Phase I study of larotaxel administered as a 1-h intravenous infusion every 3 weeks to Japanese patients with advanced solid tumours

Larotaxel (XRP9881, RPR109881), a novel semi-synthetic taxoid that shares a mode of action with the taxanes docetaxel and paclitaxel, was active in preclinical studies against a broad spectrum of tumour cells and tumour models refractory/resistant to taxanes, and have demonstrated clinical activity in taxane pre-treated/resistant metastatic breast cancer (MBC) patients. The current phase I dose-escalation study sought to define in Japanese patients with advanced solid tumours the maximum tolerated dose (MTD) and recommended dose (RD) of larotaxel administered as a 1-h intravenous infusion every 3 weeks. Eighteen patients were treated in total with 11 of those (61%) having previously received a docetaxel- or paclitaxel-based regimen. The MTD was defined as 90 mg/m(2) following the occurrence of dose-limiting toxicities (DLTs) in two of five patients treated at this dose level including grade 4 neutropenia lasting > 7 days or febrile neutropenia. The RD for phase II was consequently 75 mg/m(2) q3w, with no DLTs in the six patients treated. The principal toxicity and DLT was neutropenia, with or without neutropenic complications. Partial responses were reported for 2 of 18 (11%) treated patients and a further 8 achieved stable disease (44%). The clearance 19.1-31.9 L/h was similar to that observed in Caucasian subjects with value of 33.0 +/- A 10.7 L/h. In conclusion, larotaxel 75 mg/m(2), administered as a 1-h infusion every 3 weeks, appeared to be clinically tolerable in this Japanese patient population and showed early indications of activity.