title: Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients.
abstract: 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 Cmaxranged from 1 to 2.7 ng/ml (Tmax1.1 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 AUC0-24dayincreased 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.
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Di Desidero
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Derosa
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Galli
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Orlandi
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fioravanti
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Marconcini
authors.affiliation: Department of Veterinary Sciences, University of Pisa, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Giorgi
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Campi
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Saba
authors.affiliation: Oncology Unit, Azienda USL Toscana Nord Ovest, Civil Hospital of Pontedera, Pisa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lucchesi
authors.affiliation: Urology Unit, Civil Hospital of Pontedera, Azienda USL Toscana Nord Ovest, Pisa, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Felipetto
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.affiliation: Oncology Unit, Azienda USL Toscana Nord Ovest, Civil Hospital of Pontedera, Pisa, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Allegrini
authors.affiliation: Oncology Unit 2, University Hospital of Pisa, Pisa, Italy.|Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 55, I-56126, Pisa, Italy. guido.bocci@med.unipi.it.
authors.forename: Guido
authors.initials: G
authors.lastname: Bocci
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D003907:Dexamethasone / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D014018:Tissue Distribution; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D014747:Vinblastine; D003907:Dexamethasone; D000077235:Vinorelbine
keywords: B7-H3; Metronomic chemotherapy; Pharmacodynamic markers; Pharmacokinetics; Prostate cancer; TSP-1; VEGF; Vinorelbine