A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors

Kaposiform hemangioendotheliomas (KHE) are extremely rare life threatening tumors which can
be associated with Kasabach-Merritt Phenomenon consisting of profound thrombocytopenia and
hypofibrinogenemia causing a significant risk of bleeding and an associated mortality rate as
high as 20% to 30%. Despite the severity of potential complications, we lack uniform
guidelines for the treatment and response to treatment of children and young adults with
these tumors. KHE patients have been treated with a multitude of aggressive drug regimens
without prospective evaluation of response or safety. Presently, vincristine is considered
the standard of practice. We have treated a subset of these patients on study SIR-DA-0901
(FDA Grant# 5RO1FD003712-01). This study is a phase II trial assessing the efficacy and
safety of sirolimus for the treatment of complicated vascular anomalies. Although the numbers
are small, the response has been extremely promising with excellent tolerability. There is
pre-clinical and clinical data supporting the essential regulatory function of the PI3
kinase/AKT/mTOR pathway in vascular growth and organization which suggests a therapeutic
target for patients with complicated vascular anomalies. The overall goal of this trial is to
objectively assess the efficacy of sirolimus compared to vincristine for the treatment of
patients with high risk KHE.

Hypothesis: Sirolimus treatment for children and young adults with Kaposiform
hemangioendotheliomas will be more effective than vincristine, assessed by time to response
in an induction period and provide equivalent safety parameters.

Study Rationale We propose a multi-center, phase II trial with participation from 8 sites.
The study will consist of two phases. The first of these is an initial induction phase in
which vincristine and steroids will be compared to sirolimus and steroids. Response in the
induction phase will be assessed as time to hematologic response. At the end of induction
phase, cross over can occur if there is failure to respond. Part 2 is a maintenance phase
which will be 1 year in length. Continued safety and efficacy data will be collected during
maintenance and there will be cross over at any time for patients who lose their response
following induction. Failure will be defined as worsening of hematological parameters on two
separate laboratory evaluations at any time during maintenance or if they meet the definition
of progressive disease following response assessments. Formal response in maintenance will be
evaluated by imaging studies, functional assessment, and quality of life as per study
SIR-DA-0901. Present therapies are very limited and new therapies are desperately needed for
this devastating disease. Based on our preliminary data, there is a very good rationale for
sirolimus therapy in KHE patients and so a phase II trial is urgently needed to determine if
this therapy is to become the new standard of care for KHE patients.

Our secondary aims will be addressing biomarker analysis. There are limited studies
describing the biology of these tumors. Per study SIR-DA-0901 there is some preliminary data
indicating the importance of VEGF-C and other upregulated markers in the mTor pathway. This
needs to be further investigated especially in KHE patients. Furthermore there are no clear
objective measurements to determine response data.

Inclusion Criteria:

- Diagnosis: All patients must have one of the following vascular anomalies as
determined by clinical, radiologic and histologic criteria (when possible). Biopsy
strongly recommended (but not required) with suggested immunostains: CD34, PROX-1 or
D240, Glut-1 and MIB-1.

1. Kaposiform Hemangioendotheliomas

2. Tufted angioma

High Risk Stratification: In addition to the above diagnosis, all of the following criteria
need to be met:

a. Kasabach Merritt Syndrome defined at a platelet counts less than 50,000 K/µl and/or
fibrinogen level < 100 mg/dl at the time of diagnosis.

- 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:

1. Adequate liver function defined as:

1. Total bilirubin ≤ 1.5 x ULN for age, and

2. SGPT (ALT) ≤ 5 x ULN for age, and

3. Serum albumin >/= 2 g/dL.

4. Fasting LDL cholesterol of <160 mg/dL

5. Fasting triglyceride <400 mg/dl

2. Adequate Bone Marrow Function defined as:

1. Peripheral absolute neutrophil count (ANC) >/= 1000/uL

2. Hemoglobin >/= 8.0 g/dL (may receive RBC transfusions)

3. No Platelet requirement

3. Adequate Renal Function Defined as:

1. A serum creatinine based on age as follows:

Age (Years) Maximum Serum Creatinine (mg/dL)

- 5 0.8 6 to ≤10 1.0 11 to ≤15 1.2 >15 1.5

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

- Performance Status: Karnofsky >/= 50 (≥16 years of age) and Lansky >/= 50 for patients
<16 years of age.

- Prior therapy

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. Radiation: > 6 months from involved field radiation

4. Prior vincristine therapy is permitted. Patients may also have received up to 2
doses of vincristine prior to randomization.

Exclusion Criteria:

- Concurrent severe and/or uncontrolled medical disease that 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).

- Patients who require medications that are strong inhibitors/inducers CYP3A4 enzyme
activity, including anticonvulsants, (Appendix II) to control concurrent medical
conditions are not eligible. Patients who discontinue use of prohibited medications
with a one week washout prior to start of study treatment are eligible.

- 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.

- Females 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. Females of childbearing potential will be given a pregnancy test within 7
days prior to administration of study treatment 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.