Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel

Sessa, Cristiana; Tosi, Diego; Viganò, Lucia; Albanell, Joan; Hess, Dagmar; Maur, M; Cresta, Stefania; Locatelli, Alberta; Angst, R.; Rojo, Federico; Coceani, N.; Rivera, Victor M.; Berk, Lori; Haluska, Frank G.; Gianni, Luca

doi:10.1093/annonc/mdp504

Cited by 51 publications

(22 citation statements)

References 20 publications

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“…However, since strong inhibition was observed in all patients, including the four patients administered the lowest doses studied, no association between the dose of ridaforolimus and the pharmacodynamic effect in PBMCs could be discerned. It is important to note that this robust assay, the development of which we describe here, was subsequently used to examine the pharmacodynamic activity of ridaforolimus in PBMCs in other phase 1 trials with results obtained that were generally similar to those reported here [21][22][23].…”

Section: Discussionsupporting

confidence: 62%

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

Berk

Mita

Kreisberg

et al. 2012

Cancer Chemother Pharmacol

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Section: Discussionsupporting

confidence: 62%

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

Berk

Mita

Kreisberg

et al. 2012

Cancer Chemother Pharmacol

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“…Preclinical studies have shown additive or synergistic activity when ridaforolimus is combined with a variety of other anticancer agents (14,15). The feasibility of administering ridaforolimus in combination with cytotoxic agents has already been showed in adults with advanced malignancies (35,36). An ongoing study of oral ridaforolimus in combination with dalotuzumab in children with refractory solid tumors will help inform dosing in combination and tolerance to different doses of the oral formulation of ridaforolimus.…”

Section: Discussionmentioning

confidence: 99%

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

Gore

Trippett

Katzenstein

et al. 2013

Clinical Cancer Research

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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 þ 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.

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“…The starting dose of ridaforolimus was 12.5 mg, which was selected based on its safety and tolerability in phase 1 studies conducted in patients with advanced malignancies [22,23]. Dose escalation was to be performed in 20% increments (i.e., 15,18,20,22, and 26 mg) until the MTD was identiWed.…”

Section: Methodsmentioning

confidence: 99%

Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose trial

Reardon

Wen

Yung

et al. 2011

Cancer Chemother Pharmacol

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Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel

Abstract: Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.

Cited by 51 publications

References 20 publications

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial

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

Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose trial

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