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Colorectal CancerPhase 4FLOXTOX2NCT01641458

Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients

A Phase 4 study testing 5FU and capecitabine (Xeloda®) dosing based on DPYD genotype and Therapeutic drug monitoring of 5FU in people with Colorectal Cancer, run by Cantonal Hospital of St. Gallen at 2 sites in Switzerland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer
What is being tested?
5FU and capecitabine (Xeloda®) dosing based on DPYD genotype and Therapeutic drug monitoring of 5FU
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
37 participants
Where
2 sitesSwitzerland
Study dates
Oct 2012to Nov 2015
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)

Who cannot join

  • 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

Trial locations and contacts

2 sites in 1 country.

Switzerland2 sites

  • Inselspital

    Bern, 3010

  • Cantonal Hospital

    Sankt Gallen, 9007

Other trials in Switzerland

About this study

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

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.

Being tested
5FU and capecitabine (Xeloda®) dosing based on DPYD genotype, Therapeutic drug monitoring of 5FU
Keywords
Genotyping, Area-under-the concentration-time curve, Toxicity, 5-fluorouracil, Capecitabine
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 5FU and capecitabine (Xeloda®) dosing based on DPYD genotypeOther

    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).

  • Therapeutic drug monitoring of 5FUOther

    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 groups in NCT01641458
Study groupRoleWhat they receive
fluoropyrimidine-based chemotherapyExperimentalDPYD-genotype and TDM-driven dosing of 5FU/Capecitabine
Receives: Other: 5FU and capecitabine (Xeloda®) dosing based on DPYD genotype; Other: Therapeutic drug monitoring of 5FU

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Predefined fluoropyrimidine-related (index) toxicity

    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

    Measured: After 6 weeks of fluoropyrimidine-based treatment

Secondary outcomes (4)

  1. Area-under-the plasma-concentration time curve of 5-fluorouracil

    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

    Measured: at 8 weeks

  2. Endogenous dihydrouracil/uracil ratio in plasma

    Endogenous UH2 to U ratio as analysed at the time of PK sampling of 5FU or Cp, and repeated for each treatment cycle.

    Measured: at start of each treatment cycle

  3. Objective treatment response (best response) according to RECIST v.1.1

    Objective treatment response according to the RECIST criteria v1.1 is assessed in all patients

    Measured: end of first-line treatment

  4. Progression-free survival

    Defined as the time interval between start of study treatment and disease progression or death, whatever comes first.

    Measured: time of disease progression or death

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jul 2012 (estimated)
  2. Study startOct 2012
  3. Primary completionNov 2015
  4. Study completionNov 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01641458
Sponsor's protocol ID
SG 343/12
Acronym
FLOXTOX2
Status last verified
Jan 2016
First submitted
11 Jul 2012
Last updated
2 Feb 2016
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing 5FU and capecitabine (Xeloda®) dosing based on DPYD genotype and Therapeutic drug monitoring of 5FU in people with Colorectal Cancer, run by Cantonal Hospital of St. Gallen at 2 sites in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Predefined fluoropyrimidine-related (index) toxicity (time frame: After 6 weeks of fluoropyrimidine-based treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01641458.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2016.

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