Effect of Vorinostat on Nervous System Hemangioblastomas in Von Hippel-Lindau Disease (Missense Mutation Only)

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Brief Title

Effect of Vorinostat on Nervous System Hemangioblastomas in Von Hippel-Lindau Disease (Missense Mutation Only)

Official Title

Pilot Study of the Effect of Vorinostat on Nervous System Hemangioblastomas In Von Hippel-Lindau Disease

Brief Summary

      Background:

      - Von Hippel-Lindau (VHL) disease is a rare gene disease. People with VHL often have a brain
      tumor called hemangioblastoma. Standard treatment for these tumors is risky surgery.
      Researchers want to find new ways to treat people who have the tumors. They want to see if a
      drug that fights other cancers might slow the growth of hemangioblastomas in some people with
      VHL. Some people with VHL have mutations that make abnormal proteins. Tumors form in such
      people because the abnormal protein is broken down quickly. The cancer drug may work in these
      tumors by preventing breakdown of protein.

      Objective:

      - To study how the drug vorinostat affects hemangioblastomas in people with VHL.

      Eligibility:

      - Adults at least 18 old with hemangioblastomas from VHL.

      Design:

        -  Participants must already be in study 03-N-0164. They must have tumor surgery scheduled.

        -  Participants must stop taking most medications 14 days before surgery.

        -  One week before surgery, participants will enter the hospital. They will be screened
           with medical history and physical and neurological exams. They will give blood and urine
           samples. Participants will have an electrocardiogram. For this test, small sticky
           patches are put on the arms, legs, and chest. Participants will lie still for a few
           minutes while a machine records heart rate and rhythm.

        -  Participants will take one vorinostat by mouth each day for 7 days.

        -  Participants will have blood drawn during the week to check for any side effects.

        -  Participants will have their tumor removed in surgery. Researchers will study the tumor
           tissue for the effects of the study drug.

        -  A nurse will call participants 1 month after surgery to check for side effects.
    

Detailed Description

      Background

      Central Nervous System (CNS) hemangioblastomas are the most common tumor found in the
      familial neoplasia syndrome, Von Hippel-Lindau (VHL).

      Hemangioblastomas cause significant morbidity and mortality. While surgical resection is the
      treatment of choice for CNS hemangioblastomas, it is associated with morbidity and death.
      There is a critical need for new non-invasive treatments of VHL-associated CNS
      hemangioblastomas.

      Vorinostat is a histone deacetylase inhibitor (HDACi) that is FDA-approved for the treatment
      of refractory cutaneous T-cell lymphoma (CTCL). Vorinostat has been tested in other
      hematologic malignancies and solid tumors. Recent data suggests that vorinostat may have a
      potent therapeutic effect in the treatment of VHL-associated hemangioblastomas in patients
      with missense germline mutations of the VHL gene. In most VHL mutation types, the abnormal
      VHL protein content is not active, which leads to tumor formation and growth. In missense
      mutation VHL disease, tumor cells contain a malformed VHL protein that is partially active.
      However, the protein is degraded quickly by normal cellular mechanisms. Vorinostat prevents
      degradation of a malformed protein within the tumors. Increased protein leads to slower
      growth in these tumors.

      Objective

      To determine whether vorinostat reduces degradation of mutant VHL protein in VHL patients
      with germline missense mutations.

      Eligibility

      Adult patients (age greater than or equal to 18 years) with a known germline missense VHL
      gene mutation that require surgical resection of a hemangioblastoma.

      Design

      We intend to conduct a pilot study with vorinostat in six patients with hemangioblastomas
      causing significant symptoms from tumor growth. Vorinostat will be administered if the
      patients are deemed surgical candidates. Patients will receive one (1) dose of 400 mg of
      vorinostat daily for seven (7) days prior to surgery. On the day of surgery, the patients
      will not receive vorinostat. Patients will undergo surgery as usual, with no change in
      planning or technique of the procedure. The tumor specimens from surgery will be examined for
      presence and quantity of mutant VHL protein. Comparisons for levels of mutant VHL protein
      will be made with tissue banked from previous surgical resections under 03-N-0164.
      Measurements of genetic expression of vascular endothelial growth factor (VEGF) and
      erythropoietin (EPO) will also be performed on these specimens.

      Outcome Measures

        1. The presence and quantity of mutant VHL protein in resected hemangioblastoma specimens,
           including comparison of specimens without vorinostat treatment and those with
           presurgical vorinostat treatment.

        2. Measurement of VEGF and EPO results from resected hemangioblastoma specimens, including
           comparison of specimens without vorinostat treatment and those with presurgical
           vorinostat treatment.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

The presence and quantity of mutant VHL protein in resected hemangioblastoma specimens, including comparison of specimens without vorinostat treatment and those with presurgical vorinostat treatment.


Condition

Von Hippel-Lindau Disease

Intervention

Vorinostat


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

7

Start Date

April 5, 2014

Completion Date

September 12, 2018

Primary Completion Date

September 12, 2018

Eligibility Criteria

        -  INCLUSION CRITERIA

               1. Adult patients (age greater than or equal to 18 years)

               2. Known VHL disease arising from a missense mutation.

               3. Demonstrated clinical progression of CNS hemangioblastoma.

               4. Enrolled in 03-N-0164, Evaluation of Neurosurgical Disorders.

               5. Able to provide written informed consent.

        EXCLUSION CRITERIA

          1. Patients who have been previously treated with vorinostat.

          2. Significant medical illnesses that in the investigator s opinion cannot be adequately
             controlled with appropriate therapy or would compromise the patient s ability to
             tolerate this therapy.

          3. History of a second cancer (except non-melanoma skin cancer or carcinoma in-situ of
             the cervix), unless in complete remission and off of all therapy for that disease for
             a minimum of 3 years.

          4. Active infection or serious concurrent medical illness.

          5. Pregnancy and breast-feeding.

          6. Presence of any disease that will obscure toxicity or dangerously alter drug
             metabolism (such as uncontrolled diabetes, liver disease, bleeding disorder)

          7. Currently receiving other investigational agents.

          8. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to vorinostat, such as valproate.

          9. Currently taking another HDACi, such as valproate.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Prashant Chittiboina, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02108002

Organization ID

140067

Secondary IDs

14-N-0067

Responsible Party

Sponsor

Study Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)


Study Sponsor

Prashant Chittiboina, M.D., Principal Investigator, National Institute of Neurological Disorders and Stroke (NINDS)


Verification Date

September 12, 2018