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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether vorinostat, a drug currently used to treat a type of cancer, can assist patients with Cushing's disease by targeting tumor cells and balancing hormone levels. Cushing's disease involves a non-cancerous tumor in the pituitary gland that causes an overproduction of certain hormones, leading to serious health issues. This study may suit adults diagnosed with Cushing's disease who are scheduled for surgery to remove the tumor. Participants will stay in the hospital for eight days, during which they will take the drug and undergo tests to assess its effects on their condition. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering participants a chance to contribute to significant advancements in Cushing's disease treatment.

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.

Is there any evidence suggesting that vorinostat is likely to be safe for humans?

Research has shown that vorinostat is generally safe. Already approved for treating a type of lymphoma, it is usually well-tolerated. Studies have found that vorinostat, which affects certain proteins in cells, has been used safely in treating blood cancers.

Patients in these studies experienced some side effects, but they were usually manageable. Common side effects include fatigue, diarrhea, and low blood cell counts. Not everyone will experience these side effects, and healthcare providers will monitor participants closely to address any issues.

In summary, research and its approval for treating lymphoma suggest that vorinostat is generally safe, although side effects can occur and will be monitored during trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Vorinostat is unique because it offers a new approach to treating Cushing's Disease by targeting histone deacetylases (HDACs), enzymes involved in gene expression regulation. Most current treatments for Cushing's Disease, like surgery, radiation, or medications such as ketoconazole, aim to reduce cortisol production or block its effects. Vorinostat's mechanism of action could potentially normalize hormone levels by affecting the genes controlling hormone production, providing a novel avenue for treatment. Researchers are excited about vorinostat because it might offer an alternative for patients who don't respond well to traditional therapies, potentially improving symptoms more effectively and with fewer side effects.

What evidence suggests that vorinostat might be an effective treatment for Cushing's disease?

Studies have shown that vorinostat, also known as SAHA, can reduce the growth of certain tumor cells and lower levels of the hormone ACTH, which causes issues in Cushing's disease. Lab studies found that vorinostat makes tumor cells die and stop producing ACTH. This trial will evaluate vorinostat's effectiveness in reducing midnight ACTH levels in patients with Cushing's disease. Although more research in humans is needed, these findings offer hope that vorinostat could be an effective treatment option. ^{2 6 7 8 9}

Who Is on the Research Team?

Prashant Chittiboina, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28505327/

Histone Deacetylase Inhibitor SAHA Is a Promising ... Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5546859/

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment ... Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/ ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04339751

Effect of Vorinostat on ACTH Producing Pituitary ... This is a single center, prospective pilot study of effectiveness of vorinostat to reduce midnight ACTH levels in patients with Cushing s Disease.

4. academic.oup.com academic.oup.com/jcem/article/104/3/925/5231872

Tumor-Directed Therapeutic Targets in Cushing Disease The histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) was shown to induce apoptosis and inhibit ACTH synthesis in murine and human ...

5. researchgate.net researchgate.net/publication/305732645_213_Histone_Deacetylase_Inhibitor_Vorinostat_Is_a_Novel_Promising_Treatment_for_Cushing_Disease

213 Histone Deacetylase Inhibitor Vorinostat Is a Novel ... Results: Vorinostat (1 µM) reduced AtT20 survival to 75% at 24 hours, 43% at 48 hours (analysis of variance, P = .002). Valproate/Panabinostat had no effect on ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26827693/

The safety profile of vorinostat (suberoylanilide hydroxamic ... This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies.

7. researchgate.net researchgate.net/publication/274732061_The_safety_profile_of_vorinostat_suberoylanilide_hydroxamic_acid_in_hematologic_malignancies_A_review_of_clinical_studies

The safety profile of vorinostat suberoylanilide hydroxamic ... This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies, ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03167437

NCT03167437 | An Open-Label, Proof of Consent Study ... To see if it is safe for people with moderate-to-sever CD to receive maintenance therapy using Ustekinumab after successful treatment of Vorinostat. Eligibility ...

9. academic.oup.com academic.oup.com/jcem/article-pdf/104/3/925/27715969/jc.2018-02080.pdf

Tumor-Directed Therapeutic Targets in Cushing Disease The histone deacetylase inhibitor vorinostat (sub- eroylanilide hydroxamic acid) was shown to induce apoptosis and inhibit ACTH synthesis in ...