| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced progressive pNETs |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced pancreatic neuroendocrine tumours |
|
| 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 | 20.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068909 |
| E.1.2 | Term | Pancreatic neuroendocrine tumour metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare the progression free survival rate at 12 months which is the proportion of patients who are alive without progression to Course 1 therapy at 12 months from the date of randomization in STZ based CT vs Everolimus arms.
|
|
| E.2.2 | Secondary objectives of the trial |
•To compare efficacy of the combination STZ-5FU followed by Everolimus upon progression vs. the reverse sequence in treatment of advanced pNET, in terms of rate of patients with 2nd PFS at 140 +/-8 weeks of treatment, assessed by RECIST criteria 1.0.
•To describe efficacy of the two treatment sequences as continuous variable Hazard Ratio, in advanced pNETs at 12 months (main analysis) and 140+/8weeks.
• To determine whether overall survival of patients with advanced pNETs could be modified by upfront administration of each other treatment upon progression.
• To compare clinical activity of STZ-5FU and Everolimus given in 1st or 2nd place in advanced pNETS, in terms of time to 1st and 2nd progression, response rate, early biochemical response, Quality of Life, cost-effectiveness of each sequence, to investigate the criteria for measuring PFS that correlate better with overall survival.
• To compare safety, tolerability, cost-effectiveness of the two treatment sequences. |
|
| 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) Detection of predictive markers
Version 2.0 of date 30th of January 2014
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."
2) Evaluation of a blood-based transcriptional assay - the NETest - as a biomarker of neuroendocrine tumor response
NETest - Detection of a circulating NET fingerprint
Ver 1.0, 13th March 2015
The objective of this sub-study is to use the NETest as a measure of treatment response in the SEQTOR study. Including the NETest will provide additional information that can be used to evaluate therapeutic efficacy.
3) PanNETassigner molecular subtypes assay
Ver 1.0, 7th August 2018
The aim of this sub-study is to evaluate the predictive value of the PanNET assigner assay for patients undergoing treatment with chemotherapy and everolimus. This test uses molecular technologies, looking at changes in RNA seen in tumor samples, to divide pancreatic NET patients into different molecular subtypes. It will be evaluated whether these molecular subtype results in combination with clinical data from the SEQTOR study can be used for patient prognostication and classification as well as prediction of treatment response for pNET patients. |
|
| 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 to be sent by courier (Section 7.2.10).
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. Treatment naive patients can be also
included if, under investigator's judgment, 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. |
|
| 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 tirosyne 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. (notice that this criterion includes patients with known dihydropyrimidine dehydrogenase deficiency)
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 during the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients who are alive without progression to Course 1 therapy at 12 months from the date of randomization in STZ based CT vs Everolimus arms. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 12 months of treatment from the date of randomization |
|
| E.5.2 | Secondary end point(s) |
1. Second progression free survival 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.
It will be expressed as the rate of second progression free survival; this is the proportion of patients which are free of second progression at 140±8 weeks.
2. Second progression free survival (PFS of Course 1 + interval between treatments + PFS of course 2) as a continuous time variable.
3. Time to first progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
4. Time to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
5. Time from first progression to second progression of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs.
6. Response rate of STZ-5FU and Everolimus 10 mg/day or the reverse sequence in advanced pNETs assessed every 12 weeks.
7. Quality of life score at baseline, upon progression and 30 days after the last dose of study treatment (both sequences).
8. CgA levels at baseline and at 4 weeks of treatment start.
9. 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.
10. 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).
11. 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.
12. Cost per progression free survival gained: Incremental cost-effectiveness ratio (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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At LVLS.
2. At LVLS.
3. At First visit of second treatment.
4. At LVLS.
5. At LVLS.
6. Every 12 weeks.
7. At baseline, upon progression and 30 days after the last dose of study treatment.
8. At baseline and at 4 weeks of treatment start.
9. At every tumor assessment (every 12 weeks)
10. At LVLS.
11. At every cycle.
12. At LVLS. |
|
| 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 | Yes |
| 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 | 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) | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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
|
| The study will end when all patients are followed up to patient death, or 140+/-8 weeks + 30days safety FU. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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