Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies
Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies
The purpose of this study is to determine if the use of sirolimus in the treatment of
 children and young adults with complicated vascular anomalies will prove to be safe and
 provide objective response resulting in improved clinical status and quality of life.

 Funding Source - FDA OOPD (Food and Drug Administration - Office of Orphan Products
 Development)
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. There are
 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. 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. We
 propose 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.
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

 -  Phenytoin (Dilantinl®)

 -  Primidone (Mysoline®)

 -  Oxcarbazepine (Trileptal®)

 Exclusion Criteria:

 -  Dental braces or prosthesis only if it interferes with radiologic analysis of vascular
 anomaly.

 -  Concurrent severe and/or uncontrolled medical disease which could compromise
 participation in the study (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
 with endocrine deficiencies are allowed to receive physiologic or stress doses of
 steroids if necessary. Patients with the diagnosis of a vascular tumor (KHE, TA) can
 be on a weaning dose of steroids.

 -  Patients who require medications that inhibit/induce CYP3A4 enzyme activity to control
 concurrent medical conditions.

 -  Known history of HIV seropositivity or known immunodeficiency. Testing is not required
 unless a condition is suspected.

 -  Impairment of gastrointestinal function or gastrointestinal disease that may
 significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled
 nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A
 gastric tube or nasogastric tube is allowed.

 -  Women who are pregnant or breast feeding.

 -  Males or females of reproductive potential may not participate unless they have agreed
 to use an effective contraceptive method during the period they are receiving the
 study drug and for 3 months thereafter. Abstinence is an acceptable method of birth
 control. Women of childbearing potential will be given a pregnancy test within 7 days
 prior to administration of sirolimus and must have a negative urine or serum pregnancy
 test.

 -  Patients who have received prior treatment with an mTOR inhibitor.

 -  Patients unwilling or unable to comply with the protocol, or who in the opinion of the
 investigator may not be able to comply with the safety monitoring requirements of the
 study.

 -  Patients who currently have an uncontrolled infection, defined as receiving
 intravenous antibiotics.