Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease

This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of two
of three potential doses/schedules of oral seliciclib in patients with newly diagnosed,
persistent, or recurrent Cushing disease. Up to 29 subjects will be treated with up to 800
mg/day oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts
based on efficacy outcomes. The study will also evaluate effects of seliciclib on quality of
life and clinical signs and symptoms of Cushing disease.

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
corticotropin-releasing hormone (CRH) stimulation

- Recurrent or persistent Cushing disease 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 disease. Washout periods must be
completed before screening assessments are performed.

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, Multiple endocrine neoplasia (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 hypothalamic-pituitary-adrenal (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 atrioventricular (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 alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum
total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal
(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 long-acting release (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)