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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03774446
Recruitment Status : Recruiting
First Posted : December 13, 2018
Last Update Posted : November 29, 2019
Sponsor:
Information provided by (Responsible Party):
Shlomo Melmed, MD, Cedars-Sinai Medical Center

Tracking Information
First Submitted Date  ICMJE November 6, 2018
First Posted Date  ICMJE December 13, 2018
Last Update Posted Date November 29, 2019
Actual Study Start Date  ICMJE November 2, 2018
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2018)
  • Number of participants with a normalized 24-hour urinary free cortisol (UFC) at study completion [ Time Frame: 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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03774446 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2018)
  • Plasma adrenocorticotrophic hormone [ Time Frame: Baseline and week 4 ]
  • Salivary cortisol [ Time Frame: Baseline and week 4 ]
  • Serum cortisol [ Time Frame: Baseline and week 4 ]
  • Glycated hemoglobin (HbA1c) [ Time Frame: Baseline and week 4 ]
  • Fasting blood glucose [ Time Frame: Baseline and week 4 ]
  • Weight and height to report body mass index (BMI) in kg/m^2 [ Time Frame: Baseline and week 4 ]
  • Blood pressure [ Time Frame: Baseline and week 4 ]
  • Change on visual field exam [ Time Frame: Baseline and week 4 ]
  • Change in tumor size on pituitary MRI [ Time Frame: Baseline and week 4 ]
  • Change in quality of life measured using the CushingQOL questionnaire [ Time Frame: 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease
Official Title  ICMJE A Phase 2 Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease
Brief 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)

Detailed Description This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of two of three potential doses/schedules of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to 29 subjects will be treated with up to 800 mg/day oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. The study will also evaluate effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cushing Disease
Intervention  ICMJE Drug: Seliciclib
Drug: Seliciclib
Other Name: R-roscotivine
Study Arms  ICMJE Experimental: Seliciclib
Up to 800 mg/day oral seliciclib for 4 days each week for 4 weeks
Intervention: Drug: Seliciclib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 11, 2018)
29
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2022
Estimated Primary Completion Date November 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 h UFC levels at least 1.5x the upper limit of normal
    • Normal or elevated ACTH levels
    • Pituitary macroadenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and >3 after corticotropin-releasing hormone (CRH) stimulation
    • Recurrent or persistent Cushing disease 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 24 hour UFC above the upper limit of normal reference range 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
      • Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4 weeks
      • Progesterone receptor antagonist (mifepristone): 2 weeks
      • Dopamine agonists (cabergoline): 4 weeks
      • CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug

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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal (LLN) at screening
  • Serum creatinine > 2 x ULN
  • 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 month 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 seliciclib for the tumor
  • Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors.
  • Patients who were receiving mitotane and/or long-acting somatostatin receptor ligands octreotide long-acting release (LAR) or lanreotide
  • 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 presence of Hepatitis B surface antigen (HbsAg)
  • Patients with presence of Hepatitis C antibody test (anti-HCV)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Vivian Hwe, CCRP 424-315-4489 Vivian.Hwe@cshs.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03774446
Other Study ID Numbers  ICMJE Pro52406
FD-R-6106 ( Other Grant/Funding Number: Food & Drug Administration )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Shlomo Melmed, MD, Cedars-Sinai Medical Center
Study Sponsor  ICMJE Cedars-Sinai Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Shlomo Melmed, MD Cedars-Sinai Medical Center
Study Director: Ning-Ai Liu, MD, PhD Cedars-Sinai Medical Center
PRS Account Cedars-Sinai Medical Center
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP