A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors
Condition: Kaposiform Hemangioendothelioma (KHE); Kasabach-Merritt Syndrome; Tufted Angioma
MeSH terms: Sarcoma, Kaposi; Hemangioendothelioma; Hemangioma; Kasabach-Merritt Syndrome
Intervention: Vincristine; Sirolimus
Intervention description: Vincristine dose dependent upon weight. Weekly for 2 months (Induction); Weekly 2 months; every 2 weeks for next 5 months; every 3 weeks for 5 months (Maintenance); Continuous dosing to maintain trough level of 10-15ng/ml.
Intervention MeSH terms: Sirolimus; Vincristine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Maximum age: 31 Years
Healthy volunteers: No
Keywords: KHE; Vascular anomaly; Kasabach-Merritt Syndrome; Tufted angioma; hemangioendothelioma

Summary:

      In this research study we want to learn more about which treatment works better for patients
      diagnosed with a vascular tumor called Kaposiform Hemangioendothelioma (KHE) or other high
      risk vascular tumors such as Tufted Angioma (TA). In these tumors, the blood cells that help
      your blood clot called platelets become trapped in the tumor causing swelling, pain, and
      bruising. Vascular tumors can be life threatening. There are few medical treatments that will
      work to shrink the vascular tumor. Some doctors will use steroids and vincristine to try and
      shrink vascular tumors.

      In this research study, the study doctor will compare two different drugs to see which one
      will work better to help shrink your vascular tumor. One of the drugs is vincristine.
      Vincristine is approved by the Food and Drug Administration (FDA) to treat people with
      cancer. Vincristine is used to stop the abnormal cells from growing such as cells that make
      up blood vessels.

      The other drug to be used in this study is sirolimus. Sirolimus is currently approved by the
      Food and Drug Administration (FDA) to prevent transplanted organ rejection. Sirolimus is not
      approved by the FDA for treatment of vascular abnormalities and is considered experimental.
      Sirolimus belongs to a class of drugs call 'mTOR inhibitors'. mTOR (mammilian target of
      rapamycin) helps cells to grow and may also help blood vessels to grow in a more normal
      fashion. Sirolimus is currently being tested in patients with vascular tumors and cancer. In
      vascular tumors, we hope sirolimus will stop the blood vessel growth.

      Funding Source: FDA - OOPD (Office of Orphan Products Development)
    

Eligibility criteria:

        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.