Clinical trial NCT02324452: Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
Official title: Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Neoplasms
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
First posted: 2014-12-24
Enrollment: 1103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.


Eligibility criteria: Inclusion Criteria:

1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
2. Age ≥ 18 years
3. Able and willing to give written informed consent
4. WHO performance status of 0, 1 or 2
5. Life expectancy of at least 12 weeks
6. Able to swallow and retain oral medication
7. Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis
8. Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function)

Additional inclusion criteria for patients in subgroup of study:

1. Able and willing to undergo blood sampling and breath sampling at several time points
2. Able and willing to receive uracil for the test dose assay
3. Able and willing to receive \[2-13C\] -labeled uracil for the breath test

Exclusion Criteria:

1. Prior treatment with fluoropyrimidines
2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety
3. Women who are pregnant or breast feeding
4. 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)
5. Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Primary outcomes:
measure: Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)
timeFrame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Secondary outcomes:
measure: Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective
timeFrame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year
measure: DPD phenotype, defined as deficient or not deficient
timeFrame: Prior to start of fluoropyrimidine treatment of the patient (pre dose)
measure: Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life
timeFrame: At first week of start of fluoropyrimidine treatment of the patient
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
city: Assen
country: Netherlands
facility: Wilhelmina Hospital Assen
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Delft
country: Netherlands
facility: Reinier de Graaf Hospital
city: Deventer
country: Netherlands
facility: Deventer Hospital
city: Ede
country: Netherlands
facility: Hospital Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Hospital
city: Roermond
country: Netherlands
facility: Laurentius Hospital
city: Roosendaal
country: Netherlands
facility: Bravis Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis & Vlietland
city: the Hague
country: Netherlands
facility: Haga Hospital
city: the Hague
country: Netherlands
facility: Medical Center Haaglanden
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: The Netherlands Cancer Institute
name: JHM Schellens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.