Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors

Clin Cancer Res. 2011 Mar 1;17(5):1131-9. doi: 10.1158/1078-0432.CCR-10-1220. Epub 2011 Jan 10.


Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.

Experimental design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.

Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.

Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.

Trial registration: NCT00225121.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Biomarkers, Tumor
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • ErbB Receptors / antagonists & inhibitors*
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Genotype
  • Heptanoic Acids / administration & dosage*
  • Heptanoic Acids / adverse effects
  • Heptanoic Acids / pharmacokinetics
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacokinetics
  • Quinazolines / therapeutic use
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-4
  • Signal Transduction
  • Treatment Outcome


  • 7-(2-(4-fluorophenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)-2H-pyrazol-3-yl)-3,5-dihydroxyheptanoic acid
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Heptanoic Acids
  • Pyrazoles
  • Quinazolines
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ERBB2 protein, human
  • ERBB4 protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Receptor, ErbB-4
  • Gefitinib

Associated data