PHASE-I STUDY OF NKT-01

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative st udy group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily admi nistration for 5 consecutive days. In all, 5 and 33 patients with vari ous malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administr ation study, all patients were evaluable and no clear adverse effect w as observed at doses ranging from 20 to 320 mg/m(2). In the daily-admi nistration study, 28 evaluable patients (16 men and 12 women; median a ge, 55.5 years) were treated with a daily dose of 20-500mg/m(2). Toxic ities such as myelosuppression, mild nausea/vomiting, anorexia, alopec ia, tongue and perioral numbness, and hypotension were observed dose-d ependently during or after the treatment. Grade 2 leukopenia, thromboc ytopenia, and anemia were experienced at a dose of 500 mg/m(2). These usually recovered to normal values by approximately 3 weeks after trea tment. A pharmacokinetic analysis of single administration revealed ra pid plasma clearance, with mean half-lives for the alpha and beta phas es being 28 min and 6.9 h, respectively. Approximately 12% of the infu sed dose was excreted into the urine in unmetabolized form. The pharma cokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment re sponse, a transient but significant reduction in the number of leukemi c cells was observed in one patient with adult T-cell leukemia. In thi s study, perioral numbness, hypotension, and hematological toxicity we re concluded to be dose-limiting, with the maximal acceptable dose bei ng 500 mg/m(2). The recommended dose for a phase II study of NKT-01 ag ainst solid tumors was judged to be 400 mg/m(2) given daily by 3-h inf usion for 5 days, every 3 weeks. In hematological malignancies, howeve r, higher myelosuppressive schedules of administration should be inves tigated.