Cushings Disease
Conditions
Keywords
Cushings disease, 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 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.
Interventions
DRUGR-roscovitine
See Arm Description
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Shlomo Melmed, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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
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, 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 * 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Baseline, 4 weeks | 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. |
| Number of Participants That Have a Visible Change in Tumor Size | Baseline, 4 weeks | A visible change in tumor size as determined by the investigator after reviewing MRI reports between baseline and 4 weeks of treatment. |
| Number of Participants That Experience Changes in Clinical Signs of Hypercortisolemia | Baseline, Week 4 | 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. |
| Fasting Glucose at Baseline and 4 Weeks | Baseline, 4 Weeks | Mean change between baseline and week 4 of fasting blood glucose levels. |
| Change in Mean HbA1c Levels Between Baseline and 4 Weeks | Baseline, 4 Weeks | HbA1c levels are measured at baseline and at study end, these are averaged across all subjects. |
| Change in Clinical Symptoms | Baseline, 4 weeks | Change in typical Cushing's syndrome clinical signs and symptoms defined by mean weight at baseline and 4 weeks. |
| Changes in Serum Cortisol Between Baseline and 4 Weeks | Baseline, 4 weeks | Mean serum cortisol values at baseline and 4 weeks |
| Change in Systolic Blood Pressure | Baseline, 4 weeks | Mean change in systolic blood pressure between baseline and 4 weeks. |
| Change in Diastolic Blood Pressure | Baseline, 4 weeks | Mean diastolic blood pressure between baseline and 4 weeks. |
| Plasma ACTH at Baseline and 4 Weeks | Baseline, 4 weeks | Mean change in Plasma ACTH between baseline and 4 weeks. |
Countries
United States
Participant flow
Pre-assignment details
Patients on medical treatment for CD must complete washout periods before screening assessments are performed: Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks; somatostatin receptor ligand (SRL; pasireotide): short-acting, 2 weeks; long active, 4 weeks; progesterone receptor antagonist (mifepristone): 2 weeks; dopamine agonists (cabergoline): 4 weeks; CYP3A4 strong inducers or inhibitors: varies between drugs, minimum 5-6 x the drug half-life.
Participants by arm
| Arm | Count |
|---|---|
| R-roscovitine • R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | R-roscovitine | — |
|---|---|---|
| Age, Continuous | 46.5 years STANDARD_DEVIATION 12.9 | — |
| Baseline Mean Urine Free Cortisol (mcg/24hr) | 233.3 mcg/24hr STANDARD_DEVIATION 108.7 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 4 participants | — |
| Sex: Female, Male Female | 4 Participants | — |
| Sex: Female, Male Male | 0 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 2 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
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.
Time frame: Baseline, 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R-roscovitine | Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks | 0 Participants |
Secondary
Change in Clinical Symptoms
Change in typical Cushing's syndrome clinical signs and symptoms defined by mean weight at baseline and 4 weeks.
Time frame: Baseline, 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Change in Clinical Symptoms | Baseline | 217 lbs | Standard Deviation 78.6 |
| R-roscovitine | Change in Clinical Symptoms | 4 Weeks | 217.4 lbs | Standard Deviation 80.6 |
Secondary
Change in Diastolic Blood Pressure
Mean diastolic blood pressure between baseline and 4 weeks.
Time frame: Baseline, 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Change in Diastolic Blood Pressure | Baseline | 76.5 mmHg | Standard Deviation 12.2 |
| R-roscovitine | Change in Diastolic Blood Pressure | 4 Weeks | 71 mmHg | Standard Deviation 10 |
Secondary
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.
Time frame: Baseline, 4 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Change in Mean HbA1c Levels Between Baseline and 4 Weeks | Baseline | 6.9 Percentage | Standard Deviation 1.02 |
| R-roscovitine | Change in Mean HbA1c Levels Between Baseline and 4 Weeks | Study End-4 weeks | 7 Percentage | Standard Deviation 1.18 |
Secondary
Change in Systolic Blood Pressure
Mean change in systolic blood pressure between baseline and 4 weeks.
Time frame: Baseline, 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Change in Systolic Blood Pressure | Baseline | 150.3 mmHg | Standard Deviation 18.8 |
| R-roscovitine | Change in Systolic Blood Pressure | 4 weeks | 128.3 mmHg | Standard Deviation 6 |
Secondary
Changes in Serum Cortisol Between Baseline and 4 Weeks
Mean serum cortisol values at baseline and 4 weeks
Time frame: Baseline, 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Changes in Serum Cortisol Between Baseline and 4 Weeks | Baseline | 25.6 mg/dL | Standard Deviation 5.5 |
| R-roscovitine | Changes in Serum Cortisol Between Baseline and 4 Weeks | 4 Weeks | 27.1 mg/dL | Standard Deviation 8.7 |
Secondary
Fasting Glucose at Baseline and 4 Weeks
Mean change between baseline and week 4 of fasting blood glucose levels.
Time frame: Baseline, 4 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Fasting Glucose at Baseline and 4 Weeks | Baseline | 121.4 g/dL | Standard Deviation 30.5 |
| R-roscovitine | Fasting Glucose at Baseline and 4 Weeks | 4 weeks | 104.3 g/dL | Standard Deviation 25 |
Secondary
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.
Time frame: Baseline, Week 4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R-roscovitine | Number of Participants That Experience Changes in Clinical Signs of Hypercortisolemia | 2 Participants |
Secondary
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.
Time frame: Baseline, 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R-roscovitine | Number of Participants That Have a Visible Change in Tumor Size | 0 Participants |
Secondary
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.
Time frame: Baseline, 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| R-roscovitine | Number of Participants With Adverse Events | 2 Participants |
Secondary
Plasma ACTH at Baseline and 4 Weeks
Mean change in Plasma ACTH between baseline and 4 weeks.
Time frame: Baseline, 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| R-roscovitine | Plasma ACTH at Baseline and 4 Weeks | Baseline | 79.3 pg/mL | Standard Deviation 30.3 |
| R-roscovitine | Plasma ACTH at Baseline and 4 Weeks | 4 weeks | 79.9 pg/mL | Standard Deviation 32.1 |