Topical Rapamycin/Sirolimus for Complicated Vascular Anomalies and Other Susceptible Lesions

Vascular Anomaly

Proposed Study: Treatment protocol for the use of the topical Rapamycin/Sirolimus for Complicated Vascular Anomalies and other susceptible lesions 1. Aim The aim of this treatment study is to evaluate the benefit and tolerability of topical sirolimus applied to cutaneous vascular anomalies in pediatric patients. The primary end point will be individually determined based on improvement in lesional clinical characteristics over baseline 2. Rationale for topical sirolimus use in VA The rationale for the use of topical sirolimus is to minimize these potential side effects and risks. Data for the use of topical sirolimus for vascular anomalies at this time are anecdotal and case reports only. As such, this prospective protocol seeks to determine the effectiveness and tolerability of topical sirolimus on patients with vascular anomalies that have a cutaneous component. 3. Experimental design This is an open-labeled efficacy trial with the aim to determine if topical sirolimus can be safe and efficacious in treating the cutaneous component of complicated vascular anomalies. Patients who meet eligibility criteria with a diagnosis of vascular anomaly (VA) with cutaneous component will be offered treatment with the investigational topical sirolimus. Patients will receive topical sirolimus therapy for a total of six months and will be monitored regularly at the research site for clinical response. Response will be based on pre-determined clinical criteria. Patients will be removed from study if there is no response at three months after initiation of therapy. Clinical response will be defined as improvement in measurable parameters defined at the time of initiation of therapy. These include 1. Size of lesions, measured in two parallel longest diameters 2. Flattening of lesion 3. Number of vesicles 4. Episodes of superinfection or bleeding 5. Improvement in pain 4. Drug Information The topical sirolimus formulation will be made at a concentration of 1% sirolimus ointment. Bulk sirolimus powder will be compounded in a liposomal base in a GMP level pharmaceutical company. This base will enhance drug penetration into the skin. It ensures adequate adhesion to the application area and a low degree of systemic absorption. Due to limited absorption only mild side effects are expected.

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, we lack uniform guidelines for the treatment and response to treatment of children and young adults with these diseases. Pre-clinical and clinical data supporting the essential regulatory function of the PI3K/Akt/mTOR pathway in vascular growth and organization, and suggest a therapeutic target for patients with complicated vascular anomalies. Nemours Children's Hospital (NCH) and other groups have been successfully using the mTOR inhibitor siroli-mus in a selected group of patients with VA. NCH exclusively uses the systemic oral formulation of sirolimus. The potential toxicities of systemic sirolimus is well documented, and many patients do not tolerate systemic sirolimus. We hypothesize this study will advance our treatment options of vascular anomalies by offering topical sirolimus. This prospective open labeled study will allow us to determine the efficacy and tolerability of topical sirolimus in the treatment of complicated vascular anomalies. This will potentially generate data for the use of topical sirolimus as an alternative to systemic sirolimus for patients with complicated VA with a cutaneous component.

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