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Phase I and pharmacologic study of PKI166, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients
Ronald Hoekstra1, Herlinde Dumez, Ferry A L M Eskens
1Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. r.hoekstra@zgt.nl
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.
Insights
The oral tyrosine kinase inhibitor PKI166 shows good tolerability and linear pharmacokinetics in patients with advanced solid tumors. A recommended dose of 750 mg, administered for 2 weeks every 4 weeks, is established for further research.
Area of Science:
- Oncology
- Pharmacology
Background:
- Advanced solid malignancies represent a significant therapeutic challenge.
- Targeted therapies, such as tyrosine kinase inhibitors, offer a promising approach.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and antitumor effects of PKI166, an oral selective epidermal growth factor receptor tyrosine kinase inhibitor.
- To determine the maximum tolerated dose (MTD) of PKI166 in patients with advanced solid tumors.
Main Methods:
- Phase I clinical trial with two dosing schedules: continuous daily and intermittent (2 weeks on, 2 weeks off).
- Pharmacokinetic analysis of PKI166 after single and multiple doses.
- Assessment of dose-limiting toxicities and antitumor activity.
Main Results:
- Fifty-four patients received PKI166, with MTD established at 750 mg in the intermittent dosing arm.
- Dose-limiting toxicities included diarrhea, skin rash, and transaminase elevations.
- PKI166 demonstrated linear pharmacokinetics, rapid absorption, and no significant food effect at MTD. Stable disease was observed in 11 patients.
Conclusions:
- The intermittent dosing schedule of PKI166 (750 mg once daily for 2 weeks every 4 weeks) is well-tolerated.
- PKI166 exhibits predictable pharmacokinetics suitable for once-daily administration.
- The recommended dose for future clinical trials is 750 mg using the intermittent schedule.
