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 C ranged from 1 to 2.7 ng/ml (T 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 increased in non-responders (P < 0.0001), whereas responders maintained higher plasma TSP-1 AUC (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.

All-oral metronomic DEVEC schedule in elderly patients with peripheral T cell lymphoma

“…Furthermore, their concomitant metronomic combination revealed to be highly synergistic in HH cells, suggesting that the interaction between the two drugs could be more effective that the use of single drug schedules. Moreover, these effective concentrations are fully compatible with the drug plasma levels found in patients treated with metronomic 30 mg VNR schedule [17] and with daily 50 mg ETO [18], the same doses adopted by the DEVEC schedule.…”

Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

“…Oral metronomic vinorelbine was also evaluated with serum markers of tumor response and activity. PSA response was 61%, and a decrease in VEGF and TSP-1 was observed in responders [126]. Vinorelbine alone was compared to weekly docetaxel in frail CRPC patients for efficacy, tolerability, toxicity, and compliance.…”

Pharmacodynamic biomarkers in metronomic chemotherapy: multiplex cytokine measurements in gastrointestinal cancer patients

“…Our results suggest that a metronomic chemotherapy regimen involving CTX, UFT, and celecoxib may impact the immune system (as indirectly assessed by cytokine levels) as could be inferred form an increase in the levels in plasma of IL-6 and IL8, but not of other cytokines such as IL-2. The data need to be confirmed in larger patient studies, as well as with additional metronomic regimens, and in different tumor types (e.g., such as in prostate cancer, for which metronomic chemotherapy has been evaluated in a number of phase II clinical trials [10][11][12]33]) to identify statistically significant differences [34] in biomarker levels. The results we present may also be useful for evaluating whether emerging immunotherapies (e.g., targeting CTLA-4 and PD-1, among other targets) can be effectively combined with metronomic chemotherapy, as we have so far reported in a preclinical model of breast cancer.…”

“…not expanded beyond a focus on CTX, and it remains to be elucidated whether (a) other chemotherapeutic drugs exert the same effect when given metronomically and (b) whether low-dose CTX retains its immune stimulating properties when mixed with other drugs in metronomic drug cocktails (as opposed to being given as a monotherapy). This second point is important, since many recent clinical trials of metronomic chemotherapy involve CTX given in combination [5,[8][9][10][11][12][13][14] with other drugs (sometimes as many as 4 more [13]), any of which might impact the mechanisms that have been reported with CTX alone.…”