A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer: A Joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group Study

Purpose: To determine the maximum tolerated dose and describe the toxicitie s of 9-cis-retinoic acid (9cRA, ALRT1057) administered p.o. tid in pediatri c patients with refractory cancer and to stud), the pharmacokinetics of 9cR A and determine whether systemic drug exposure changes with chronic dosing. Patients and Methods: Children with refractory cancer (stratified by age, l ess than or equal to 12 and > 12 years) were treated with p.o. 9cRA for 28 consecutive days. The starting dose was 50 mg/m(2)/day divided into 3 doses with planned escalations to 65, 85, and 110 mg/m(2)/day. Pharmacokinetic s ampling was performed on days I and 29 of the first cycle. Results: Of the 37 patients entered, 18 patients less than or equal to 12 y ears of age and I I patients > 12 years of age were evaluable for toxicity. In patients > 12 years of age, dose-limiting headache occurred in 2/2 pati ents at the 110 mg/m2/day dose level; 1/8 patients at 85 mg/m(2)/day develo ped dose-limiting pseudotumor cerebri. In patients less than or equal to 12 years of age, 3/5 patients at the starting dose level of 50 mg/m(2)/day de veloped dose-limiting pseudotumor cerebri; and 0/6 patients experienced dos e-limiting toxicity at 35 mg/m(2)/day. Reversible non-dose-limiting hepatot oxicity was observed in 15 patients across all of the dose levels. There wa s considerable interpatient variability in 9cRA plasma concentrations. Peak plasma concentrations of 9cRA occurred at a median of 1.5 h after a p.o. d ose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9cRA administration, the plasma 9cRA area under the curve declined by an averag e of 65% from day I values. Conclusions: The dose-limiting toxicity of 9cRA in pediatric patients was n eurotoxicity, primarily pseudotumor cerebri. Younger children tolerate sign ificantly lower doses of 9cRA than older children. Similar to all-trans-ret inoic acid, the pharmacokinetics of 9cRA demonstrated a wide degree of inte rpatient variability and decreased over time when administered on a daily b asis. The recommended Phase It dose of 9cRA in patients :less than or equal to2 and > 12 years of age is 35 and 85 mg/m(2)/day, respectively.