Clinical Trial: Treatment of Cushing's Disease With R-roscovitine

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Treatment of Pituitary Cushing Disease With a Selective CDK Inhibitor, R-roscovitine

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.

Detailed Summary: To date, R-roscovitine (seliciclib) has been evaluated in several Phase I and II studies and has shown early signs of anti-cancer activity in approximately 240 patients. Studies included a Phase I study in which single agent seliciclib was administered to patients with advanced non-small cell lung cancer (NSCLC) and two Phase IIa studies in which seliciclib was administered in combination with gemcitabine and cisplatin as first-line treatment and with docetaxel as second-line treatment in NSCLC. Seliciclib was also evaluated in a Phase I study in patients with nasopharyngeal cancer (NPC) with evidence of tumor shrinkage and concomitant reduction in copy counts of the EBV virus that is causally associated with the pathogenesis of NPC. Results from APPRAISE, a randomized discontinuation, double-blinded, placebo-controlled, Phase IIb study of oral seliciclib capsules as a monotherapy in heavily pretreated patients with NSCLC, demonstrated no difference between the seliciclib and placebo arms in progression free survival but a substantial increase in overall survival was observed (388 versus 218 days respectively (Cyclacel Pharmaceuticals press release Dec 21, 2010). Here, the investigators propose an exploratory, proof of concept clinical trial to determine if seliciclib can safely normalize urinary free cortisol levels by reducing pituitary corticotroph tumor ACTH production in patients with Cushing disease.
Sponsor: Shlomo Melmed, MD

Current Primary Outcome: Number of participants with a normalized 24 hour urinary free cortisol after 4 weeks [ Time Frame: 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.


Original Primary Outcome: Number of participants with a normalized 24 hour urinary free cortisol after 4 weeks [ Time Frame: 4 weeks ]

To evaluate the efficacy of seliciclib 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.


Current Secondary Outcome:

  • Change in levels of pituitary hormones [ Time Frame: Baseline, Week 4 ]
    • Pituitary Panel (TSH,FT4, FT3, PRL, IGF-1, FSH, Testosterone Total, Free Testosterone, Estradial, SHBG)
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 4 weeks ]
  • Changes in tumor size [ Time Frame: 4 weeks ]
  • Changes in clinical signs [ Time Frame: Baseline, Week 4 ]
    • A urinary free cortisol level above the upper limit of the normal range but reduced by ≥50% from baseline at week 4
  • Change in levels metabolic abnormality [ Time Frame: Baseline, Week 4 ]
    • Hemoglobin A1C (HbA1C), fasting blood glucose and blood electrolytes, e.g. K+
  • Changes in clinical signs [ Time Frame: 4 weeks ]
    • Plasma ACTH, 24 hour urinary free cortisol, serum and salivary cortisol levels over time
  • Change in clinical symptoms [ Time Frame: 4 weeks ]
    • Cushing's syndrome clinical signs and symptoms, e.g. weight, body mass index, blood pressure


Original Secondary Outcome: Same as current

Information By: Cedars-Sinai Medical Center

Dates:
Date Received: May 21, 2014
Date Started: May 2014
Date Completion: June 2019
Last Updated: January 30, 2017
Last Verified: January 2016