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Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors

Authors :
Emiko Ohki
Haruyasu Murakami
Keiji Imai
Tateaki Naito
Nozomu Machida
Ana Ruiz-Garcia
Junichiro Watanabe
Yukiko Nakamura
Kentaro Yamazaki
Narikazu Boku
Toshiaki Takahashi
Asuka Tsuya
Nobuyuki Yamamoto
Akira Ono
Source :
Investigational New Drugs
Publication Year :
2012
Publisher :
Springer Science and Business Media LLC, 2012.

Abstract

Summary Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.

Details

ISSN :
15730646, 01676997, and 00299804
Volume :
30
Database :
OpenAIRE
Journal :
Investigational New Drugs
Accession number :
edsair.doi.dedup.....718874b872de49059719b4e75dc7d2aa
Full Text :
https://doi.org/10.1007/s10637-011-9789-z