Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies.
OBJECTIVE
To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity.


METHODS
Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized.


RESULTS
Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL).


CONCLUSIONS
The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.
Hidalgo
M
M
Institute for Drug Development, Cancer Therapy and Research Center, and the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. manuelh@oncology.uthscsa.edu
Siu
L L
LL
Nemunaitis
J
J
Rizzo
J
J
Hammond
L A
LA
Takimoto
C
C
Eckhardt
S G
SG
Tolcher
A
A
Britten
C D
CD
Denis
L
L
Ferrante
K
K
Von Hoff
D D
DD
Silberman
S
S
Rowinsky
E K
EK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000209:etiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D066246:ErbB Receptors