Background: Deregulation of the PI3K/AKT/mTOR signaling pathway occurs in many poor prognosis childhood malignancies and inhibition of this pathway is a promising novel therapeutic strategy. Ridaforolimus (MK-8669) is a highly selective orally bioavailable small molecule inhibitor of mTOR. This multi-centre, phase I dose escalation study of orally administered Ridaforolimus was designed to evaluate the maximum tolerated dose (MTD), safety profile, pharmacokinetic profile (PK), antitumor activity and pharmacodynamic (PD) biomarkers (phosphorylated Akt [pAkt] in platelet-rich plasma). Methods: Patients (pts) from 6 to <18 years (yrs) with advanced solid tumors were enrolled. Dose escalation was by a modified Toxicity Probability Intervals method (mTPI, Ji Y, et al. Clin Trials 2007) targeting a 30% dose limiting toxicity (DLT) ratio. Pts received 28 day cycles of Ridaforolimus (MK-8669), orally, five days out of seven. Dosing started at 22 mg/m², escalated to 28 and 33 mg/m², with an expansion cohort treated at the maximum administered dose. Results: 19 pts, age 8-17 (median 13.5 years), were enrolled and 18 treated from 6 international sites. Diagnoses included ependymoma (5), osteosarcoma (3), Ewings sarcoma (3) and other histologies (7). Four pts received dose level (DL) 1; 3 DL 2 and 11 DL 3. Pts received between 1-12+ courses. There was only one DLT (DL 2: grade 3 elevated alanine transaminase [ALT]) and no other grade 3-4 treatment-related toxicities. Preliminary analysis shows the most frequent drug-related adverse events were manageable grade 1-2 stomatitis (70.6%) and fatigue (52%). Dose escalation stopped at DL3 (33 mg/m2, 150% of the adult recommended phase 2 dose [RP2D]). There were no objective responses by RECIST1.1. Two pts remain on study, with continuing stable disease (pineoblastoma [12 courses], diffuse intrinsic pontine glioma [6 courses]). PK and PD analyses will be presented. Conclusions: Ridaforolimus is a safe and well tolerated, orally bioavailable mTOR inhibitor. The RP2D for Ridaforolimus in children is 33 mg/m². Prolonged disease stabilization was observed in two patients. PK/PD data will provide further data to support the RP2D. Further combination studies are warranted. Clinical trial information: NCT01431547.