Phase i study of dovitinib (TKI258), an oral FGFR, VEGFR, and PDGFR inhibitor, in advanced or metastatic renal cell carcinoma

Eric Angevin, Jose A. Lopez-Martin, Chia Chi Lin, Jürgen E. Gschwend, Andrea Harzstark, Daniel Castellano, Jean Charles Soria, Paramita Sen, Julie Chang, Michael Shi, Andrea Kay, Bernard Escudier

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    115 Citations (Scopus)

    Résumé

    Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. Experimental Design: Patients with advanced ormetastatic renal cell carcinoma(RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.

    langue originaleAnglais
    Pages (de - à)1257-1268
    Nombre de pages12
    journalClinical Cancer Research
    Volume19
    Numéro de publication5
    Les DOIs
    étatPublié - 1 mars 2013

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