A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors

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A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors

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Title: A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors
Author: Pearson, Andrew D.J.; Federico, Sara M.; Aerts, Isabelle; Hargrave, Darren R.; DuBois, Steven G.; Iannone, Robert; Geschwindt, Ryan D.; Wang, Ruixue; Haluska, Frank G.; Trippett, Tanya M.; Geoerger, Birgit

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Citation: Pearson, A. D., S. M. Federico, I. Aerts, D. R. Hargrave, S. G. DuBois, R. Iannone, R. D. Geschwindt, et al. 2016. “A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors.” Oncotarget 7 (51): 84736-84747. doi:10.18632/oncotarget.12450. http://dx.doi.org/10.18632/oncotarget.12450.
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Abstract: Purpose Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors. Experimental Design In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D. Results: Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1–2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively. Conclusions: Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.
Published Version: doi:10.18632/oncotarget.12450
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356695/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630610
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