AACR Adaptive Biomarker-Driven Organ Preservation Trial in Gastroesophageal Adenocarcinomas

NCT07290985 | Not Yet Recruiting Phase 2 FDA Drug

• 1 other identifier: AACR-ADOPT-GEA
• Study Type: interventional
• Target: 121
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study will test a new personalized treatment approach for patients with stomach or esophageal cancer. It will take place in two stages and aims to find the best combination of chemotherapy, immunotherapy, and targeted drugs based on each patient's tumor biomarkers. Upon enrollment onto the study, patients will consent to tumor biomarker testing and may receive one cycle of standard chemotherapy while awaiting results. Those with a matching biomarker will join the corresponding treatment group that combines chemotherapy, an immune checkpoint inhibitor, and/or a targeted therapy. In Stage I of the study, treatment lasts about four months before surgery, followed by an additional eight months of therapy for a total of one year. The most effective treatments from Stage I will be studied further in Stage II of the study to see whether some patients can safely avoid surgery. Those patients enrolled during Stage II will receive four months of the same combination treatment (chemotherapy, an immune checkpoint inhibitor, and/or a targeted therapy) but may be eligible to skip surgery if their cancer completely disappears after pre-surgery therapy. All patients will then receive an additional eight months of therapy and those who skipped surgery will be closely monitored with scans and endoscopies.

Conditions

Gastroesophageal Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Pathological Complete Response (pathCR) Rate (Stage I).

  Proportion of patients achieving a pathCR in the surgical specimen after perioperative biomarker-directed systemic therapy.

  At time of surgery.

• Organ Preservation Rate (Stage II)

  Proportion of patients able to avoid surgery and preserve the affected organ due to biomarker-driven treatment response.

  Up to 12 months post-treatment.

Secondary Outcomes (7)

• Event-Free Survival (Stage I).

  Up to 24 months post-treatment.

• Overall Survival (Stage I).

  Up to 24 months post-treatment.

• Tumor Regression Grade.

  At time of surgery (Stage I).

• Correlation between event-free survival and changes in circulating tumor DNA concentration.

  Through study completion, an average of 3 years for Stage I and 6 years for Stage II.

• Correlation between overall survival and changes in circulating tumor DNA concentration.

  Through study completion, an average of 3 years for Stage I and 6 years for Stage II.

Study Arms (1)

Zanidatamab + Tislelizumab (HER2) Sub-Study

EXPERIMENTAL

Patients will receive zanidatamab on Day 1 of each 14-day cycle, followed by tislelizumab and mFOLFOX6 chemotherapy: leucovorin (Day 1), oxaliplatin (Day 1), and 5-FU as a 48-hour continuous intravenous infusion (Days 1-2). Up to 8 preoperative cycles will be given, followed by surgery or organ preservation if a complete response is achieved. Post-surgery or organ preservation, zanidatamab + tislelizumab will continue every 2 weeks for up to 1 year of perioperative therapy.

Drug: Tislelizumab; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Fluorouracil; Drug: Zanidatamab

Interventions

Tislelizumab DRUG

150 mg every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively

Zanidatamab + Tislelizumab (HER2) Sub-Study

Leucovorin DRUG

400 mg/m² every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively

Zanidatamab + Tislelizumab (HER2) Sub-Study

Oxaliplatin DRUG

85 mg/m² every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively

Zanidatamab + Tislelizumab (HER2) Sub-Study

Fluorouracil DRUG

2,400 mg/m² every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively

Zanidatamab + Tislelizumab (HER2) Sub-Study

Zanidatamab DRUG

1,200 mg for patients weighing less than 70 kg and 1,600 mg for patients weighing 70 kg or more every 2 weeks for 4 months pre-operatively and up to 8 months post-operatively

Zanidatamab + Tislelizumab (HER2) Sub-Study

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed, resectable adenocarcinoma of the stomach, esophagus, or gastroesophageal junction (Stage II or higher, T2N0 with high-risk features).
• Complete surgical resection deemed achievable by multidisciplinary evaluation.
• Willingness to undergo tumor biopsies for biomarker analysis (HER2, FGFR2b, PD-L1, MSI) at screening, progression, or pre/post- surgery.
• Life expectancy ≥ 24 weeks. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Adequate organ function:
• Hematologic: absolute neutrophil count (ANC) ≥1.5 ×10⁹/L, platelets ≥100 ×10⁹/L, hemoglobin ≥ 8 g/dL
• Hepatic: aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤2.5 × ULN, total bilirubin ≤1.5 × upper limit of normal (ULN) (≤2.5 × ULN for Gilbert's)
• Renal: creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min/1.73 m²
• Willingness for blood samples to be drawn for research purposes.
• Baseline dihydropyrimidine dehydrogenase (DPD) testing per local guidelines; dosing of 5-FU adjusted for deficiency.
• Use of two effective contraception methods for women of childbearing potential and men during and 4 months after study; pregnant or breastfeeding women excluded.
• Must have the ability to understand and the willingness to sign a written informed consent document.
• Willingness and able to comply with the protocol for the duration of the study, including attending scheduled visits, examinations, the screening procedure, and having their tumor and blood molecularly characterized.

You may not qualify if:

• FFPE tumor sample tested at a central laboratory confirming PD-L1 Tumor Area Positivity (TAP) score ≥1%.
• Histologically confirmed diagnosis of resectable (i.e., radical surgery eligible), HER2-positive (defined as 3+ HER2 expression by IHC or 2+ HER2 expression by immunohistochemistry (IHC) with in situ hybridization (ISH)-positivity per central assessment) adenocarcinoma of the stomach or esophagus, including the gastroesophageal junction.
• Formalin-fixed, paraffin-embedded (FFPE) tumor sample tested at a central laboratory confirming HER2-positive status.
• Left ventricular ejection fraction (LVEF) ≥50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA).
• Unresectable disease, peritoneal dissemination, and/or positive cytology on laparoscopy.
• Peripheral neuropathy ≥ Grade 2.
• Active infection.
• Chronic growth factor support for white blood cells or granulocytes.
• Concurrent anti-cancer therapy (exceptions: supportive care medications ≥1 month prior, low molecular weight heparin, prior adjuvant hormonal therapy \>3 years, palliative radiation
• ≤14 days prior).
• Local/systemic therapy for current gastroesophageal diagnosis (except one FLOX/ mFOLFOX6 dose during screening).
• Significant medical conditions compromising safety or protocol compliance.
• Preexisting cardiac conditions.
• Stroke, transient ischemic attack (TIA), or myocardial infarction within 6 months.
• Prior FGFR-targeted therapy.

Sponsors & Collaborators

• American Association for Cancer Research: lead
• Jazz Pharmaceuticals: collaborator
• BeOne Medicines: collaborator

MeSH Terms

Interventions

tislelizumab; Leucovorin; Oxaliplatin; Fluorouracil; zanidatamab

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Denise Gallagher, MS

CONTACT

215-446-8297; denise.gallagher@aacr.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 17, 2025
• First Posted: December 18, 2025
• Study Start: March 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: January 15, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share