Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease

Cushing Disease Clinical Trial

Official title:

A Phase 2 Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03774446
• Other study ID #: Pro52406
• Secondary ID: FD-R-6106
• Status: Recruiting
• Phase: Phase 2
• Start date: November 2, 2018
• Est. completion date: August 2025

Study information

• Verified date: September 2023
• Source: Cedars-Sinai Medical Center
• Contact: Vivian Hwe
• Phone: 424-315-4489
• Email: vivian.hwe[@]cshs.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Description:

This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to 13 subjects will be treated with 80 mg each day for 4 weeks. The study will also evaluate effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 13
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female patients at least 18 years old

• Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH) production:

• Persistent hypercortisolemia established by two consecutive 24-hour UFC assessment =1.5× the upper limit of normal

• Normal or elevated ACTH levels

• Pituitary adenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and >3 after CRH stimulation

• Recurrent or persistent CD defined as pathologically confirmed resected pituitary ACTH-secreting tumor or IPSS central to peripheral ACTH gradient >2 at baseline and >3 after CRH stimulation, and 24h-UFC >ULN beyond post-surgical week 6

• Patients on medical treatment for Cushing disease. The following washout periods must be completed before screening assessments are performed:

• Inhibitors of steroidogenesis: metyrapone, ketoconazole: 2 weeks; Levoketoconazole: 3 weeks; osilodrostat: 6 weeks

• Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4 weeks

• Progesterone receptor antagonist mifepristone: 2 weeks

• Dopamine agonist cabergoline: 4 weeks

• Patients treated with CYP3A or CYP2B6 strong inducers or inhibitors, including those listed below. Required washout time varies between drugs; minimum 5-6 times the half-life of the drug.

• Strong CYP3A inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort

• Moderate CYP3A inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone

• Weak CYP3A inducers: armodafinil, modafinil, rufinamide

• Strong CYP2B6 inducer: carbamazepine

• Moderate CYP2B6 inducers: efavirenz, rifampin

• Weak CYP2B6 inducers: nevirapine, ritonavir

• Strong CYP3A inhibitors: boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole, clarithromycin, idelalisib, nefazodone, nelfinavir.

• Moderate CYP3A inhibitors: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, verapamil

• Strong CYP2B6 inhibitor: ticlopidine

Exclusion criteria:

• Patients with compromised visual fields, and not stable for at least 6 months

• Patients with abutment or compression of the optic chiasm on MRI and normal visual fields

• Patients with Cushing's syndrome due to non-pituitary ACTH secretion

• Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia

• Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e., Carney Complex, McCune-Albright syndrome, Multiple endocrine neoplasia (MEN) 1

• Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)

• Patients with cyclic Cushing's syndrome defined by any measurement of UFC over the previous 1 months within normal range

• Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism due to overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and uncontrolled diabetes mellitus

• Patients who have undergone major surgery within 1 month prior to screening

• Patients with serum K+< 3.5 while on replacement treatment

• Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%

• Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one year prior to study entry

• Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with abnormal alanine transferase (ALT) or aspartate aminotransferase (AST) at screening or patients with advanced liver fibrosis (=10 kPa) on elastography at screening

• Patients with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2

• Patients not biochemically euthyroid

• Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as

• History of immunocompromise, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required, however, previous medical history will be reviewed

• Presence of active or suspected acute or chronic uncontrolled infection

• History of, or current alcohol misuse/abuse in the 12 month period prior to screening

• Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three months afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)

• Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with seliciclib

• Patients with any ongoing or likely to require additional concomitant medical treatment to treat CD

• Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit

• Patients who have been treated with radionuclide at any time prior to study entry

• Patients with known hypersensitivity to seliciclib

• Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study

• Patients with hepatitis B surface antigen (HbsAg) positivity

• Patients with hepatitis C antibody (anti-HCV) positivity

• Patients with prolonged QTcF on screening electrocardiogram (QTcF >450 msec)

Related Conditions & MeSH terms

• ACTH-Secreting Pituitary Adenoma
• Cushing Disease
• Pituitary ACTH Hypersecretion

Intervention

Drug:
• Seliciclib
Drug: Seliciclib

Locations

Country	Name	City	State
United States	Cedars-Sinai Medical Center	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (2)

Liu NA, Araki T, Cuevas-Ramos D, Hong J, Ben-Shlomo A, Tone Y, Tone M, Melmed S. Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease. J Clin Endocrinol Metab. 2015 Jul;100(7):2557-64. doi: 10.1210/jc.2015-1606. Epub 2015 May 5. — View Citation

Liu NA, Jiang H, Ben-Shlomo A, Wawrowsky K, Fan XM, Lin S, Melmed S. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8414-9. doi: 10.1073/pnas.1018091108. Epub 2011 May 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with a normalized 24-hour urinary free cortisol (UFC) at study completion		4 weeks
Primary	Number of participants with UFC above the upper limit of normal (ULN) but reduced by =50% from baseline at study completion		4 weeks
Secondary	Plasma adrenocorticotrophic hormone		Baseline and week 4
Secondary	Salivary cortisol		Baseline and week 4
Secondary	Serum cortisol		Baseline and week 4
Secondary	Glycated hemoglobin (HbA1c)		Baseline and week 4
Secondary	Fasting blood glucose		Baseline and week 4
Secondary	Weight and height to report body mass index (BMI) in kg/m^2		Baseline and week 4
Secondary	Blood pressure		Baseline and week 4
Secondary	Change on visual field exam		Baseline and week 4
Secondary	Change in tumor size on pituitary MRI		Baseline and week 4
Secondary	Change in quality of life measured using the CushingQOL questionnaire		Baseline and week 4
Secondary	Number of treatment-emergent adverse events graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 4.0		Baseline and week 4