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

Invest New Drugs. 2012 Dec;30(6):2352-63. doi: 10.1007/s10637-011-9789-z. Epub 2012 Jan 17.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Asian Continental Ancestry Group
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Drug Administration Schedule
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Quinazolinones / administration & dosage*
  • Quinazolinones / blood
  • Quinazolinones / pharmacokinetics
  • Tumor Burden / drug effects
  • ras Proteins / genetics

Substances

  • Antineoplastic Agents
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinazolinones
  • dacomitinib
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Associated data

  • ClinicalTrials.gov/NCT00783328