| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pancreatic neuroendocrine tumour neuroendocrine tumour (pNET) |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067518 |
| E.1.2 | Term | Pancreatic neuroendocrine tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy and safety of the combination Streptozocin (STZ) with 5-fluorouracil (5FU), STZ - 5FU chemotherapy followed by Everolimus 10 mg/day upon progression versus the reverse sequence in the treatment of advanced pancreatic neuroendocrine tumours (pNET), in terms of rate of patients with second progression free survival at 84 weeks of treatment, assessed by local investigator using RECIST criteria 1.0. |
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| E.2.2 | Secondary objectives of the trial |
To describe the efficacy of the two sequences of treatment STZ-5FU and everolimus 10 mg/day, as a continuous variable Hazard Ratio (HR), in advanced pNETs.
To determine whether the overall survival of patients with advanced pNETs could be modified by the upfront administration of each other treatment, STZ - 5FU and everolimus 10 mg/day, upon progression.
To compare the clinical activity of STZ - 5FU and everolimus 10 mg/day treatment given in 1st or 2nd place in advanced pNETS, in terms of time to first and second progression, response rate (RR), and early biochemical response (4 week CgA levels), Quality of Life and cost-efficacy of each sequence, and to investigate the criteria for measuring progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) that correlates better with overall survival.
To compare the safety and tolerability of treatment with STZ-5FU and everolimus 10 mg/day, given upfront each other upon progression, in patient |
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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 |
TUMOUR BLOCK ANALYSIS SUB-STUDY
Detection of predictive markers, Version 2.0, 30th January 2014
SEQTOR Study Protocol code GETNE1206.
Annex Objective
The objective of this sub-study is the detection of predictive markers of pNET and patients’ outcome, on paraffin embedded tumour blocks from patients included in SEQTOR clinical trial.
Endpoint
Mutational status of selected pancreas neuroendocrine-specific genes, including chromatin remodelling genes (MEN1, ATRX and DAXX) and mTOR pathway genes (PTEN, TSC2). Imunohistochemical staining of MEN1, ATRX, DAXX and PTEN.
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| E.3 | Principal inclusion criteria |
1. Adult patients ≥18 years old.
2. Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.
3. Documented confirmation of pancreatic NET G1 or G2 as per ENETS classification system:
G1: <2 mitoses per 2 mm2 and/or Ki-67 index ≤2%
G2: 2–20 mitoses per 2 mm2 and/or Ki-67 index >2% and ≤20%
4. Patients from whom a paraffin-embedded primary tumour or metastasis block is available and sent by courier. Patient should give his/her consent for its use in future investigations.
5. Before study inclusion, patients must show progressive disease documented by radiology within 12 months prior to study inclusion. If patient received anti-tumour therapy during the past 12 months, he/she must have radiological documentation of progressive disease while on or after receiving that anti-tumour therapy. Naive patients can be also included if, under investigator’s judgement, the patient needs active treatment with either chemotherapy or everolimus.
6. Before starting with the second treatment in sequence, patients must show documented disease progression by RECIST 1.0 (local assessment) while on anti-tumour therapy or in case of toxicity caused by the first treatment period.
7. ECOG Performance status score 0 - 2.
8. Life expectancy >12 months.
9. Presence of measurable disease as per RECIST criteria 1.0, documented by a Triphasic Computed Tomography (CT) scan or multiphase MRI radiological assessment.
10. Previous treatment with somatostatin (SS) analogues is allowed. Only those patients with active functioning syndrome at entry can continue with SS analogues during the study.
11. Adequate bone marrow function, documented by ANC >1.5 x 109/L, platelets >100 x 109/L, haemoglobin >9 g/dL.
12. Adequate liver function documented by: serum bilirubin ≤2.0 mg/dL, INR ≤2, ALT and AST ≤2.5 x ULN (≤ 5 x ULN in patients with liver metastasis).
13. Adequate renal function documented by: serum creatinine <1.5 x ULN.
14. Fasting serum cholesterol <300 mg/dL or <7.75 mmol/L and fasting triglycerides <2.5 x ULN. If one or both thresholds are exceeded, the patient may only be included after starting treatment with an adequate lipid-lowering agent.
15.Women with child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and/or a urine pregnancy test 48 hours before the administration of the first study treatment.
16.Written Informed Consent obtained according to local regulations.
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| E.4 | Principal exclusion criteria |
1. Patients with poorly differentiated pancreatic neuroendocrine tumor; this is, pNET G3 as per ENETS classification system:
G3: 21 or more mitoses per 2 mm2 and/or Ki-67 index >20%
2. Previous treatment with chemotherapy and/or mTOR inhibitors (sirolimus, temsirolimus, everolimus, deforolimus) or tyrosine kinase inhibitors (sunitinib, sorafenib, axitinib, pazopanib, regerafenib).
3. Immune therapy or radiation therapy within 4 weeks prior to the patient entering the study.
4. 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 enrolment.
5. Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within the last 6 months and/or without progression following PRRT.
6. Uncontrolled diabetes mellitus defined as: fasting serum glucose > 1.5 x ULN.
7. Patients with any severe and/or uncontrolled medical conditions such as: a. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia,
b. active or uncontrolled severe infection,
c. severe hepatic impairment (Child Pugh C) is not allowed; moderate hepatic impairment (Child Pugh B and A) requires a reduced dose of everolimus (5mg and 7.5 mg daily respectively). Positive HBV-DNA and or HBsAg patients at screening should receive prophylaxis treatment.
d. severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air),
e. active, bleeding diathesis
8. Treatment with potent inhibitors or inducers of CYP3A isoenzyme (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) within 5 days immediately before the start of treatment (a list of clinically significant drug interactions is shown in section 6. Concomitant Medication).
9. Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.
10. Patients known to be HIV seropositive.
11. Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
12. Known intolerance or hypersensitivity to 5FU or STZ or its excipients.
13. Participation in any other clinical trial or concomitant treatment with any other investigational drug.
14. 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.
15. Pregnant, lactating women or fertile adults not using effective birth control methods. If barrier contraceptives are used, these must be continued to be used throughout the trial by both sexes and for up to 8 weeks after the end of treatment.
16. For administrative matters (insurance) patients ≥ 95 are not allowed.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of second progression free survival is defined as: PFS of Course 1 + interval between treatments + PFS of Course 2, where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 84 weeks from first treatment |
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| E.5.2 | Secondary end point(s) |
Hazard Ratio of second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2).
Time to first progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
Time to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
Time from first progression to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs assessed every 12 weeks.
Quality of life score at baseline, upon progression and 30 days after the last dose of study treatment (both sequences).
CgA levels at baseline and at 4 weeks of treatment start.
Correlation between the four criteria for second progression free survival (RECIST 1.0, RECIST 1.1, composite RECIST 1.0 and composite RECIST 1.1) and Kendall tau variables.
Overall survival (OS) of patients on treatment with the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression or the reverse sequence, in the treatment of advanced pancreatic neuroendocrine tumours (pNET).
Number of adverse events, dose reductions, and total dose administered on patients treated with STZ-5FU followed by everolimus 10 mg/day or the reverse sequence, in advanced pNETs.
Ratio of Incremental cost-efficacy (ICER) of the differential of costs incurred on by each treatment arm (A and B): ICER= (Arm A costs – Arm B costs)/(Arm A 2nd PFS – Arm B 2nd PFS). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to 84 weeks from first treatment |
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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) | 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 | 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 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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| Last Patient 30 Day Follow-up |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 | 2 |
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