Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients

Last updated: January 31, 2016
Sponsor: Cantonal Hospital of St. Gallen
Overall Status: Completed

Phase

4

Condition

Colorectal Cancer

Colon Cancer; Rectal Cancer

Cancer

Treatment

N/A

Clinical Study ID

NCT01641458
SG 343/12
  • Ages > 18
  • All Genders

Study 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 mgh/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 mgh/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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Cytological or histological proven diagnosis of colorectal cancer, metastatic orinoperable advanced disease, not amenable to curative therapy

  • Measurable disease, defined as at least one lesion (outside of irradiated areas) thatcan be measured in at least one dimension as ≥ 10 mm (≥ 15 mm in case of lymph nodes)according to RECIST v1.1

  • Tumor either wild-type KRAS or KRAS-mutated

  • Indication for the therapeutic use of continuous intravenous 5FU over 48 hours ("deGramont" regimen) or oral Cp, either alone or in combination with other anticancerdrugs (including monoclonal antibodies or other molecularly-targeted drugs)

  • Eligible treatment regimens include: FOLFOX (FOLFOX 4, FOLFOX 6, modified FOLFOX 6,FOLFOX 7), FOLFIRI, 5FU or Cp mono-chemotherapy ("deGramont" regimen), XELOX, XELIRI,Capecitabine mono-chemotherapy

  • All regimens may be combined with anti-VEGF or anti-EGFR targeted treatment such asbevacizumab or cetuximab

  • Patients receive first-line systemic treatment (previous adjuvant chemotherapy isallowed, previous rectal radiochemotherapy is allowed if completed >/=1 months beforeregistration to the study)

  • Written informed consent before registration to the trial

  • The patient is willing to undergo pharmacogenetic and pharmacokinetic sampling andanalysis

  • WHO performance status 0 or 1

  • Female or male patients >18 years of age

  • Adequate organ function (ANC, PLT, bilirubin 2xULN, creatinine clearance)

Exclusion

Exclusion Criteria:

  • Known hypersensitivity to trial drug or any compounds of the drug

  • Pregnant or breastfeeding women

  • Patients with cerebral and/or leptomeningeal metastases are eligible, unless there isa need for treatment with steroids

  • Risk of rapid deterioration due to tumor symptoms or tumor complications

  • Severe or uncontrolled cardiovascular disease (e.g. ACS, cardiac failure NYHA III orIV, clinically relevant myopathy, history of myocardial infarction within the last 12months, significant arrhythmias)

  • Concurrent use of reversible or irreversible DPD-inhibitors, including brivudin,sorivudin, eniluracil 5-chloro-2,4-dihydroxypyridine or with substances interferingwith the immunoassay, including theophylline and theobromine.

  • Concurrent severe uncontrolled medical illness (judged by the investigator) whichcould impair the ability of the patient to participate in the trial

Study Design

Total Participants: 37
Study Start date:
October 01, 2012
Estimated Completion Date:
November 30, 2015

Connect with a study center

  • Inselspital

    Bern, 3010
    Switzerland

    Site Not Available

  • Cantonal Hospital

    St.Gallen, 9007
    Switzerland

    Site Not Available

Not the study for you?

Let us help you find the best match. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.