Research Papers:

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

Andrew D.J. Pearson _, Sara M. Federico, Isabelle Aerts, Darren R. Hargrave, Steven G. DuBois, Robert Iannone, Ryan D. Geschwindt, Ruixue Wang, Frank G. Haluska, Tanya M. Trippett and Birgit Geoerger

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Oncotarget. 2016; 7:84736-84747. https://doi.org/10.18632/oncotarget.12450

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Andrew D.J. Pearson1, Sara M. Federico2, Isabelle Aerts3, Darren R. Hargrave4, Steven G. DuBois5, Robert Iannone6, Ryan D. Geschwindt6, Ruixue Wang7, Frank G. Haluska8, Tanya M. Trippett9, Birgit Geoerger10

1Paediatric Drug Development Unit, Children and Young People’s Unit, Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom (Retired)

2Department of Pediatric Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

3Department of Pediatric, Adolescent and Young Adult Oncology, Institut Curie, Paris, France

4Haematology and Oncology Department, Great Ormond Street Hospital for Children, London, United Kingdom

5Department 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)

6Clinical Research, Merck & Co., Inc., North Wales, PA, USA

7BARDS, MSD R&D (China) Co. Ltd., Beijing, China

8Clinical Research & Development, ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA

9Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

10Department of Childhood and Adolescent Oncology, Gustave Roussy, University Paris-Sud, Villejuif, France

Correspondence to:

Andrew D.J. Pearson, email: [email protected]

Keywords: phase I-III trials_pediatric cancers, phase I-III trials_sarcoma/soft-tissue malignancies, ridaforolimus, mTOR, pharmacokinetics

Received: June 30, 2016    Accepted: September 16, 2016    Published: October 04, 2016


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.

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