This is a single-arm clinical trial to evaluate the feasibility of a chemotherapy regimen using adaptive, individualized dose escalation of 5-FU chemotherapy for patients who have good tolerance of the initial dose. Study participants will also receive oxaliplatin chemotherapy together with 5-FU, at standard doses. The goal of the study is to examine the feasibility and effectiveness of this approach, using individualized dose escalation of 5-FU in patients who do not have serious side effects at lower doses.

Inclusion Criteria:

• Age ≥ 18 years
• Diagnosis of metastatic or locally advanced/inoperable colorectal cancer or non-colorectal gastrointestinal cancer (including cancers of the stomach, esophagus, appendix, small bowel, and ampulla)
• Clinically appropriate staging imaging of the chest, abdomen, and pelvis performed within 30 days prior to registration
• ECOG Performance Status: 0-1

Exclusion Criteria:

• Any prior receipt of oxaliplatin or fluoropyrimidine chemotherapy (other than radiation-sensitizing fluoropyrimidine chemotherapy)

• Prior receipt of systemic chemotherapy in the 6 months prior to Day 1 of Cycle 1 of FOX (other than radiation-sensitizing chemotherapy)

• Known mismatch repair deficiency or microsatellite instability-high disease

• Known dihydropyrimidine dehydrogenase (DPD) deficiency, as identified by clinically indicated screening

• Any confirmed second malignancy that is likely to require systemic therapy during the course of the six-month study period, in the opinion of the enrolling investigator

• Any of the following baseline laboratory abnormalities:

  • Absolute neutrophil count (ANC) < 2,500/mm3
  • Platelet count < 100,000/mm3
  • Hemoglobin < 9 g/dL
  • Creatinine > 1.5 x ULN
  • Total bilirubin > 1.5 x ULN
  • AST/ALT > 5 x ULN
  • Patients who are unable to provide informed consent
  • Patients who are pregnant or breastfeeding
  • Patients who are incarcerated, homeless, or have active substance use disorders