AACR Adaptive Biomarker-Driven Organ Preservation Trial In Gastroesophageal Adenocarcinomas (AACR-ADOPT-GEA)
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.
• 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.
• Understands they must meet all Inclusion and Exclusion criteria in the sub-protocol for the treatment for which they will be later assigned
∙ Additional inclusion criteria for all sub-studies:
∙ • FFPE tumor sample tested at a central laboratory confirming PD-L1 Tumor Area Positivity (TAP) score ≥1%.
∙ Additional inclusion criteria specific to HER2 sub-study:
• 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).