Single dose of
DA-125, 20 (n = 3), 40 (n = 3), 60 (n = 3), 80 (n = 6), or 100 (n = 6) mg/m2 body surface area, was administered intravenously in 5 min to 21 patients with various types of
cancer as phase I clinical trial. The main side-effects of
DA-125 were
nausea,
vomiting,
leukopenia (especially
neutropenia), and
thrombocytopenia. Among those, hematological side-effects increased with increased doses of
DA-125. No patient developed side-effects equal to or higher than grade III up to
DA-125 dose of 60 mg/m2. However, at
DA-125 dose of 80 mg/m2, 1 out of 3 patients developed grade III
leukopenia and grade IV
neutropenia. Therefore, 3 additional patients participated taking the dose of 80 mg/m2; no patient developed side-effects equal to or higher than grade III. Hence,
DA-125 dose increased to 100 mg/m2. At
DA-125 dose of 100 mg/m2, 2 out of 3 patients developed side-effects equal to or higher than grade III and, therefore, 3 additional patients participated taking this dose. Among the 3 additional patients, 1 patient developed both grade III
leukopenia and
neutropenia. Therefore, further accrual was stopped at this dose (100 mg/m2). The maximally tolerated dose (MTD) of
DA-125 was determined to be 100 mg/m2, and the dose-limiting factor for
DA-125 was bone marrow suppression.
DA-125 dose of 80 mg/m2, 80% of MTD of
DA-125, was recommended as the dose for phase II clinical trial.
Cardiotoxicity was not observed in any of the 21 patients according to the ECG and RVG. Neither
fever,
stomatitis,
diarrhea, and renal and nervous system toxicity, nor abnormality in blood coagulation was observed in any of the patients, and death or life-threatening side-effects due to
DA-125 were also not observed. Antitumor effects of
DA-125 were evaluated from the 21 patients; 6 progressive disease, 14 stable disease, and 1 partial response. Pharmacokinetic parameters of M1, such as AUC, t1/2, CL, VSS, and MRT, seemed to be independent of i.v. doses of
DA- 125, 20-100 mg/m2 and less than 0.75% of M1 were excreted in 96 h urine when expressed in terms of
DA-125 i.v. dose. M2 was the main metabolite of
DA-125 among M1-M4 excreted in urine; 10.1 approximately 22.3% of M2 was excreted in 96 h urine when expressed in terms of
DA-125 i.v. dose. Bile was collected via the T-tube in 1 additional patient at the dose of 100 mg/m2. Biliary excretion of M1 and M2 was negligible; less than 0.320 and 4.76% of M1 and M2, respectively, were excreted in 96 h bile when expressed in terms of
DA-125 i.v. dose.