Pasireotide LAR Therapy of Silent Corticotroph Pituitary Tumors
Condition: Pituitary Tumor; ACTH-producing Pituitary Tumour
MeSH terms: Neoplasms; Pituitary Neoplasms; Pituitary Diseases
Intervention: Pasireotide LAR
Intervention description: 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.
Intervention MeSH terms: Pasireotide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Clinically non-functioning pituitary adenomas (CNFAs); silent corticotroph adenomas

Summary:

      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.
    

Eligibility criteria:

        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.