Phase I and Pharmacokinetic Study of XRP6258 (RPR 116258A), a Novel Taxane, Administered as a 1-Hour Infusion Every 3 Weeks in Patients with Advanced Solid Tumors

Abstract

Purpose:To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1protein, as a 1-hour i.v. infusion every 3 weeks.The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. Experimental Design: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m 2 . Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLTat the first course. Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m 2 dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V ss , 2,034 L/m 2 ). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m 2 . The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

“…To overcome the emergence of taxane resistance (26,27), a new semi-synthetic taxane, cabazitaxel (XRP6258), was tested in preclinical and clinical studies. It has been shown to exert similar efficacy compared with docetaxel against sensitive cell lines and tumor models, in that it was active against tumor cells/models resistant to currently available taxanes and was more potent than docetaxel against multidrug resistance transporter (MDR-1)-expressing tumor cells resistant to taxanes (27,28).…”

Avances en el tratamiento de cáncer de próstata resistente a la castración: énfasis en nuevas terapias hormonales

“…En pacientes con progresión post docetaxel, el uso de cabazitaxel (Taxano de segunda generación) 48 ha demostrado beneficios en sobrevida global y Nuevas terapias en cáncer de próstata -A. Berlin et al respuestas de la enfermedad (radiológicas y bioquímicas). Sin embargo, no existirían mejorías significativas en términos de respuesta analgésica o en el tiempo de progresión sintomática relacionada a metástasis óseas 49 .…”

How to approach castration-resistant prostate cancer?

“…In phase I trials, cabazitaxel at a dose of 25 mg/m 2 was well tolerated; the most frequently reported adverse events were low-grade diarrhea (52%), nausea (40%) and vomiting (16%). The dose-limiting toxicity was grade 4 neutropenia [41].…”