Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.
OBJECTIVE
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.


METHODS
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.
Hoekstra
Ronald
R
Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. r.hoekstra@zgt.nl
Dumez
Herlinde
H
Eskens
Ferry A L M
FA
van der Gaast
Ate
A
Planting
Andre S T
AS
de Heus
Gerda
G
Sizer
Kurt C
KC
Ravera
Christina
C
Vaidyanathan
Sujata
S
Bucana
Corazon
C
Fidler
Isaiah J
IJ
van Oosterom
Allan T
AT
Verweij
Jaap
J
D000042:Absorption; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012984:Software; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D011743:Pyrimidines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C410026:PKI 166; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases