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

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT04339751

Collaborator

(none)

Enrollment

Location

Arm

21.3

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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

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.

Objectives

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

Endpoints

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

Study Design

Study Type:

Interventional

Anticipated 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

Anticipated Study Start Date :

Aug 23, 2022

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

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

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

Primary Outcome Measures

Midnight Plasma ACTH [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

Urinary Free Cortisol [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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