Treatment of Cushing's Disease With R-roscovitine

NCT02160730 | Terminated Phase 2 Results DMC

• 2 other identifiers: Pro357201R21DK103198-01
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators hypothesize that R-roscovitine will suppress pituitary corticotroph tumor ACTH production and normalize urinary free cortisol levels in patients with Cushing disease. To date, R-roscovitine has been evaluated in several Phase I and II studies and has shown early signs of anti-cancer activity in approximately 240 patients.

Conditions

Cushings Disease

Keywords

Cushings disease; R-roscovitine

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks

  To evaluate the efficacy of R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks on normalizing 24 hour urinary free cortisol (24 h UFC) levels in CD patients. "Normalizing" is defined as having urine free cortisol levels within the normal range for that lab value.

  Baseline, 4 weeks

Secondary Outcomes (10)

• Change in Mean HbA1c Levels Between Baseline and 4 Weeks

  Baseline, 4 Weeks

• Number of Participants With Adverse Events

  Baseline, 4 weeks

• Number of Participants That Have a Visible Change in Tumor Size

  Baseline, 4 weeks

• Number of Participants That Experience Changes in Clinical Signs of Hypercortisolemia

  Baseline, Week 4

• Fasting Glucose at Baseline and 4 Weeks

  Baseline, 4 Weeks

Study Arms (1)

R-roscovitine

EXPERIMENTAL

• R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks.

Drug: R-roscovitine

Interventions

R-roscovitine DRUG

See Arm Description

Also known as: Seliciclib, CYC202

R-roscovitine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 CRH stimulation
• Recurrent or persistent Cushing disease is defined as pathologically confirmed resected pituitary ACTH-secreting tumor, and 24 hour UFC above the upper limit of normal reference range beyond post-surgical week 6
• Patients on medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed:
• Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks
• Somatostatin analogs (pasireotide): 2 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

You may not qualify if:

• 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, 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 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 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 ALT or AST more than 1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x LLN at screening
• Serum creatinine \> 2 x ULN

Sponsors & Collaborators

• Shlomo Melmed, MD: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Related Publications (27)

• Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 10.1210/jc.2008-0125. Epub 2008 Mar 11.

  PMID: 18334580 BACKGROUND

• Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62. doi: 10.1210/jc.2007-2734. Epub 2008 Apr 15.

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  BACKGROUND

• Yeo et al. J Clin Oncol 2009 27-15s (Suppl abstr 6026).

  BACKGROUND

MeSH Terms

Conditions

Adrenocortical Hyperfunction

Interventions

Roscovitine

Condition Hierarchy (Ancestors)

Adrenal Gland Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Ning-Ai Liu
• Organization: Cedars-Sinai Medical Center

ning-ai.liu@cshs.org

310-423-7382

Study Officials

• Shlomo Melmed, MD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

• Ning-Ai Liu, MD, PhD

  Cedars-Sinai Medical Center

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sr. Vice President of Academic Affairs

Study Record Dates

• First Submitted: May 21, 2014
• First Posted: June 11, 2014
• Study Start: May 1, 2014
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: November 4, 2021
• Results First Posted: October 29, 2021

Record last verified: 2021-11

Locations

US (1)