Individualized Dose Escalation of 5-FU for Gastrointestinal Cancer

Study Overview
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Brief Summary
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This is a single-arm clinical trial that will evaluate the feasibility of a chemotherapy regimen 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.

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

Conditions
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Colorectal Cancer, Esophagus Cancer, Appendix Cancer, Small Bowel Cancer, Ampullary Cancer

Intervention / Treatment
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* Other: FOX dose-escalation algorithm


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm<br>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. | Other: FOX dose-escalation algorithm<br>* Chemotherapy dose-escalation algorithm based on the FOLFOX and FOLFOXIRI regimens<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients that receive dose intensified infusional 5-FU in Cycle 6 of the FOX regimen | 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. | Through day 1 of Cycle 6 of FOX regimen (cycle length is 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate to chemotherapy | Response rate (stratified by colorectal cancer vs. gastroesophageal cancer) as defined using RECIST 1.1 imaging criteria | Through 6 months from Cycle 1 Day 1 of FOX regimen | 
| Progression-free survival | Progression-free survival (PFS, stratified by colorectal cancer vs. gastroesophageal cancer, determined by retrospective review of medical records) | Through 12 months from Cycle 1 Day 1 of FOX regimen | 
| Dose intensity of 5-FU and oxaliplatin | 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). | Through day 1 of Cycle 6 of FOX regimen (cycle length is 14 days) | 
| Mean plasma uracil concentration | 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) | Single treatment visit 0-30 days before Day 1 of Cycle 1 of FOX regimen, (cycle length is 14 days) | 
| 5-FU drug exposure | 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. | Single treatment visit on Day 3 of treament Cycle 5 or Cycle 6 of FOX regimen, (cycle length is 14 days) |