Phase I study of AG 331, a novel thymidylate synthase inhibitor, in patients with refractory solid tumors

Pra pose: This was a phase I study of AG 331 to determine systemic toleranc e and pharmacokinetics following single and multiple escalating intravenous doses. Methods: The study was an open-label phase I trial that was divided into two components. In phase IA (single dose), six dose levels from 12.5 to 225 mg/m(2) were administered to 18 patients (3 at each dose level) and serial blood samples were collected for 72 h. Upon achieving satisfactory p harmacologic parameters, the multiple dosing component (phase IB) was initi ated. Six dose levels from 50 to 800 mg/m(2) per day were administered for 5 consecutive days to 18 patients. Pre- and postdose blood samples were obt ained on days 1-4 and serial blood samples were collected over 24 h followi ng dose 5. Nonhematologic and hepatic toxicities were assessed, serum AG 33 1 concentrations were measured and pharmacokinetic parameters determined. R esults: Other than fatigue, no severe toxicities were encountered in phase IA. Liver toxicity was manifested by elevations in transaminase first noted at multiple doses of 200 mg/m2 per day for 5 days. Fever and malaise but n o myelosuppression were noted. The mean terminal t(1/2) following single do ses was significantly shorter than the t1/2 following multiple dosing (6.8 vs 9.9 h) and clearance was significantly faster following single doses tha n following multiple dosing (51.7 vs 30.4 1/h), but no significant differen ce in V-d was noted. Conclusions: The dose-related toxicity profile preclud es further clinical development at this time. The pharmacokinetics of AG 33 1 following single and multiple doses showed significant differences.