Phase I clinical trial with ametantrone (NSC-287513)

Ametantrone is a new aminoanthraquinone derivative that achieves antitumor activity in a large variety of animal models. It is a dark blue dye. In this phase I study, the drug was given as a 30-min i.v. infusion repeated every 2–3 weeks. Nineteen patients were entered into the trial and received a total of 43 courses. All were adult patients with advanced solid tumors, mainly squamous cell carcinoma of the head and neck and nonsmall cell carcinoma of the lung. Sixteen had undergone prior chemotherapy; only one had not been previously treated. The trial was initiated at a starting dose of 10 g/m² and dose levels were escalated up to 180 mg/m². Leukopenia was dose-related, well predictable, rapidly reversible and dose-limiting. At 135 mg/m², the median WBC nadir was 1800/mm³ (1000–4400) and the median PMN was 950/mm³ (460–2240). Among all courses, WBC nadir occurred on median day 12 (8–18) and recovery was seen on medianday 16 (10–29). Thrombocytopenia (< 100,000/mm³) was encountered in two courses. There was no evidence of cumulative myelosuppression with repeated courses. Non-hematological toxic effects were negligible and included stomatitis in one course, minor alopecia in three patients, and questionably drug-related orthostatic hypotension in three patients. Reversible blue skin discoloration was seen in five patients. All patients treated with ≧ 40 mg/m² had dark blue urine for 2 or 3 days. Antitumor activity with response 50% could not be documented. Ametantrone appears to be very well tolerated and easy to handle. Its clinical anticancer potential remains to be determined. A dose-schedule of 135 mg/m² q 2–3 weeks may be recommended for phase II studies in solid tumors.