A clinical and pharmacokinetic phase I study of 1,2,4-triglycidylurazol (TGU, NSC 332488).
Twenty-six patients with advanced malignancies received TGU given as an intravenous (i.v.) bolus in physiological saline at 3 weekly intervals. The starting dose was 30 mg/m2 with standard graded escalations to 900 mg/m2. Myelosuppression occurred at 800 mg/m2, with a mean nadir of 2.0 +/- 0.8 X 10(9)/l and a mean nadir platelet count of 41 +/- 31 X 10(9)/l. At 800 or 900 mg/m2 nausea and vomiting was WHO grade 0 in 5, grade I in 6, grade II in 11 and grade III in 10 courses of therapy. Alopecia did not occur. TGU was given by i.v. infusion at 800 mg/m2 in 2 patients, both of whom developed severe thrombophlebitis. Five patients given TGU by i.v. bolus developed mild phlebitis. No renal, hepatic or cardiac toxicity was noted. Two patients had partial responses; both had adenocarcinoma of unknown primary origin, one of whom had been resistant to prior therapy with FAM. An HPLC analytical method was developed with a sensitivity of 250 ng/ml. The data from 7 patients studied best fit a one compartment pharmacokinetic model with an exponential decay and a t1/2 of only 2.1 min. In conclusion, the dose limiting toxicity of TGU appears to be myelosuppression and we would recommend a dose of 800 mg/m2 given as an intravenous bolus every 4 weeks for future phase II trials.
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014230:Triazoles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014230:Triazoles; C041113:anaxirone