Pearson, ADJ;
Federico, SM;
Aerts, I;
Hargrave, DR;
DuBois, SG;
Iannone, R;
Geschwindt, RD;
... Geoerger, B; + view all
(2016)
A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors.
Oncotarget
, 7
(51)
pp. 84736-84747.
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.
| Type: | Article |
|---|---|
| Title: | A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.18632/oncotarget.12450 |
| Publisher version: | http://doi.org/10.18632/oncotarget.12450 |
| Language: | English |
| Additional information: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
| Keywords: | mTOR, pharmacokinetics, phase I-III trials_pediatric cancers, phase I-III trials_sarcoma/soft-tissue malignancies, ridaforolimus |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1459289 |
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