PURPOSE: This phase I study was conducted to assess the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor tyrosine kinase inhibitor PKI166 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: PKI166 was first given once daily continuously and in the second part of the study once daily for 2 weeks every 4 weeks to establish the maximum tolerated dose (MTD). Ten additional patients were studied at MTD to acquire additional safety information and characterize the effect of food intake on PKI166 pharmacokinetics. Pharmacokinetics of PKI166 were characterized after single and multiple doses at all dose levels. RESULTS: Fifty-four patients received a total of one hundred sixteen 28-day cycles of PKI166. Dose-limiting transaminase elevations were observed in two of seven and two of eight patients using 50 and 100 mg PKI166 continuously. In the second part with PKI166 once daily for 2 weeks every 4 weeks, MTD was set at 750 mg. Dose-limiting toxicity consisted of diarrhea, skin rash, and transaminase elevations. Pharmacokinetic analysis revealed fast absorption, a linear dose-response relationship without drug accumulation after multiple doses. At MTD, no significant influence of food intake on PKI166 pharmacokinetics was observed. Stable disease for more than two cycles was observed in 11 patients. CONCLUSIONS: PKI166 given once daily for 2 weeks every 4 weeks is well tolerated with linear pharmacokinetics, compatible with once daily dosing, and without significant effect of food intake on absorption. The recommended dose for further studies is 750 mg once daily for 2 weeks every 4 weeks.

Additional Metadata
Keywords Absorption, Adult, Aged, Antineoplastic Agents/pharmacology, Area Under Curve, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Male, Maximum Tolerated Dose, Middle Aged, Models, Chemical, Neoplasms/*drug therapy/*metabolism, Protein-Tyrosine Kinases/metabolism, Pyrimidines/*pharmacokinetics/*therapeutic use, Pyrroles/*pharmacokinetics/*therapeutic use, Receptor, Epidermal Growth Factor/*metabolism, Software, Time Factors, Vascular Endothelial Growth Factor A/metabolism
Persistent URL dx.doi.org/10.1158/1078-0432.CCR-05-0720, hdl.handle.net/1765/13931
Journal Clinical Cancer Research
Hoekstra, R, Dumez, H, Eskens, F.A.L.M, van der Gaast, A, Planting, A.S.Th, de Heus, G, … Verweij, J. (2005). Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. Clinical Cancer Research, 11(19 I), 6908–6915. doi:10.1158/1078-0432.CCR-05-0720