Seliciclib for Cushing's Disease

Overseen By Daniel Gomez

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cedars-Sinai Medical Center

Must not be taking: Steroidogenesis inhibitors, CYP3A inducers

Disqualifiers: Visual field issues, Non-pituitary ACTH, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

13 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of the drug seliciclib for people with Cushing's disease. Cushing's disease occurs when the body produces too much cortisol, often due to a pituitary gland issue in the brain. Participants will take an oral dose of seliciclib daily for four weeks. The trial seeks individuals diagnosed with Cushing's disease, especially those with a confirmed pituitary source of the hormone imbalance. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

Yes, you may need to stop taking certain medications before joining the trial. There are specific 'washout' periods (time without taking certain medications) required for drugs like metyrapone, ketoconazole, and others, ranging from 2 to 6 weeks, depending on the medication.

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

Research shows that seliciclib may help treat Cushing's disease. In earlier studies, most patients tolerated seliciclib well, with few reports of serious side effects. However, the researchers are still gathering safety information, so some risks might not be fully understood yet.

This trial is in an early stage, focusing on understanding the safety of seliciclib. Testing in humans suggests it has shown some safety in earlier research. Participants in the trial will be closely monitored by medical professionals. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Cushing's Disease, which typically involve surgery to remove the tumor causing excess cortisol production or medications like ketoconazole and metyrapone that inhibit cortisol synthesis, Seliciclib offers a novel approach. This experimental drug is a CDK inhibitor, meaning it targets specific enzymes involved in cell cycle regulation, potentially reducing the tumor's ability to produce hormones. Researchers are excited because this mechanism offers a targeted approach that could minimize side effects and provide an oral treatment option, making it more convenient for patients.

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

Research has shown that seliciclib, the treatment under study in this trial, might help reduce symptoms of Cushing's disease. In some studies, patients experienced significant decreases in their urine free cortisol (UFC) levels, a measure of cortisol. Specifically, three patients saw their cortisol levels drop by 55% to 75%, while two others had a 48% reduction. Although these results are promising, none of the patients reached normal cortisol levels. This suggests that seliciclib could be helpful, but more research is needed to confirm its benefits. ^{1 2 4 6 7}

Who Is on the Research Team?

Shlomo Melmed, MD

Principal Investigator

Cedars-Sinai Medical Center

Ning-Ai Liu, MD, PhD

Principal Investigator

Cedars-Sinai Medical Center

Are You a Good Fit for This Trial?

Adults with Cushing's disease from a pituitary source, who have high cortisol levels and are not currently well-controlled on other treatments. They must be at least 18 years old, have completed specific medication washout periods, and cannot have had pituitary radiation in the last 5 years or any major surgery within the past month.

Inclusion Criteria

I have a large pituitary tumor and specific test results showing a hormone imbalance.

My condition is caused by an excess of ACTH from the pituitary gland.

I have not taken mifepristone in the last 2 weeks.

Exclusion Criteria

I have tested positive for hepatitis B.

You are allergic to seliciclib.

You have had problems with alcohol in the past year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 80 mg of oral seliciclib each day for 4 weeks

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Seliciclib

Trial Overview

The trial is testing Seliciclib, an oral medication given for four weeks to see if it's safe and effective for treating Cushing's disease. It’s an open-label study funded by the FDA Office of Orphan Products Development.

How Is the Trial Designed?

Group I: Seliciclib Experimental Treatment 1 Intervention

80 mg each day oral seliciclib for 4 weeks

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

Published Research Related to This Trial

R-roscovitine effectively inhibits ACTH production in human corticotroph tumors by targeting the cyclin E/E2F1 signaling pathway, which is crucial for regulating POMC transcription.

This study reveals a new molecular mechanism in the neuroendocrine regulation of the hypothalamic-pituitary-adrenal axis, suggesting that R-roscovitine could be a promising therapeutic option for treating Cushing disease by reducing excess cortisol production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease. Liu, NA., Araki, T., Cuevas-Ramos, D., et al.[2018]

Blocking EGFR in corticotroph tumors significantly reduced the expression of proopiomelanocortin (POMC), which is crucial for ACTH production, suggesting that targeting EGFR could effectively lower ACTH levels in Cushing disease.

Treatment with gefitinib, an EGFR inhibitor, not only decreased tumor size and serum corticosterone levels in mouse models but also reversed symptoms of hypercortisolemia, indicating its potential as a new therapeutic option for Cushing disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. Fukuoka, H., Cooper, O., Ben-Shlomo, A., et al.[2021]

Transsphenoidal surgery is the primary treatment for Cushing's disease, achieving long-term remission in 60-90% of patients, but those who cannot undergo surgery or have unsuccessful outcomes may benefit from medical therapies.

Recent studies have highlighted the efficacy of drugs like pasireotide and mifepristone, as well as new compounds like LCI699, in managing Cushing's disease, indicating a growing range of treatment options for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent developments in drug therapy for Cushing's disease. van der Pas, R., de Herder, WW., Hofland, LJ., et al.[2021]

Recent advancements in medical therapies for Cushing's syndrome include drugs that target dopamine and somatostatin receptors, which can control cortisol production in up to 40% of patients, providing a viable option when surgery is not successful.

New drug candidates like osilodrostat, levoketoconazole, and CORT125134 are being evaluated in multicenter trials, offering hope for more effective and personalized treatments for Cushing's syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the medical treatment of Cushing's syndrome. Feelders, RA., Newell-Price, J., Pivonello, R., et al.[2022]

Endogenous Cushing's syndrome is a serious condition that can lead to increased health risks if not treated properly, and medical treatments are essential for managing cortisol levels, especially after surgery or while awaiting radiation therapy.

Recent advancements in medical treatments include new steroidogenesis inhibitors, pituitary-directed drugs, and glucocorticoid receptor antagonists, which may offer fewer side effects and target the underlying causes of Cushing's syndrome more effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medical Management of Cushing's Syndrome: Current and Emerging Treatments. Hinojosa-Amaya, JM., Cuevas-Ramos, D., Fleseriu, M.[2020]

Researchers developed a transgenic zebrafish model that mimics Cushing disease, allowing for effective in vivo drug testing against ACTH-secreting pituitary adenomas.

The CDK2/cyclin E inhibitor R-roscovitine was found to significantly reduce ACTH and corticosterone levels, suppress tumor growth, and induce senescence in corticotroph tumor cells, suggesting it could be a promising treatment for Cushing disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Liu, NA., Jiang, H., Ben-Shlomo, A., et al.[2021]

Lapatinib, a dual tyrosine kinase inhibitor, effectively reduces ACTH production and cell proliferation in corticotroph tumor cells, indicating its potential as a treatment for Cushing's disease.

In vivo studies in mice showed that lapatinib significantly decreased tumor weight and lowered levels of key markers associated with pituitary tumors, suggesting it could be a promising therapeutic option for patients with ACTH-producing adenomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. Asari, Y., Kageyama, K., Sugiyama, A., et al.[2020]

Pasireotide is the only approved medication specifically targeting pituitary tumors in Cushing's disease, providing a pharmacological option for patients who cannot undergo surgery or experience recurrence after surgery.

Emerging treatments, such as roscovitine and gefitinib, show promise in targeting the underlying mechanisms of Cushing's disease, although their efficacy and safety profiles are still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pituitary-Directed Therapies for Cushing's Disease. Langlois, F., Chu, J., Fleseriu, M.[2019]

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Treatment of Cushing Disease With Pituitary-Targeting ...

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A recent study investigated the role of seliciclib in regulating biochemical parameters in a small number of patients with Cushing's disease, ...

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Treatment of Cushing Disease With Pituitary-Targeting Seliciclib

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This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4 weeks of oral seliciclib in patients with newly diagnosed, ...

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This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4 weeks of oral seliciclib in patients with newly diagnosed, persistent ...