PHARMACOGENOMIC AND PHARMACOKINETIC SAFETY AND COST-SAVING ANALYSIS IN PATIENTS TREATED WITH FLUOROPYRIMIDINES

Fluoropyrimidines are a group of widely prescribed anticancer agents. Although
5-FU is in clinical use for 50 years, it remains a drug with poorly predictable
severe toxicity, which in some cases is fatal. An important factor for
fluoropyrimidine-associated toxicity is polymorphism in dihydropyrimidine
dehydrogenase (DPD), the enzyme that metabolizes 85% of 5-FU to inactive
compounds.
The polymorphism IVS14+1G>A (DPYD*2A) has been shown to have a great impact on
DPD-activity. Retrospectively, the DPYD*2A mutation is found in about 25% of
all patients who developed severe hematological and/or gastro-intestinal
toxicity after full-dose treatment with capecitabine or 5-FU.
This single nucleotide polymorphism is a point mutation, which leads to
complete skipping of exon 14 during pre-mRNA splicing, resulting in a protein
with absent activity. In the Netherlands DPYD*2A has a heterozygous frequency
of 1.8%. It is reported that heterozygote individuals for DPYD*2A have a 50%
reduction in DPD-activity, whereas in homozygotes DPD is complete deficient.
The reduced or absent capacity to metabolize 5-FU by DPD, leads to a higher and
longer exposure of 5-FU to the body, which in turn causes typical
fluoropyrimidine (non-)hematological toxicity such as bone marrow suppression,
leucopenia, diarrhea and mucositis. Prolonged periods of hospitalization of
several weeks are indicated for the treatment of the toxicity.
We develop a rapid screening method for DPYD*2A, which is suitable for routine
assessment prior to therapy. Other methods described in literature such as
activity measurements in leucocytes or determination of the uracil /
dihydrouracil ratio in urine for predicting DPD activity are time-consuming,
highly variable and above all not predictive, thereby not suitable for clinical
practise. There is an unmet need for other methods for predicting
DPD-deficiency.
The aim is to demonstrate that total number and degree of toxicity, and related
costs for the treatment of the toxicity, can be prevented by adaptive dosing in
DPYD*2A mutant individuals.

The primary objective of the study is to prospectively determine whether
fluoropyrimidine-induced toxicity is preventable by dose adjustment prior to
start of the first administration based on the polymorphic status of the
DPYD*2A polymorphism in DPYD, in comparison with retrospectively determined
full-dose treated heterozygous patients and to determine whether this strategy
is cost-saving.
Secondary objectives of the study are to validate an individualized treatment
algorithm for capecitabine and 5-FU therapy based on the polymorphic status of
DPYD*2A and to assess the pharmacokinetic profile of capecitabine and 5-FU in
DPYD*2A mutants given reduced dosages of the respective drugs.

Prospective, clinical, non-randomized, pharmacogenetic, -kinetic and *economic
non-randomized safety analysis in patients treated with capecitabine or 5-FU.

The polymorphic status of DPYD*2A will be assessed prospectively, prior to
fluoropyrimidine treatment. Wild-type patients will drop out of the study after
determination. Hetero- and homozygous mutant patients are given a dose
reduction of at least 50% and 85%, respectively. If the first 2 cycles are
fully completed and considered safe, doses may be increased in subsequent
cycles.
Further dose reductions may be applied at any time.

4 ml of blood will be obtained prior to start of therapy for the assessment of
DPYD*2A status. In DPYD*2A mutant patients a maximum of 12 plasma samples (8 ml
blood / sample) will be obtained on day 1 of course number 1. This will require
only one extra venapuncture for the whole blood sampling procedure on that day.
If patients receive a dose modification in any further cycle, the same blood
sampling procedure will be performed on day one of the respective course. Any
risk hereby is negligible.