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NeoplasmsNCT02324452

Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

A study testing Fluoropyrimidine (capecitabine or 5-fluorouracil) in people with Neoplasms, run by The Netherlands Cancer Institute at 17 sites in Netherlands.

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

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Neoplasms
What is being tested?
Fluoropyrimidine (capecitabine or 5-fluorouracil)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,103 participants
Where
17 sitesNetherlands
Study dates
Mar 2015to Mar 2018
Phase
Interventional
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

  • Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
  • Age ≥ 18 years
  • Able and willing to give written informed consent
  • WHO performance status of 0, 1 or 2
  • Life expectancy of at least 12 weeks
  • Able to swallow and retain oral medication
Show all 12Show fewer
  • Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis
  • Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function)
  • Additional inclusion criteria for patients in subgroup of study:
  • Able and willing to undergo blood sampling and breath sampling at several time points
  • Able and willing to receive uracil for the test dose assay
  • Able and willing to receive [2-13C] -labeled uracil for the breath test

Who cannot join

  • Prior treatment with fluoropyrimidines
  • Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety
  • Women who are pregnant or breast feeding
  • Both men and women who refuse to use reliable contraceptive methods throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)
  • Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

Netherlands17 sites

  • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

    Amsterdam

  • Wilhelmina Hospital Assen

    Assen

  • Amphia Hospital

    Breda

  • Reinier de Graaf Hospital

    Delft

  • Deventer Hospital

    Deventer

  • Hospital Gelderse Vallei

    Ede

  • Catharina Hospital

    Eindhoven

  • Leiden University Medical Center

    Leiden

  • Maastricht University Medical Center

    Maastricht

  • Canisius-Wilhelmina Hospital

    Nijmegen

  • Laurentius Hospital

    Roermond

  • Bravis Hospital

    Roosendaal

  • Erasmus MC

    Rotterdam

  • Franciscus Gasthuis & Vlietland

    Rotterdam

  • Haga Hospital

    The Hague

  • Medical Center Haaglanden

    The Hague

  • University Medical Center Utrecht

    Utrecht

Other trials in Netherlands

About this study

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

In addition to the genotyping, the DPD phenotype of all patients will be determined by measuring the baseline dihydrouracil/uracil (DHU/U) ratio, in order to investigate whether phenotype-guided treatment can further improve patient safety. In a subgroup of patients, other phenotyping methods will be tested: measuring the plasma levels of uracil after a uracil test dose and a uracil breath test after a dose of [2-13C] -labeled uracil. To validate these tests, these phenotyping results will be compared with the results of a DPD activity assay (which measures DPD enzyme activity in peripheral blood mononuclear cells), which is considered the gold standard in measuring DPD phenotype.

Conditions
Neoplasms
Being tested
Fluoropyrimidine (capecitabine or 5-fluorouracil)
Medical subject headings
Neoplasms

What participants receive

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

  • Fluoropyrimidine (capecitabine or 5-fluorouracil)Drug

    Also called Xeloda, Capecitabine, 5-fluorouracil, fluorouracil

    Patient that are a heterozygous carrier of a DPYD variant will receive a reduced dosage of capecitabine or 5-fluorouracil (25-50% reduction, depending on which SNP is identified). The dose will be titrated in subsequent cycles, to achieve maximal safe exposure. Patients that are wild type (not carrying any of the for DPYD variants) will receive a normal (full) dose.

Study groups in NCT02324452
Study groupRoleWhat they receive
heterozygous carrier of DPYD variantExperimentalPatients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD*2A, c.2846A>T, c.1236G>A/HapB3 and DPYD*13) that are found to be heterozygous for one of these SNPs
Receives: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)
wild type for DPYDExperimentalPatients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD*2A, c.2846A>T, c.1236G>A/HapB3 and DPYD*13) that are found to be wild type for these SNPs
Receives: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

What is being measured

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

  1. Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)

    The incidence of severe treatment-related toxicity (CTC grade 3 to 5) in patients carrying DPYD variants compared to wild type patients and compared to a historical cohort of DPYD heterozygous patients treated with a full dose of fluoropyrimidines

    Measured: patients will be followed during fluoropyrimidine treatment, expected average of 1 year

Secondary outcomes (3)

  1. Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective

    Costs in the group where dose individualization of fluoropyrimidines based on upfront genotyping is performed is compared to a historic cohort without dose individualization. Costs include costs for genotyping, fluoropyrimidine drug therapy and costs related to adverse events.

    Measured: patients will be followed during fluoropyrimidine treatment, expected average of 1 year

  2. DPD phenotype, defined as deficient or not deficient

    Several phenotyping tests that assess DPD enzyme activity will be compared and clinical sensitivity, specificity, positive predictive value and negative predictive value of each test will be determined

    Measured: Prior to start of fluoropyrimidine treatment of the patient (pre dose)

  3. Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life

    In patients with heterozygous DPYD mutations the plasma levels of capecitabine, 5-FU and metabolites will be determined to assess the pharmacokinetic (PK) profile in these patients given reduced doses of capecitabine and 5-FU

    Measured: At first week of start of fluoropyrimidine treatment of the patient

Timeline

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

  1. First posted24 Dec 2014 (estimated)
  2. Study startMar 2015
  3. Primary completionJan 2018
  4. Study completionMar 2018

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 N/A
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
1,103 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02324452
Sponsor's protocol ID
M14DPD
Other IDs
2014-005064-15, 2014
Status last verified
May 2018
First submitted
9 Dec 2014
Last updated
11 May 2018
Results posted
No
Data monitoring committee
Yes

Publications

  • Knikman JE, Lopez-Yurda M, Meulendijks D, Deenen MJ, Schellens JHM, Beijnen J, Cats A, Guchelaar HJ. A Nomogram to Predict Severe Toxicity in DPYD Wild-Type Patients Treated With Capecitabine-Based Anticancer Regimens. Clin Pharmacol Ther. 2024 Feb;115(2):269-277. doi: 10.1002/cpt.3100. Epub 2023 Nov 29.

    PubMed 37957132

  • Knikman JE, Wilting TA, Lopez-Yurda M, Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Nieboer P, Droogendijk HJ, Creemers GJ, Mandigers CMPW, Imholz ALT, Mathijssen RHJ, Portielje JEA, Valkenburg-van Iersel L, Vulink A, van der Poel MHW, Baars A, Swen JJ, Gelderblom H, Schellens JHM, Beijnen JH, Guchelaar HJ, Cats A. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis. J Clin Oncol. 2023 Dec 10;41(35):5411-5421. doi: 10.1200/JCO.22.02780. Epub 2023 Aug 28.

    PubMed 37639651

  • Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers CMPW, Rosing H, Beijnen JH, Werkhoven EV, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 2018 Nov;19(11):1459-1467. doi: 10.1016/S1470-2045(18)30686-7. Epub 2018 Oct 19.

    PubMed 30348537

  • Jacobs BA, Deenen MJ, Pluim D, van Hasselt JG, Krahenbuhl MD, van Geel RM, de Vries N, Rosing H, Meulendijks D, Burylo AM, Cats A, Beijnen JH, Huitema AD, Schellens JH. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. Br J Clin Pharmacol. 2016 Sep;82(3):706-16. doi: 10.1111/bcp.13007. Epub 2016 Jun 3.

    PubMed 27161955

Questions about this trial

What is this clinical trial studying?

A study testing Fluoropyrimidine (capecitabine or 5-fluorouracil) in people with Neoplasms, run by The Netherlands Cancer Institute at 17 sites in Netherlands.

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 5 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 11 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Netherlands. 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.

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?

Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5) (time frame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year). 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 NCT02324452, which also lists 4 linked publications.

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 11 May 2018.

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