Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas

• ClinicalTrials.gov Identifier: NCT01620138
• Recruitment Status: Completed
• First Posted: June 15, 2012
• Results First Posted: June 16, 2016
• Last Update Posted: August 22, 2016
• Sponsor: Universidade Federal do Rio de Janeiro
• Information provided by (Responsible Party): Monica Gadelha, Universidade Federal do Rio de Janeiro

Tracking Information

• First Submitted Date: September 18, 2011
• First Posted Date: June 15, 2012
• Results First Submitted Date: June 1, 2015
• Results First Posted Date: June 16, 2016
• Last Update Posted Date: August 22, 2016
• Study Start Date: March 2010
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 10, 2016)

Tumor Volume Changes for NFPA and Prolactin Level Changes for Prolactinoma [ Time Frame: Baseline to six months ]

Magnetic resonance imaging (MRI) of the sella and prolactin will be performed before (baseline) and after 6 months of treatment with cabergoline or pasireotide. Disease progression will be defined as tumor growth > 25%, stable disease as changes < 25% and significant tumor shrinkage as > 25% in tumor volume compared to baseline MRI (baseline to six months).

Original Primary Outcome Measures (submitted: June 14, 2012)

• Tumor volume reduction [ Time Frame: Six months ]
  Magnetic resonance imaging (MRI) of the sella will be performed before and after 6 months of treatment with cabergoline or pasireotide. Disease progression will be defined as tumor growth > 25%, stable disease as changes < 25% and significant tumor shrinkage as > 25% in tumor volume compared to baseline MRI.
• Prolactin levels normalization [ Time Frame: Six months ]
  Normalization of prolactin levels during treatment with pasireotide in patients with prolactinoma.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Response to Cabergoline and Pasireotide in Non-functioning Pituitary Adenomas and Resistant Prolactinomas
• Official Title: Somatostatin and Dopamine Receptors Expression in Non-functioning Pituitary Adenomas and Resistant Prolactinomas: Correlation With in Vitro and in Vivo Responsiveness to Somatostatin Analogs and Dopamine Agonist
• Brief Summary: There are no available medical treatment options for patients with non-functioning pituitary adenomas (NFPA) or with resistant prolactinomas to dopamine agonists (DA) who are not cured by surgery. The study of the receptors by quantitative messenger ribonucleic acid (mRNA) expression levels and immunohistochemistry analysis might end with a better understanding of these tumors. Besides that, it will be assessed the in vitro and in vivo responses to pasireotide (for NFPA and prolactinomas) and cabergoline (for NFPA). These responses will be compared with the receptor expressions which may be a tool as a predicting element of the response to these compounds.
• Detailed Description: The goals of this study are: to verify whether cabergoline and pasireotide are effective in NFPA to control tumor re-growth as adjuvant therapy after neurosurgery and whether pasireotide is capable of normalizing the prolactin levels in patients with prolactinomas resistant to cabergoline; to assess the mRNA levels of dopamine receptor type 2 (DR2) and SSTR1-5 and their protein expression; to evaluate the in vitro hormonal response to cabergoline, octreotide and pasireotide; and to determine whether the mRNA DR2/SSTR1-5 and/or protein expression and/or in vitro hormonal response to cabergoline, octreotide and pasireotide correlates with the in vivo response to the former and to the last one. With this data the investigators intend to establish if the mRNA analysis and/or protein expression in NFPA and resistant prolactinomas might be predictive or foretelling factors concerning drug treatment in patients with this kind of pituitary tumors and also evaluate if there is any response in vitro or in vivo to the treatment with pasireotide in NFPA and resistant prolactinomas and with cabergoline in NFPA.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Non-functioning Pituitary Adenomas
• Prolactinomas

Intervention

• Drug: Pasireotide

  The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at the dosage of 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for six months.

  The patients with resistant prolactinomas will be treated with pasireotide at the dosage of 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

  Other Name: Signifor
• Drug: cabergoline

  The patients with NFPA will be randomized into two groups: (A) the first one will be treated with pasireotide at 900 µg s.c. twice a day for 6 months; (B) the second one, with cabergoline 3 mg/week for 6 months.

  The patients with resistant prolactinomas will be treated with pasireotide at 600 µg s.c. twice a day. After four weeks of treatment, the patients who normalize serum prolactin level will be maintained at the same dosage, the others who do not achieve normal prolactin level will have their dosage raised to 900 µg s.c. twice a day for six months.

  Other Name: Dostinex

Study Arms

• Active Comparator: Pasireotide

  For non-cured patients with prolactinomas resistant to cabergoline, MRI will be performed immediately before and six months after the onset of pasireotide treatment. The anti-secretory effect will be evaluated by prolactin dosage every month.

  For patients harboring a NFPA, treatment will be started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. In this case, the drug efficacy will be evaluated clinically by visual field and by MRI six months after pasireotide treatment.

  Intervention: Drug: Pasireotide
• Active Comparator: cabergoline
  In patients with non-functioning pituitary adenoma, treatment will be started at least 3 months after neurosurgery, when a pituitary MRI clearly shows the presence of a residual tumor without any possible misinterpretation of postsurgical changes. The drug response will be evaluated clinically by visual field and by Magnetic resonance imaging (MRI) before medical treatment and after six months of cabergoline treatment at maximum dose.
  Intervention: Drug: cabergoline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 10, 2016): 21
• Original Estimated Enrollment (submitted: June 14, 2012): 30
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

• Male or female patients aged 18 years or greater
• Patients with confirmed diagnosis of NFPA evidenced by: magnetic resonance imaging (MRI) confirmation of pituitary adenoma and No pituitary tumoral hormone hypersecretion
• Patients with no previous medical treatment
• Patients who had been submitted to surgery but not cured. Lack of cure is defined as presence of remnant tumor on MRI at least three months after surgery (without any possible misinterpretation of postsurgical changes)
• Patients with confirmed diagnosis of resistant prolactinoma by lack of prolactin normalization with a tolerated cabergoline dosage during 12 weeks
• Patients who had been submitted to surgery due to resistance to cabergoline and not cured. Lack of cure is defined as lack of serum prolactin normalization or complete removal of tumor load
• Patients who signed the informed consent

Exclusion Criteria

• Previous pituitary radiotherapy
• High risk for transsphenoidal surgery
• Patients with symptomatic cholelithiasis
• Diabetic patients on antidiabetic medications those fasting blood glucose is poorly controlled as evidenced by HbA1C > 8%
• Patients with abnormal coagulation (prothrombin time (PT) or partial thromboplastin time (PTT) elevated by 30% above normal limits);
• Patients receiving anticoagulants that affect PT or PTT
• 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
• Patients with risk factors for torsade de pointes, i.e. patients with a baseline corrected QT interval (QTc) > 480 ms, hypokalemia, family history of long QT syndrome, and concomitant medications known to prolong QT interval
• Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with (alanine aminotransferase) ALT/ (aspartate aminotransferase) AST more than 2 X upper limit of normal (ULN), serum creatinine > 2.0 X ULN, serum bilirubin > 2.0 X ULN, serum albumin < 0.67 X lower limit of normal (LLN)
• Patients with white blood cell (WBC) < 3 X 109/L; Hgb < LLN; Platelet count (PLT) < 100 X 109/L
• Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator
• Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms. If oral contraception is used, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study and for one month after the last dose of study drug. Male patients who are sexually active are required to use condoms during the study and for 1 month afterwards
• Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT01620138
• Other Study ID Numbers: CSOM230BBR01T
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Monica Gadelha, Universidade Federal do Rio de Janeiro
• Original Responsible Party: Same as current
• Current Study Sponsor: Universidade Federal do Rio de Janeiro
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Mônica R. Gadelha, PhD; Endocrinology Section - Hospital Universitário Clementino Fraga Filho/Federal University of Rio de Janeiro

• PRS Account: Universidade Federal do Rio de Janeiro
• Verification Date: July 2016