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

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

Sponsors

Lead sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Source National Institutes of Health Clinical Center (CC)
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.-

Overall Status Recruiting
Start Date June 5, 2020
Completion Date June 15, 2021
Primary Completion Date June 15, 2021
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Midnight Plasma ACTH Day -1, Day 0-1, Day 2, Day 4-6, Discharge
Secondary Outcome
Measure Time Frame
Urinary Free Cortisol Day -1, Day 0-1, Day 2, Day 4-6, Discharge
Enrollment 22
Condition
Intervention

Intervention type: Drug

Intervention name: Vorinostat

Description: Administration of Vorinostat

Arm group label: single center, prospective pilot study

Eligibility

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

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Prashant Chittiboina, M.D. Principal Investigator National Institute of Neurological Disorders and Stroke (NINDS)
Overall Contact

Last name: Gretchen C Scott, R.N.

Phone: (301) 496-2921

Email: [email protected]

Location
facility status contact National Institutes of Health Clinical Center For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 TTY8664111010 [email protected]
Location Countries

United States

Verification Date

April 3, 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Arm group label: single center, prospective pilot study

Arm group type: Experimental

Description: effectiveness of vorinostat to reduce midnight ACTH levels in patients with Cushing s Disease

Study Design Info

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov