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Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease

Information source: Novartis
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Cushing's Disease

Intervention: Pasireotide (Drug); Cabergoline (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Novartis Pharmaceuticals

Official(s) and/or principal investigator(s):
Novartis Pharmaceuticals, Study Director, Affiliation: Novartis Pharmaceuticals

Overall contact:
Novartis Pharmaceuticals, Phone: 1-888-669-6682

Summary

This study is to assess whether pasireotide alone and combined with cabergoline will give reliefs on patients with recurrent, persistent and newly diagnosed Cushing's disease. The study will also assess study drug safety, the changes in Quality of Life and on clinical signs and symptoms of Cushing's disease.

Clinical Details

Official title: A Phase II Trial to Assess the Efficacy and Safety of Pasireotide s.c. Alone or in Combination With Cabergoline in Patients With Cushing's Disease

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

mUFC

mUFC

Secondary outcome:

Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured

Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured

Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when UFC is measured

Duration of controlled or partially controlled response

Change from baseline in plasma ACTH and serum cortisol over time

Ctrough at baseline

Ctrough at week 8

Ctrough

Cmax at baseline

Cmax at week 8

Cmax

Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments

Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured

Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured

Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when UFC is measured

Change from baseline in plasma ACTH and serum cortisol over time

Toxicity will be assessed using NCI-CTCAE v.4 and for laboratory assessments

Detailed description: This study is to assess whether pasireotide alone and combined with cabergoline will give reliefs on patients with recurrent, persistent and newly diagnosed Cushing's disease. The study will also assess study drug safety, the changes in Quality of Life and on clinical signs and symptoms of Cushing's disease. The study will enroll two groups of patients. Pasireotide naive patients at the time of screening (Group 1), and patients receiving maximal tolerated dose of pasireotide at the time of screening (Group 2). Group 1 patients will begin study treatment of pasireotide at 0. 6mg twice a day for 8 weeks. After 8 weeks, if cortisol level is not controlled and the dose is tolerated well, pasireotide will be increased to 0. 9mg for another 8 weeks. If during or at the end of the 8 week period, cortisol level is still not controlled cabergoline will be added at 0. 5mg once a day. Cabergoline can be increased up to 1. 0mg once a day in combination with pasireotide. Group 2 patients will immediately begin combination treatment by adding cabergoline at 0. 5mg once a day to the current pasireotide treatment. Cabergoline dose can be increased up to 1. 0mg once a day if cortisol is not controlled at a lower dose.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion criteria for Group 1: 1. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following: 1. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 out of 3 samples >ULN 2. Morning plasma ACTH within the normal or above normal range 3. Either MRI confirmation of pituitary adenoma > 6 mm, or inferior petrosal sinus gradient >3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm*. For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma *If IPSS had previously been performed without CRH (e. g. with DDAVP), then a central to peripheral pre-stimulation gradient > 2 is required. If IPSS had not previously been performed, IPSS with CRH stimulation is required. 2. Patients with de novo Cushing's disease can be included only if they are not considered candidates for pituitary surgery (e. g. poor surgical candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment) 3. Male or female patients aged 18 years or greater 4. Karnofsky performance status ≥ 60 (i. e. requires occasional assistance, but is able to care for most of their personal needs) 5. Patients on medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed

- Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

- Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and

PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks

- Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks

- Octreotide (immediate release formulation): 1 week

- Progesterone receptor antagonist (mifepristone): 4 weeks

6. Patients have been on pasireotide in the past but discontinued because of lack of efficacy are also allowed to enter Group 1. Patients treated with pasireotide subcutaneously must have been discontinued from the treatment for at least 4 weeks before screening. Patients treated with pasireotide LAR must have been discontinued from the treatment for at least 12 weeks before screening. 7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using highly effective methods of contraception during dosing and for 30 days after stopping study medication. Inclusion criteria for Group 2: 1. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following: 1. The mean of three 24-hour urine samples collected within 2 weeks > 1xULN with 2 out of 3 samples >ULN 2. Morning plasma ACTH within the normal or above normal range 3. Either MRI confirmation of pituitary adenoma > 6 mm, or inferior petrosal sinus gradient >3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm*. For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma *If **IPSS had previously been performed without CRH (e. g. with DDAVP), then a central to peripheral pre-stimulation gradient > 2 is required. If IPSS had not previously been performed, IPSS with CRH stimulation is required. 2. Patients with de novo Cushing's disease can be included only if they are not considered candidates for pituitary surgery (e. g. poor surgical candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment) 3. Patients currently treated with maximal tolerated doses of pasireotide for at least 8 weeks at the time of screening but have not achieved biochemical control. These patients will enter the study starting combination therapy. 4. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using highly effective methods of contraception during dosing and for 30 days after stopping study medication. Exclusion criteria for Group 1 and Group 2: 1. Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention 2. Diabetic patients with poor glycemic control as evidenced by HbA1c >8% 3. Patients with risk factors for torsade de pointes, i. e. patients with a baseline QTcF >450 ms in males, and > 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval. 4. Patients with clinically significant valvular disease. 5. Patients with Cushing's syndrome due to ectopic ACTH secretion 6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia 7. 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 8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST > 2 X ULN, serum bilirubin >2. 0 X ULN 9. Patients with serum creatinine >2. 0 X ULN 10. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L 11. Patients with presence of Hepatitis B surface antigen (HbsAg) 12. Patients with presence of Hepatitis C antibody test (anti-HCV) 13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline 14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome. 15. 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 hCG laboratory test (> 5 mIU/ml) 16. Patients with end-stage renal failure and/or hemodialysis

Locations and Contacts

Novartis Pharmaceuticals, Phone: 1-888-669-6682

Novartis Investigative Site, Buenos aires C1120AAF, Argentina; Withdrawn

Novartis Investigative Site, Brugge 8310, Belgium; Withdrawn

Novartis Investigative Site, Gent 9000, Belgium; Recruiting

Novartis Investigative Site, Leuven 3000, Belgium; Recruiting

Novartis Investigative Site, Sofia 1431, Bulgaria; Terminated

Novartis Investigative Site, Brest 29200, France; Withdrawn

Novartis Investigative Site, Bron Cedex 69677, France; Recruiting

Novartis Investigative Site, Marseille cedex 05 13385, France; Recruiting

Novartis Investigative Site, Pessac Cedex 33604, France; Recruiting

Novartis Investigative Site, Vandoeuvre Cedex 54511, France; Recruiting

Novartis Investigative Site, Berlin 10117, Germany; Withdrawn

Novartis Investigative Site, Erlangen 91054, Germany; Recruiting

Novartis Investigative Site, Essen 45147, Germany; Recruiting

Novartis Investigative Site, Frankfurt 60590, Germany; Recruiting

Novartis Investigative Site, Würzburg 97080, Germany; Recruiting

Novartis Investigative Site, Budapest 1062, Hungary; Recruiting

Novartis Investigative Site, Budapest 1085, Hungary; Recruiting

Novartis Investigative Site, Chandigarh 160 012, India; Recruiting

Novartis Investigative Site, New Delhi 110 029, India; Recruiting

Novartis Investigative Site, Napoli 80131, Italy; Recruiting

Novartis Investigative Site, Wilayah Persekutuan 62502, Malaysia; Recruiting

Novartis Investigative Site, Durango 34270, Mexico; Recruiting

Novartis Investigative Site, Rotterdam 3015 CE, Netherlands; Recruiting

Novartis Investigative Site, Balcova / Izmir 35340, Turkey; Recruiting

Novartis Investigative Site, Fatih / Istanbul 34098, Turkey; Recruiting

Novartis Investigative Site, Pendik / Istanbul 1330, Turkey; Recruiting

Novartis Investigative Site, Sihhiye/Ankara 06100, Turkey; Recruiting

Novartis Investigative Site, Ancona, AN 60126, Italy; Recruiting

University of Alabama at Birmingham The Kirklin Clinic, Birmingham, Alabama 35294, United States; Recruiting
Melanie Smith, Phone: +1 205 934 4112, Email: Melanie@uab.edu
Tom Brooks Vaughan, Principal Investigator

Novartis Investigative Site, Malaga, Andalucia 29010, Spain; Recruiting

St. Joseph's Hospital & Medical Center SC - SOM230B2411, Phoenix, Arizona 85013, United States; Not yet recruiting
Steve Borwege, Phone: 602-406-3614, Email: steve.borwege@dignityhealth.org
Laura Knecht, Principal Investigator

Novartis Investigative Site, Mexicali, Baja California 21100, Mexico; Withdrawn

Novartis Investigative Site, Caba, Buenos Aires C1280AEB, Argentina; Recruiting

Novartis Investigative Site, Fortaleza, CE 04636-000, Brazil; Withdrawn

Cedars Sinai Medical Center SOM230B2411, Los Angeles, California 90048, United States; Recruiting
Alicia Ortega, Phone: 310-423-3395, Email: alicia.ortega@cshs.org
Anat Ben-Shlomo, Principal Investigator

Novartis Investigative Site, Alzira, Comunidad Valenciana 46600, Spain; Recruiting

Novartis Investigative Site, Bogota, Cundinamarca 111411, Colombia; Withdrawn

Novartis Investigative Site, Bogotá, Cundinamarca 110111, Colombia; Recruiting

Novartis Investigative Site, Caracas, Distrito Capital 1040, Venezuela; Not yet recruiting

Novartis Investigative Site, México, Distrito Federal 02990, Mexico; Withdrawn

Novartis Investigative Site, México, Distrito Federal 14269, Mexico; Recruiting

Novartis Investigative Site, Athens, GR 106 76, Greece; Recruiting

Novartis Investigative Site, Thessaloniki, GR 546 35, Greece; Recruiting

Northwestern Memorial Hospital SOM230B2411, Chicago, Illinois 60611, United States; Withdrawn

University of Chicago Hospitals SOM230B2411, Chicago, Illinois 60637, United States; Withdrawn

Novartis Investigative Site, Milano, MI 20149, Italy; Recruiting

Novartis Investigative Site, Mumbai, Maharashtra 400012, India; Withdrawn

Sinai Hospital of Baltimore SOM230B2411, Baltimore, Maryland 21215, United States; Withdrawn

Washington University SC - SOM230B2411, St. Louis, Missouri 63110, United States; Withdrawn

Novartis Investigative Site, Darlinghurst, New South Wales 2010, Australia; Withdrawn

Mount Sinai School of Medicine Mt. Sinai Medical Center, New York, New York 10029, United States; Withdrawn

Oregon Health & Science University SOM230B2411, Portland, Oregon 97239, United States; Recruiting
Shirley McCartney, Phone: 503-494-4314, Email: mccartns@ohsu.edu
Maria Fleseriu, Principal Investigator

Novartis Investigative Site, Padova, PD 35128, Italy; Recruiting

Novartis Investigative Site, Curitiba, PR 80030-110, Brazil; Recruiting

Novartis Investigative Site, Londrina, PR 86050-190, Brazil; Withdrawn

Novartis Investigative Site, Woolloongabba, Queensland 4102, Australia; Terminated

Novartis Investigative Site, Niteroi, RJ 24033900, Brazil; Withdrawn

Novartis Investigative Site, Rio de Janeiro, RJ 21941-913, Brazil; Recruiting

Novartis Investigative Site, Porto Alegre, RS 90560-030, Brazil; Recruiting

Novartis Investigative Site, Joinville, SC 89201260, Brazil; Recruiting

Novartis Investigative Site, Botucatu, SP 18618-970, Brazil; Withdrawn

Novartis Investigative Site, Sao Paulo, SP 04039-004, Brazil; Not yet recruiting

Novartis Investigative Site, Sao Paulo, SP 05403-000, Brazil; Not yet recruiting

Novartis Investigative Site, São Paulo, SP 05403 000, Brazil; Not yet recruiting

Novartis Investigative Site, Vellore, Tamil Nadu 632004, India; Recruiting

Mid South Endocrine Associates Midstate Endocrinology Assoc., Nashville, Tennessee 37203, United States; Withdrawn

Additional Information

Starting date: March 2014
Last updated: August 11, 2015

Page last updated: August 23, 2015

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