E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The study will evaluate the safety of everolimus in patients with advanced neuroendocrine tumors of gastrointestinal, lung or pancreatic origin. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 evaluate additional safety of everolimus in patients with advanced neuroendocrine tumors of gastrointestinal, lung or pancreatic origin. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate investigator-assessed best overall response in patients with advanced NETs of gastrointestinal, lung or pancreatic origin treated with everolimus
• To estimate investigator-assessed progression free survival (PFS)
• To provide expanded access to everolimus in patients with advanced NETs of gastrointestinal, lung or pancreatic origin
• To assess disease related symptoms and changes in health related quality of life (HRQoL) over time in advanced neuroendocrine patients treated with everolimus
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years old.
2. Advanced (unresectable or metastatic) biopsy-proven neuroendocrine tumor of gastrointestinal, lung or pancreatic origin.
3. Performance Status 0-2 on the WHO scale.
4. Adequate bone marrow function as shown by:
• ANC ≥ 1.5 x 109/L,
• Platelets ≥ 100 x 109/L,
• Hemoglobin >9 g/dL
5. Adequate liver function as shown by:
• Serum bilirubin ≤ 1.5 x ULN,
• ALT and AST ≤ 2.5 x ULN. Patients with known liver metastases who have an AST and ALT ≤ 5 x ULN,
• INR < 1.3 (INR < 3 in patients treated with anticoagulants)
6. Adequate renal function as shown by: serum creatinine ≤ 1.5 x ULN.
7. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN.
8. Written informed consent obtained before any trial related activity and according 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 enrollment
3. Hepatic artery embolization within the last 2 months or cryoablation or radiofrequency ablation of hepatic metastasis within 2 months of enrollment
4. Prior therapy with mTOR inhibitors (for example sirolimus, temsirolimus, everolimus).
5. Patients with a known hypersensitivity to everolimus or other rapamycin analogs (sirolimus, temsirolimus), or to its excipients.
6. Patients receiving chronic treatment with immunosuppressives
7. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN.
8. 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 enrollment, serious uncontrolled cardiac arrhythmia,
• active or uncontrolled severe infection,
• Patients with a history of invasive fungal infections,
• severe hepatic impairment (Child-Pugh class C),
• severely impaired lung function
9. Active bleeding diathesis
10. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required.
11. 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.
12. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry. Note: Patients must have recovered from the acute effects of surgery prior to enrollment.
13. Female patients who are pregnant or nursing (lactating).
14. Adults of reproductive potential who are not using effective birth control methods. Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in female patients. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug.
15. Patients unwilling to or unable to comply with the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety:
grade 3 or 4 adverse events, serious adverse events |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 81 |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |