Intervention: Pasireotide
Trial phase: Phase 2
ATC code: H01CB05
SMILES: NCCCC[C@@H]1NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](c2ccccc2)NC(=O)[C@@H]2C[C@@H](OC(=O)NCCN)CN2C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC1=O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 4
Group description: Subjects will receive Pasireotide LAR monthly. Safety labs and Pituitary MRI will be performed.

Pasireotide LAR: Pasireotide LAR (SIGNIFOR® LAR) is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option. It is a long acting release injectable suspension for intramuscular use.

The starting dose is Pasireotide LAR 40 mg/month intramuscular (IM), this will be increased to 60 mg/month at 6 months if a fall in POMC levels and/or tumor shrinkage are not attained.
Eligibility criteria:
Inclusion criteria:

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

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)
Plasma POMC level > upper limit of normal
Prior pituitary tumor surgery with residual or recurrent pituitary tumor visible on MRI scan that is ≥ 5 mm from the optic chiasm.
Surgical resection of the pituitary adenoma must have occurred two or more months prior to enrollment
If patients have undergone pituitary radiotherapy they must have completed their course of radiotherapy at least 2 months prior to study screening
No prior somatostatin analog therapy
No concurrent use of dopamine agonist therapy
No active malignancy
Stable pituitary hormone supplements (x 2 months) prior to baseline visit
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:

Patients with Cushing's disease (biochemical evidence of hypercortisolism)
Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention
Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
Patients who are hypothyroid or adrenally insufficient and not on adequate replacement therapy
Patients with symptomatic cholelithiasis and acute or chronic pancreatitis
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
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
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
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
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
Presence of Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody test (anti-HCV)
Patients with serum creatinine >2.0 X ULN
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
Patients with the presence of active or suspected acute or chronic uncontrolled infection
Patients who have undergone major surgery/surgical therapy for any cause within 4 weeks prior screening
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)
History of syncope or family history of idiopathic sudden death
History of immunocompromise, including a positive HIV test result (ELISA and Western blot)
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
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

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):

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

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.