title: 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.
abstract: 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.
authors.affiliation: Shizuoka Cancer Center, Shizuoka, Japan. t.takahashi@scchr.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Tateaki
authors.initials: T
authors.lastname: Naito
authors.forename: Asuka
authors.initials: A
authors.lastname: Tsuya
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Ono
authors.forename: Nozomu
authors.initials: N
authors.lastname: Machida
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Junichiro
authors.initials: J
authors.lastname: Watanabe
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: Keiji
authors.initials: K
authors.lastname: Imai
authors.forename: Emiko
authors.initials: E
authors.lastname: Ohki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D052999:Quinazolinones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins