NCT01641458

Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients

Pharmacogenetics and Therapeutic Drug Monitoring for the Optimization of Fluoropyrimidine Treatment in Patients With Advanced Colorectal Cancer

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 37 (actual)
• Sponsor: Cantonal Hospital of St. Gallen · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The fluoropyrimidines 5-fluorouracil (5FU) and capecitabine (Cp) are among the most commonly used anticancer drugs. Still, there is much controversy about the correct dosing, and the fact that a minority of patients experience severe, sometimes even lethal toxicity following treatment. One important factor predisposing patients to severe toxicity is deficiency in the 5FU-catabolic enzyme dihydropyrimidine dehydrogenase (DPD). Our group identified 4 DPD risk alleles in over 300 Swiss cancer patients, that resulted in a 8-times increased risk of experiencing severe toxicity from 5FU or Cp. In patients receiving 5FU as a continuous infusion, there are accumulating data that keeping the AUC of 5FU between 20-30 mg\*h/L is beneficial in terms of treatment toxicity and activity. In this study, patients carrying at least 1/4 DPD risk alleles will receive a 50% dose reduction of either 5FU or Cp, with the potential of later dose increases in the abscence of severe toxicity. Additionally, patients receiving i.v. 5FU will undergo therapeutic drug monitoring at the end of the 2-day continuous infusion, with subsequent dose adaptations to target a 5FU AUC of 20-30 mg\*h/L. The primary study objective is to reduce the incidence of severe treatment-related toxicity from 13% (in historical controls) to 5% in study patients.

Conditions

• Colorectal Cancer

Interventions

Type	Name	Description
OTHER	5FU and capecitabine (Xeloda®) dosing based on DPYD genotype	Multiplex amplification of each sample is performed in an individual well of a 24-well plate using a Mastercycler platform. Template and Platinum Taq Polymerase (Life Technologies, Carlsbad, California) are added to an analyte-specific amplification mix (AutoGenomics Inc., Carlsbad, California). After amplification, the plate is transferred into the Infinity analyzer (AutoGenomics Inc.), followed by primer extension and hybridization of detection primers to individual oligonucleotides arrayed on the Bio-FilmChip. After hybridization, the BioFilmChips are washed and scanned in the Infiniti optics module. The Autogenomics DPYD assay is used to detect the presence of the four risk alleles (IVS14+G\>A, c.1679T\>G, HapB3/c.1129-5923C\>G and c.2846A\>T).
OTHER	Therapeutic drug monitoring of 5FU	Repeated PK plasma sampling is done in all patients receiving 5FU. Blood is taken from venipuncture into one 5 ml heparin tube and into one 3 ml EDTA tube for the analysis of 5FU steady-state plasma concentrations in every (2-weekly) treatment cycle. Special attention has to be paid not to take PK blood from the site of drug infusion. For 5FU, PK sampling is done two hours before the calculated end of the 5FU pump on day 3 of every treatment cycle. The quantitative 5FU exposure expressed as the area-under-the concentration-time curve in mg•h/L is calculated from the measured steady-state plasma concentrations of 5FU and the duration of 5FU infusion. In all patients, 5FU doses for the second and subsequent administrations are adjusted to target a 5FU AUC between 20 and 30 mg•h/L

Timeline

• Start date: 2012-10-01
• Primary completion: 2015-11-01
• Completion: 2015-11-01
• First posted: 2012-07-16
• Last updated: 2016-02-02

Locations

2 sites across 1 country: Switzerland