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 toxicities of 9- cis- retinoic acid (9 c RA, ALRT1057) administered p.o. tid in pediatric patients with refractory cancer and to study the pharmacokinetics of 9 c RA and determine whether systemic drug exposure changes with chronic dosing. Patients and Methods: Children with refractory cancer (stratified by age, ≤12 and >12 years) were treated with p.o. 9 c RA 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 sampling was performed on days 1 and 29 of the first cycle. Results: Of the 37 patients entered, 18 patients ≤12 years of age and 11 patients >12 years of age were evaluable for toxicity. In patients >12 years of age, dose-limiting headache occurred in 2/2 patients at the 110 mg/m 2 /day dose level; 1/8 patients at 85 mg/m 2 /day developed dose-limiting pseudotumor cerebri. In patients ≤12 years of age, 3/5 patients at the starting dose level of 50 mg/m 2 /day developed dose-limiting pseudotumor cerebri; and 0/6 patients experienced dose-limiting toxicity at 35 mg/m 2 /day. Reversible non-dose-limiting hepatotoxicity was observed in 15 patients across all of the dose levels. There was considerable interpatient variability in 9 c RA plasma concentrations. Peak plasma concentrations of 9 c RA occurred at a median of 1.5 h after a p.o. dose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9 c RA administration, the plasma 9 c RA area under the curve declined by an average of 65% from day 1 values. Conclusions: The dose-limiting toxicity of 9 c RA in pediatric patients was neurotoxicity, primarily pseudotumor cerebri. Younger children tolerate significantly lower doses of 9 c RA than older children. Similar to all- trans- retinoic acid, the pharmacokinetics of 9 c RA demonstrated a wide degree of interpatient variability and decreased over time when administered on a daily basis. The recommended Phase II dose of 9 c RA in patients ≤12 and >12 years of age is 35 and 85 mg/m 2 /day, respectively.