Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease

This study is to assess whether pasireotide alone and combined with cabergoline will give
reliefs on patients with recurrent, persistent and newly diagnosed Cushing's disease. The
study will also assess study drug safety, the changes in Quality of Life and on clinical
signs and symptoms of Cushing's disease. The study consists pasireotide-untreated patients at
screening and patients currently treated with maximal tolerated doses of pasireotide. Core
phase will consist of pasireotide-untreated patients at screening - this includes patients
who have never received pasireotide or patients who have received pasireotide sometime in the
past but it was not discontinued because of safety. These patients will start pasireotide at
0.6mg twice a day for 8 weeks. Should biochemical control not be achieved the dose will be
increased to 0.9mg twice a day. If biochemical control is still not achieved, cabergoline at
increasing dose will be added. Patients currently treated with maximal tolerated doses of
pasireotide monotherapy for at least 8 weeks at 0.3mg twice a day, 0.6mg twice a day or 0.9mg
twice a day, but still did not achieve biochemical control will add cabergoline at increasing
dose. After 35 weeks of treatment at core phase, patients will have the option to continue
study treatment in extension phase if pasireotide is not yet approved for commercial use
and/or reimbursed - if country reimbursement is applicable.

Inclusion criteria:

1. Written informed consent obtaine prior to screening procedures

2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as
evidenced by all of the following:

1. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2
out of 3 samples >ULN

2. Morning plasma ACTH within the normal or above normal range

3. Either MRI confirmation of pituitary adenoma > 6 mm, or inferior petrosal sinus
gradient >3 after CRH stimulation for those patients with a tumor less than or
equal to 6 mm*. For patients who have had prior pituitary surgery, histopathology
confirming an ACTH staining adenoma *If IPSS had previously been performed
without CRH (e.g. with DDAVP), then a central to peripheral pre-stimulation
gradient > 2 is required. If IPSS had not previously been performed, IPSS with
CRH stimulation is required.

3. Patients with de novo Cushing's disease can be included only if they are not
considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically
unapproachable tumors, patients who refuse to have surgical treatment)

4. Male or female patients aged 18 years or greater

5. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to
care for most of their personal needs)

6. Patients on medical treatment for Cushing's disease the following washout periods must
be completed before screening assessments are performed

- Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

- Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and
PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks

- Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks

- Octreotide (immediate release formulation): 1 week

- Progesterone receptor antagonist (mifepristone): 4 weeks

7. Patients can be considered to enter the trial if they meet any one of the following
criteria: 1) They are naive to pasireotide 2) They have received pasireotide in the
past and have been discontinued because of lack of efficacy (2 weeks for washout prior
to screening for patients treated with pasireotide subcutaneously and 12 weeks of
washout prior to screening for patients treated with pasireotide LAR) 3) Patients who
are on maximal tolerated dose but have not achieved biochemical control

8. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, if they are using highly effective methods of contraception during
dosing and for 30 days after stopping study medication.

9. Male participants in the trial must agree to use a condom during intercourse, and not
to father a child during the study and for the period of 30 days following stopping of
the study treatment.

Exclusion criteria:

1. Patients with compression of the optic chiasm causing any visual field defect that
requires surgical intervention

2. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%

3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF
>450 ms in males, and > 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled
hypothyroidism, family history of long QT syndrome, or concomitant medications known
to prolong QT interval.

4. Patients with clinically significant valvular disease.

5. Patients with Cushing's syndrome due to ectopic ACTH secretion

6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary)
bilateral adrenal hyperplasia

7. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina,
sustained ventricular tachycardia, clinically significant bradycardia, advanced heart
block, history of acute MI less than one year prior to study entry or clinically
significant impairment in cardiovascular function

8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic
persistent hepatitis, or patients with ALT/AST > 2 X ULN, serum bilirubin >2.0 X ULN

9. Patients with serum creatinine >2.0 X ULN

10. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L

11. Patients with presence of Hepatitis B surface antigen (HbsAg)

12. Patients with presence of Hepatitis C antibody test (anti-HCV)

13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to
pasireotide or cabergoline

14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer
or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled
hypertension and Raynauds syndrome.

15. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/ml)

16. Patients with end-stage renal failure and/or hemodialysis

17. Patients with presence of active or suspected acute or chronic uncontrolled infection

18. Patients with a history of non-complance to medical regimens or who are considered
potentially unreliable or whill be unable to complete the entire study

19. Patients with presence of Hepatitis B surface antigen (HbsAg)

20. Patients with presence of Hepatitis C antibody test (anti-HCV)

21. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to
pasireotide or cabergoline

22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or
digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled
hypertension and Raynaud's syndrome

23. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a
female after conception and until the terminiation of gestation, confirmed by a
positive hCG laboratory test (> 5mIU/mL)

24. Patients with end-stage renal failure and/or hemodialysis