| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The following tumors are included:
1. NETs of the pancreas or duodenum: Insulinoma, Gastrinoma, VIPoma, glucagonoma,
2. Pituitary NETs: Thyrotropic-pituitary adenoma (TSH), Gonadotropic adenoma, Prolactinoma (PRL) and non-functioning pituitary adenoma (NFPA)
3. Ectopic ACTH-secreting (EAS) tumors
4. Nelson's syndrome
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062476 |
| E.1.2 | Term | Neuroendocrine tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of pasireotide LAR in pancreatic and duodenum NETs (Insulinoma, Gastrinoma, VIPoma, and Glucagonoma) based on disease specific primary biochemical tumor markers. |
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| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of pasireotide LAR in each of the pancreatic and duodenum NETs (Insulinoma, Gastrinoma, VIPoma and Glucagonoma) based on disease specific primary biochemical tumor markers
- To assess the efficacy of pasireotide LAR in each of the other rare NETs including Prolactinoma, Thyrotropic adenoma, Gonadotropic adenoma, Non functioning pituitary adenoma, Ectopic ACTH-secreting tumors and Nelsons syndrome based on disease specific primary biochemical tumor markers.
- To evaluate the overall safety and tolerability of pasireotide LAR
- To evaluate the effect of pasireotide LAR on disease-related symptoms.
- To evaluate the pharmacokinetics (PK) trough plasma concentrations of pasireotide LAR
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients ?18 years.
2. Patients who have failed standard of care treatment or for whom no standard of care treatment is available.
3. Patients with rare neuroendocrine tumors of pancreas or duodenum must meet each of the following:
� Pathologic confirmation: Patients must have histologically or cytologically confirmed low or intermediate grade neuroendocrine carcinoma. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, or goblet cell carcinoid are not eligible. If the pathology report states only neuroendocrine carcinoma, then the pathology subtype must be reconfirmed.
� Advanced metastatic or unresectable disease
� Patients must have biochemical evidence of hormone production and clinical symptoms consistent with diagnosis Insulinoma, Gastrinoma, VIPoma or Glucagonoma. Biochemical evidence can include values of a historical nature: (1) values used to establish the original diagnosis and/or (2) most recently available abnormal value(s).
4. Patients with rare neuroendocrine tumors of pituitary must meet each of the following:
� MRI documenting the presence of a pituitary tumor
� Patients must have biochemical evidence of hormone production (and clinical symptoms consistent with diagnosis of TSH-secreting, gonadotropic secreting, prolacting secreting or non-functioning pituitary adenoma. Biochemical evidence can include values of a historical nature: (1) values used to establish the original diagnosis and/or (2) most recently available abnormal value(s).
5. Patient with EAS tumors and Nelson�s syndrome should have confirmed diagnosis by the investigator with criteria consistent with [Post Text Supplement 1]. Biochemical evidence can include values of a historical nature: (1) values used to establish the original diagnosis and/or (2) most recently available abnormal value(s).
6. ECOG performance status ? 2.
7. Patients must observe the following intervals between the last injection of their previous treatment and the first injection of study drug:
� Octreotide LAR = 28 days (4 weeks)
� Octreotide s.c. = 8 hours
� Lanreotide Autogel = 28 days (4 weeks)
� Lanreotide SR = 14 days (2 weeks)
8. Written informed consent obtained prior to any screening procedures.
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| E.4 | Principal exclusion criteria |
1. Patients with active gallbladder disease.
2. Patients with any ongoing or planned anti-neoplastic therapy.
3. Patients with any ongoing or planned therapy with interferon.
4. Poorly controlled diabetes mellitus as indicated by the presence of HbA1c > 8% (Not applicable for glucagonoma patients).
5. Patients with radiolabelled somatostatin analogue therapy within 6 months of visit 1, cytotoxic therapy or interferon within 2 months of visit 1 or radiotherapy within 1 month of visit 1.
6. Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor�s Medical Monitor.
7. Any of the following cardiac abnormalities:
� QTcF at screening > 450 msec
� History of syncope or family history of idiopathic sudden death
� Sustained or clinically significant cardiac arrhythmias
� Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade AV block
� Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure
� Concomitant medication(s) known to increase the QT interval
8. Any of the following hepatic related exclusion criteria:
• History of liver disease, such as cirrhosis or chronic active hepatitis B and C
• Presence of Hepatitis B surface antigen (HbsAg)
• Presence of Hepatitis C antibody (anti-HCV)
• History of, or current alcohol misuse/abuse within the past 12 months
• Known gallbladder or bile duct disease, acute or chronic pancreatitis
• Baseline ALT or AST > 3 x ULN
• Baseline total bilirubin > 1.5x ULN
9. Patients with abnormal coagulation (PT or APTT elevated by 30% above normal limits)
10. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control.
� Female patients of child-bearing potential must use barrier contraception with condoms. The use of intra uterine device for all women and oral contraception for all women is allowed except for those patients diagnosed with non-functioning pituitary adenoma and gonadotroph adenoma.
� If oral contraception is used in addition to condoms, 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 three months after the study has ended.
� Male patients who are sexually active are required to use condoms during the study and for three months afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs). Female partners of these male patients must use a secondary barrier contraception.
11. Patients who have participated in any clinical investigation with an investigational drug within 30 days prior to dosing.
12. 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Patient response criteria: Patient response will be assessed for each tumor type by the change in the primary biochemical tumor marker value from baseline after 6 months of pasireotide LAR treatment. A patient will be considered a responder if there is a >50% decrease or normalization in the level of the primary biochemical tumor marker from baseline after 6 months of pasireotide LAR treatment. Biochemical tumor markers (including primary and non-primary markers) are presented for each specific disease in [Post Text Supplement 1]. In general, these rare tumors are not well characterized and while normalization of the primary biochemical tumor marker is the optimal goal, a 50% decrease in a biochemical tumor marker is anticipated to correlate with improvement in clinical signs/symptoms.
- Primary Efficacy: The proportion of responders among the patients with pancreatic and duodenum NETs (Insulinoma, Gastrinoma, VIPoma, and Glucagonoma).
- Secondary Efficacy:
1. The proportion of responders in each type of pancreatic and duodenum NETs including Insulinoma, Gastrinoma, VIPoma and Glucagonoma.
2. The proportion of responders in each of the other rare NETs including Prolactinoma, Thyrotropic adenoma, Gonadotropic adenoma, Non functioning pituitary adenoma, Ectopic ACTH-secreting tumors and Nelsons syndrome
3. The associated disease related symptoms present at baseline will be followed throughout the study using Memorial Symptom Assessment Scale (MSAS).
- Exploratory Efficacy: The primary biochemical tumor markers will be summarized longitudinally, i.e. % change from baseline by visit.
- Safety: Overall safety and tolerability of pasireotide LAR will be assessed by changes in vital signs and laboratory values including ECGs, urinalyses and blood chemistries. Additionally, patients will be monitored for the occurrence of adverse events at each study visit.
- PK: The PK of pasireotide LAR will be assessed by measurements of trough plasma concentrations.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Colombia |
| Mexico |
| Russian Federation |
| South Africa |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| After 6 months treatment, patients who don't demonstrate clinical benefit will be discontinued, those who don't meet prespecified criteria but benefit from treatment and those who demonstrate clinical benefit may continue in the extension study.Extension:up to 4 years or until lack of clinical benefit as assessed by the investigator, unacceptable AEs, withdrawal of consent or until pasireotide LAR or other effective therapy becomes commercially available (whichever comes first). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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