A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.
OBJECTIVE
The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors.


METHODS
Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration.


RESULTS
Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients.


CONCLUSIONS
The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.
Wong
Kwok-K
KK
Dana-Farber Cancer Institute, and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. kwong1@partners.org
Fracasso
Paula M
PM
Bukowski
Ronald M
RM
Lynch
Thomas J
TJ
Munster
Pamela N
PN
Shapiro
Geoffrey I
GI
Jänne
Pasi A
PA
Eder
Joseph P
JP
Naughton
Michael J
MJ
Ellis
Matthew J
MJ
Jones
Suzanne F
SF
Mekhail
Tarek
T
Zacharchuk
Charles
C
Vermette
Jennifer
J
Abbas
Richat
R
Quinn
Susan
S
Powell
Christine
C
Burris
Howard A
HA