A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors.

Abstract

PURPOSE:

Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (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. Antitumor 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 to 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 DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas.

CONCLUSIONS:

This first-in-pediatrics study shows 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.

• Authors: Lia Gore, Tanya M Trippett, Howard M Katzenstein, Jessica Boklan, Aru Narendran, Amy Smith, Margaret E Macy, Katherine Rolla, Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), Narayana Narashimhan, Rachel M Squillace, Christopher D Turner, Frank G Haluska, Michael Nieder
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 13 Pg. 3649-58 (Jul 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23659969 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• ridaforolimus
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adolescent
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Child
• Child, Preschool
• Female
• Humans
• Male
• Neoplasms (diagnosis, drug therapy)
• Sirolimus (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Treatment Outcome