Clinical trial NCT01641458: Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
Official title: Pharmacogenetics and Therapeutic Drug Monitoring for the Optimization of Fluoropyrimidine Treatment in Patients With Advanced Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Colorectal Cancer
Keywords: Genotyping
Area-under-the concentration-time curve
Toxicity
5-fluorouracil
Capecitabine
Lead sponsor: Cantonal Hospital of St. Gallen
Sponsor class: OTHER
Collaborators: name: University of Bern
First posted: 2012-07-16
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: Inclusion Criteria:

* Cytological or histological proven diagnosis of colorectal cancer, metastatic or inoperable advanced disease, not amenable to curative therapy
* Measurable disease, defined as at least one lesion (outside of irradiated areas) that can 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 anticancer drugs (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 as bevacizumab or cetuximab
* Patients receive first-line systemic treatment (previous adjuvant chemotherapy is allowed, previous rectal radiochemotherapy is allowed if completed \>/=1 months before registration to the study)
* Written informed consent before registration to the trial
* The patient is willing to undergo pharmacogenetic and pharmacokinetic sampling and analysis
* WHO performance status 0 or 1
* Female or male patients \>18 years of age
* Adequate organ function (ANC, PLT, bilirubin 2xULN, creatinine clearance)

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 is a 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 or IV, clinically relevant myopathy, history of myocardial infarction within the last 12 months, significant arrhythmias)
* Concurrent use of reversible or irreversible DPD-inhibitors, including brivudin, sorivudin, eniluracil 5-chloro-2,4-dihydroxypyridine or with substances interfering with the immunoassay, including theophylline and theobromine.
* Concurrent severe uncontrolled medical illness (judged by the investigator) which could impair the ability of the patient to participate in the trial

Primary outcomes:
measure: Predefined fluoropyrimidine-related (index) toxicity
timeFrame: After 6 weeks of fluoropyrimidine-based treatment
Secondary outcomes:
measure: Area-under-the plasma-concentration time curve of 5-fluorouracil
timeFrame: at 8 weeks
measure: Endogenous dihydrouracil/uracil ratio in plasma
timeFrame: at start of each treatment cycle
measure: Objective treatment response (best response) according to RECIST v.1.1
timeFrame: end of first-line treatment
measure: Progression-free survival
timeFrame: time of disease progression or death
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Inselspital
city: St.Gallen
country: Switzerland
facility: Cantonal Hospital
Study officials:
affiliation: Cantonal Hospital St. Gallen, Switzerland
name: Markus Joerger, MD PhD
role: STUDY_CHAIR
References: