Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT00975819
• Date of registration: 10/09/2009
• Prospective Registration: Yes
• Primary sponsor: Children's Hospital Medical Center, Cincinnati
• Public title: Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies
• Scientific title: A Phase 2 Study - Clinical Trial Assessing Efficacy and Safety of the mTOR Inhibitor Sirolimus in the Treatment of Complicated Vascular Anomalies
• Date of first enrolment: October 2009
• Target sample size: 60
• Recruitment status: Active, not recruiting
• URL: http://clinicaltrials.gov/show/NCT00975819
• Study type: Interventional
• Study design: Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Denise M Adams, MD
• Affiliation: Children's Hospital Medical Center, Cincinnati

Key inclusion & exclusion criteria

Inclusion Criteria:

Inclusion will be strictly limited to children and young adults with vascular anomalies
with complications that require systemic therapy for control.

Diagnosis: All patients must have one of the following vascular anomalies as determined by
clinical, radiographic and histologic criteria (when possible):

- Kaposiform Hemangioendotheliomas with Kasabach-Merritt Phenomenon

- Kaposiform Hemangioendotheliomas without Kasabach-Merritt Phenomenon

- Tufted Angioma with Kasabach-Merritt Phenomenon

- Tufted Angioma without Kasabach-Merritt Phenomenon

- Capillary Lymphatico-Venous Malformation (CLVM)

- Venous Lymphatic Malformation (VLM)

- Microcystic Lymphatic Malformation (MLM)

- Multifocal Lymphangiomatosis and Thrombocytopenia (MLT)/Cutaneovisceral Angiomatosis
and Thrombocytopenia (CAT)

- Capillary Lymphatic Arterial Venous Malformations (CLAVM)

- PTEN Overgrowth syndrome with vascular anomaly

- Lymphangiectasia Syndromes

If archived tissue is available, histological diagnosis will be confirmed by the pathology
lab at the enrolling site.

Complications: Patients must have vascular anomalies that have potential to cause
significant morbidity. In addition to the above diagnosis, one or more of the following
criteria needs to be met:

- Coagulopathy

- Chronic pain

- Recurrent cellulitis (>3 episodes/year)

- Ulceration

- Visceral and/or bone involvement

- Cardiac dysfunction

Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes
patients of both genders and all ethnic groups.

Organ function requirements:

Adequate liver function defined as:

- Total bilirubin (sum of conjugated and unconjugated) =1.5 x ULN for age, and

- SGPT (ALT) <5 x ULN for age, and

- Serum albumin > or = 2 g/dL.

Fasting LDL and cholesterol:

- Fasting LDL cholesterol of <160 mg/dL

- Patients taking a cholesterol lowering agent must be on a single medication and on a
stable dose for at least 4 weeks

Adequate Bone Marrow Function defined as:

- Peripheral absolute neutrophil count (ANC) > or = 1000/microL

- 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 enrollment)

Note: There is NO platelet requirement for patients with Kasabach-Merritt Phenomenon

Adequate Renal Function Defined as:

• A serum creatinine based on age as follows:

- = 5 years of age maximum serum creatinine (mg/dL) of 0.8

- 6 < age = 10 years of age maximum serum creatinine (mg/dL) of 1.0

- 11 < age = 15 years of age maximum serum creatinine (mg/dL) of 1.2

- > 15 years of age maximum serum creatinine (mg/dL) of 1.5

AND cystatin C equal to or less than the upper limit of normal for the patient. If
cystatin C does not initially meet this criterion, it may be repeated or a more sensitive
screening by nuclear GFR must be = 70 ml/min.

• Urine protein to creatinine ratio (UPC) < 0.3 g/l

Performance Status: Karnofsky > or = 50 (>10 years of age) and Lansky > or = 50 for
patients < or = 10 years of age

Prior therapy requirements:

1. Patients who have undergone surgical resection or interventional radiology procedures
for disease control are eligible if they meet all inclusion criteria after
surgery/procedure

2. Surgery: At least 2 weeks since undergoing any major surgery

3. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or
stress doses of steroids if necessary. Other patients, such as vascular tumor
patients, need to be on a weaning dose of steroids (steroid use defined as
intravenous or oral steroids required for more than one day).

4. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
this study.

5. Hematopoietic GFs: At least 7 days since the completion of therapy with a GF that
supports platelet, red or white cell number or function.

6. Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy
with a biologic agent. For agents that have known AEs occurring beyond 14 days after
administration, this period must be extended beyond the time during which AEs are
known to occur. These patients must be discussed with the Study Chair on a
case-by-case basis.

7. Patients diagnosed with Kaposiform Hemangioendotheliomas or Tufted Angiomas will not
require a washout period prior to enrollment, but will be required to discontinue the
use of prohibited concomitant medications upon enrollment in the study following the
guidelines of the protocol.

8. Investigational Drugs: Patients must not have received any non-FDA approved drug
within 4 weeks.

9. XRT: > or = 6 months from involved field radiation to vascular tumor.

10. CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of
CYP3A4, and may not have received these medications within 1 week of entry. (See
Appendix II). These include:

- Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin,
troleandomycin.

- Gastrointestinal prokinetic agents: cisapride, metoclopramide.

- Antifungals: itraconazole, ketoconazole, fluconazole (doses > 200 mg/day),
voriconazole, clotrimazole

- Calcium channel blockers: verapamil, diltiazem, nicardipine

- Other drugs: rifampin, bromocriptine, cimetidine (Tagamet®), danazol,
cyclosporine oral solution, lansoprazole (Prevacid®).

- Grapefruit juice.

11. CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4, and may not
have received these medications within 1 week of entry. These include:

- Anticonvulsants: carbamazepine, phenobarbital, phenytoin

- Antibiotics: rifabutin, rifapentine.

- Herbal preparations: St. John's Wort (Hypericum perforatum, hypericine).

12. Enzyme inducing anticonvulsants: Patients may not be taking enzyme-inducing
anticonvulsants, and may not have received these medications within 1 week of entry,
as these patients may experience different drug disposition. These medications
include:

- Carbamazepine (Tegretol®)

- Felbamate (Felbtol®)

- Phenobarbitol



Age minimum: N/A
Age maximum: 31 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Lymphangiectasia Syndromes

Mucocutaneous Lymphangiomatosis and Thrombocytopenia

Microcystic Lymphatic Malformation

PTEN Overgrowth Syndrome With Vascular Anomaly

Venous Lymphatic Malformation

Kaposiform Hemangioendotheliomas

Tufted Angioma

Capillary Venous Lymphatic Malformation

Capillary Lymphatic Arterial Venous Malformations

Intervention(s)

Drug: sirolimus

Primary Outcome(s)

Evaluation of Disease Response - Clinical Criteria and Functional Impairment [Time Frame: baseline, 3, 6, 12 months]

Evaluation of Disease Response - Volumetric MRI [Time Frame: Baseline, 3, 6, and 12 months]

Evaluation of Disease Response - Quality of Life and Pain Assessments [Time Frame: Baseline, 3, 6, 12 months]

Secondary Outcome(s)

Tissue (only baseline) and Serum Sample analysis [Time Frame: baseline, 6, 12 months]

Secondary ID(s)

SIR-DA-0901

5RO1FD003712-04

Source(s) of Monetary Support

Please refer to primary and secondary sponsors