Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors.
OBJECTIVE
The maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors.


METHODS
Planned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort.


RESULTS
Thirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean +/- standard deviation terminal half-life was 21.7 +/- 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non-small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively.


CONCLUSIONS
The MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.
Erlichman
Charles
C
Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA. erlichman.charles@mayo.edu
Hidalgo
Manuel
M
Boni
Joseph P
JP
Martins
Patricia
P
Quinn
Susan E
SE
Zacharchuk
Charles
C
Amorusi
Peter
P
Adjei
Alex A
AA
Rowinsky
Eric K
EK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009930:Organic Chemicals / Q000008:administration & dosage / Q000009:adverse effects*
D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009930:Organic Chemicals; D066246:ErbB Receptors; C413879:EKB 569