INITIAL CLINICAL-TRIAL AND PHARMACOKINETICS OF THYMITAQ(TM) (AG337) BY 10-DAY CONTINUOUS-INFUSION IN PATIENTS WITH ADVANCED SOLID TUMORS

Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq(TM). Method s: The drug was given by 10-day infusion via a portable pump. The star ting dose was 286 mg/m(2) per day with escalation to 572 and 716 mg/m( 2) per day. Thymitaq in plasma was assayed by a validated isocratic re verse-phase HPLC assay with detection at 273 nm. Results: The dose of 716 mg/m(2) per day x 10 was considered too high as none of three pati ents completed a 10-day infusion and two of three developed grade IV m yelotoxicity. At 572 mg/m(2) per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of f our but owing to a high incidence of thrombotic phenomena, no further patients were added. Conclusion: Continuous 10-day infusions of Thymit aq should be limited to low doses until further studies can be done.