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Cushings DiseasePhase 2NCT02160730

Treatment of Cushing's Disease With R-roscovitine

A Phase 2 study testing R-roscovitine in people with Cushings Disease, run by Shlomo Melmed, MD at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Cushings Disease
What is being tested?
R-roscovitine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
1 siteUnited States
Study dates
May 2014to Oct 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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

Who cannot join

  • 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)
Show all 32Show fewer
  • 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
  • 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 analogs (octreotide LAR or lanreotide)
  • Patients who were receiving pasireotide or ketoconazole before study entry must complete a 2 week washout period prior to receiving seliciclib
  • 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)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Cedars-Sinai Medical Center

    Los Angeles, California, 90048

Other trials in United States

About this study

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

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.

Read the detailed description

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.

Being tested
R-roscovitine
Keywords
Cushings disease, R-roscovitine
Medical subject headings
Adrenocortical Hyperfunction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • R-roscovitineDrug

    Also called Seliciclib, CYC202

    See Arm Description

Study groups in NCT02160730
Study groupRoleWhat they receive
R-roscovitineExperimental• R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks.
Receives: Drug: R-roscovitine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline, 4 weeks

Secondary outcomes (10)

  1. Change in Mean HbA1c Levels Between Baseline and 4 Weeks

    HbA1c levels are measured at baseline and at study end, these are averaged across all subjects.

    Measured: Baseline, 4 Weeks

  2. Number of Participants With Adverse Events

    The number of participants that experience an adverse event between baseline and study end likely related to study drug as a measure of safety and tolerability.

    Measured: Baseline, 4 weeks

  3. Number of Participants That Have a Visible Change in Tumor Size

    A visible change in tumor size as determined by the investigator after reviewing MRI reports between baseline and 4 weeks of treatment.

    Measured: Baseline, 4 weeks

  4. Number of Participants That Experience Changes in Clinical Signs of Hypercortisolemia

    The number of participants that achieved a urinary free cortisol level above the upper limit of the normal range but reduced by ≥50% from baseline at week 4.

    Measured: Baseline, Week 4

  5. Fasting Glucose at Baseline and 4 Weeks

    Mean change between baseline and week 4 of fasting blood glucose levels.

    Measured: Baseline, 4 Weeks

  6. Plasma ACTH at Baseline and 4 Weeks

    Mean change in Plasma ACTH between baseline and 4 weeks.

    Measured: Baseline, 4 weeks

  7. Change in Clinical Symptoms

    Change in typical Cushing's syndrome clinical signs and symptoms defined by mean weight at baseline and 4 weeks.

    Measured: Baseline, 4 weeks

  8. Changes in Serum Cortisol Between Baseline and 4 Weeks

    Mean serum cortisol values at baseline and 4 weeks

    Measured: Baseline, 4 weeks

  9. Change in Systolic Blood Pressure

    Mean change in systolic blood pressure between baseline and 4 weeks.

    Measured: Baseline, 4 weeks

  10. Change in Diastolic Blood Pressure

    Mean diastolic blood pressure between baseline and 4 weeks.

    Measured: Baseline, 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jun 2014 (estimated)
  2. Study startMay 2014
  3. Primary completionOct 2018
  4. Study completionOct 2018

Why it stopped: NIH grant ended.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02160730
Sponsor's protocol ID
Pro35720
Other IDs
1R21DK103198-01
Status last verified
Nov 2021
First submitted
21 May 2014
Last updated
4 Nov 2021
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 18334580

  • 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.

    PubMed 18413427

  • Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013 Aug;98(8):3446-53. doi: 10.1210/jc.2013-1771. Epub 2013 Jun 3.

    PubMed 23733372

  • Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C; SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012 Jun;97(6):2039-49. doi: 10.1210/jc.2011-3350. Epub 2012 Mar 30.

    PubMed 22466348

  • Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol. 2011 May;7(5):257-66. doi: 10.1038/nrendo.2011.40. Epub 2011 Mar 22.

    PubMed 21423242

  • Quereda V, Malumbres M. Cell cycle control of pituitary development and disease. J Mol Endocrinol. 2009 Feb;42(2):75-86. doi: 10.1677/JME-08-0146. Epub 2008 Nov 5.

    PubMed 18987159

  • Jordan S, Lidhar K, Korbonits M, Lowe DG, Grossman AB. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol. 2000 Jul;143(1):R1-6. doi: 10.1530/eje.0.143r001.

    PubMed 10870044

  • Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell. 2000 Mar 31;101(1):79-89. doi: 10.1016/S0092-8674(00)80625-X.

    PubMed 10778858

  • Geng Y, Eaton EN, Picon M, Roberts JM, Lundberg AS, Gifford A, Sardet C, Weinberg RA. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene. 1996 Mar 21;12(6):1173-80.

    PubMed 8649818

  • Sengupta T, Abraham G, Xu Y, Clurman BE, Minella AC. Hypoxia-inducible factor 1 is activated by dysregulated cyclin E during mammary epithelial morphogenesis. Mol Cell Biol. 2011 Sep;31(18):3885-95. doi: 10.1128/MCB.05089-11. Epub 2011 Jul 11.

    PubMed 21746877

  • Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008 Jun 15;22(12):1677-89. doi: 10.1101/gad.1650208.

    PubMed 18559482

  • Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest. 2010 Nov;120(11):3820-33. doi: 10.1172/JCI41959. Epub 2010 Oct 11.

    PubMed 20978349

  • Ma Y, Fiering S, Black C, Liu X, Yuan Z, Memoli VA, Robbins DJ, Bentley HA, Tsongalis GJ, Demidenko E, Freemantle SJ, Dmitrovsky E. Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4089-94. doi: 10.1073/pnas.0606537104. Epub 2007 Feb 27.

    PubMed 17360482

  • Loeb KR, Kostner H, Firpo E, Norwood T, D Tsuchiya K, Clurman BE, Roberts JM. A mouse model for cyclin E-dependent genetic instability and tumorigenesis. Cancer Cell. 2005 Jul;8(1):35-47. doi: 10.1016/j.ccr.2005.06.010.

    PubMed 16023597

  • Roussel-Gervais A, Bilodeau S, Vallette S, Berthelet F, Lacroix A, Figarella-Branger D, Brue T, Drouin J. Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis. Mol Endocrinol. 2010 Sep;24(9):1835-45. doi: 10.1210/me.2010-0091. Epub 2010 Jul 21.

    PubMed 20660298

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing R-roscovitine in people with Cushings Disease, run by Shlomo Melmed, MD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 4 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks (time frame: Baseline, 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02160730, which also lists 27 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2021.

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