A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors

A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors

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 combin...

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Bibliographic Details
Published in:Clinical cancer research Vol. 19; no. 13; pp. 3649 - 3658
Main Authors: GORE, Lia, TRIPPETT, Tanya M, TURNER, Christopher D, HALUSKA, Frank G, NIEDER, Michael, KATZENSTEIN, Howard M, BOKLAN, Jessica, NARENDRAN, Aru, SMITH, Amy, MACY, Margaret E, ROLLA, Katherine, NARASHIMHAN, Narayana, SQUILLACE, Rachel M
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 01-07-2013
Subjects:
Adolescent
Antineoplastic agents
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Child
Child, Preschool
Female
Humans
Male
Medical sciences
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplasms - diagnosis
Neoplasms - drug therapy
Pharmacology. Drug treatments
Sirolimus - adverse effects
Sirolimus - analogs & derivatives
Sirolimus - pharmacokinetics
Sirolimus - therapeutic use
TOR Serine-Threonine Kinases - antagonists & inhibitors
Treatment Outcome
Tumors
Human
Pediatrics
Pharmacokinetic pharmacodynamic relationship
Solid tumor
Treatment resistance
Multicenter study
Patient
Malignant tumor
Child
Cancer
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Summary: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. 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. 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. 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-12-3166