Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic il ludin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Iroful ven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS) . Irofulven was given as an intravenous infusion over five minutes daily fo r five days. The starting dose was 10 mg/m(2)/day (50 mg/m(2)/course). Cour ses were scheduled to be given every 3-4 weeks according to toxicity and an tileukemic efficacy. Twenty patients {AML: 17 patients; MDS: one patient; A LL: one patient; mixed lineage acute leukemia: one patient} were treated. N ausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulm onary edema were dose limiting toxicities, occurring in two of five patient s treated at 20 mg/m(2)/day and two of three patients treated at 12.5 mg/m( 2)/day. The MTD was defined as 10 mg/m(2)/day for five days. One patient wi th primary resistant AML achieved complete remission. Proposed phase II stu dies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single age nt and in combination regimens, particularly with topoisomerase 1 inhibitor s.