Background: DA-125 {(7-0-12.6-dioxy-2-fluoro-2-L-talopyranosyl)- adriamycinone-14-b-alaninate HC1}, is a novel water soluble derivative of fluorinated doxorubicin. Our previous studies showed that DA-125 is more stable and effective than doxorubicin, especially to doxorubicin resistant tumor cell lines in vitro and in vivo. We initiated phase I clinical trial to evaluate the toxicities and the pharmacokinetics of DA-l25 in advanced cancer patients. Method: Advanced cancer patients who were refractory to the standard treatment with normal hepatic and renal functions were eligible after informed consent. Drug was administered intravenously for 5 minutes with initial starting dose of 20 mg/§³(10% of murine LD10). For each dose level, 3 patients were enrolled and the next increased dose was administered if there were no toxicities greater than WHO grade III. Blood, urine and bile (if possible) were collected for the pharmacokinetic evaluation. Result: Twenty three patients were enrolled with 22 evaluable patients (3 at 20 mg/§³, 3 at 40 mg/§³, 3 at 60 mg/§³, 6 at 80 mg/§³ and 7 at 100 mg/§³ of DA-125). All treated patients did not suffer from life-threatening side effects. Hematologic alterations especially neutropenia were major toxicities. Up to 60 mg/§³ dose, toxicities greater than WHO grade II were not observed. At 80 mg/§³ dose, one heavily pretreated patient developed grade III neutropenia. At 100 mg/§³ dose, one patient developed grade IV thrombocytopenia without evidence of clinical bleeding and 2 patients showed grade III neutropenia Grade I and II nausea and vomiting were observed at 80 mg/§³ and 100 mg/§³ dose level. Cardiac toxicities did not occur in any patient. DA-125 was rapidly hydralized to Ml(active metabolite), after IV administration. The plasma half life of M1 was 1.1~2.6 hours and that of M2 was 7.8~9.4 hours. The AUC of both metabolites were dose dependent(Ml: 0.154~0.638ug.hr/ml, M2: 0.684~3.07 ug.hr;ml). Urinary excretion of Ml wss less than 1% of administered dose until 96 hours and that of M2 was 10~22%. In one patient with periampullary cancer, 52.3% of the metabolites were excreted through bile. Conclusion: The results of the present study demonstrated that DA-125 was well tolerable to the advanced cancer patients and 100 mg/§³ was considered as maximally tolerated dose. We are planning the phase II trial on the basis of these results.
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