Pasireotide LAR Therapy of Silent Corticotroph Pituitary Tumors (PASSILCORT)

Study Description

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Brief 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 LAR (long-acting release) 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.

Condition or disease	Intervention/treatment	Phase
Pituitary Tumor; ACTH-producing Pituitary Tumour	Drug: Pasireotide LAR	Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	10 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pilot Study of Pasireotide LAR Treatment of Silent Corticotrophin Pituitary Tumors and Effects on Plasma Levels of POMC
Actual Study Start Date :	July 10, 2017
Estimated Primary Completion Date :	May 2018
Estimated Study Completion Date :	May 2018

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Pasireotide LAR Therapy; Subjects will receive Pasireotide LAR monthly. Safety labs and Pituitary MRI will be performed.

Drug: 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 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.; Other Name: Signifor LAR

Outcome Measures

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Primary Outcome Measures :

1. Change in plasma Proopiomelanocortin (POMC) levels [ Time Frame: Baseline, 12 months ]
   This is to measure the effect of Pasireotide LAR (long-acting release) treatment.

Secondary Outcome Measures :

1. Change in pituitary tumor volume [ Time Frame: Baseline, 12 months ]
   This is to measure the effect of Pasireotide LAR (long-acting release) treatment.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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) (ages18- 80 years) 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 >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 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 ALT/AST > 2.0 X 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 WBC <3 X 109/L; Hb 90% < LLN; PLT <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 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.

Contacts and Locations

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Contacts

Contact: Pamela U. Freda, MD	212-305-2254	csr52@cumc.columbia.edu
Contact: Carlos M. Reyes-Vidal, MD	212-305-4921	csr52@columbia.edu

Locations

United States, New York
Neuroendocrine Unit and Pituitary Center, Columbia University	Recruiting
New York, New York, United States, 10032
Contact: Pamela U. Freda, MD 212-305-2254
Contact: Carlos M. Reyes-Vidal, MD 212-305-4921 csr52@cumc.columbia.edu

Sponsors and Collaborators

Columbia University

Investigators

Principal Investigator:	Pamela Freda, MD	Professor of Medicine at the Columbia University Medical Center, Dept of Medicine Endocrinology

More Information

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Responsible Party:	Pamela U. Freda, Professor of Medicine at the Columbia University Medical Center, Dept of Medicine Endocrinology, Columbia University
ClinicalTrials.gov Identifier:	NCT02749227 History of Changes
Other Study ID Numbers:	AAAQ6255; CSOM230GUS44T ( Other Identifier: Novartis )
First Posted:	April 22, 2016
Last Update Posted:	April 12, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Pamela U. Freda, Columbia University:

Clinically non-functioning pituitary adenomas (CNFAs); silent corticotroph adenomas

Additional relevant MeSH terms:

Neoplasms; Pituitary Diseases; Pituitary Neoplasms; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site	Hypothalamic Neoplasms; Supratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Pasireotide; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs