- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03774446
Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease
A Phase 2 Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease
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)
Study Overview
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Vivian Hwe
- Phone Number: 424-315-4489
- Email: Vivian.Hwe@cshs.org
Study Locations
-
-
California
-
Los Angeles, California, United States, 90048
- Recruiting
- Cedars-Sinai Medical Center
-
Contact:
- Vivian Hwe
- Phone Number: 424-315-4489
- Email: Vivian.Hwe@cshs.org
-
Principal Investigator:
- Shlomo Melmed, MD
-
Sub-Investigator:
- Ning-Ai Liu, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Seliciclib
80 mg each day oral seliciclib for 4 weeks
|
Drug: Seliciclib
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of participants with a normalized 24-hour urinary free cortisol (UFC) at study completion
Time Frame: 4 weeks
|
4 weeks
|
Number of participants with UFC above the upper limit of normal (ULN) but reduced by ≥50% from baseline at study completion
Time Frame: 4 weeks
|
4 weeks
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Plasma adrenocorticotrophic hormone
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Salivary cortisol
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Serum cortisol
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Glycated hemoglobin (HbA1c)
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Fasting blood glucose
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Weight and height to report body mass index (BMI) in kg/m^2
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Blood pressure
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Change on visual field exam
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Change in tumor size on pituitary MRI
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Change in quality of life measured using the CushingQOL questionnaire
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Number of treatment-emergent adverse events graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 4.0
Time Frame: Baseline and week 4
|
Baseline and week 4
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Shlomo Melmed, MD, Cedars-Sinai Medical Center
- Study Director: Ning-Ai Liu, MD, PhD, Cedars-Sinai Medical Center
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Endocrine System Diseases
- Endocrine Gland Neoplasms
- Hypothalamic Diseases
- Hyperpituitarism
- Pituitary Diseases
- Adenoma
- Pituitary Neoplasms
- ACTH-Secreting Pituitary Adenoma
- Pituitary ACTH Hypersecretion
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Roscovitine
Other Study ID Numbers
- Pro52406
- FD-R-6106 (Other Grant/Funding Number: Food & Drug Administration)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Cushing Disease
-
University of LeedsCompletedAdrenal; Insufficiency Gluccorticoid-Induced | Cushing; Syndrome or Disease, Glucocorticoid-Induced
-
Centre hospitalier de l'Université de Montréal...Recordati Rare DiseasesActive, not recruitingEndogenous Cushing SyndromeCanada
-
Sparrow PharmaceuticalsRecruitingAutonomous Cortisol Secretion (ACS) | ACTH-Independent Cushing Syndrome | ACTH-Independent Adrenal Cushing Syndrome, SomaticUnited States, United Kingdom, France, Romania
-
National Cancer Institute (NCI)Not yet recruitingHyperaldosteronism | Hypercortisolism | Cushing s SyndromeUnited States
-
Memorial Sloan Kettering Cancer CenterRecruitingCushing Syndrome | Cushing's Disease | Cushing DiseaseUnited States
-
HRA PharmaRecruitingCushing SyndromeSweden, France, Croatia, Spain
-
RECORDATI GROUPActive, not recruitingCushing's SyndromeUnited States, Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, China, Costa Rica, France, Germany, India, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Thailand, Turkey
-
Eunice Kennedy Shriver National Institute of Child...Completed
-
Corcept TherapeuticsCompletedCushing's SyndromeUnited States
-
HRA PharmaCompletedCushing's SyndromeGermany, Belgium, Italy, Hungary, Poland, Romania, Spain, Turkey
Clinical Trials on Seliciclib
-
University Hospital, BrestCyclacel Pharmaceuticals, Inc.; ManRos TherapeuticsTerminated
-
Cyclacel Pharmaceuticals, Inc.TerminatedNon-small Cell Lung CancerUnited States
-
Shlomo Melmed, MDNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Terminated
-
Cyclacel Pharmaceuticals, Inc.CompletedAdvanced Solid TumorsUnited States
-
M.D. Anderson Cancer CenterNational Institutes of Health (NIH)Withdrawn
-
Engelhard Arzneimittel GmbH & Co.KGClinCompetence Cologne GmbHCompletedBronchitis | Rhinosinusitis Chronic | Rhinosinusitis AcuteGermany