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Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.

AbstractPURPOSE:
BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514.
PATIENTS AND METHODS:
In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD.
RESULTS:
In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways.
CONCLUSION:
This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.
AuthorsJean-Charles Soria, José Baselga, Nasser Hanna, Scott A Laurie, Rastislav Bahleda, Enriqueta Felip, Emiliano Calvo, Jean-Pierre Armand, Frances A Shepherd, Christopher T Harbison, David Berman, Jong-Soon Park, Steven Zhang, Blisse Vakkalagadda, John F Kurland, Ashutosh K Pathak, Roy S Herbst
JournalEuropean journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 8 Pg. 1815-24 (May 2013) ISSN: 1879-0852 [Electronic] England
PMID23490650 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • BMS-690514
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrroles
  • Quinazolines
  • Triazines
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Receptor, ErbB-2
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-3
Topics
  • Administration, Oral
  • Adult
  • Aged
  • Area Under Curve
  • Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
  • Diarrhea (chemically induced)
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm (drug effects)
  • ErbB Receptors (antagonists & inhibitors)
  • Erlotinib Hydrochloride
  • Exanthema (chemically induced)
  • Female
  • Humans
  • Lung Neoplasms (drug therapy, metabolism, pathology)
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasms (drug therapy, metabolism, pathology)
  • Piperidines (adverse effects, pharmacokinetics, therapeutic use)
  • Protein Kinase Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
  • Pyrroles (adverse effects, pharmacokinetics, therapeutic use)
  • Quinazolines (therapeutic use)
  • Receptor, ErbB-2 (antagonists & inhibitors)
  • Treatment Outcome
  • Triazines (adverse effects, pharmacokinetics, therapeutic use)
  • Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors)
  • Vascular Endothelial Growth Factor Receptor-3 (antagonists & inhibitors)

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