Phase II Study Evaluating Efficacy, Safety and Pharmacokinetics of Pasireotide in Patients With Dumping Syndrome

Study Overview
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Brief Summary
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multi-center, phase II study evaluating efficacy, safety and pharmacokinetics of pasireotide in patients with dumping syndrome

Detailed Description
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43 adult patients with dumping syndrome received pasireotide s.c. during the dose escalation phase (3 months dose could be increased based on the presence of hypoglycemia during OGTT). After completing Month 3, patients were switched to pasireotide LAR for 3 months (up to Month 6). The core phase of the study was completed at the end of Month 6. Patients were allowed to enter the 6 month extension phase if they experienced benefit with pasireotide LAR treatment.

Official Title
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A Multi-center, Intra-patient Dose Escalation Phase II Study to Evaluate the Preliminary Efficacy, Safety and Pharmacokinetics of Pasireotide (SOM230) Subcutaneous (s.c.) Followed by Pasireotide LAR in Patients With Dumping Syndrome

Conditions
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Dumping Syndrome

Intervention / Treatment
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* Drug: SOM230


Participation Criteria
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Eligibility Criteria
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Inclusion criteria:. Male or female patients ≥ 18 years of age. Post-gastric or esophageal bypass surgery, matching one of the criteria below: Bariatric surgery: more than 6 months before signing the informed consent Esophageal cancer surgery: were disease free at study entry Gastric cancer surgery: were at stage 0 or I and were disease free at study entry Patient with a documented diagnosis of Dumping Syndrome defined as having: History of/or active symptoms associated with dumping syndrome (e.g. post-prandial tachycardia, bloating, diarrhea) and Documented history of hypoglycemia based on either: glucose <50 mg/dL or 2.8 mmol/L on a sporadic or scheduled blood analysis -or glucose value <60 mg/dL or ≤ 3.3 mmol/L at 90, 120, 150 or 180 min during an OGTT Patients had at least one glucose level <60 mg/dL (or ≤ 3.3 mmol/L) at 90, 120, 150 or 180 min during the 3-hour OGTT at screening. Patients with esophageal cancer with a negative computed tomography (CT) or Magnetic resonance imaging (MRI) scan (neck, thoracic, and upper abdominal) and albumin ≥ 3.5 g/dl at baseline. Patients with gastric cancer with a negative CT or MRI scan (total abdomen). Karnofsky Performance Status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs) Patients who received other therapies for dumping syndrome (such as acarbose, gama guar, pectin) must have stopped all treatments and had a wash out period prior to signing the informed consent (i.e. at least 2 weeks between last previous therapy and first dose of study medication in this study). Patients who had provided signed written informed consent prior to study participation. Exclusion Criteria: Bariatric patients who had lap band. Patients with a current diagnosis of diabetes mellitus. Patients who had failed treatment with somatostatin analogues for dumping syndrome in the past. Patients who had been treated with somatostatin analogues in the past, must have had an appropriate interval between the last administration of somatostatin analogues treatment and the study drug as follows Octreotide sc for ≥ 72 hours Octreotide LAR for ≥ 56 days (8 weeks) Lanreotide Autogel for ≥ 98 days (14 weeks) Lanreotide SR ≥ 28 days (4 weeks) Patients who were already treated with pasireotide. Patients who had a known hypersensitivity to somatostatin analogues. Patients who were receiving anti-cancer therapy (chemotherapy and/or radiotherapy). Patients who had any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive human immunodeficiency virus (HIV) test result (ELISA and Western blot). An HIV test was not required; however, previous medical history was reviewed. Non-malignant medical illnesses that were uncontrolled or whose control may have been jeopardized by the treatment with this study treatment. Life-threatening autoimmune and ischemic disorders. Patients with the presence of active or suspected acute or chronic uncontrolled infection. Inadequate end organ function as defined by: Inadequate bone marrow function: White blood cells (WBC) <2.5 x 109/L Absolute neutrophil count <1.5 x 109/L Platelets <100 x 109/L Hemoglobin <9 g/dL International normalized ratio (INR) ≥ 1.3 Serum creatinine >2.0 mg/dL Alkaline phosphatase (ALP) >2.5 x upper limit of normal (ULN) Serum total bilirubin >1.5 x ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2 x ULN History of liver disease, such as cirrhosis or chronic active hepatitis B and C. Presence of Hepatitis B surface antigen (HbsAg) and/ or presence of Hepatitis C antibody test (anti-Hepatitis C Virus).

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOM230<br>Subjects with dumping syndrome treated with pasireotide | Drug: SOM230<br>* Pasireotide (SOM230) sc injection was provided as solution for injection in individual 1-point-cut 1 mL ampule, containing nominally 200 μg of pasireotide (as free base). Doses: 50, 100, 150 and 200 μg. Pasireotide im LAR depot injection was provided as micro particles powder in vials containing nominally 10, 20, 40 & 60 mg of pasireotide (as free base) & solvent for suspension for injection in ampules for the reconstitution of the LAR micro particles. Doses: 10, 20, 30, 40 or 60 mg<br>* Other names: pasireotide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Plasma Glucose Level | Response rate is defined as percentage of patients with no glucose values < 60 mg/dL at 90,120, 150 and 180 min during the Oral Glucose Tolerance Test (OGTT) at the end of s.c. dose escalation phase | at Month 3 (M3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Plasma Glucose Level | Response rate is defined as percentage of patients with no glucose values < 60 mg/dL at 90,120, 150 and 180 min during the Oral Glucose Tolerance Test (OGTT) at the end of 6 months (end of LAR/Core phase) and at the end of 12 months (extension phase) | at Month 6 (M6), Month 12 (M12) | 
| Response Rate in Pulse Rate | Pulse rate was defined as percentage of patients with change in pulse rate >=10 bpm from pre-OGTT to 30 minutes post OGTT. | at baseline, M3, M6, M12 | 
| Response Rate in Hematocrit Levels | Percentage of patients with change in hematocrit >= 3% from pre-OGTT to 30 minutes post OGTT. | M3, M6, M12 | 
| Insulin Levels During OGTT | Absolute insulin levels at the end of M3, M6, M12 | M3, M6, M12 | 
| Glucagon Levels During OGTT | Absolute glucagon levels at the end of Months 3, 6 & 12 | M3, M6, M12 | 
| Glucagon-like Peptide 1 (GLP-1) Levels During OGTT | Absolute Glucagon-like peptide 1 (GLP-1) levels at the end of at the end of Months 3, 6 and 12 at different time points. | M3, M6, M12 | 
| Gastric Inhibitory Polypeptide (GIP) Levels at During OGTT | Absolute Gastric Inhibitory Polypeptide (GIP) levels at the end of Months 3, 6 and 12 at different time points. | M3, M6, M12 | 
| Health-related Quality of Live (HRQoL) Short Form- 36 (SF-36) Score(s) | Absolute HRQoL SF-36 Scores at end of the Months 3, 6 and 12 from s.c. baseline. SF-36, a 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. | M3, M6, M12 | 
| Dumping Severity Score (DSS) at the End of Months 3, 6 and 8 | Absolute Dumping Severity Score (DSS) scores at end of M3, M6 & M8. At study start patients were assessed using DSS (older version of DSQ); however after the implementation of protocol amendment 2, all patients were expected to use DSQ. No results available for M12 as last patient that answered the DSS was at M8. DSS = disease-specific patient (Pt.) reported outcome (PRO) questionnaire uses a 4-point Likert scale (0, absent; 1, mild; 2, relevant; 3, severe; 4) to ask Pt. to evaluate intensity of early dumping symptoms (within 30 minutes (<30 minutes) after food ingestion). The questionnaire also evaluates 65 late dumping symptoms (more than 1.5 hours (>90 minutes) after food ingestion). Early & late dumping score calculated by adding the scores of the respective questions. Cumulative dumping score is obtained by adding early & late scores. DSS Range (min (absent) - max (severe)): Early dumping: 0-24; Late Dumping: 0-18; Cumulative: 0-42. Lower scores represent a better outcome. | M3, M6, M8 | 
| Dumping Score Questionnaire (DSQ) at the End of Months 3, 6 and 12 | Absolute Dumping Score Questionnaire (DSQ) scores at end of Months 3, 6 & 12 from s.c. baseline. DSQ = disease-specific PRO scale. The questionnaire uses a 5-point Likert scale (0, none; 1, mild; 2, moderate; 3, severe; 4, very severe) to ask Pt. to evaluate intensity of 10 early dumping symptoms (within 30 minutes (<30 minutes) after food ingestion). The questionnaire also evaluates 5 late dumping symptoms (more than 1.5 hours (>90 minutes) after food ingestion). Early & late dumping score calculated by adding the scores of respective questions. A cumulative dumping score is obtained by adding early & late scores. At study start patients were assessed using DSS (older version of DSQ); however after the implementation of protocol amendment 2, all patients used DSQ. DSQ Range: (min (None) - max (Very severe)): Early dumping: 0-40; Late Dumping: 0-20; Cumulative: 0-60. Lower scores represent a better outcome. | M3, M6, M12 | 
| Patient Global Assessment at the End of Months 3, 6 and 12 | Treatment with pasireotide LAR (both early and late dumping scores), was assessed by patient global assessment. Patient Global Assessment served as an additional approach to symptom based measurement by DSQ. It incorporated a patient global assessment question: Considering all the ways that your disease affects you, rate how you are feeling during the last 7 days compared with your situation before starting the study .Patients Global Assessment was measured utilizing a 7 point scale (from 1=a lot worse to 7= a lot better). | M3, M6, M12 | 
| Plasma Pharmacokinetic (PK) Parameter of Pasireotide: Cmax, ss (Steady State) and Ctrough, ss, After s.c. Injection | A pre-dose PK blood sample was collected before the morning pasireotide s.c. dose of 50 μg, 100 ug, 150 ug and 200 ug. OGTT was performed right after the morning s.c. dose (Time point zero); additional PK blood samples were collected at the same time points as the OGTT evaluation at 30, 60, 90, 120, 150 and 180 minutes. 'n' = number of subjects with non-missing values | M1 to M3 | 
| Plasma Pharmacokinetic (PK) Parameter of Pasireotide: AUC0-3h, ss, After s.c. Injection | A pre-dose PK blood sample was collected before the morning pasireotide s.c. dose of 50 μg, 100 ug, 150 ug and 200 ug. OGTT was performed right after the morning s.c. dose (Time point zero); additional PK blood samples were collected at the same time points as the OGTT evaluation at 30, 60, 90, 120, 150 and 180 minutes. | M1 to M3 | 
| Plasma Pharmacokinetic (PK) Parameter of Pasireotide: Tmax, ss, After s.c. Injection | A pre-dose PK blood sample was collected before the morning pasireotide s.c. dose of 50 μg, 100 ug, 150 ug and 200 ug. OGTT was performed right after the morning s.c. dose (Time point zero); additional PK blood samples were collected at the same time points as the OGTT evaluation at 30, 60, 90, 120, 150 and 180 minutes. | M1 to M3 | 
| Plasma PK Parameter of AUC0-3h, d21, End _inj and AUC0-3h, d28, 3rd_inj Associated With LAR (LAR Core Phase) |  | M4 to M6 | 
| Summary of LAR PK Parameters by Dose | Summary of plasma PK parameter Cmax, p2 , 2nd injection and Ctrough, d28 associated with LAR injection (LAR Core phase) | M4 to M6 | 
| Pasireotide Concentrations in LAR Phase | Summary of pasireotide concentrations following monthly i.m. injections of pasireotide LAR by incident dose (LAR Pharmacokinetic set) | M7 to M12 | 
| LAR PK Parameter: Ctrough - at Steady State (ss) by Dose | In the LAR treatment phase, monthly injections of pasireotide LAR 10, 20, 30 and 40 mg were given to participants and trough concentration at steady state (Ctrough,ss) were obtained but due to only 1 participant in the 40mg arm, standard deviation could not be calculated. | M4 to M12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dumping syndrome, SOM230, pasireotide LAR