E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pancreatic neuroendocrine tumors (also called pancreatic endocrine tumors or islet cell tumors (ICT)) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033630 |
E.1.2 | Term | Pancreatic islet cell neoplasm malignant NOS |
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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 determine whether treatment with RAD001 10 mg/d plus best supportive care prolongs the progression free survival (PFS) compared to treatment with Placebo plus best supportive care in patients with advanced pancreatic neuroendocrine tumor. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of RAD001 on other tumor endpoints: objective response rate (CR or PR), response duration • To compare overall survival (OS) between the study arms • To determine the safety and tolerability of RAD001 (10 mg/d) in patients with advanced Pancreatic Neuroendocrine Tumor • To characterize the pharmacokinetics of RAD001 in Pancreatic NET indications • To compare changes from baseline in chromogranin A (CgA) and follow other biochemical tumor markers produced by the tumor that are elevated at baseline, during subsequent visits • To characterize pre-treatment tumor samples by immunohistochemical and genetic analyses indicating activation of the mTOR pathway. • To assess the relationship between RAD001 steady state levels, tumor response, and chromogranin A response (50% decrease from baseline) • To determine the effects of RAD001 on plasma antigenic molecules e.g. VEGF, basic FGF, PLGF, sVEGFR1, and sVEGFR2 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET 2. Patients must have confirmed low-grade or intermediate-grade neuroendocrine carcinoma 3. Patients must have radiological documentation of progression of disease within 12 months prior to randomization. If patient received anti-tumor therapy during the past 12 months, he/she must have radiological documentation of progression of disease while on or after receiving the therapy 4. Measurable disease per RECIST criteria using Triphasic Computed Tomography (CT) scan or multiphase MRI for radiologic assessment 5. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin >9 g/dL 6. Adequate liver function as shown by: • Serum bilirubin ≤ 1.5 x ULN • INR < 1.3 (INR < 3 in patients treated with anticoagulants) • ALT and AST ≤ 2.5 x ULN (≤ 5x ULN in patients with liver metastases) 7. Adequate renal function: serum creatinine ≤ 1.5 x ULN 8. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication 9. Performance Status 0-2 on the WHO scale 10. Adult male or female patients ≥ 18 years of age 11. Women of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and /or urine pregnancy test 48 hours prior to the administration of the first study treatment 12. Written informed consent from patients must be obtained in accordance to local guidelines |
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E.4 | Principal exclusion criteria |
1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma are not eligible 2. Cytotoxic chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to randomization 3. Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment 4. Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus). 5. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN 6. Patients who have any severe and/or uncontrolled medical conditions such as: • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia • active or uncontrolled severe infection • cirrhosis, chronic active hepatitis or chronic persistent hepatitis • severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air). • active, bleeding diathesis 7. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent 8. Patients with a known history of HIV seropositivity 9. No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for ≥ 3 years. 10. Female patients who are pregnant or nursing (lactating), or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS) |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |