Safety, pharmacokinetics and preliminary anti-tumor activity of novel (combinations of) targeted anti-cancer drugs

The development of new anti-cancer treatments is still moving from a one-fits-all approach of classic cytotoxic chemotherapies to personalized treatments based on inhibition of specific targets within a cell. In the phase I trials explored in this thesis, several of these targeted compounds were tested for safety, pharmacokinetics and preliminary anti-tumor activity. In most of these trials the targeted agent was given as monotherapy. However, in some trials they were given in combination with cytotoxic anti-cancer therapies to explore whether this would be a feasible treatment option.
Patients that were included were generally patients that had no regular treatment options available to them anymore and were considered to be good candidates for a phase I trial. They had to undergo extensive safety evaluations, including laboratory assessments for hematology and clinical chemistry, ECGs, measuring of vital signs and physical examinations. To explore the pharmacokinetic profiles of the drugs administered, extensive blood sampling was done. Additional blood samples were drawn for possible biomarkers indicating target engagement. Radiological assessments in the form of CT-scans were done at regular intervals (usually every 2 cycles) to assess preliminary anti-tumor activity.
The main goal of these studies was to determine the safety profile of these drugs and to identify a dosing regimen that could be taken into further clinical studies.
While it was initially thought that these targeted inhibitors would cause less toxicity than the conventional cytotoxic therapies, it has become clear that these drugs have their own profile of adverse events. Examples of adverse events that are related to the inhibition of a cellular signaling pathway include ocular toxicities and hyperglycemia, seen with inhibitors of the FGFR-MEK pathway and PI3K-Akt pathway, respectively. These toxicities can actually be explained by the normal physiological roles that these targets play in the body. Furthermore, while some adverse events are related to the dose (such as hyperglycemia), others appear after treating patients for a while (such as diarrhea), indicating that these events are related to accumulation of the drug. Interestingly, some of these adverse events could also be used as biomarkers that could indicate target engagement, such as hyperglycemia with PI3K inhibitors and AKT inhibitors and phosphate with FGFR inhibitors.
Preliminary anti-tumor activity in the monotherapy was mostly modest, which was probably due to the fact that many of these trials did not start with so-called “pre-screening”: screening patients’ tumor material for genetic aberrations in the targeted pathway. The parts of the trials that did include pre-screening mostly showed a higher response rate. The trials in which the targeted inhibitor was combined with cytotoxic agents showed more anti-tumor activity. This was especially true for the phase I trial in which the PARP inhibitor olaparib was combined with carboplatin and paclitaxel. However, this study was hampered by an increase in bone marrow suppression when olaparib was added to these chemotherapeutics.