The goal of this clinical trial is to assess if circulating tumor DNA, as assessed by Signatera tumor-informed MRD assay, can guide de-escalation of adjuvant therapy in patients with resectable Stage II-IVa Gastric/Gastric-Esophageal Cancer. The main question it aims to answer is:

• To demonstrate if 2-year disease-free survival (DFS) among participants with resectable clinical Stage II-IVa gastric/gastro-esophageal cancer who received neoadjuvant D-FLOT and are ctDNA negative after curative intent R0 surgery receiving adjuvant durvalumab monotherapy is non-inferior to standard of care D-FLOT.

Researchers will compare post-operative ctDNA negative participants who are receiving adjuvant durvalumab monotherapy to those who receive standard of care (D-FLOT) to see if they have similar outcomes.

Participants will be asked to:

• Receive serial ctDNA testing
• Visit their study doctor per their standard of care visits about every 3 months for first 2 years and then every 6 months for an additional 3 years
• Answer 5 questionnaires about their well-being

This is a prospective, open-label, multi-center, ctDNA-guided study with a randomized, non-inferiority component designed to examine clinical outcomes in treatment of gastric/gastric-esophageal cancer. Specifically, a component of the study will evaluate an adjuvant treatment de-escalation strategy for participants with resectable clinical Stage II-IVa gastric/gastric-esophageal cancer who have completed neoadjuvant therapy with durvalumab plus fluorouracil, leucovorin, oxaliplatin, docetaxel (D-FLOT) and R0 curative intent surgery. Concurrently, participants with post-operative ctDNA positive results will receive standard of care (SOC) D-FLOT with blinded serial ctDNA testing.

Following R0 curative intent surgery, participants will be consented for study participation. Eligible participants will undergo treatment assignment based on post-operative MRD status at 5 weeks (+/- 2 weeks), as determined by the Signatera assay.

Participants with negative post-operative circulating tumor DNA (ctDNA) results and no radiographic evidence of disease (within 6 weeks prior to randomization) will be randomized (1:1) to either SOC vs ct-DNA guided treatment. Randomized participants will be stratified according to pathologic (yp) lymph node status and tumor staging (ypT1-3, N0 vs T4 or N+), Combined Positive Score (CPS, CPS ≥ 1 vs CPS <1), and pathological complete response (yes vs no). Assigned adjuvant treatment must start no later than 12 weeks post surgery.

• Arm A (SOC Arm): Durvalumab for 1 year plus four 2 week cycles of FLOT with unblinded serial ctDNA testing and patient-reported outcomes (PROs) assessments.
• Arm B (ctDNA-guided Arm): Durvalumab monotherapy for 1 year with unblinded serial ctDNA testing and PROs assessments. Participants who become ctDNA positive up through Cycle 11 Day 1 (C11D1) will receive four 2 week cycles of FLOT added to Durvalumab.

Once adjuvant therapy is completed, all randomized participants will continue with serial ctDNA testing until recurrence and followed for up to 5 years for overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS) and disease-specific survival (DSS).

Participants with post-operative ctDNA positive results at 5 weeks (+/- 2 weeks) will not be randomized. They will continue on observation and receive SOC D-FLOT with blinded serial ctDNA testing.

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.)