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Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients (FLOXTOX2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01641458
Recruitment Status : Completed
First Posted : July 16, 2012
Last Update Posted : February 2, 2016
University of Bern
Information provided by (Responsible Party):
Markus Joerger, Cantonal Hospital of St. Gallen

Tracking Information
First Submitted Date  ICMJE July 11, 2012
First Posted Date  ICMJE July 16, 2012
Last Update Posted Date February 2, 2016
Study Start Date  ICMJE October 2012
Actual Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 12, 2012)
Predefined fluoropyrimidine-related (index) toxicity [ Time Frame: After 6 weeks of fluoropyrimidine-based treatment ]
Index toxicity is defined as follows:
  • All adverse events CTC grades ≥3, including myelosuppression but excluding nausea and vomiting (that is often due to concurrent platinum drug treatment)
  • Fluoropyrimidine-related toxicity CTC grade ≥2, including mucositis, dehydration, hand-foot syndrome
  • Diarrhea CTC grade ≥2 lasting for >/=5 days or an increase of 2 CTC grades in case of preexisting diarrhea. Diarrhea should not be evaluated in patients with a colostomy
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01641458 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2012)
  • Area-under-the plasma-concentration time curve of 5-fluorouracil [ Time Frame: at 8 weeks ]
    AUC of 5FU as derived from 5FU steady-state plasma concentrations, taken 2 hours before the planned end of the continuous drug infusion. 5FU target AUC is defined as within the range of 20-30 mg•h/L
  • Endogenous dihydrouracil/uracil ratio in plasma [ Time Frame: at start of each treatment cycle ]
    Endogenous UH2 to U ratio as analysed at the time of PK sampling of 5FU or Cp, and repeated for each treatment cycle.
  • Objective treatment response (best response) according to RECIST v.1.1 [ Time Frame: end of first-line treatment ]
    Objective treatment response according to the RECIST criteria v1.1 is assessed in all patients
  • Progression-free survival [ Time Frame: time of disease progression or death ]
    Defined as the time interval between start of study treatment and disease progression or death, whatever comes first.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
Official Title  ICMJE Pharmacogenetics and Therapeutic Drug Monitoring for the Optimization of Fluoropyrimidine Treatment in Patients With Advanced Colorectal Cancer
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE Experimental: fluoropyrimidine-based chemotherapy
DPYD-genotype and TDM-driven dosing of 5FU/Capecitabine
  • Other: 5FU and capecitabine (Xeloda®) dosing based on DPYD genotype
  • Other: Therapeutic drug monitoring of 5FU
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 31, 2016)
Original Estimated Enrollment  ICMJE
 (submitted: July 12, 2012)
Actual Study Completion Date  ICMJE November 2015
Actual Primary Completion Date November 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01641458
Other Study ID Numbers  ICMJE SG 343/12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Markus Joerger, Cantonal Hospital of St. Gallen
Study Sponsor  ICMJE Cantonal Hospital of St. Gallen
Collaborators  ICMJE University of Bern
Investigators  ICMJE
Study Chair: Markus Joerger, MD PhD Cantonal Hospital St. Gallen, Switzerland
PRS Account Cantonal Hospital of St. Gallen
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP