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

Michaela X Cortes

Prashant Chittiboina, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

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.

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.

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

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

.We do plan to share IPD. we will share all IPD that results in a publication on a public repository, as required by most journals. the data will be de-identified and anonymized.

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).

Relative change in 24-hour urinary free cortisol during 7 day administration of Vorinostat

National Institute of Neurological Disorders and Stroke (NINDS)

Symptoms and General Pathology

Infections

Digestive System Diseases

Ulcer

Communicable Diseases

Crohn Disease

Colitis

Colitis, Ulcerative

Inflammatory Bowel Diseases

Intestinal Diseases

Gastroenteritis

Gastrointestinal Diseases

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Gastrointestinal Agents

Anti-Inflammatory Agents

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Methotrexate

Ustekinumab

Tofacitinib

Ozanimod

Vedolizumab

Upadacitinib

Adalimumab

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Infliximab

Golimumab

Interleukin-12

Interleukin-23

Mirikizumab

Patients treated with anti-IL23p19 (risankizumab, guselkumab, mirikizumab, brazikumab)

Patient treated with Jak inhibitors (tofacitinib, upadacitinib, filgotinib)

Patient treated with S1P modulators (ozanimod, etrasimod)

Patient treated with anti-TNF (infliximab, adalimumab, golimumab) (with a maximal proportion of 25% as 1st first line biologic after conventional treatment (aminosalicylates, corticosteroids, thiopurines, methotrexate))

Patient treated with anti-integrins (vedolizumab)

Patient treated with anti-IL12/23 (ustekinumab)

This study is non-interventional, patients will be enrolled when initiating a treatment through standard of care procedures.

Non-interventional

Marie Coisnon

Charlotte Mailhat

Mathurin FUMERY, PHD

Julien Kirchgesner

Mathurin Fumery

This is a French prospective longitudinal observational multicentre cohort study.

Primary objective : to assess prospectively the presence and the extent of safety concerns (cancer, serious infections, arterial and venous thrombotic events) in patients with CD and UC and treated with JAKi, anti-IL23p19, and S1p modulators.

Number of patients : 6 000 at least Participating investigators : 250 at least

Recruitment period : 3 years 6 months

Primary objective : to assess prospectively the presence and the extent of safety concerns (cancer, serious infections, arterial and venous thrombotic events) in patients with CD and UC and treated with JAKi, anti-IL23p19, and S1p modulators.

Secondary objectives :

* To assess the presence and the extent of safety concerns in patients treated with JAKi, anti-IL23p19, and S1p modulators for each outcome of interest separately (cancer, serious infections, arterial thrombotic events, venous thrombotic events)
* To investigate prospectively the impact of JAKi, anti-IL23p19 and S1p modulators strategies on the natural history of IBD and their potential for disease modification by collecting validated surrogate markers such as mucosal healing and disease complications such as bowel damage (strictures, fistulas, abscess), surgeries, and hospitalizations
* To assess the evolution of ePROs on a trimester basis and the impact of JAKi, anti-IL23p19, and S1p modulators on ePROs in IBD
* To evaluate the benefit-risk ratio of strategies based on a wider use of JAKi, anti-IL23p19, and S1p modulators therapy for IBD
* To assess the healthcare costs and cost-efficacy of current therapeutic strategies in IBD.

Ibd CAncer and seRious Infections in France (I-CARE 2)

The primary objective of I-CARE 2 is to assess prospectively the presence and the extent of safety concerns (cancer, serious infections, arterial and venous thrombotic events) in patients with CD and UC and treated with JAKi, anti-IL23p19, and S1p modulators.

The risk of cancers, serious infections and vascular events will be stratified according to IBD phenotype, disease activity (clinical, radiologic and endoscopic) and main comorbidities at baseline.

To assess the presence and the extent of safety concerns in patients treated with JAKi, anti-IL23p19, and S1p modulators for each outcome of interest separately

* Cancer
* Serious infections
* Arterial thrombotic events
* Venous thrombotic events

To investigate prospectively the impact of JAKi, anti-IL23p19 and S1p modulators strategies on the natural history of IBD and their potential for disease modification by collecting validated surrogate markers such as mucosal healing and disease complications such as bowel damage (strictures, fistulas, abscess), surgeries, and hospitalizations

To assess the evolution of ePROs on a trimester basis and the impact of JAKi, anti-IL23p19, and S1p modulators on ePROs in IBD

To evaluate the benefit-risk ratio of strategies based on a wider use of JAKi, anti-IL23p19, and S1p modulators therapy for IBD

To assess the healthcare costs and cost-efficacy of current therapeutic strategies in IBD.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Vorinostat on ACTH Producing Pituitary Adenomas in Cushing s Disease	NCT04339751	Cushing's Disea...	Vorinostat	18 Years -	National Institutes of Health Clinical Center (CC)
Ibd CAncer and seRious Infections in France (I-CARE 2)	NCT06089590	IBD Ulcerative Coli... Crohn Disease	Non-interventio...	18 Years - 75 Years	Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Ibd CAncer and seRious Infections in France (I-CARE 2)	NCT06089590	IBD Ulcerative Coli... Crohn Disease	Non-interventio...	18 Years - 75 Years	Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

Spots Global Cancer Trial Database for cd

Every month we try and update this database with for cd cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for cd

Every month we try and update this database with for cd cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for cd cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.