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Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease

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ClinicalTrials.gov Identifier: NCT04339751
Recruitment Status : Recruiting
First Posted : April 9, 2020
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Study Description
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Brief Summary:

Background:

Cushing s disease is caused by excess ACTH hormone release by a benign tumor of the pituitary gland. It can lead to decreased quality of life and early death. The current best treatment for Cushing s disease is surgery. If surgery does not work or if the tumor returns, there are no more good treatment options. Vorinostat, which is approved to treat a type of lymphoma, might be a treatment option.

Objective:

To test vorinostat to see if it can kill tumor cells and change the number of hormones released in people with Cushing s disease.

Eligibility:

People ages 18 and older who have Cushing s disease and are scheduled for surgery under protocol 03-N-0164 to remove a tumor in their pituitary gland

Design:

Participants will be screened under protocol 03-N-0164.

Participants will stay in the hospital for 8 days before their surgery.

On the first day, participants will have a physical exam and blood tests. They will have their urine collected for testing all day. They will have an ECG: For this, small metal disks or sticky electrode pads will be placed on their chest to record heart activity.

For the next 7 days, participants will have blood tests and all-day urine collection. They will drink at least 2 liters of fluid per day. They will take the study drug by mouth each morning.

On the eighth day, participants will have their surgery. Leftover tissue will be collected for research.

On the day they are discharged from the hospital, participants will have a physical exam and blood tests.


Condition or disease Intervention/treatment Phase
Cushing's Disease Drug: Vorinostat Phase 2

Detailed Description:

Objective

Cushing s disease is caused by excess ACTH hormone release by a benign tumor of the pituitary gland. The resulting increase in cortisol levels caused by increased ACTH causes a severe condition that leads to decreased quality of life and early death. The current best first treatment for Cushing s disease is surgery. However, if surgery is unsuccessful or if the tumor returns, there are no good treatment options for patients. In laboratory studies, we discovered that a previously FDA approved oral medication Vorinostat was able to kill tumors cells and reduce ACTH secretion. We want to test whether this drug can be used in patients with Cushing s disease to reduce ACTH levels.

Study Population

Adult (> 18 years old) patients with a diagnosis of Cushing s disease that qualify for surgery through a different NIH protocol (#03-N-0164).

Design

We will recruit patients with Cushing s disease who have surgery planned for removal of the pituitary tumor. If they consent, we will admit them as inpatients for 8 days before surgery. After a thorough laboratory investigation, we will administer Vorinostat by mouth daily for 7 days. During this time, we will measure the levels of ACTH and glucocorticoid hormones in the blood and urine daily. On the 8th day, we will perform the surgery as planned. We also will test tissue obtained during surgery to evaluate the drug s effect on the tumors.

Outcome Measures

The main outcome measure is the midnight plasma ACTH level on the last day of drug administration. A secondary outcome measure is the serum cortisol change during drug administration.-

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease
Estimated Study Start Date : January 20, 2021
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : June 15, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Vorinostat

Arms and Interventions
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Arm Intervention/treatment
Experimental: single center, prospective pilot study
effectiveness of vorinostat to reduce midnight ACTH levels in patients with Cushing s Disease
 Drug: Vorinostat
Administration of Vorinostat


Outcome Measures
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Primary Outcome Measures :
  1. Midnight Plasma ACTH [ Time Frame: Day -1, Day 0-1, Day 2, Day 4-6, Discharge ]
    Relative change in midnight plasma ACTH. Dichotomized relative change using 20% as a cutoff (which is considered as clinical important): relative change >20% for reduction and relative change <=20% for no change).


Secondary Outcome Measures :
  1. Urinary Free Cortisol [ Time Frame: Day -1, Day 0-1, Day 2, Day 4-6, Discharge ]
    Relative change in 24-hour urinary free cortisol during 7 day administration of Vorinostat


Eligibility Criteria
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Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  • Adult patients (18 years and older)
  • Confirmed biochemical diagnosis of Cushing s disease (primary or recurrent) as evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH.
  • Surgical candidate for resection of ACTH producing pituitary adenoma
  • Enrolled in 03-N-0164, Evaluation of Neurosurgical Disorders.
  • Able to provide written informed consent at the time of study enrollment.
  • Participants who are physically able to become pregnant must use an effective form of birth control from 14 days prior to enrollment through 6 months following the last dose of vorinostat. Participants who are able to father a child must use an effective form of birth control from Day 0 through 3 months following the last dose of vorinostat.

EXCLUSION CRITERIA:

  • Patients who have been previously treated with vorinostat.
  • Patients who have received sellar radiation.
  • Significant medical illnesses that in the investigator s opinion cannot be adequately controlled or would compromise the patient s ability to tolerate this vorinostat.
  • Any history of cancer, unless in complete remission and off of all therapy for that disease for a minimum of 3 years.
  • History of thromboembolic disorder or deep vein thrombosis

  • Presence of abnormal hematological and biochemical parameters, (such as anemia or thrombocytopenia) as defined as:

    • Neutrophil count < 1.5 K//micro L
    • Hemoglobin < 8.0 g/dL.
    • Hematocrit < 0.75x LLN (lower limit of normal)
    • RBC count < 0.75x LLN
    • Platelet count < 100 x 10^3 cells/micro L.
    • Prothrombin time-international normalized ratio (PT-INR) > 1.5x ULN or Activated partial thromboplastin time (aPTT) > 1.5x ULN, with the exception of patients on prophylactic anticoagulation therapy
    • Serum bilirubin level > 1.5x ULN.
  • Active infection being currently treated with systemic antibiotics.
  • Serious concurrent medical illness including renal failure (creatinine >3.0x - 6.0x ULN) liver failure (ALT/AST >5.0x - 20.0x ULN) or severe cardio-respiratory disease.
  • Pregnancy or lactation.
  • Presence of any disease that will obscure toxicity or dangerously alter drug metabolism (such as uncontrolled diabetes or bleeding disorders)
  • Currently receiving other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat, such as valproate.
  • Currently taking another HDACi, such as valproate.
  • Currently taking coumadin or its derivative anticoagulants.
  • Currently taking any other medication to reduce cortisol or ACTH levels
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04339751


Contacts
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Contact: Gretchen C Scott, R.N. (301) 496-2921 gretchen.scott@nih.gov

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

Publications:

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Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT04339751    
Other Study ID Numbers: 200019
20-N-0019
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: January 15, 2021
Last Verified: April 3, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
SAHA
CD
Additional relevant MeSH terms:
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Adenoma
Pituitary Neoplasms
ACTH-Secreting Pituitary Adenoma
Pituitary ACTH Hypersecretion
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
 Endocrine Gland Neoplasms
Neoplasms by Site
Hypothalamic Neoplasms
Supratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Hyperpituitarism
Vorinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action