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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier:
NCT02108002
First received: April 5, 2014
Last updated: May 13, 2014
Last verified: February 2014
  Purpose

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.

Condition Intervention Phase
Von Hippel-Lindau Disease
Drug: Vorinostat
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Pilot Study of the Effect of Vorinostat on Nervous System Hemangioblastomas In Von Hippel-Lindau Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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. [ Time Frame: ongoing ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: March 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Vorinostat
    N/A
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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02108002

Contacts
Contact: Gretchen C Scott, R.N. (301) 496-2921 scottgc@mail.nih.gov
Contact: Prashant Chittiboina, M.D. (301) 496-5728 chittiboinap@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Prashant Chittiboina, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
ClinicalTrials.gov Identifier: NCT02108002     History of Changes
Other Study ID Numbers: 140067, 14-N-0067
Study First Received: April 5, 2014
Last Updated: May 13, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Missense Mutations
Hemangioblastoma
Von Hippel Lindau Disease
Histone Deacytelase Inhibitors

Additional relevant MeSH terms:
Von Hippel-Lindau Disease
Hemangioblastoma
Neurocutaneous Syndromes
Nervous System Diseases
Angiomatosis
Vascular Diseases
Cardiovascular Diseases
Hemangioma, Capillary
Hemangioma
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Neoplasms
Vorinostat
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 29, 2014