E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-resectable duodeno-pancreatic neuroendocrine tumours after first line treatment |
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E.1.1.1 | Medical condition in easily understood language |
Neuroendocrine tumors, localized in duodenum or pancreas, and which cannot be surgicaly removed after a first treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067517 |
E.1.2 | Term | Pancreatic neuroendocrine tumour |
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 |
Phase II: To evaluate the rate of patients alive and progression free at 6 months, assessed by the investigator according to RECIST criteria, version 1.1.
Phase III: To assess and compare the Progression Free Survival (PFS) of lanreotide versus placebo according to RECIST criteria (version 1.1, Appendix 3), assessed by the investigator.
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E.2.2 | Secondary objectives of the trial |
Phase II: •Rate of patients alive and progression free at 12 months, assessed by the investigator according to RECIST criteria (version 1.1) •Rate of patients alive and progression free at 6 months, according to central review •Safety •Response rate at 6 months according to RECIST criteria (version 1.1) •Time To Progression (TTP) •Quality of life assessed with the questionnaire QLQ-C30, including module NET 21, and the Spitzer visual analogue scale.
Phase III: •Overall Survival (OS) at 3 and 5 years •PFS according to central review •Safety •Response rate at 6 months according to RECIST criteria (version 1.1) •Chemotherapy / biotherapy-free time interval •Quality of life assessed with the questionnaire QLQ-C30, including module NET 21, and the Spitzer visual analogue scale. •Medico-economical evaluation: cost-effectiveness analysis at 12 months and cost-utility analysis at 18 months (using EQ-5D questionnaire). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1/ Research on biomarkers: The objective of the biological translational research project associated with this clinical study is to evaluate the prognostic and predictive value of the parameters collected during the analysis of tumour tissues and blood samples
2/ Medico-economical evaluation: - At 12 months: •To evaluate the cost-effectiveness ratio associated with treatment with lanreotide versus placebo. It will be expressed in terms of cost per progression-free life year gained (PFLYG) •To compare the average cost and average effectiveness associated with lanreotide versus placebo - At 18 months: •To evaluate the cost-effectiveness ratio, expressed in terms of cost per PFLYG •To evaluate the cost-utility ratio associated with treatment by lanreotide versus placebo. It will be expressed in terms of cost per progression-free life year gained adjusted for quality of life (QAPFLYG), using the EQ-5D questionnaire. •To compare the average cost and average utility associated with lanreotide versus placebo •To evaluate the share of the different items of expenditure in the total cost of patients’ care management at 18 months. |
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E.3 | Principal inclusion criteria |
•Metastatic (synchronous or metachronous) or locally advanced, non-resectable, well-differentiated duodeno-pancreatic neuroendocrine tumour, of grade 1 or 2 (WHO 2010 classification; Ki-67 ≤ 20%) •First-line treatment started due to (a, b OR c): a. Presence of symptomatic disease and/or hepatic invasion ≥ 50% and/or bone metastasis b. Documented tumour progression before first line therapy c. Disease progression in patients treated by Somatostatin analogues (analogues treatment must be stopped prior to starting the 1st line of therapy: •Histologically confirmed (either on primary tumour or metastases) •Pathological diagnosis validated by the NET consulting pathologist •Documented stable disease or objective response after first-line treatment, within 4 weeks (28 days) prior to randomisation •The first-line treatment will consist of either a chemotherapy or targeted therapy (everolimus or sunitinib) as referred to TNCD or ENETS guidelines. Treatment must have been administered for 3 to 6 months for chemotherapy and for 6 months for biotherapy •Non-functional tumour or gastrinoma controlled by PPIs •Age > or = 18 years •WHO 0, 1 or 2 •Highly effective contraception for male or female patients of childbearing age, defined as: oral contraceptives, intra-uterine devices or surgical sterilisation (vasectomy, tubal ligation). Female patients should use this contraception throughout the treatment period and for 6 months after the last treatment administration. Male patients should use contraception throughout the treatment period and for 3 months after the last treatment administration. •Signed informed consent prior to initiation of any study-specific procedures or treatment.
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E.4 | Principal exclusion criteria |
•History of haematological malignancy or other cancer, except those treated for more than 5 years and considered as cured, carcinoma in situ of the cervix and treated skin cancer (excluding melanoma) •Poorly differentiated neuroendocrine carcinoma or NET grade 3 ENETS (Ki-67 > 20%) •If primary resected, bone metastasis exclusively •Pre-treatment by somatostatin long-acting analogue •Total bilirubin ≥ 60 µmol/L •Uncontrolled diabetes •Contraindication to product used in the study or its components •Tumour arising in the context of a genetic disease •Pregnancy or lactation •Patients unable to undergo medical follow-up due to geographical, social, psychological or legal reasons •Concomitant participation in another clinical trial investigating a treatment during the treatment phase and within 30 days prior to the start of the study treatment. •Employment of the subject or a close relative (i.e. spouse/partner, child, parent or sibling) by the CRO, the study site. •Patients deprived of their liberty by a judicial or administrative decision, patients admitted to a hospital, social institution or who are under a measure of legal protection, patients hospitalized without consent or who are in an emergency situation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase II: The rate of patients alive and progression free at 6 months, evaluated according to the results of imaging assessment done 6 months after the randomisation. This evaluation will be done by the investigator according to RECIST criteria (version 1.1).
Phase III: The progression free survival, considering the first radiological progression of the patient (investigator’s opinion) or death (any reason). The time will be calculated between the randomisation date and the date the first event occurred. Patients who are alive and progression free will be censored at the time of the last news or cut-off date (the date the first of these occurs will be considered). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II: At 6 months
Phase III: Approximately 10 years |
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E.5.2 | Secondary end point(s) |
Phase II: •Rate of patients alive and progression free at 12 months (according to RECIST criteria version 1.1), assessed by the investigator •Rate of patients alive and progression free at 6 months, according to central review •Safety: the toxicities will be described using the NCI-CTC AE version 4.0 •Response rate according to RECIST criteria at 6 months (version 1.1), according to the investigator. Response rate will be defined as complete or partial response to the treatment •Time to progression (median). This endpoint will be calculated from the randomisation date to the date of the first progression (clinical and radiological) according to the investigator •Quality of life (QLQ-C30 including module NET 21, the Spitzer visual analogue scale) will be described at each time-point.
Phase III: The secondary endpoints of phase III will consist of the comparison between the placebo and the lanreotide, on: •Overall survival (OS) at 3 and 5 years. This endpoint will be estimated considering all deaths and the time will be calculated from the randomisation date to the date of death. Patients alive will be censored at the date of the last news or at the cut-off date •PFS according to central review, evaluated considering the first radiological progression of the patient (central review) or death (any reason). The time will be calculated from the randomisation date to the date the first event occurred. Patients alive and progression free will be censored at the date of the last news or at the cut-off date (the date the first of these occurs will be considered). •Safety: the toxicities will be described using the NCI-CTC AE version 4.0 •Response rate at 6 months according to RECIST criteria (version 1.1). Response rate will be defined as complete or partial response to the treatment •Chemotherapy/biotherapy-free time interval: the time will be calculated from the last chemotherapy/biotherapy (first-line treatment) administration, to the date of restart of first-line treatment or to the start of a new line (second-line treatment). •Quality of life (QLQ-C30 including module NET 21, the Spitzer visual analogue scale) will be described at each time-point •Average cost at 12 and 18 months •Effectiveness average at 12 and 18 months and utility index score average at 18 months using EQ-5D questionnaire. •Efficiency: - At 12 months; cost per progression free life year gained (PFLYG) - At 18 months: cost per PFLYG and cost per PFLYG adjusted for quality of life (QAPFLYG).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase II: At 6 months, 12 months and first progression (clinical and radiological) according to the investigator
Phase III: At 6 months, 12 months, 18 months, 3 years, 5 years, and first radiological progression of the patient (central review) or death (whatever the reason). |
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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 | 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) | Yes |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | No |
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 | 12 |
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 | 12 |