A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-na < ve patients with stage IIIB or stage IV non-small cell lung cancer

This primary objective of this phase I dose-escalation study was to define the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of larotaxel administered in combination with carboplatin in chemotherapy-na < ve patients with advanced/metastatic non-small cell lung cancer (NSCLC). Eighteen patients with stage IIIB or IV NSCLC, in cohorts of three to six evaluable patients, were to receive every 3 weeks: larotaxel beginning at 45 mg/m(2) administered as a 1-h infusion, followed after 30 min by carboplatin (area under the concentration-time curve (AUC) = 6 mg/mL x min, later AUC = 5) as a 1-h infusion. Dose escalation of larotaxel up to 90 mg/m(2) was permitted according to DLT occurrence. Patients received ondansetron as prophylactic anti-emetic premedication. In view of the toxicity encountered, the carboplatin dose was decreased for the later part of the study to AUC = 5 mg/mL x min. Eight of 18 treated patients experienced DLTs in the first cycle, including neutropenia and associated complications, diarrhea and fatigue. The MTD of the combination was defined as larotaxel 60 mg/m(2) with a carboplatin AUC of 6 mg/mL x min. Neutropenia, reported at grade 3/4 in 15/18 patients (83%), was the most common severe adverse event, reaching grade 4 in 14 patients (78%). Eleven patients (61%) experienced grade 3/4 non-hematological toxicity, predominantly dehydration, fatigue, infection, nausea and vomiting. One patient (6%) achieved a partial response and 11 (61%) had stable disease. The combination of larotaxel and carboplatin is feasible and shows modest activity in chemotherapy-na < ve patients with advanced/metastatic NSCLC. The principal toxicity was grade 3/4 neutropenia.