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

Prolactinomas Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01620138
• Other study ID #: CSOM230BBR01T
• Status: Recruiting
• Phase: Phase 2/Phase 3
• First received: September 18, 2011
• Last updated: June 14, 2012
• Start date: March 2010
• Est. completion date: June 2012

Study information

• Verified date: June 2012
• Source: Universidade Federal do Rio de Janeiro
• Contact: Nelma Verônica, Nurse coordinator
• Phone: +552125622323
• Email: nelmaveronica[@]yahoo.com.br
• Is FDA regulated: No
• Health authority: Brazil: National Health Surveillance Agency
• Study type: Interventional

Clinical Trial 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 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adenoma
• Non-functioning Pituitary Adenomas
• Pituitary Diseases
• Pituitary Neoplasms
• Prolactinoma
• Prolactinomas

Intervention

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.
• 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.

Locations

Country	Name	City	State
Brazil	Endocrinology Section - Hospital Universitário Clementino Fraga Filho/Federal University of Rio de Janeiro	Rio de Janeiro	RJ

Sponsors (1)

Lead Sponsor	Collaborator
Universidade Federal do Rio de Janeiro

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tumor volume reduction	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.	Six months	No
Primary	Prolactin levels normalization	Normalization of prolactin levels during treatment with pasireotide in patients with prolactinoma.	Six months	No