PHASE-I TRIAL AND PHARMACOKINETIC STUDY OF ALL-TRANS-RETINOIC ACID ADMINISTERED ON AN INTERMITTENT SCHEDULE IN COMBINATION WITH INTERFERON-ALPHA-2A IN PEDIATRIC-PATIENTS WITH REFRACTORY CANCER

Purpose: Po determine the maximum-tolerated dose (MTD) of all-trans-re tinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha 2a (IFN-alpha 2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observ ed with chronic daily oral dosing could be circum vented with an inter mittent dosing schedule. Patients and Methods: Thirty-three children w ith refractory cancer (stratified by age, less than or equal to 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IF N-alpha 2a 3 x 10(6) U/m(2) 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m(2)/d divided into three doses, with planned escalations to 90 and a 120 mg/m(2)/d. Because se vere headaches have been noted to occur on the initial day of ATRA adm inistration, only two of three doses of ATRA were administered on day 1 of each week. Results: Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at t he a 120-mg/m(2)/d dose: level and in one of six less than or equal to 12 years at the 90-mg/m(2)/d level, Other non-dose-limiting toxicitie s of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child wit h recurrent neuroblastoma had an objective response of 6 months' durat ion, and one with recurrent Wilms' turner had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to r elatively high plasma concentrations oi: ATRA on a repetitive basis, f ollowing 30-mg/m(2) doses, the ATRA area under the concentration-time curve (AUG) decreased from 96+/-14 mu mol/L/min on day a to 26+/-24 mu mol/L/min by day 3 of drug administration, but on day if of the fourt h consecutive week of therapy, the AUC averaged 110+/-16 mu mol/L/min. The recommended pediatric phase (a dose of ATRA administered an this schedule is 90 mg/m(2)/d, Conclusion: An intermittent schedule of ATRA administration appears 40 circumvent the low plasma drug exposure tha t is a result of the sustained upregulation of metabolism when this dr ug is administered an a chronic daily schedule. Based an the results o f this trial, a phase II trial of ATRA/IFN-alpha 2a in neuroblastoma a nd Wilms' tumor using this schedule is in progress.