Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Collaborators:
Washington University School of Medicine
Weill Medical College of Cornell University
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:
NCT02124083
First received: April 25, 2014
Last updated: August 15, 2014
Last verified: January 2014
  Purpose

Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. The causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead to progressive accumulation of unesterified cholesterol and other lipids in the central nervous system (CNS). Vorinostat is a histone deacetylase inhibitor that has been shown in vivo to increase mutant NPC1 protein levels and to reverse cellular accumulation of unesterified cholesterol. Vorinostat has been labeled by the FDA for treatment of cutaneous T-cell lymphoma. In this Phase I, non-randomized, open-label, single-center study, we plan to study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective is to determine the safety and tolerability of Vorinostat in NPC1 disease. Our secondary objectives will be to determine biochemical efficacy of Vorinostat to increase expression of NPC1 protein and normalize lipid and protein biomarkers. This study will enroll up to 12 NPC1 patients and test the safety of two dose levels (200 and 400 mg). Drug will be administered on a 3 days on/4 days off schedule for 3 months at each dose level. Patients will be evaluated at the NIH Clinical Center at 0, 3 and 6 months. Safety will be assessed by adverse events (AEs), clinical laboratory tests and physical examinations. Biochemical efficacy will be assessed by measurement of serum and cerebral spinal fluid biomarkers. Clinical efficacy will be evaluated by audiologic testing, assessment ataxia, and swallowing studies.


Condition Intervention Phase
Neimann-Pick Disease
Drug: Vorinostat
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

Resource links provided by NLM:


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

Primary Outcome Measures:
  • To assess the safety and tolerability of oral Vorinostat therapy in Niemann-Pick Disease, type C1 [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To obtain pilot data on Plasma and cerebrospinal fluid biomarkers and on Potential clinical endpoints [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 15
Study Start Date: April 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Vorinostat
    N/A
Detailed Description:

Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. The causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead to progressive accumulation of unesterified cholesterol and other lipids in the central nervous system (CNS). Vorinostat is a histone deacetylase inhibitor that has been shown in vivo to increase mutant NPC1 protein levels and to reverse cellular accumulation of unesterified cholesterol. Vorinostat has been labeled by the FDA for treatment of cutaneous T-cell lymphoma. In this Phase I, non-randomized, open-label, single-center study, we plan to study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective is to determine the safety and tolerability of Vorinostat in NPC1 disease. Our secondary objectives will be to determine biochemical efficacy of Vorinostat to increase expression of NPC1 protein and normalize lipid and protein biomarkers. This study will enroll up to 12 NPC1 patients and test the safety of two dose levels (200 and 400 mg). Drug will be administered on a 3 days on/4 days off schedule for 3 months at each dose level. Patients will be evaluated at the NIH Clinical Center at 0, 3 and 6 months. Safety will be assessed by adverse events (AEs), clinical laboratory tests and physical examinations. Biochemical efficacy will be assessed by measurement of serum and cerebral spinal fluid biomarkers. Clinical efficacy will be evaluated by audiologic testing, assessment ataxia, and swallowing studies.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Aged greater than or equal to 18 and less than or equal to 60 years old at time of enrollment, either gender, and any ethnicity.
  2. Diagnosis of NPC1 based upon one of the following:

    • Two NPC1 mutations;
    • Positive filipin staining and at least one NPC1 mutation;
    • Vertical supranuclear gaze palsy (VSNGP) in combination with either:
    • One NPC1 mutation, or
    • Positive filipin staining and no pathogenic NPC2 mutations.
  3. Patients with at least one neurological manifestation of NPC1. For example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia.
  4. A patient s cultured skin fibroblasts when treated with 10 M Vorinostat must exhibit a reduction in the filipin lysosomal storage organelle ratio equivalent to 75% of the response measured in GM3123 fibroblasts.
  5. Ability to travel to the NIH Clinical Center repeatedly for evaluation and follow-up.
  6. If taking miglustat, the patient must have been taking a constant dose of the medication for no less than three months prior to baseline evaluation and must be willing to maintain that dose level for the duration of the trial.
  7. Willing to discontinue all non-prescription supplements, with the exception of an age-appropriate multivitamin.
  8. Women of reproductive age must be willing to use an effective method of contraception for the duration of the trial.
  9. Willing to participate in all aspects of trial design including serial blood and CSF collections.

EXCLUSION CRITERIA:

  1. Aged below 18 or above 60 years of age at enrollment in the trial.
  2. Severe manifestations of NPC1 that would interfere with the patient s ability to comply with the requirements of this protocol.
  3. Neurologically asymptomatic patients.
  4. Patients who have received any form of cyclodextrin or an HDACi in an attempt to treat NPC1.
  5. History of hypersensitivity reactions to Vorinostat or components of the formulation.
  6. Pregnancy or breastfeeding at any time during the study.
  7. Patients with suspected infection of the CNS or any systemic infection.
  8. Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter.
  9. Thrombocytopenia defined as a platelet count less than 75,000 per microliter, or a history of greater than or equal to grade 2 thrombocytopenia (50,000-75,000 platelets/microliter).
  10. Prior use of anticoagulants or history/presence of a bleeding disorder.
  11. Hepatic laboratory parameters (aspartate aminotransferase (AST), alanine aminotransferase, (ALT)) greater than four-times upper limit of normal.
  12. Presence of anemia defined as two standard deviations below normal for age and gender.
  13. Serum creatinine level greater than 1.5 times the upper limit of normal.
  14. Hematuria (greater than15 RBC/mcL or positive hemoglobin). This exclusion criteria will not apply to a female currently menstruating who has no history of renal disease or other evidence of renal impairment (eg hypertension, serum creatinine above upper limit of normal, history of renal disease). Urinalyis will be repeated after menses has ended and drug discontinued if hematuria persists. Efforts will be made to avoid menses in scheduling the initial admission.
  15. Proteinuria (1+ protein on urinalysis) Patient will not be excluded if urine protein/creatinine ratio is normal or if classified as benign by either patient's primary medical provider or upon obtaining a nephrology consult.
  16. Serum potassium or Magnesium outside of the normal laboratory range prior to initiation of vorinostat therapy.
  17. Diabetes or a fasting glucose greater than 106 mg/dl.
  18. Active pulmonary disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation, pulmonary therapy, or requiring active suction.
  19. Patients with uncontrolled seizures per either of the criteria below.

    1. Unstable frequency, type or duration of seizures. Quantified by a seizure log over the two months prior to enrollment.
    2. Patients requiring antiepileptic medication changes (other than dose adjustments for weight) in the two months prior to enrollment, or requiring three or more antiepileptic medications to control seizures.
  20. Use of another HDAC inhibitor or compounds with established HDAC inhibitory activity, including valproic acid, unless discontinued at least 2 months prior to enrollment.
  21. History of a thromboembolic event (such as DVT or Pulmonary embolism).
  22. Patients, who in the opinion of the investigators, are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation.
  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: NCT02124083

Contacts
Contact: Nicole M Farhat, C.R.N.P. (301) 594-1765 nicole.farhat@nih.gov
Contact: Forbes D Porter, M.D. (301) 435-4432 fdporter@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
Washington University School of Medicine
Weill Medical College of Cornell University
Investigators
Principal Investigator: Forbes D Porter, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier: NCT02124083     History of Changes
Other Study ID Numbers: 140102, 14-CH-0102
Study First Received: April 25, 2014
Last Updated: August 15, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Niemann Pick Disease, Type C1
Phase I, Phase 2
Vorinostat

Additional relevant MeSH terms:
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Dementia
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Dementia
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations

ClinicalTrials.gov processed this record on September 15, 2014