Pasireotide LAR Therapy of Silent Corticotroph Pituitary Tumors
Pasireotide LAR Therapy of Silent Corticotroph Pituitary Tumors
This is a phase II, open-label, 12-month pilot study in 10 patients with silent corticotroph
 pituitary tumors testing the hypotheses that Pasireotide long-acting release (LAR) treatment
 of patients with silent corticotroph pituitary tumors and elevated plasma Proopiomelanocortin
 (POMC) levels will reduce plasma POMC levels and this will be associated with a reduction in
 pituitary tumor size. Pasireotide LAR 40 mg will be administered monthly. Baseline and
 monthly visits on therapy will monitor plasma levels of POMC, other pituitary function,
 safety labs, glucose tolerance, physical examination, and visual fields. Pituitary magnetic
 resonance imaging (MRI) will be done at baseline, 6 months and 12 months of therapy. The
 eligible patient population will consist of adult patients with known silent corticotroph
 pituitary tumors and elevated plasma levels of POMC.
Clinically non-functioning pituitary adenomas (CNFAs), the subtype of pituitary adenomas that
 does not appear to secrete biologically active hormone nor to have a characteristic clinical
 phenotype, are the most common type of pituitary macroadenoma at diagnosis. There is
 currently no option for medical therapy of CNFA, in general, or specifically of silent
 corticotroph tumors. Silent corticotroph tumors can range from being completely asymptomatic
 to becoming large and causing significant hypothalamic/pituitary dysfunction and visual
 symptoms, and most data support that this type of tumor has a more aggressive phenotype.
 Current therapy consists primarily of surgical removal of the tumor and for recurrent or
 residual tumors, repeated surgery and/or radiotherapy. In very aggressive tumors,
 chemotherapy has been tried with some success. Therefore, a need exists for a medical
 therapeutic option for the treatment of this tumor type. This project assesses this clinical
 need.
Inclusion criteria:

 Subjects must meet all of the following inclusion criteria to be eligible for enrollment
 into the study:

 1. Adults (males and females) with a diagnosis of a clinically nonfunctioning pituitary
 tumor of the silent corticotroph tumor type (i.e., positive adrenocorticotropin (ACTH)
 staining on immunohistochemical staining of the pituitary tumor obtained at surgery)

 2. Plasma POMC level > upper limit of normal

 3. Prior pituitary tumor surgery with residual or recurrent pituitary tumor visible on
 MRI scan that is ≥ 5 mm from the optic chiasm.

 4. Surgical resection of the pituitary adenoma must have occurred two or more months
 prior to enrollment

 5. If patients have undergone pituitary radiotherapy they must have completed their
 course of radiotherapy at least 2 months prior to study screening

 6. No prior somatostatin analog therapy

 7. No concurrent use of dopamine agonist therapy

 8. No active malignancy

 9. Stable pituitary hormone supplements (x 2 months) prior to baseline visit

 10. Sign and date an informed consent document indicating that the subject has been
 informed of and agrees to all pertinent aspects of the trial

 Exclusion criteria:

 Subjects must not meet any of the following exclusion criteria to be eligible for
 enrollment into the study:

 1. Patients with Cushing's disease (biochemical evidence of hypercortisolism)

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

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

 4. Patients who are hypothyroid or adrenally insufficient and not on adequate replacement
 therapy

 5. Patients with symptomatic cholelithiasis and acute or chronic pancreatitis

 6. Patients with risk factors for torsade de pointes, i.e., patients with a baseline QTcF
 (Fridericia's Correction Formula value) >450 ms in males, and >460 ms in females

 7. Hypokalaemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT
 syndrome or concomitant medications with known risk of Torsades de pointes (TdP).
 Drugs with possible risk of TdP should be avoided whenever feasible

 8. 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 myocardial infarction (MI) less than one year prior to study
 entry or clinically significant impairment in cardiovascular function

 9. Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy
 (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled
 hypothyroidism or cardiac failure

 10. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic
 persistent hepatitis, or patients with alanine aminotransferase (ALT)/aspartate
 aminotransferase (AST) > 2.0 X upper limit of normal (ULN), serum bilirubin >2.0 X ULN

 11. Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test
 (anti-HCV)

 12. Patients with serum creatinine >2.0 X ULN

 13. Patients with white blood cell (WBC) count <3 X 109/L; Hb 90% < lower limit of normal
 (LLN); platelet (PLT) count <100 X 109/L

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

 15. Patients who have undergone major surgery/surgical therapy for any cause within 4
 weeks prior screening

 16. Patients with abnormal coagulation (PT and/or activated partial thromboplastin time
 (APTT) elevated by 30% above normal limits) or patients receiving anticoagulants that
 affect PT (prothrombin time) or APTT (activated partial thromboplastin time)

 17. History of syncope or family history of idiopathic sudden death

 18. History of immunocompromise, including a positive HIV test result (ELISA and Western
 blot)

 19. Sexually active males unless they use a condom during intercourse while taking drug
 and for 3 months following last dose of pasireotide and should not father a child in
 this period. A condom is required to be used also by vasectomized men in order to
 prevent delivery of the drug via seminal fluid

 20. 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 urine pregnancy test

 21. Women of child-bearing potential, defined as all women physiologically capable of
 becoming pregnant, unless they are using highly effective methods of contraception
 during dosing and 3 months following last dose of pasireotide. Highly effective
 contraception methods include:

 -  Total abstinence when this is in line with the preferred and usual lifestyle of
 the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
 post-ovulation methods) and withdrawal are not acceptable methods of
 contraception

 -  Female sterilization (have had surgical bilateral oophorectomy with or without
 hysterectomy) or tubal ligation at least six weeks before taking study treatment.
 In case of oophorectomy alone, only when the reproductive status of the woman has
 been confirmed by follow up hormone level assessment

 -  Male sterilization (at least 6 months prior to screening). For female subjects on
 the study the vasectomized male partner should be the sole partner for that
 subject

 -  Combination of any two of the following (a+b or a+c, or b+c):

 1. Use of oral, injected or implanted hormonal methods of contraception or
 other forms of hormonal contraception that have comparable efficacy (failure
 rate <1%), for example hormone vaginal ring or transdermal hormone
 contraception.

 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
 cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
 suppository

 -  In case of use of oral contraception women should have been stable on
 the same pill for a minimum of 3 months before taking study treatment.

 -  Women are considered post-menopausal and not of child bearing potential
 if they have had 12 months of natural (spontaneous) amenorrhea with an
 appropriate clinical profile (e.g. age appropriate, history of
 vasomotor symptoms) or have had surgical bilateral oophorectomy (with
 or without hysterectomy) or tubal ligation at least six weeks ago. In
 the case of oophorectomy alone, only when the reproductive status of
 the woman has been confirmed by follow up hormone level assessment is
 she considered not of child bearing potential.