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 illudin analog with broad in vitroanti-neoplastic activity. In this leukemia phase I study, weinvestigated the toxicity profile and activity of Irofulven inpatients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ormyelodysplastic syndromes (MDS). Irofulven was given as anintravenous infusion over five minutes daily for five days.The starting dose was 10 mg/m2/day (50mg/m2/course). Courses were scheduled to be givenevery 3-4 weeks according to toxicity and antileukemicefficacy. Twenty patients {AML: 17 patients; MDS: onepatient; ALL: one patient; mixed lineage acute leukemia: onepatient} were treated. Nausea, vomiting, hepatic dysfunction,weakness, renal dysfunction, and pulmonary edema were doselimiting toxicities, occurring in two of five patientstreated at 20 mg/m2/day and two of three patientstreated at 12.5 mg/m2/day. The MTD was defined as10 mg/m2/day for five days. One patient withprimary resistant AML achieved complete remission. Proposedphase II studies will further define the activity of Irofulvenin patients with better prognosis AML and in otherhematological malignancies, both as a single agent and incombination regimens, particularly with topoisomerase 1inhibitors.