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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) )

Tracking Information
First Submitted Date  ICMJE April 8, 2020
First Posted Date  ICMJE April 9, 2020
Last Update Posted Date January 15, 2021
Estimated Study Start Date  ICMJE January 20, 2021
Estimated Primary Completion Date June 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2020)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2020)
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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease
Official Title  ICMJE The Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease
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.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cushing's Disease
Intervention  ICMJE Drug: Vorinostat
Administration of Vorinostat
Study Arms  ICMJE Experimental: single center, prospective pilot study
effectiveness of vorinostat to reduce midnight ACTH levels in patients with Cushing s Disease
Intervention: Drug: Vorinostat
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2020)
22
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 15, 2021
Estimated Primary Completion Date June 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Gretchen C Scott, R.N. (301) 496-2921 gretchen.scott@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04339751
Other Study ID Numbers  ICMJE 200019
20-N-0019
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
Study Sponsor  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Prashant Chittiboina, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date April 3, 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP