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

  • End date
    Dec 1, 2024
  • participants needed
  • sponsor
    National Institute of Neurological Disorders and Stroke (NINDS)
Updated on 16 September 2023
tumor cells
cushing's syndrome
free cortisol
urinary free cortisol
hormones released



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.


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


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


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.


Study Description

This is a single center, prospective pilot study of effectiveness of vorinostat to reduce midnight ACTH levels in patients with Cushing s Disease. Surgery for resection of ACTH producing pituitary adenoma will be offered at the NIH under another protocol (03-N-0164) as part of standard clinical care. Eligible subjects will be admitted to the Clinical Center for one week prior to surgery, during which time oral vorinostat will be administered daily.


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.

Primary Objective: to determine whether vorinostat reduces midnight plasma ACTH level

Secondary Objectives: to evaluate the effect of vorinostat on urine cortisol levels


Primary Endpoint: midnight plasma ACTH level on the last day of drug administration. Secondary Endpoints: serum cortisol change during drug administration.

Condition Cushing's Disease
Treatment Vorinostat
Clinical Study IdentifierNCT04339751
SponsorNational Institute of Neurological Disorders and Stroke (NINDS)
Last Modified on16 September 2023


Yes No Not Sure

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
Surgical candidate for resection of ACTH producing pituitary adenoma
evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning
plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH
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

Exclusion Criteria

Patients who have been previously treated with vorinostat
Patients who have received sellar radiation
History of thromboembolic disorder or deep vein thrombosis
Neutrophil count < 1.5 K//micro L
Hemoglobin < 8.0 g/dL
Hematocrit < 0.75x LLN (lower limit of normal)
Significant medical illnesses that in the investigator s opinion cannot be adequately
controlled or would compromise the patient s ability to tolerate this vorinostat
RBC count < 0.75x LLN
Any history of cancer, unless in complete remission and off of all therapy for that
Platelet count < 100 x 10^3 cells/micro L
disease for a minimum of 3 years
Serum bilirubin level > 1.5x ULN
Presence of abnormal hematological and biochemical parameters, (such as anemia or
Active infection being currently treated with systemic antibiotics
thrombocytopenia) as defined as
Pregnancy or lactation
Currently receiving other investigational agents
Currently taking another HDACi, such as valproate
Currently taking coumadin or its derivative anticoagulants
Prothrombin time-international normalized ratio (PT-INR) > 1.5x ULN or Activated
Currently taking any other medication to reduce cortisol or ACTH levels
partial thromboplastin time (aPTT) > 1.5x ULN, with the exception of patients on
prophylactic anticoagulation therapy
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
Presence of any disease that will obscure toxicity or dangerously alter drug
metabolism (such as uncontrolled diabetes or bleeding disorders)
History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat, such as valproate
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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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