primary tumor bed and resected lymph nodes after neoadjuvant treatment.
At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
R0 Resection Rate
Tidsramme: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
R0 resection is defined as microscopically complete tumor removal with all margins negative on histopathological examination.
At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Down-Staging Rate
Tidsramme: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Down-staging is defined as any decrease in pathological T stage or N stage compared to pretreatment clinical stage (cTNM).
At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Tumor Regression Grade 0/1 Rate (NCCN TRG)
Tidsramme: At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Proportion of patients achieving complete (TRG 0, no residual tumor) or near-complete (TRG 1, minimal residual tumor cells) pathological response per NCCN TRG criteria.
At the time of surgery, approximately 4-6 weeks after completion of neoadjuvant treatment
Recurrence-Free Survival (RFS)
Tidsramme: From date of complete response after treatment until date of recurrence or death, assessed up to 60 months
Time from complete response after neoadjuvant/conversion therapy to tumor recurrence or death from any cause. DFS and EFS are considered equivalent to RFS.
From date of complete response after treatment until date of recurrence or death, assessed up to 60 months
Overall Survival (OS)
Tidsramme: From date of enrollment until date of death from any cause, assessed up to 36 months
From date of enrollment until date of death from any cause, assessed up to 36 months
Objective Response Rate (ORR) - Conversion Cohort
Tidsramme: Every 3 cycles during conversion treatment (up to 8 cycles, each cycle is 21 days), assessed per RECIST v1.1
Proportion of patients achieving CR or PR per RECIST v1.1. For suspected pseudoprogression, iRECIST used for confirmation.
Every 3 cycles during conversion treatment (up to 8 cycles, each cycle is 21 days), assessed per RECIST v1.1
Progression-Free Survival (PFS) - Conversion Cohort
Tidsramme: From date of enrollment until date of disease progression or death, assessed up to 36 months
From date of enrollment until date of disease progression or death, assessed up to 36 months
Neoadjuvant Treatment Completion Rate
Tidsramme: At the end of neoadjuvant treatment period, approximately 9 weeks (3 cycles of 21 days each)
Proportion of patients in the neoadjuvant cohort who complete all 3 planned cycles and proceed to surgery as scheduled.
At the end of neoadjuvant treatment period, approximately 9 weeks (3 cycles of 21 days each)
Surgical Conversion Rate - Conversion Cohort
Tidsramme: During conversion treatment period, up to 8 cycles (each cycle is 21 days)
Proportion of patients initially deemed unresectable who successfully undergo R0 resection after conversion therapy.
During conversion treatment period, up to 8 cycles (each cycle is 21 days)
Incidence of Treatment-Emergent Adverse Events
Tidsramme: From first dose through 30 days after last dose of study treatment
Adverse events assessed by NCI CTCAE v5.0, including incidence and severity of AEs, SAEs, and postoperative complications within 30 days (Clavien-Dindo classification).
From first dose through 30 days after last dose of study treatment

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Zhifeng Zhao, PhD

Efterforskere

  • Ledende efterforsker: Jianjun Yang, Prof., Department of Digestive Surgery, Xijing Hospital, Air Force Medical University

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Anslået)

1. juli 2026

Primær færdiggørelse (Anslået)

1. juni 2028

Studieafslutning (Anslået)

1. december 2028

Datoer for studieregistrering

Først indsendt

29. juni 2026

Først indsendt, der opfyldte QC-kriterier

29. juni 2026

Først opslået (Faktiske)

6. juli 2026

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

6. juli 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

29. juni 2026

Sidst verificeret

1. juni 2026

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • KY20252609-F-1

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