Individualized Dose Escalation of 5-FU for Gastrointestinal Cancer

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Small Bowel Cancer; Appendix Cancer; Esophagus Cancer; Ampullary Cancer
• Intervention / Treatment: Other: FOX dose-escalation algorithm

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Casey O'Quinn, M.S.; Phone Number: 603-653-9338; Email: Casey.M.O'Quinn@hitchcock.org

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Dartmouth-Hitchcock Medical Center
      • Contact: Gabriel A Brooks, MD; Phone Number: 603-650-9474; Email: gabriel.a.brooks@hitchcock.org
      • Principal Investigator: Gabriel A Brooks, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Study Arm; 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; Chemotherapy dose-escalation algorithm based on the FOLFOX and FOLFOXIRI regimens

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Gabriel A Brooks, M.D., Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: March 10, 2023
• First Submitted That Met QC Criteria: March 10, 2023
• First Posted (Actual): March 22, 2023

Study Record Updates

• Last Update Posted (Actual): July 17, 2023
• Last Update Submitted That Met QC Criteria: July 14, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Intestinal Diseases; Intestinal Neoplasms; Esophageal Diseases; Cecal Diseases; Cecal Neoplasms; Gastrointestinal Neoplasms; Esophageal Neoplasms; Appendiceal Neoplasms
• Other Study ID Numbers: STUDY02001873; 22BRO873 (Other Identifier: Dartmouth Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes