Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previouslyuntreated patients 60 years of age or older with acute myeloid leukemia: Results of cancer and leukemia group B study 9420

Purpose: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P ), a modulator of p-glycoprotein-mediated multidrug resistance, Patients and Methods: One hundred ten newly diagnosed patients greater than or equal to 60 years of age with de navo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 day s at 100 mg/m(2)/d. The starting dose of daunorubicin was 30 mg/m(2)/d for 3 days. Etoposide was administered at a dose of 100 mg/m2/d for 3 days, exc ept in the last cohort administered ADEP, who received 60 mg/m(2). PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours af ter the last dose of daunorubicin or etoposide, Results: There was no toxicity attributed to the PSC-833, Dose-limiting tox icity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group ). The estimated maximum-tolerated doses, calculated using a logistic regre ssion model, were daunorubicin 40 mg/m2/d for 3 days with etoposide 60 mg/m (2) for 3 days in the ADEP group and daunorubicin 60 mg/m(2)/d for 3 days a nd etoposide 100 mg/m(2)/d for 3 days in the ADE group, Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) o f 66 patients treated with ADEP. Conclusion: It is necessary to decrease the doses of daunorubicin and etopo side when they are administered with PSC-833, presumably because of the eff ect of the modulator on the pharmacokinetics of these agents. A phase III t rial comparing the regimens derived from this phase I trial has recently be gun. (C) 1999 by American Society of Clinical Oncology.