Patients with vascular anomalies (VA) have a spectrum of diseases that can be broadly classified into vascular tumors and malformations. Complicated vascular anomalies can cause disfigurement, chronic pain, and organ dysfunction with significant morbidity and mortality. Despite the severity of potential complications, there is a lack of uniform guidelines for the treatment and response to treatment of children and young adults with these diseases. There are preclinical and clinical data supporting the essential regulatory function of the phosphatidylinositol-3-kinase/Protein Kinase B /mammalian target of rapamycin (PI 3-kinase/Akt/mTOR) pathway in vascular growth and organization and suggest a therapeutic target for patients with complicated vascular anomalies. The overall goal of this trial is to objectively determine the effectiveness and safety of the mTOR inhibitor rapamycin in the treatment of children and young adults diagnosed with complicated vascular anomalies. The applicant proposes a Phase 2 trial with the diagnostic, therapeutic and response criteria experimentally determined in this study used as a framework for future Phase 3 clinical trials. It is hypothesized that Rapamycin treatment of children and young adults with complicated vascular anomalies will prove to be safe and provide objective disease response resulting in improved clinical status and quality of life. The primary aim is to determine the efficacy of oral rapamycin in children and young adults with complicated vascular anomalies. For this purpose, 60 patients with complicated vascular anomalies who meet criteria for systemic treatment will receive oral rapamycin. Serum drug levels will be monitored with a target range of 10-15 ng/mL. Disease response will be assessed at 3, 6 and 12 months using radiographic, clinical and quality of life measures. In addition, the safety of oral rapamycin in children and young adults with complicated vascular anomalies will be determined. Toxicities will be assessed and recorded at specific intervals throughout therapy. Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) will be used to categorize and grade all toxicities. Safety monitoring and stopping rules will be instituted to ensure that serious treatment-related toxicities are reported and study continuation re-evaluated. The secondary aims are to assess biomarker analysis on serum and tissue from children and young adults with vascular anomalies. Biomarkers will be tested at baseline, 6 months and 12 months on a limited number of subjects.

Public Health Relevance

Vascular anomalies are tumors or malformations both of which can grow or expand and cause significant morbidity, mortality and effect on a patients quality of life. Limited knowledge is known about the biology of these anomalies and because of this there no standard guidelines for treatment or clinical trials. Recent use of Rapamycin in a limited number of patients with vascular anomalies revealed improvement in clinical parameter and quality of life in these patients. (Adams, Dasgupta, Elluru, et al 2008;Dickie, Dasgupta, Elluru, et al 2008).

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (01))
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Needleman, Katherine
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Cincinnati Children's Hospital Medical Center
United States
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Emoto, C; Fukuda, T; Mizuno, T et al. (2016) Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants. CPT Pharmacometrics Syst Pharmacol 5:411-7
Adams, Denise M; Trenor 3rd, Cameron C; Hammill, Adrienne M et al. (2016) Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137:e20153257
Emoto, C; Fukuda, T; Johnson, T N et al. (2015) Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants. CPT Pharmacometrics Syst Pharmacol 4:e17