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

Treatment Protocol for the Use of the Topical Rapamycin/Sirolimus for Complicated Vascular Anomalies and Other Susceptible Lesions

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.

Study Overview

• Status: Terminated
• Conditions: Vascular Anomaly
• Intervention / Treatment: Drug: Topical Sirolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Health, Jacksonville
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital, Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients will be more than 36 months and less than 21 years of age.
• Newly diagnosed with vascular anomalies (VA) or have a VA that failed therapy with systemic sirolimus or other systemic or surgical therapies.
• Patients who have undergone surgical resection or interventional radiology procedures for disease control are eligible to start topical sirolimus
• At least 2 weeks since undergoing any major surgery.
• Must not have received Myelosuppressive chemotherapy within 4 weeks of starting sirolimus.
• At least 7 days since the completion of therapy with a GF that supports platelet, red or white cell number or function.
• At least 14 days since the completion of therapy with a biologic agent.
• Patients with Kaposiform Hemagioendothelioma who have failed or are intolerant of systemic sirolimus therapy.
• Patients must not have received any non-FDA approved drug within 4 weeks or 5 half-lives, whichever is longer, prior to starting sirolimus and during treatment with sirolimus.
• XRT: > or = 6 months from involved field radiation to vascular tumor.
• Patients may not be currently receiving strong inhibitors of CYP3A4 and may not have received medications within 1 week of starting sirolimus.
• Patients may not be taking enzyme-inducing anticonvulsants, and may not have received these medications within 1 week of starting topical sirolimus, as these patients may experience different drug disposition.
• Adequate organ function
• Total bilirubin ≤1.5 x ULN for age
• SGPT (ALT) <5 x ULN for age
• Serum albumin > or = 2 g/dL.
• Fasting LDL cholesterol of <160 mg/dL
• Adequate Bone Marrow Function
• Hemoglobin > or = 8.0 gm/dL (may receive RBC transfusions)
• Platelet count > or = 50,000/microL (transfusion independent defined as not receiving a platelet transfusion within a 7 day period prior to sirolimus use)
• Adequate Renal Function
• A serum creatinine based on age
• Urine protein to creatinine ratio (UPC) < 0.3 g/l
• Karnofsky > or = 50 (>/=16 years of age) and Lansky >/ = 50 for patients < 16 years of age

Exclusion Criteria:

• Concurrent severe and/or uncontrolled medical disease which could compromise compliance with safety monitoring requirements for sirolimus (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
• Chronic treatment with systemic steroids or another immunosuppressive agent.
• Patients who require medications that inhibit/induce CYP3A4 enzyme activity to control concurrent medical conditions.
• Known history of HIV seropositivity or known immunodeficiency.
• Women who are pregnant or breast feeding.
• Males or females of reproductive potential should agree to use an effective contraceptive method during the period they are receiving topical sirolimus and for 3 months thereafter.
• Patients unwilling or unable to comply with the safety monitoring requirements for sirolimus.
• Patients who currently have an uncontrolled infection, defined as receiving intravenous antibiotics.
• Patients with hemangioma
• Patients with symptomatic complicated vascular anomalies with severe systemic symptoms that will need systemic therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label, topical sirolimus arm; Single arm, open label study of1% sirolimus ointment applied to affected area twice daily for the first four weeks followed by once daily for 5 months.	Drug: Topical Sirolimus; Open label, topical sirolimus (1%) cream will be applied to cutaneous component of complicated vascular anomalies twice daily for 4 weeks and once daily thereafter- for the duration of study.; Other Names: rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Pain or local irritation	Response will be evaluated by physical exam and documented at 24 weeks of therapy.	24 weeks
Cyst formation	Response will be evaluated by physical exam and documented at 24 weeks of therapy.	24 weeks
Decrease in discharge	Response will be evaluated by physical exam and documented at 24 weeks of therapy.	24 weeks
Decrease in cyst formation	Response will be evaluated by physical exam and documented at 24 weeks of therapy.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sirolimus level	Sirolimus level in ng/ml.	24 weeks
Bilirubin level	Total bilirubin in mg/dL	24 weeks
Neutrophil level	Neutrophil count in mm3	24 weeks
ALT level	ALT level in units/liter	24 weeks
Serum Albumin	Serum Albumin level in g/liter	32 weeks
Fasting LDL	Fasting LDL level in mg/dl	24 weeks
Hemoglobin level	Hemoglobin level in g/dl	24 weeks
Platelet count	Platelet count in microliter	24 weeks
Urine Protein/creatinine	Urine Protein/creatinine levels in mL/min	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in vital signs	Pre and Post vital signs evaluations (Pulse)Pulse, Respiration and Blood Pressure.	24 weeks
Temperature	Temperature in C/F	24 weeks
Respirations	Pre and Post vital signs evaluation (Respirations)	24 weeks
Blood pressure	Pre and Post vital signs evaluations (Blood pressure)	24 weeks
Changes in Weight	Weight will be collected in Kilograms.	24 weeks
Changes in Height	Height will be collected in meters	24 weeks
Changes in daily topical ointment applications	Medication diary(QOL) for Sirolimus topical ointment application documentation	24 weeks

Collaborators and Investigators

• Sponsor: Nemours Children's Clinic
• Investigators: Principal Investigator: Craig Johnson, DO, Nemours

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2020
• Primary Completion (Actual): February 15, 2024
• Study Completion (Actual): February 15, 2024

Study Registration Dates

• First Submitted: November 8, 2019
• First Submitted That Met QC Criteria: November 19, 2019
• First Posted (Actual): November 21, 2019

Study Record Updates

• Last Update Posted (Actual): December 31, 2025
• Last Update Submitted That Met QC Criteria: December 24, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Vascular Malformations; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: NOVA0118

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No