Expression Profile of Somatostatin Receptors and Dopamine Receptor 2 in Non-functioning Pituitary Adenomas and Resistant Prolactinomas: Correlation With in Vivo Response to Pasireotide and Cabergoline

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2012 by Universidade Federal do Rio de Janeiro.
Recruitment status was  Recruiting
Sponsor:
Information provided by (Responsible Party):
Monica Gadelha, Federal University of Rio de Janeiro
ClinicalTrials.gov Identifier:
NCT01620138
First received: September 18, 2011
Last updated: June 14, 2012
Last verified: June 2012
  Purpose

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 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.


Condition Intervention Phase
Non-functioning Pituitary Adenomas
Prolactinomas
Drug: Pasireotide
Drug: cabergoline
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Quantitative Analysis of All Somatostatin Receptors and Dopamine Receptor Subtype 2 mRNA and Protein Expression Study in Non-functioning Pituitary Adenomas and Resistant Prolactinomas: Correlation With in Vitro and in Vivo Responsiveness to Somatostatin Analogs and Dopamine Agonist

Resource links provided by NLM:


Further study details as provided by Universidade Federal do Rio de Janeiro:

Primary Outcome Measures:
  • Tumor volume reduction [ Time Frame: Six months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Normalization of prolactin levels during treatment with pasireotide in patients with prolactinoma.


Estimated Enrollment: 30
Study Start Date: March 2010
Estimated Study Completion Date: June 2012
Estimated Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: Pasireotide

The patients with NFPA and residual tumor on MRI at least three months after surgery 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 six months; (B) the second one, with cabergoline that will be administered, during the titration period, at an initial dose of 0.5 mg on the first week and afterward will be increased 0.5 mg per week until the dose reaches 3 mg/week, according to drug tolerability by patients. After dose reaches 3.0 mg/week, patients will be maintained at this dose for six months.

The patients with prolactinomas resistant to DA 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. The patients will be treated for six months.

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.
Drug: cabergoline

The patients with NFPA and residual tumor on MRI at least three months after surgery 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 six months; (B) the second one, with cabergoline that will be administered, during the titration period, at an initial dose of 0.5 mg on the first week and afterward will be increased 0.5 mg per week until the dose reaches 3 mg/week, according to drug tolerability by patients. After dose reaches 3.0 mg/week, patients will be maintained at this dose for six months.

The patients with prolactinomas resistant to DA 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. The patients will be treated for six months.


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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (for patients with NFPA):

  • Male or female patients aged 18 years or greater;
  • Patients with confirmed diagnosis of NFPA evidenced by:
  • MRI confirmation of pituitary adenoma.
  • 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); and
  • Patients who signed the informed consent;

Inclusion Criteria (for patients with resistant prolactinomas):

  • Male or female patients aged 18 years or greater;
  • 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; and
  • Patients who signed the informed consent.

Exclusion Criteria (for both):

  • Previous pituitary radiotherapy;
  • High risk for transsphenoidal surgery;
  • Patients with symptomatic cholelithiasis;
  • Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as evidenced by HbA1C > 8%;
  • Patients with abnormal coagulation (PT or 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 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 ALT/AST more than 2 X ULN, serum creatinine > 2.0 X ULN, serum bilirubin > 2.0 X ULN, serum albumin < 0.67 X LLN;
  • Patients with WBC < 3 X 109/L; Hgb < LLN; 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; and
  • Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01620138

Contacts
Contact: Nelma Verônica, Nurse coordinator +552125622323 nelmaveronica@yahoo.com.br
Contact: Leonardo Vieira Neto, M.D. +552199853378 netolv@gmail.com

Locations
Brazil
Endocrinology Section - Hospital Universitário Clementino Fraga Filho/Federal University of Rio de Janeiro Recruiting
Rio de Janeiro, RJ, Brazil, 21941-913
Contact: Nelma Verônica, Nurse coordinator    +552125622323    nelmaveronica@yahoo.com.br   
Contact: Leonardo Vieira Neto, M.D.    +552199853378    netolv@terra.com.br   
Sub-Investigator: Leonardo Vieira Neto, M.D.         
Principal Investigator: Mônica R. Gadelha, PhD         
Sponsors and Collaborators
Universidade Federal do Rio de Janeiro
Investigators
Principal Investigator: Mônica R. Gadelha, PhD Endocrinology Section - Hospital Universitário Clementino Fraga Filho/Federal University of Rio de Janeiro
  More Information

No publications provided

Responsible Party: Monica Gadelha, Principal Investigator, Federal University of Rio de Janeiro
ClinicalTrials.gov Identifier: NCT01620138     History of Changes
Other Study ID Numbers: CSOM230BBR01T
Study First Received: September 18, 2011
Last Updated: June 14, 2012
Health Authority: Brazil: National Health Surveillance Agency

Keywords provided by Universidade Federal do Rio de Janeiro:
Non-functioning pituitary adenomas
Prolactinomas
Cabergoline
Pasireotide
somatostatin receptors
Dopamine receptors

Additional relevant MeSH terms:
Pituitary Neoplasms
Adenoma
Prolactinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Hypothalamic Neoplasms
Supratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hypothalamic Diseases
Pituitary Diseases
Endocrine System Diseases
Dopamine
Dopamine Agents
Cabergoline
Somatostatin
Cardiotonic Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on September 18, 2014