A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days.

BACKGROUND: The epothilones are a novel class of microtubule-stabilizing agents. Ixabepilone (BMS-247550; NSC 710428) is a semisynthetic analog of the natural product epothilone B. The authors conducted a Phase I study by administering ixabepilone to patients as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days.

METHODS: Twenty-six patients were enrolled and received ixabepilone at a starting dose of 8 or 10 mg/m(2) per day for 3 consecutive days.

RESULTS: One hundred and nineteen cycles were administered to 26 patients. The maximum-tolerated dose was 8 mg/m(2) per day of ixabepilone administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days. The dose-limiting toxicity (DLT) was neutropenia. Other nonhematologic Grade 3 toxicities included fatigue (3 cycles), hyponatremia (1 cycle), anorexia (1 cycle), ileus (1 cycle), stomatitis (1 cycle), and emesis (1 cycle). Prolonged disease stabilization was observed in patients with mesothelioma, ovarian carcinoma, and renal cell carcinoma.

CONCLUSIONS: The recommended Phase II dose of ixabepilone on the daily schedule for 3 days was 8-10 mg/m(2) per day. Neutropenia was the DLT. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.