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

Trial Summary

What is the purpose of this trial?

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, or recurrent Cushing disease. Funding Source - FDA Office of Orphan Products Development (OOPD)

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.

What data supports the effectiveness of the drug Seliciclib for Cushing's Disease?

Research shows that Seliciclib, also known as R-roscovitine, can reduce the production of ACTH (a hormone that stimulates cortisol production) and slow down the growth of pituitary tumors in animal models. This suggests it might help manage Cushing's Disease by targeting the underlying tumor activity. ^{1 2 3 4 5}

Is Seliciclib safe for humans?

Seliciclib, also known as R-roscovitine or CYC202, has been studied in mice and zebrafish, where it was found to inhibit certain proteins involved in hormone production. However, specific safety data for humans is not provided in the available research. ^{1 2 4 5 6}

How is the drug Seliciclib different from other treatments for Cushing's Disease?

Seliciclib is unique because it targets the cyclin-dependent kinase 2/cyclin E signaling pathway, which is involved in the regulation of ACTH production in corticotroph tumors, unlike other treatments that focus on inhibiting steroid synthesis or blocking cortisol receptors. ^{1 2 5 7 8}

Research Team

Shlomo Melmed, MD

Principal Investigator

Cedars-Sinai Medical Center

Ning-Ai Liu, MD, PhD

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

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

You are allergic to seliciclib.

I have tested positive for hepatitis B.

You have had problems with alcohol in the past year.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

Advances in the medical treatment of Cushing's syndrome. [2022]

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

Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease. [2018]

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

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. [2021]

4. Japan pubmed.ncbi.nlm.nih.gov

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. [2020]

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

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Medical Management of Cushing's Syndrome: Current and Emerging Treatments. [2020]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Recent developments in drug therapy for Cushing's disease. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pituitary-Directed Therapies for Cushing's Disease. [2019]