Personalized prediction and regulation of 5-FU exposure

It is widely well-known that 5-FU dosing based on body surface area (BSA) is
associated with wide variations of 5-FU systemic exposure and 5-FU toxicity.
Beumer et al. summarized previous clinical studies of 5-FU and observed
approximately 40% inter-individual variability in 5-FU exposure in these
studies. Furthermore, only 25% of the patients are within the therapeutic
window and 60% of the patients are underdosed after the first cycle. Recently,
Beumer et al. presented a strong case for 5-FU dose adjustment based on 5-FU
plasma concentrations, so called Therapeutic Drug Monitoring (TDM), in order to
reduce inter-individual variability in 5-FU exposure and toxicity, while
preserving efficacy. Despite sufficient evidence on the efficacy of TDM of 5-FU
to reduce toxicity, while maintaining the efficacy of treatment in patients,
several problems such as technical handling of blood samples, accurate
measurements, calculation of 5-FU exposure and 5-FU dosing advice need to be
clarified before introducing TDM of 5-FU in standard routine clinical care.
Therefore the aim of this study is to validate whether TDM of 5-FU is an
effective tool to regulate individual 5-FU exposure in both Amsterdam UMCs.

Primary objective:
To determine the percentage of the patients that achieve optimal 5-FU exposure
within two dose cycles of 5-FU, which is defined by an AUC target of 5-FU
between 20 and 30 mg h/L or dose limiting toxicity.

Secondary objectives:
-To determine whether minimal sampling of 5-FU blood samples is sufficient to
safely adjust 5-FU dosing in our routine clinical practice.
-To develop 5-FU PK model for our Amsterdam UMC 5-FU patients using NONMEM
statistics.
-To investigate the contribution of bolus 5-FU exposure in PK model as compared
to the exposure calculations with the simple formula (Css x t).
All 5-FU exposure correlations below this point will be calculated with the
simple formula as well as with PK modelling:
-To determine the frequency and severity of AEs at 5-FU exposure with below,
within and above the target window,
-To determine the correlation between DPD activity with 5-FU exposure in the
first 5-FU dose cycle
-To determine the intra-individual variation in 5-FU AUCs in all six 5-FU
cycles.
-To investigate the correlation between AEs and the total 5-FU exposure in six
dose cycles.

Exploratory objectives:
-To explore the utility of DPD-phenotyping in predicting the exposure of the
first dose of 5-FU.
-Searching for new predictors in DPYD DNA variants that contribute to increased
5-FU exposure or toxicity.

Multicentre intervention study to determine the percentage of patients that
achieve optimal 5-FU exposure in the Amsterdam UMCs

A 5-FU dosing algorithm will be applied in this study to adjust the 5-FU
exposure in patients until the target window of 20-30 mg*h/L or dose limiting
toxicity has been reached. All other procedures will be a part of standard
care.

The risk associated with participation in this clinical trial is low. The
difference between the current procedure in standard care and this study is
extra 5-FU blood sampling that is required to adjust dosages. Because patients
may experience 5-FU side effects upon dose increase, a maximum dose increase of
40% per cycle is applied in this study. Dose escalation will only be applied
when 5-FU toxicity is absent in patients. On the other hand, dose decrease
might lead to less 5-FU toxicity in patients with high 5-FU exposure.

The study burden is additional of 10 to 15 times 4 ml blood sampling and
additional 15 ml blood for DPD phenotyping in VUmc patients or 5 ml blood for
DPYD genotyping in AMC patients. Five blood samples from the 1st cycle is used
to develop 5-FU PK model and to calculate the exposure of 5-FU for new 5-FU
dose advice for the 2nd cycle. A venflon will be introduced in the peripheral
vein of the patients to reduce the burden of multiple blood sampling.

In the 2nd to 5th cycle one or two samples will be drawn by venipuncture to
calculate the new 5-FU dose advice for the next cycles. The blood samples in
the 6th cycle are used to complete the dataset. The second blood sample in the
2nd to the 6th cycle will only be drawn if the patient is in the hospital at
the end of 5-FU continuous infusion.
The number of blood samples was designed to collect the minimum amount of blood
that is required to accurately and completely calculate the AUC of 5-FU and to
develop 5-FU PK model.

The benefit for the patient participating in this study is that the 5-FU
exposure will be personalized to reduce potential toxicity while preserving
efficacy.

When toxicity can be limited through personalized regulation of 5-FU exposure,
TDM of 5-FU will be applied in our standard routine care. In the future this
will benefit all patients that are treated with 5-FU based chemotherapy. After
this trial, future 5-FU patients might benefit from minimal 5-FU blood sampling
as this study determines the minimal number of blood samples to accurately
measure and calculate 5-FU exposure.