THerapeutic Oncolytic Monitoring AS a tool for effective exposure to 5-FU in patients with locally advanced, resectable gastric or gastro-oesophageal junction cancer treated with perioperative FLOT

Traditional dosing of 5-FU is based on body surface area and DPD enzyme
activity. However, BSA-based dosing is associated with wide inter-individual
variations in 5-FU systemic exposure, and also 5-FU-induced toxicity. The
international association for therapeutic drug monitoring and clinical
toxicology (IATDMCT) state in there clinical guideline, in which all previous
clinical pharmacokinetic studies of 5-FU were reviewed, that only 25% of the
patients are within the therapeutic range. In the traditional treatment
regimens a bolus of 400 mg/ m2 5-FU is given, followed by a dose of 2400 mg/m2
as a 46-hour infusion. The therapeutic range of 5-FU in these older regimens is
defined by a target AUC of 20-30 mg*h/L. In contrast, 5-FU in FLOT regimen is
given without a bolus, and in a high dose of 2600 mg/m2 as a 24-hour infusion.
This means that a comparable absolute dose of 5-FU is given with FLOT and the
older regimens, however, the manner and duration of administration differ.
Based on this administration, it is expected that the FLOT regimen will result
in an approximately two-fold higher steady state concentration (Css), as it is
given in an approximately two-fold shorter period of time (t). As a result of
this pharmacokinetic predictions, the exposure to 5-FU (AUC = Css x t) will be
comparable between these different 5-FU regimens. Therefore, we hypothesise
that the therapeutic range of 5-FU in FLOT will be comparable to the target AUC
of 20-30 mg*h/L in the older regimens. Similar to the older treatment regimens,
we expect that a significant part of patients will be outside this therapeutic
window. To test these hypotheses, the aim of this study is to establish the
population exposure of 5-FU in FLOT treatment regimen, and to determine the
percentage of patients that achieves this therapeutic range.

Primary Objective:
- To establish the population range (24-h AUC) of high-dose infusional 5-FU in
patients with locally advanced, resectable gastric or gastro-esophageal
junction cancer treated with perioperative FLOT.

Secondary objectives:
- To determine the percentage of patients in FLOT treatment regimen that
achieves the therapeutic range of 5-FU, which is defined by an AUC target of
5-FU between 20 and 30 mg*h/L.
- 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 the percentage of patients in FLOT
treatment regimen that needed dose reduction of 5-FU and subtherapeutic,
therapeutic and supratherapeutic AUC of 5-FU.
- To determine the intra-individual variation in 5-FU exposure between the
different cycles by drawing blood samples in cycles 1, 2, 5 and 6
- To determine the inter-individual variation in 5-FU exposure

Exploratory objectives:
- To develop a population 5-FU pharmacokinetic model to get a better
substantiated 5-FU dose in the first cycle for future patient treated with FLOT.
- To establish whether there is a difference in 5-FU exposure pre-surgery and
post-surgery
- To determine the correlation between the baseline endogenous DPD substrate
plasma ratios of DHU/U and DHT/T with the pharmacokinetics of 5-FU in patients
with locally advanced, resectable gastric or gastro-esophageal junction cancer
treated with perioperative FLOT.
- To determine the intra-patient variation in DHU/U and DHT/T ratios over time
during 5-FU treatment cycles in FLOT regimen.

Multicentre, non-randomized pharmacokinetic study to determine the percentage
of patients that achieves optimal 5-FU exposure and to establish the population
exposure of 5-FU in FLOT regimen.

The risk associated with participation in this clinical trial is low. The
patients receiving the FLOT treatment are treated conform standard of care. The
difference between the current procedure in standard care and this study is
extra 5-FU blood sampling that is required to establish therapeutic range. 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 the 5-FU PK model.
In the future this study 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.