Safety, pharmacokinetics and pharmacodynamics of targeted anti-cancer drugs

Abstract

With the emergence of novel, rationally designed anti-cancer drugs there is also a need for novel endpoints when evaluating these drugs in clinical trials. The combined PET/CT scanner can be a very useful tool in the process of drug development in several ways, which is described in the first chapter of this thesis. PET/CT can be used for patient selection, for measuring the early response to treatment, and for determining the pharmacokinetics and pharmacodynamics of novel anti-cancer drugs. The next chapter describes the novel drug class of the aurora kinase inhibitors. First, the clinical experience with inhibitors of aurora kinase A, B, or both is reviewed. Following this review article, a phase I study with one of these agents, AZD1152, is described. In the subsequent chapters of this thesis, several phase I trials are described with a variety of novel anti-cancer drugs, with various mechanisms of action. These agents include: AZD5438, an inhibitor of cyclin dependent kinases; olaparib (AZD2281), a PARP inhibitor; E7080, an angiogenesis inhibitor; and PF00299804, an inhibitor of HER-1, HER-2, and HER-4 receptor tyrosine kinases. Also, several phase I studies combining targeted anti-cancer drugs with conventional chemotherapy are described. The main goal for all of the described phase I trials in this thesis was to determine the maximum tolerable dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the investigational drugs. However, increasingly important in these studies are pharmacodynamic endpoints, which can give early indications of the activity of the investigational drugs. Several of the studies in this thesis have successfully implemented pharmacodynamic assays, with the olaparib phase I trial as best example. In this study, target inhibition (reduced activity of the target enzyme poly(ADP-ribose)polymerase) was demonstrated in white blood cells as well as in tumor cells from patients following treatment with olaparib. One of the important conclusions from these results was that there is no need to dose the patients at the MTD since maximal target inhibition is already obtained with lower doses of olaparib. Several of the investigational anti-cancer drugs described in this thesis showed promising activity. Olaparib, for instance, appeared very effective in patients with BRCA deficient breast and ovarian cancer (over half of the patients with BRCA deficient tumors derived clinical benefit from treatment with olaparib). In the phase I trial with E7080, treatment with the angiogenesis inhibitor led to reductions in tumor volume in all patients with melanoma who entered the study. Finally, several partial responses were observed in patients with non-small cell lung cancer following treatment with the pan-HER inhibitor PF00299804. In conclusion, this thesis describes phase I studies with novel anti-cancer agents. Several of the described compounds are now under evaluation in phase II and phase III studies. Future studies with targeted agents should focus more on pharmacodynamic endpoints, and patients for future phase I studies should be included based on their tumor characteristics. PET/CT might be a helpful tool for both these purposes.