Individualized Dose Escalation of 5-FU for Gastrointestinal Cancer

NCT05780684 — Not applicable, Recruiting, 36 participants, Dartmouth-Hitchcock Medical Center

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Adaptive, Individualized Dose Escalation of Fluorouracil-Based Chemotherapy for Gastrointestinal Cancer: Pilot Study of the FOX Regimen

Registry	NCT05780684
Status	Recruiting
Phase	Not applicable
Study type	Interventional; na, single group, masking: none, treatment
Enrollment	36 (Estimated)
Sponsor	Dartmouth-Hitchcock Medical Center (Other)
Conditions	Colorectal Cancer, Esophagus Cancer, Appendix Cancer, Small Bowel Cancer, Ampullary Cancer
Interventions	FOX dose-escalation algorithm (Other)
Dates	start 2023-07-14, primary completion 2027-09-01 (estimated), completion 2027-12-01 (estimated), first posted 2023-03-22, last updated 2026-06-22
Locations	1 site in United States

-Summary

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.

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+Arms and interventions

Arm	Type	Interventions	Description
Study Arm	Experimental	Other: FOX dose-escalation algorithm	All patients in this single-study arm will be exposed to the FOX regimen, an adaptively dose-escalated chemotherapy regimen. The FOX regimen is comprised of oxaliplatin 85 mg/m2 IV on Day 1; leucovorin calcium 350 mg IV on Day 1; and infusional 5-FU IV over 46 hours (Days 1 and 2) - starting at a dose of 2,400 mg/m2 and adaptively adjusted toward a maximum dose of 3,200 mg/m2 over Cycles 2-4 using a clinical algorithm.

FOX dose-escalation algorithm (Other): Chemotherapy dose-escalation algorithm based on the FOLFOX and FOLFOXIRI regimens

+Outcome measures

Primary outcomes

Proportion of patients that receive dose intensified infusional 5-FU in Cycle 6 of the FOX regimen [Through day 1 of Cycle 6 of FOX regimen (cycle length is 14 days)]: The proportion of patients who receive dose-intensified infusional 5-FU (dosed at greater than or equal to 2,800 mg/m2) in Cycle 6 of the FOX regimen.

Secondary outcomes

Response rate to chemotherapy [Through 6 months from Cycle 1 Day 1 of FOX regimen]: Response rate (stratified by colorectal cancer vs. gastroesophageal cancer) as defined using RECIST 1.1 imaging criteria
Progression-free survival [Through 12 months from Cycle 1 Day 1 of FOX regimen]: Progression-free survival (PFS, stratified by colorectal cancer vs. gastroesophageal cancer, determined by retrospective review of medical records)
Dose intensity of 5-FU and oxaliplatin [Through day 1 of Cycle 6 of FOX regimen (cycle length is 14 days)]: Dose intensity of 5-FU and oxaliplatin over Cycles 1-6. Dose intensity will be calculated separately for each component of the FOLFOX regimen (5-FU infusion and oxaliplatin).
Mean plasma uracil concentration [Single treatment visit 0-30 days before Day 1 of Cycle 1 of FOX regimen, (cycle length is 14 days)]: Difference in mean plasma uracil concentration between patients who did and did not achieve sustained 5-FU dose escalation to ≥ 2,800 mg/m2 (primary endpoint)
5-FU drug exposure [Single treatment visit on Day 3 of treament Cycle 5 or Cycle 6 of FOX regimen, (cycle length is 14 days)]: 5-FU drug exposure, measured as the area under the drug concentration curve (AUC). AUC will be calculated by multiplying the measured 5-FU concentration at steady state by the 5-FU infusion duration in hours.

+Eligibility

Sex: All, ages: 18 Years to any

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

+Locations (1)

Facility	City	Country	Status
Dartmouth-Hitchcock Medical Center	Lebanon, New Hampshire	United States	Recruiting

+Investigators

Gabriel A Brooks, M.D., Principal investigator, Dartmouth-Hitchcock Medical Center