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01-12-2016 | PHASE II STUDIES

Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients

Authors: Teresa Di Desidero, Lisa Derosa, Luca Galli, Paola Orlandi, Andrea Fontana, Anna Fioravanti, Riccardo Marconcini, Mario Giorgi, Beatrice Campi, Alessandro Saba, Sara Lucchesi, Renato Felipetto, Romano Danesi, Giulio Francia, Giacomo Allegrini, Alfredo Falcone, Guido Bocci

Published in: Investigational New Drugs | Issue 6/2016

Summary

The aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92 % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA. Plasma VNR was detected using a LC-MS-MS system. The fraction of patients free of progression, defined by criteria of the Prostate Cancer Clinical Trials Working Group 2, at 3 months was 61 %. PSA decrease ≥50 % from baseline was observed in 35 % of patients. Median PFS and OS were 4 months (95 % CI, 2.8–6.9) and 17.5 months (95 % CI, 10.8–24.5), respectively. Toxicity was mild, and no grade 4 toxicities were found. The mean plasma VNR C_max ranged from 1 to 2.7 ng/ml (T_max 1.1 h) and no evidence of drug accumulation was found. A moderate relationship was found between plasma sB7-H3 and PSA values (r = 0.565; P = 0.0094) at the baseline. Increased PFS (11.3 vs. 2.8 months; P = 0.0298) was observed in patients with sB7-H3 levels <30.25 ng/mL. Plasma VEGF AUC_0-24day increased in non-responders (P < 0.0001), whereas responders maintained higher plasma TSP-1 AUC_0-24day (P = 0.0063). In conclusion, metronomic VNR plus DEX showed favourable activity, and a low toxicity profile, in mCRPC patients. Plasma sB7-H3, VEGF and TSP-1 levels are potential pharmacodynamic markers at the reached low plasma concentrations of vinorelbine metronomically administered.

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Title: Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients
Authors: Teresa Di Desidero
Lisa Derosa
Luca Galli
Paola Orlandi
Andrea Fontana
Anna Fioravanti
Riccardo Marconcini
Mario Giorgi
Beatrice Campi
Alessandro Saba
Sara Lucchesi
Renato Felipetto
Romano Danesi
Giulio Francia
Giacomo Allegrini
Alfredo Falcone
Guido Bocci
Publication date: 01-12-2016
Publisher: Springer US
Published in: Investigational New Drugs / Issue 6/2016
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-016-0385-0

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