Intervention: Seliciclib
Trial phase: Phase 2
SMILES: CC[C@H](CO)Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 4
Group description: • R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 weeks.
Eligibility criteria:
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)