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

Autor:	Pearson AD; Paediatric Drug Development Unit, Children and Young People's Unit, Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom., Federico SM; Department of Pediatric Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Aerts I; Department of Pediatric, Adolescent and Young Adult Oncology, Institut Curie, Paris, France., Hargrave DR; Haematology and Oncology Department, Great Ormond Street Hospital for Children, London, United Kingdom., DuBois SG; Department of Pediatrics, University of California San Francisco School of Medicine, and Benioff Children's Hospital, San Francisco, CA, USA.; Current affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA., Iannone R; Clinical Research, Merck & Co., Inc., North Wales, PA, USA., Geschwindt RD; Clinical Research, Merck & Co., Inc., North Wales, PA, USA., Wang R; BARDS, MSD R&D (China) Co. Ltd., Beijing, China., Haluska FG; Clinical Research & Development, ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA., Trippett TM; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Geoerger B; Department of Childhood and Adolescent Oncology, Gustave Roussy, University Paris-Sud, Villejuif, France.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Dec 20; Vol. 7 (51), pp. 84736-84747.
DOI:	10.18632/oncotarget.12450
Abstrakt:	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.
Databáze:	MEDLINE
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