Vorinostat for Cushing's Disease

Overseen By Michaela X Cortes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must not be taking: HDACi, Coumadin, Cortisol reducers

Disqualifiers: Cancer, Thromboembolic disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medication that reduces cortisol or ACTH levels, as well as certain anticoagulants like coumadin. If you're on these medications, you may need to stop them before participating.

How is the drug Vorinostat unique for treating Cushing's Disease?

Vorinostat is unique because it is a histone deacetylase inhibitor (a type of drug that affects gene expression) originally approved for cancer treatment, and it works by altering the structure and function of proteins involved in cell growth and death. This mechanism is different from traditional treatments for Cushing's Disease, which typically focus on reducing cortisol production. ^{1 2 3 4 5}

Research Team

Prashant Chittiboina, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

This trial is for adults over 18 with Cushing's disease who are scheduled for pituitary tumor surgery. They must be able to use effective birth control, have not had radiation on the sellar region, no history of cancer in the last 3 years, and cannot have been treated with vorinostat before. Participants should not have significant illnesses that could affect their participation or serious blood count abnormalities.

Inclusion Criteria

I am eligible for surgery to remove a tumor in my pituitary gland causing ACTH production.

I have been diagnosed with Cushing's disease, confirmed by specific hormone tests.

Enrolled in 03-N-0164, Evaluation of Neurosurgical Disorders

Exclusion Criteria

I have had blood clots or deep vein thrombosis in the past.

I have undergone radiation therapy targeting the pituitary gland area.

I have been cancer-free and off treatment for at least 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Not specified

Treatment

Participants receive oral vorinostat daily for 7 days to test its effect on ACTH levels

1 week

Daily monitoring during hospital stay

Surgery

Participants undergo surgery to remove the pituitary adenoma

1 day

In-hospital procedure

Follow-up

Participants are monitored for safety and effectiveness after treatment

Not specified

Treatment Details

Interventions

• Vorinostat

Trial Overview The trial tests Vorinostat's effectiveness on ACTH-producing pituitary adenomas in patients with Cushing’s disease. It involves an 8-day hospital stay where participants take Vorinostat orally before undergoing surgery to remove the tumor, alongside regular physical exams, blood tests, and urine collection.

Participant Groups

Group I: single center, prospective pilot study Experimental Treatment 1 Intervention

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

Vorinostat is already approved in United States, European Union for the following indications:

Approved in United States as Zolinza for:

• Cutaneous T-cell lymphoma

Approved in European Union as Zolinza for:

• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Findings from Research

Vorinostat's solubility was significantly enhanced when complexed with cyclodextrins, particularly with randomly methylated-β-cyclodextrin (RM-β-CD), which increased its solubility from 0.724 mm to 70.8 mm, making it nearly 100 times more soluble.

Molecular simulations supported these findings and suggested that using cyclodextrins could improve vorinostat's delivery methods, indicating potential for better oral absorption and parenteral delivery in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. Cai, YY., Yap, CW., Wang, Z., et al.[2018]

Vorinostat (SAHA) shows varying effectiveness in treating breast cancer, with some tumors and cell lines being resistant due to differences in gene expression related to cell adhesion and glutathione metabolism.

Depleting glutathione with buthionine sulfoximine (BSO) can enhance the effectiveness of SAHA, suggesting that evaluating antioxidant gene expression may help predict which tumors will respond to this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. Chiaradonna, F., Barozzi, I., Miccolo, C., et al.[2018]

Vorinostat, a histone deacetylase inhibitor, did not cause maternal toxicity or major fetal malformations in Sprague-Dawley rats and Dutch Belted rabbits, indicating a relatively safe profile during pregnancy at lower doses.

However, at high doses, vorinostat was associated with developmental toxicity, such as decreased fetal weight and skeletal variations, suggesting that while it is generally safe, caution is needed with higher dosages due to potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. Wise, LD., Turner, KJ., Kerr, JS.[2018]

Vorinostat, the first FDA-approved HDAC inhibitor, has shown safety and efficacy in treating cutaneous T-cell lymphoma (CTCL) with an overall response rate of 24-30% in advanced, refractory cases during Phase II trials.

Common side effects of vorinostat include gastrointestinal issues, fatigue, and thrombocytopenia, with thrombosis being the most serious adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Duvic, M., Vu, J.[2022]

SAHA (vorinostat) is effective in causing growth arrest and death in various cancer cells while showing minimal toxicity to normal cells, making it a promising treatment option.

SAHA works by inhibiting histone deacetylases (HDACs), which play a crucial role in regulating gene expression and cell behavior, and it has been approved for treating cutaneous T-cell lymphoma, with ongoing clinical trials for other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery and development of SAHA as an anticancer agent. Marks, PA.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Solubilization of vorinostat by cyclodextrins. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Discovery and development of SAHA as an anticancer agent. [2021]