Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors
| Autor: | Massimo Zucchetti, F. Debraud, Maurizio D'Incalci, Andrew R. Allen, Josep Tabernero, B. Adamo, Ratislav Bahleda, Renata Robert, Angelo Delmonte, M. G. Camboni, Jean-Charles Soria, R. Dientsmann, Fabrice Andre, Jeffrey D. Isaacson, C. Saba, Jason B. Litten, Roberta Cereda, F. Dubois |
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| Rok vydání: | 2014 |
| Předmět: |
Oncology
Adult medicine.medical_specialty Drug-Related Side Effects and Adverse Reactions Pharmacology Naphthalenes Disease-Free Survival chemistry.chemical_compound Growth factor receptor Internal medicine Neoplasms medicine Humans Receptors Platelet-Derived Growth Factor Progression-free survival Receptor Fibroblast Growth Factor Type 1 Receptor Fibroblast Growth Factor Type 2 Lung cancer Protein Kinase Inhibitors Aged Vascular Endothelial Growth Factor Receptor-1 Dose-Response Relationship Drug Neovascularization Pathologic business.industry Fibroblast growth factor receptor 1 Hematology Middle Aged medicine.disease Vascular endothelial growth factor Vascular endothelial growth factor A chemistry Response Evaluation Criteria in Solid Tumors Pharmacodynamics Quinolines Female business |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 25(11) |
| ISSN: | 1569-8041 |
| Popis: | Background Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. Methods This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). Results Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31–40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. Conclusion Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned. |
| Databáze: | OpenAIRE |
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