Phase I-II and pharmacokinetic study of a new fotemustine schedule in advanced non-small cell lung cancer

Fotemustine, a new nitrosourea derivative has already demonstrated activity in non-small cell lung cancer (NSCLC). In order to improve its therapeutic index, we designed a protocol in which Fotemustine was delivered with dose escalation on 3 consecutive days as induction therapy followed by a 5-week rest period. Maintenance therapy consisted of 100 mg/m2 once every 3 weeks. Pharmacokinetic data were assessed during this Phase I-II study and reported here.

Nineteen patients with metastatic (17) or locally advanced (2) NSCLC were included in the present study. Ten of those with metastatic disease had brain metastases and 15 had previously received chemotherapy. Fotemustine was given at 50 mg/m2 on day 1-2-3 (group 1: four patients), 75 mg/m2 on day 1-2-3 (group 2: 16 patients including two who had already received 50 mg/m2) and 100 mg/m2 on day 1-2-3 (group 3: one patient).

The maximal tolerated dose was 75 mg/m2 on day 1-2-3 (total cumulated dose 225 mg/m2). At this dose level, we observed 25% of Grade 3-4 neutropenia and 31% of Grade 3-4 thrombocytopenia. One patient died of pulmonary infection during aplasia. No other significant toxicity occurred. Of the 17 evaluable patients, one obtained a PR lasting 6 months in group 2 and 1 PR lasting 3 months in group 3. No significant difference was noted in the AUC between days 1, 2 or 3 in any of the seven patients in whom a pharmacokinetic study of Fotemustine was performed.

Administered on 3 consecutive days, Fotemustine seems to be less effective and more toxic than other schedules tested in NSCLC. Despite the quality of the two responses observed, this protocol has been discontinued and the standard administration on days 1 and 8 remains the schedule of choice in NSCLC.