Signatera-Guided De-escalation of Adjuvant Therapy in Resectable Stage II-IVa Gastric/Gastric-Esophageal Cancer (SIGNAL GEC-101)

Inclusion Criteria:

1. Signed and dated informed consent form (ICF) obtained prior to any trial-specific enrollment procedure.
2. Age is ≥ 18 years-old at the time of ICF signature.
3. Able to submit adequate archival tumor tissue (eg, 6 to 10 unstained slides at 10 microns (μm) each or 12-19 unstained slides at 5-microns (μm) plus one hematoxylin and eosin slide (see study lab manual) obtained per standard of care procedures for submission to a central laboratory for Signatera testing OR prior commercial Signatera Genome test results.
4. Histologically confirmed adenocarcinoma of the stomach, esophagus and/or gastroesophageal junction (GEJ), resectable clinical Stage II-IVa per AJCC 9th edition.
5. Completion of full or modified course (based on Dosing and Modification Guidelines) of neoadjuvant D-FLOT therapy (ie, two 4-week cycles of durvalumab, four 2-week cycles of FLOT) .
6. Has undergone complete surgical resection of the gastric/GEJ tumor with pathologically confirmed negative margins (R0 resection).
7. Eligible to receive adjuvant D-FLOT treatment within 12 weeks postoperative per standard of care (SOC) as assessed by the treating clinician.

8. Known statuses pertaining to randomization stratification factors:

   1. Post neoadjuvant, post-operative (yp) lymph node status and tumor staging (ypT1-3, N0 vs T4 or N+)
   2. Combined Positive Score ( ≥ 1 vs <1)Tumor PD-L1 status confirmed by immunohistochemistry/CPS score.
   3. Post neoadjuvant, post-operative major pathological response (MPR): Yes/No
9. ECOG performance status 0-1.
10. No evidence of disease by radiographic imaging.
11. Must be willing to and able to comply with adjuvant treatment plans based on ctDNA results and other trial-mandated procedures.
12. Women of child bearing potential must have a confirmed negative pregnancy test within 14 days of enrollment per institutional standards.

Exclusion Criteria:

1. Histologic presence of adenosquamous cell carcinoma, squamous cell carcinoma, gastrointestinal stromal tumor, or neuroendocrine tumors.
2. Radiographic evidence of unresectable metastatic disease (ie, IVb).
3. Presence of peritoneal dissemination.
4. Any prior therapy (eg, radiation, chemoradiation, chemotherapy) for gastric or gastroesophageal cancer other than neoadjuvant D-FLOT and R0 curative intent surgery.
5. Known contradiction or hypersensitivity to durvalumab per the prescribing information; known contraindication or hypersensitivity to Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel or any of the drug excipients.
6. Known history of active primary immunodeficiency (eg, HIV), other contraindications of immunotherapy or receiving immunosuppressive medication per approved label.
7. Female participants who are pregnant or breastfeeding.
8. Concurrent enrollment in another clinical trial unless the study is observational, non-interventional.
9. Use of any commercial ctDNA or liquid biopsy monitoring outside of the study protocol during the primary 36-month monitoring period.
10. Concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 5 years before ICF signature. Note: Participants with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to enrollment.
11. Any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate participant participation in the clinical trial or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic antibacterial therapy, etc.)