E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with histologically confirmed advanced (unresectable or metastatic) non syndromic NET from foregut, midgut and hindgut, with exclusion of pancreatic NET, who have progressed within 12 months prior to study enrollment and with measurable disease at baseline. Patients with poorly differentiated tumours are excluded. |
|
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 | 10052399 |
E.1.2 | Term | Neuroendocrine tumour |
|
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 the efficacy of everolilmus as monotherapy in patients with non syndromic neuro-endocrine tumours (NET). Efficacy is defined as the proportion of patients with complete (CR) or partial response (PR) according to RECIST criteria. |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the disease control rate (CR + PR + SD) • To evaluate the biochemical response rate based on the tumour marker CgA • To evaluate progression-free survival in this patient population • To evaluate overall survival in this patient population • To further characterize the safety profile of everolimus |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Adult male or female patients ≥ 18 years of age • Advanced (unresectable or metastatic) biopsy-proven non syndromic neuro-endocrine carcinoma, low- or intermediate grade • Radiological documentation of disease progression within 12 months prior to study entry. If patients received anti-tumour therapy during the past 12 months, they must have radiological documentation of progression of disease while on or after receiving the therapy. • Patients may have received previous treatment (chemotherapy, biotherapy, peptide-receptor radionuclide therapy); an overall maximum of 3 systemic treatments is allowed, as follows: -previous ≤ 1 CT line for advanced disease; -previous ≤ 1 RT line; -previous ≤ Biiotheraph (e.g. IFN etc); octreotide and/ or interferon. IN case of provious octreotide and previous interferon, these will be counted as 2 previous systemic treatment lines -previous ≤ 1 VEGFi treatment line (e.g. bevacizumab, sunitinib, etc) • Measurable disease as defined by RECIST using instrumental assessment (CT or MRI) • Adequate bone marrow function as shown by: • ANC ≥ 1.5 x 109/L, • Platelets ≥ 100 x 109/L, • Hb >9 g/dL • Adequate liver function as shown by: • Serum bilirubin ≤ 1.5 x ULN • INR < 1.3 (or < 3 on anticoagulants) • ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) • Adequate renal function: serum creatinine ≤ 2.0 x ULN • 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. • ECOG performance status of 0-2 • Life expectancy ≥ 6 months • Women of childbearing potential must have had a negative urine or blood pregnancy test within one week prior to the administration of the study treatment start. • Patients who give a written informed consent obtained according to local guidelines |
|
E.4 | Principal exclusion criteria |
• Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma are not eligible • Patients with carcinoid with hormone related symptoms (diarrhea ≥4 stools per day and/or flushes). • Patients with Islet Cell carcinomas or pancreatic NET • Patients who receive currently following therapies have to undergo washout period prior to study entry • The patient should have recovered from the treatment and have a good clinical condition before entering this study. • Patients who received peptide-receptor radionuclide therapy within 3 months prior to study entry • Patients who received VEGFi therapy within 4 weeks prior to study entry. • Patients who received hepatic artery embolisation within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation or radiofrequency ablation of hepatic metastasis within 2 months of study entry • Patients who received prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus) • Patients with a known hypersensitivity to RAD001(everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients • Patients with uncontrolled central nervous system (CNS) metastases. • Patients with an active, bleeding diathesis. • Patients receiving chronic systemic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisone or equivalent) or another immunosuppressive agent. Inhaled and topical steroids are acceptable. • Patients with a known history of HIV seropositivity. • Patients with autoimmune hepatitis. • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study. • Patients who have a history of another primary malignancy and off treatment for ≤3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix • Patients that are currently, or in the 4 weeks preceding initiation of study treatment, receiving other investigational agents • Patients unwilling or unable to comply with the requisites of the protocol • Female patients who are pregnant or breast feeding, 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. Oral contraceptives are not acceptable. • Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to randomization. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Objective Response Rate (CR + PR) • Biochemical response (CgA) • Disease control rate (CR + PR + SD) • Progression-free survival • Overall survival |
|
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 | 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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
|
|
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |