PHASE-I AND PHARMACOKINETIC TRIAL OF PACLITAXEL IN PATIENTS WITH HEPATIC-DYSFUNCTION - CANCER AND LEUKEMIA GROUP-B-9264

Purpose: To characterize the maximum-tolerated dose, dose-limiting tox icities (DLTs), and pharmacokinetics of paclitaxel in patients with ab normal liver function. Patients and Methods: Adults with tumors approp riate for paclitaxel therapy who herd abnormal liver function tests we re eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL, Doses were explored in at least three patients within each cohere, Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinet ics were to be studied in all patients. Results: Eighty-one patients w ere assessable for toxicity, Patients with bilirubin levels greater th an 1.5 mg/dL had substantial toxicity at all doses explored, whereas t he toxicity for patients with elevated AST levels occurred at doses th at ranged from 50 to 175 mg/m(2) administered over 24 hours. In most p atients, the DLT was myelosuppression. The pharmacokinetic data were i nsufficient to adequately evaluate the relationship between pharmacoki netics and toxicity in patients who received 24-hour infusions but pro vided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. Conclusion : If paclitaxel is used for patients with elevated levels of AST or bi lirubin, dose reductions are necessary, and an increase in toxicity ca n be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patie nts. (C) 1998 by American Society of Clinical Oncology.