Phase I dose-escalation and pharmacokinetic trial of lapatinib (GW572016), a selective oral dual inhibitor of ErbB-1 and -2 tyrosine kinases, in Japanese patients with solid tumors.
OBJECTIVE
The Phase I dose-escalation study was conducted to evaluate the safety and pharmacokinetics of lapatinib (GW572016), a dual ErbB-1 and -2 inhibitor, in Japanese patients with solid tumors that generally express ErbB-1 and/or overexpress ErbB-2.


METHODS
Patients received oral lapatinib once daily until disease progression or in an event of unacceptable toxicity.


RESULTS
Twenty-four patients received lapatinib at dose levels of 900, 1200, 1600 and 1800 mg/day; six subjects enrolled to each dose level. The majority of drug-related adverse events was mild (Grade 1-2); the most common events were diarrhea (16 of 24; 67%), rash (13 of 24; 54%) and dry skin (8 of 24; 33%). No Grade 4 adverse event was observed. There were four Grade 3 drug-related adverse events in three patients (i.e. two events of diarrhea at 1600 and 1800 mg/day each and gamma-glutamyl transpeptidase increase at 1800 mg/day). The maximum tolerated dose was 1800 mg/day. The pharmacokinetic profile of lapatinib in Japanese patients was comparable to that of western subjects.


CONCLUSIONS
Lapatinib was well tolerated at doses of 900-1600 mg/day in Japanese solid tumor patients. Overall, our findings were similar to those of overseas studies.
Nakagawa
Kazuhiko
K
Kinki University School of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-0014, Japan. nakagawa@med.kindai.ac.jp
Minami
Hironobu
H
Kanezaki
Masayuki
M
Mukaiyama
Akihira
A
Minamide
Yoshiyuki
Y
Uejima
Hisao
H
Kurata
Takayasu
T
Nogami
Toshiji
T
Kawada
Kenji
K
Mukai
Hirofumi
H
Sasaki
Yasutsuna
Y
Fukuoka
Masahiro
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D044466:Asian People; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007564:Japan; D000077341:Lapatinib; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases