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

Jean 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

Research output: Contribution to journalArticle

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Abstract

Purpose: 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 200 mg 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 (≥4 months) 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 200 mg/d, including those with EGFR mutations conferring resistance to erlotinib.

Original languageEnglish
Pages (from-to)1815-1824
Number of pages10
JournalEuropean Journal of Cancer
Volume49
Issue number8
DOIs
StatePublished - May 2013

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Vascular Endothelial Growth Factor Receptor-1
Protein-Tyrosine Kinases
Maximum Tolerated Dose
Neoplasms
Non-Small Cell Lung Carcinoma
Exanthema
Diarrhea
Safety
Mutation
Vascular Endothelial Growth Factor Receptor
BMS-690514
3-tyrosine
Epidermal Growth Factor Receptor
Oral Administration
Pharmacokinetics
Biomarkers
Growth
Pharmaceutical Preparations

Keywords

  • Pan-HER/VEGFR inhibitor
  • Phase I-II
  • Solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Soria, Jean Charles; Baselga, José; Hanna, Nasser; Laurie, Scott A.; Bahleda, Rastislav; Felip, Enriqueta; Calvo, Emiliano; Armand, Jean Pierre; Shepherd, Frances A.; Harbison, Christopher T.; Berman, David; Park, Jong Soon; Zhang, Steven; Vakkalagadda, Blisse; Kurland, John F.; Pathak, Ashutosh K.; Herbst, Roy S.

In: European Journal of Cancer, Vol. 49, No. 8, 05.2013, p. 1815-1824.

Research output: Contribution to journalArticle

Soria, JC, Baselga, J, Hanna, N, Laurie, SA, Bahleda, R, Felip, E, Calvo, E, Armand, JP, Shepherd, FA, Harbison, CT, Berman, D, Park, JS, Zhang, S, Vakkalagadda, B, Kurland, JF, Pathak, AK & Herbst, RS 2013, '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', European Journal of Cancer, vol. 49, no. 8, pp. 1815-1824. https://doi.org/10.1016/j.ejca.2013.02.012
Soria, Jean Charles ; Baselga, José ; Hanna, Nasser ; Laurie, Scott A. ; Bahleda, Rastislav ; Felip, Enriqueta ; Calvo, Emiliano ; Armand, Jean Pierre ; Shepherd, Frances A. ; Harbison, Christopher T. ; Berman, David ; Park, Jong Soon ; Zhang, Steven ; Vakkalagadda, Blisse ; Kurland, John F. ; Pathak, Ashutosh K. ; Herbst, Roy S. / 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. In: European Journal of Cancer. 2013 ; Vol. 49, No. 8. pp. 1815-1824.
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abstract = "Purpose: 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-na{\"i}ve (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 200 mg 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 (≥4 months) 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 200 mg/d, including those with EGFR mutations conferring resistance to erlotinib.",
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T1 - 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

AU - Soria, Jean Charles

AU - Baselga, José

AU - Hanna, Nasser

AU - Laurie, Scott A.

AU - Bahleda, Rastislav

AU - Felip, Enriqueta

AU - Calvo, Emiliano

AU - Armand, Jean Pierre

AU - Shepherd, Frances A.

AU - Harbison, Christopher T.

AU - Berman, David

AU - Park, Jong Soon

AU - Zhang, Steven

AU - Vakkalagadda, Blisse

AU - Kurland, John F.

AU - Pathak, Ashutosh K.

AU - Herbst, Roy S.

PY - 2013/5

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N2 - Purpose: 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 200 mg 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 (≥4 months) 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 200 mg/d, including those with EGFR mutations conferring resistance to erlotinib.

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