期刊
ONCOTARGET
卷 7, 期 51, 页码 84736-84747出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12450
关键词
phase I-III trials_ pediatric cancers; phase I-III trials_ sarcoma/soft-tissue malignancies; ridaforolimus; mTOR; pharmacokinetics
资金
- Great Ormond Street Hospital Childrens Charity [W1075F] Funding Source: researchfish
- The Brain Tumour Charity [16/193] Funding Source: researchfish
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/m(2) and increased to 28 mg/m(2) and 33 mg/m(2), 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/m(2). Dose escalation concluded at 33 mg/m(2); the maximum tolerated dose was not determined. The most common treatmentrelated 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/m(2) exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m(2). 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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