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

Last updated: September 11, 2024
Sponsor: Cedars-Sinai Medical Center
Overall Status: Active - Recruiting

Phase

2

Condition

Cushing's Disease

Treatment

Seliciclib

Clinical Study ID

NCT03774446
Pro52406
FD-R-6106
  • Ages > 18
  • All Genders

Study 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)

Eligibility Criteria

Inclusion

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 UFCassessment ≥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 resectedpituitary ACTH-secreting tumor or IPSS central to peripheral ACTH gradient >2at baseline and >3 after CRH stimulation, and 24h-UFC >ULN beyond post-surgicalweek 6

  • Patients on medical treatment for Cushing disease. The following washout periodsmust 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, 4weeks

  • Progesterone receptor antagonist mifepristone: 2 weeks

  • Dopamine agonist cabergoline: 4 weeks

  • Patients treated with CYP3A or CYP2B6 strong inducers or inhibitors, includingthose listed below. Required washout time varies between drugs; minimum 5-6times 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 andritonavir 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

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 visualfields

  • 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 theprevious 1 months within normal range

  • Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism dueto overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolleddepression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, anduncontrolled 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 orare at risk thereof, as evidenced by congestive heart failure (NYHA Class III orIV), unstable angina, sustained ventricular tachycardia, clinically significantbradycardia, high grade atrioventricular (AV) block, history of acute MI less thanone year prior to study entry

  • Patients with liver disease or history of liver disease such as cirrhosis, chronicactive hepatitis B and C, or chronic persistent hepatitis, or patients with abnormalalanine transferase (ALT) or aspartate aminotransferase (AST) at screening orpatients 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 theconduct of the study or the evaluation of its results, such as

  • History of immunocompromise, including a positive HIV test result (ELISA andWestern blot). An HIV test will not be required, however, previous medicalhistory 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 toscreening

  • Female patients who are pregnant or lactating, or are of childbearing potential andnot practicing a medically acceptable method of birth control. If a woman isparticipating in the trial then one form of contraception is sufficient (pill ordiaphragm) and the partner should use a condom. If oral contraception is used inaddition to condoms, the patient must have been practicing this method for at leasttwo months prior to screening and must agree to continue the oral contraceptivethroughout the course of the study and for 3 months after the study has ended. Malepatients who are sexually active are required to use condoms during the study andfor three months afterwards as a precautionary measure (available data do notsuggest any increased reproductive risk with the study drugs)

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

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

  • Patients who have received pituitary irradiation within the last 5 years prior tothe 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 consideredpotentially 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 Design

Total Participants: 13
Treatment Group(s): 1
Primary Treatment: Seliciclib
Phase: 2
Study Start date:
November 02, 2018
Estimated Completion Date:
August 31, 2025

Study 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.

Connect with a study center

  • Cedars-Sinai Medical Center

    Los Angeles, California 90048
    United States

    Active - Recruiting

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