A PHASE-I TRIAL OF VINORELBINE IN COMBINATION WITH MITOXANTRONE IN PATIENTS WITH REFRACTORY SOLID TUMORS

Vinorelbine (Navelbine(R)) is a unique semi-synthetic vinca-alkaloid w ith a favorable safety profile that has demonstrated significant antit umor activity in patients with non-small cell lung cancer, advanced br east cancer, advanced ovarian cancer and Hodgkin's disease. The most c ommon dose-limiting toxicity is neutropenia, while other reported toxi cities are minimal. Mitoxantrone (Novantrone(R)) is an anthracene deri vative that has demonstrated antitumor activity in patients with breas t cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone a lso has a very favorable toxicity profile with significantly less naus ea and vomiting, alopecia, and stomatitis as compared with anthracycli nes. The dose-limiting toxicity for mitoxantrone is leukopenia. The st udy was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantron e for the treatment of patients with refractory solid tumors. Vinorelb ine was administered on days 1 and 8 of the treatment regimen as a sho rt IV infusion. The starting dose was 15 mg/m(2). Mitoxantrone was adm inistered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/ m(2) Seventeen patients with solid malignancies were entered in the st udy. For personal reasons, one patient decided to discontinue the trea tment after day 1 of cycle 1. Therefore, 16 patients were evaluable fo r toxicity. The main toxicity was myelosuppression which was dose-limi ting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m(2) on days 1 and 8 and mitoxantrone 10 mg/m(2) on day 1 without growth factor su pport. These doses can be recommended for phase II study of the regime n as salvage treatment.