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

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 Cmax ranged from 1 to 2.7 ng/ml (Tmax 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 AUC0-24day increased in non-responders (P < 0.0001), whereas responders maintained higher plasma TSP-1 AUC0-24day (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.

Investigational new drugs. 2016 Aug 24 [Epub ahead of print]

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

Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy., Oncology Unit 2, University Hospital of Pisa, Pisa, Italy., Department of Veterinary Sciences, University of Pisa, Pisa, Italy., Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy., Oncology Unit, Azienda USL Toscana Nord Ovest, Civil Hospital of Pontedera, Pisa, Italy., Urology Unit, Civil Hospital of Pontedera, Azienda USL Toscana Nord Ovest, Pisa, Italy., Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA., Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy. .