Pharmacokinetics of novel anticancer drugs and dynamics of circulating tumor cells in early clinical studies

Cancer has an enormous impact on the lives of patients and on society and there is an urgent need for improvements in therapy. In this thesis, early-clinical studies into both safety and pharmacokinetics of novel anti-cancer drugs as well as into circulating tumor cells (CTCs) are reported. Safety, tolerability and pharmacokinetics of pazopanib, a novel anti-cancer drug that targets new blood-vessel formation, was investigated in combination with oral topotecan, a topoisomerase-I inhibitor. Pharmacokinetic analysis showed that pazopanib increased the exposure to topotecan considerably, whereas topotecan did not increase exposure to pazopanib. The most frequently reported treatment-related side-effects were anemia, leukocytopenia, neutropenia and fatigue. In another study, dosing recommendations were established for oral topotecan in patients with renal impairment. The data currently available demonstrate that no dose adjustments are required in patients with prior platinum-based chemotherapy or mildly impaired renal function (2.3 mg/m2/day on days 1 to 5 in a 21-day cycle). Three studies investigated pharmacokinetics of eribulin mesylate, an intravenous drug derived from a marine sponge that interferes with cellular replication and division, leading to cell death. Dose recommendations were formulated for eribulin in patients with an impaired liver function (1.1 for Child-Pugh A and 0.7 mg/m2 for Child-Pugh B on days 1 and 8 of a 21-day cycle). The results of two other studies with co-administration of ketoconazole and rifampicin, respectively, on eribulin pharmacokinetics indicated that eribulin can be safely co-administrated with these drugs and that drug-drug interactions with other CYP3A4 inhibitors or inducers are not expected. The pharmacokinetic interaction between food and lapatinib, an oral tyrosine kinase inhibitor targeting the Epidermal Growth Factor Receptor 1 and 2 (EGFR and HER2), was also investigated. These observations can be put to use in dosing recommendations for use in clinical practice, which should lead to reduced drug toxicity. The second part of this thesis focused on CTCs. CTCs were detected by multi-marker quantitative polymerase chain reaction (QPCR) in peripheral blood samples from 20% of 82 early-stage breast cancer patients. Presence of CTCs predicted a significantly worse relapse-free survival (multivariate hazard ratio = 5.13 [95% CI: 1.62 – 16.31, P = 0.006]), compared to absence of CTCs. An exploratory study on the detection of CTCs in advanced NSCLC patients and healthy controls resulted in the development of an assay using QPCR to detect the presence of CTCs. Another assay was developed and validated using fluorescence activated cell sorting that enabled CTC detection, measurements of specific proteins in CTCs and their level of activation, CTC morphology and DNA content. Pharmacodynamics of activation of a specific protein (extracellular-signal-regulated kinase; ERK) down-stream of the EGFR signaling transduction cascade, as a marker for EGFR pathway inhibition, was also studied in CTCs of patients who were receiving an anti-cancer drug inhibiting activation of EGFR. This proof-of-principle demonstrated that CTCs can be used for pharmacodynamic analyses which can be applied in early-stage drug development