SOM230 Ectopic ACTH-producing Tumors

Study Overview
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Brief Summary
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The purpose of this prospective open-label phase II study, is to evaluate the efficacy of pasireotide twice daily subcutaneous injections for normalizing 24 hour urine free cortisol in patients with ectopic ACTH-producing tumors as measured by the proportion of patients achieving normal UFC at the end of the study period.

Official Title
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A Proof of Concept and Open-label Study to Test the Efficacy and Safety of Pasireotide in Patients With Ectopic ACTH-producing Tumors

Conditions
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Ectopic ACTH Syndrome

Intervention / Treatment
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* Drug: Pasireotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained prior to any screening procedures Male or female patients aged 18 years or greater Confirmed non-pituitary ectopic-ACTH secreting tumor Well differentiated, and low or intermediate grade (WHO classification G1-2) neuroendocrine tumor Tumor size increase < 10% in 6 months prior to screening on CT or MRI Mean 24-hour urinary free cortisol level of at least 1.5 x the upper limit of the normal range, and a morning plasma ACTH level of > 5 ng/L Exclusion Criteria: Patients with highly malignant ACTH-secreting tumors, i.e. small-cell lung carcinomas, medullary thyroid carcinomas, and pheochromocytomas Patients with poorly differentiated neuroendocrine tumors (WHO classification G3) Patients with >10% increase of tumor size in 6 months prior to screening by CT or MRI Patients with Cushing's syndrome due to pituitary ACTH secretion Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1) Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA) Patients who have undergone major surgery within 1 month prior to screening Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included) Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8% Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by Congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade AV block, history of acute MI less than one year prior to study entry QTcF >450 msec at screening History of syncope or family history of idiopathic sudden death Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, cardiac failure Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism, concomitant medication(s) known to increase the QT interval Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST more than 2 x ULN, serum creatinine >2.0 x ULN, serum bilirubin >1.5 x ULN, serum albumin < 0.67 x LLN at screening Patients with any ongoing or planned anti-neoplastic therapy Has been treated with radionuclide at any time prior to study entry Is likely to require any additional concomitant treatment to pasireotide for the tumor Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as History of immunocompromise, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed Presence of active or suspected acute or chronic uncontrolled infection History of, or current alcohol misuse/abuse in the 12 month period prior to screening Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs) Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with pasireotide Known hypersensitivity to somatostatin analogues Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study Patients with presence of Hepatitis B surface antigen (HbsAg) Patients with presence of Hepatitis C antibody test (anti-HCV)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pasireotide<br>Each patient will be treated with pasireotide at an initial dose of 600 μg twice daily for one month. The dose will be further increased to 900 μg twice daily for month 2 and 3. After month 3, patients who continue to meet the inclusion and exclusion criteria will be entered into an additional 3 months of treatment. | Drug: Pasireotide<br> <br> * Other names: SOM230;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of pasireotide twice daily subcutaneous injections for normalizing 24 hour urine free cortisol in patients with ectopic ACTH-producing tumors | Effectiveness of pasireotide as measured by 24 hour urine free cortisol | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with abnormal laboratory values for urine free cortisol | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by urine free cortisol | 6 months | 
| Number of participants with abnormal laboratory values for serum cortisol levels | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by serum cortisol levels | 6 months | 
| Number of participants with abnormal laboratory values for salivary cortisol levels | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by salivary cortisol levels | 6 months | 
| Number of participants with abnormal laboratory values for Hemoglobin A1C (HbA1C) | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by Hemoglobin A1C (HbA1C) | 6 months | 
| Number of participants with abnormal laboratory values for fasting blood glucose | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by fasting blood glucose | 6 months | 
| Number of participants with abnormal laboratory values for blood electrolytes | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by blood electrolytes | 6 months | 
| Number of participants with abnormal laboratory values for plasma adrenocorticotropic hormone (ACTH) | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by plasma adrenocorticotropic hormone (ACTH) | 6 months | 
| Number of participants with abnormal laboratory values for plasma beta-lipotropin | Number of participants with abnormal laboratory values for hormones and metabolism as assessed by plasma beta-lipotropin | 6 months | 
| Number of participants with changes in clinical signs and symptoms | Number of participants with changes in clinical signs and symptoms of Cushing's disease as defined by changes in weight, body mass index, and blood pressure | 6 months | 
| Changes in Tumor Size | To evaluate changes in tumor size | From baseline at months 3 and 6 | 
| Number of participants with changes in blood chemistry (safety) | Number of participants with abnormal laboratory values for blood chemistry as assessed by total proteins, amylase, lipase, total cholesterol (TC), low-density lipids (LDL)-cholesterol, m creatinine, creatinine clearance, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, albumin, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) | Baseline and 6 months | 
| Number of participants with changes in hematology (safety) | Number of participants with abnormal laboratory values for hematology as assessed by prothrombin time (PT), and international normalized ratio (INR) | Baseline and 6 months | 
| Number of participants with changes in cardiac activity | Number of participants with changes in cardiac activity as measured by electrocardiogram (ECG) | Baseline and 6 months | 
| Number of participants with changes in liver health | Number of participants with changes in liver health as determined by an abdominal ultrasound | Baseline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pasireotide, Ectopic ACTH, SOM230, ectopic ACTH-dependent Cushing's syndrome