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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
- 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.
- Subjects :
- Adult
Male
medicine.drug_class
PF-00299804
Tyrosine kinase inhibitor
Administration, Oral
Antineoplastic Agents
Pharmacology
Models, Biological
Drug Administration Schedule
Tyrosine-kinase inhibitor
Proto-Oncogene Proteins p21(ras)
chemistry.chemical_compound
Phase I
Asian People
Pharmacokinetics
Phase I Studies
Carcinoma, Non-Small-Cell Lung
Neoplasms
Proto-Oncogene Proteins
medicine
Humans
Pharmacology (medical)
Epidermal growth factor receptor
Protein Kinase Inhibitors
Aged
Quinazolinones
biology
business.industry
Middle Aged
medicine.disease
Dacomitinib
Tumor Burden
ErbB Receptors
stomatognathic diseases
Japanese patients
Oncology
Tolerability
chemistry
Toxicity
ras Proteins
biology.protein
Adenocarcinoma
Female
business
Tyrosine kinase
Subjects
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