Phase I Clinical Trials with targeted
The development of anti-cancer therapies has undergone a radical
change over the last decades: from conventional cytotoxic drugs
that don't discriminate between normal and tumor cells, to
so-called targeted therapies which inhibit a specific target within
a tumor cell.
The targets are mostly comprised of receptors or tyrosine kinases
that have become aberrant in tumor cells, which can cause
uncontrolled cellular signaling and growth.
Within our research group, we perform many phase I studies with
inhibitors of these specific targets, both in the form of
small-molecule inhibitors as well as monoclonal antibodies. Since
this is the first time these anti-cancer therapies are administered
to humans, the main goal of these studies is to characterize the
safety and pharmacokinetic profile and to determine a recommended
dose for further clinical development.
In recent years, it has become apparent that these targeted
therapies have relatively modest anti-tumor activity, which is
mostly due to the tumor cells developing resistance through
mutations in parallel cellular signaling pathways. Thus,
development of these compounds has steered more towards combining
For more information about our phase I trial unit, click
In support of clinical trials, our research group also focuses
heavily on the development of pharmacodynamic assays, which could
help us in diagnosis, but also in determining which patients
benefit more from treatment.
These assays include the quantification of poly(ADP-ribose)
polymerase (PARP) inhibition in peripheral blood mononuclear cells
(PBMCs), which is currently validated in phase I clinical trials
with the PARP-inhibitor olaparib, and circulating endothelial cells
(CECs) in plasma.
Furthermore, we are in the process of validating a new assay to
determine circulating tumor cells (CTCs) both in blood samples and
in cerebrospinal fluid. With this assay, we could possibly detect
signs of disease progression at an earlier stage.
Lastly, we are involved in optimizing assays for the determination
of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase
(TS) activity. These enzymes plays an important part in the
metabolism and activity of fluoropyrimidines. Patients with
decreased metabolism are at risk of developing serious toxicities
and thus determining the DPD activity before starting treatment
could warrant a dose adjustment.
In collaboration with our pharmacy department, our research groups
conducts trials to test the safety and pharmacokinetics new oral
formulations of intravenous anti-cancer drugs, such as docetaxel
Furthermore, to optimize treatment of tyrosine kinase inhibitors,
we aim to develop and/or optimize therapeutic drug monitoring (TDM)
for both new and existing anti-cancer treatments.
Additionally, the collaboration with the pharmacy also allows us
to explore other types of pharmacological research, such as mass
balance studies, measurements of intracellular metabolites of
anti-cancer drugs and pharmacokinetic and pharmacodynamics modeling
More about the Pharmacology group