A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors
Mené sur 15 patients pédiatriques atteints d'une tumeur solide réfractaire aux traitements existants, cet essai de phase I évalue la toxicité et l'activité antitumorale du ridaforolimus, un inhibiteur de mTOR
Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mTOR inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Anti-tumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies. Experimental Design: Eligible children ages 1-18 years with advanced solid tumors were enrolled in a 3+3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics and pharmacodynamics were characterized. Results: Fifteen patients were treated. No dose-limiting toxicity was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grade 3 and 4 adverse events (AEs) were hematologic, including thrombocytopenia and anemia. Non-hematologic AEs were mostly electrolyte disturbances. The observed PK profile of ridaforolimus in children was consistent with that previously demonstrated in adults. PD confirms that the dose range tested has pharmacological/pharmacodynamic activity. 40% of patients achieved stable disease including 4 of 6 with CNS tumors and 2 of 8 with sarcomas. Conclusions: This first-in-pediatrics study demonstrates that the second-generation mTOR inhibitor ridaforolimus is well-tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies.