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

Abstract

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 or metastatic 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 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 5 Pg. 1257-68 (Mar 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23339124 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
• Benzimidazoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinolones
• Niacinamide
• Sorafenib
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• Receptor, Platelet-Derived Growth Factor beta
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Adenocarcinoma (drug therapy, mortality, secondary)
• Adult
• Aged
• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Benzimidazoles (pharmacokinetics, therapeutic use)
• Carcinoma, Renal Cell (drug therapy, mortality, secondary)
• Drug Evaluation, Preclinical
• Female
• Follow-Up Studies
• Humans
• Kidney Neoplasms (drug therapy, mortality, pathology)
• Male
• Maximum Tolerated Dose
• Mice
• Mice, Nude
• Middle Aged
• Neoplasm Staging
• Niacinamide (analogs & derivatives, therapeutic use)
• Phenylurea Compounds (therapeutic use)
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Quinolones (pharmacokinetics, therapeutic use)
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, metabolism)
• Sorafenib
• Survival Rate
• Tissue Distribution
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, metabolism)