| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with inoperable, progressive, somatostatin receptor-positive(SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET) |
|
| E.1.1.1 | Medical condition in easily understood language |
| This trial aims to investigate metastasised and / or locally advanced neuroendocrine tumours (NET) in patients with pancreatic NET or nonfunctional gastroenteric NET. |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077559 |
| E.1.2 | Term | Gastroenteropancreatic neuroendocrine tumour disease |
| 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 demonstrate the efficacy of PRRT with 177Lu-edotreotide to prolong progression-free survival (mPFS) in patients with inoperable, progressive, SSTR+ GEP-NET, compared to everolimus |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives
1. To assess objective response rates (ORR), defined as the proportion of patients achieving partial response (PR) or complete response (CR) as best outcome after treatment with 177Lu-edotreotide vs. everolimus
2. To assess overall survival (OS), defined as the time from date of randomisation until death
Exploratory secondary objectives
3. To assess the duration of disease control (DDC) defined as the time of initial diagnosis of response (SD, PR or CR) until diagnosis of progression, after treatment with 177Lu-edotreotide vs. everolimus
4. To determine disease control rates (DCR)
5. To determine response rate (RR)
6. To assess the safety and tolerability of 177Lu-edotreotide in GEP-NET patients
7. To determine the health-related quality of life (HRQL) in GEP-NET
patients during and after therapy
8. To evaluate symptomatic tumour response
9. To evaluate the impact of patient characteristics
10. To evaluate the impact of tumour histology |
|
| 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 |
Sub-study A: Repetitive Full Dosimetry Imaging (D1 – D4):
Objective: The total absorbed doses (AD) to kidneys and tumour from four cycles of 177Lu-edotreotide (D1 – D4) will be estimated, by linear extrapolation of the AD measured on D1 with 7.5 ± 0.7 GBq to the full dose of 30 GBq. Dosimetry will be measured, using serial planar and single time point SPECT imaging. To verify the accuracy of total AD estimations, based on a linear extrapolation of AD measured during D1, full dosimetric imaging will be repeated during subsequent cycles (D2 –
D4) in a subgroup of approximately 20 patients, ready and able to undergo repetitive dosimetric imaging. At selected sites only.
Sub-study B: 3D Dosimetry SPECT/CT Imaging:
Objective: Abdominal SPECT images (1-2 bed positions, covering liver, kidneys, tumour, as appropriate) will be acquired in a subgroup of approximately 20 patient of 177Lu-edotreotide group in addition to the compulsatory planar images at the following time points of 0.5, 6, 24, and 72 – 96 h after injection of 177Lu-edotreotide. SPECT imaging will be performed after planar imaging. The absorbed doses determined by 3D dosimetry, will be analysed in comparison to absorbed doses values
obtained by planar (2D) and hybrid (2D/3D) dosimetry. At selected sites only.
Sub-study C: "Pharmacokinetic Urine Analysis and Bone Marrow Dosimetry"
Objective: This sub-study C will be conducted to assess the in vivo (in a living organism) stability of 177Lu-edotreotide and its radioactivity in bone marrow. Sub-study C will be performed during any one of the four 177Lu-edotreotide treatment cycles, in a subgroup of 20 patients. At selected sites only. |
|
| E.3 | Principal inclusion criteria |
All patients must meet all of the following criteria:
1. Written informed consent
2. Male or female ≥ 18 years of age
3. Histologically confirmed diagnosis of well-differentiated neuroendocrine tumour of non-functional gastroenteric origin (GE-NET) or both functional or non-functional pancreatic origin (P-NET), tumour
grade G1 or G2 (Ki-67 < 20%), unresectable or metastatic in a patient who is either treatment-naïve (1st line) or who has progressed under prior therapy (2nd line)
4. Availability of existing biopsy specimen from primary tumour or metastasis or, if unavailable, willingness to undergo current biopsy for secondary central analysis
5. Measurable disease per RECIST 1.1, on CT/MRI scans, defined as at least 1 lesion with ≥ 1 cm in longest diameter, and ≥ 2 radiological tumour lesions in total. A maximum of 5 target lesions visible on CT/MRI will be defined, thereof not more than 2 lesions per organ
6. Somatostatin receptor positive (SSTR+) disease, as evidenced by SSTR imaging (SRI) within 4 months prior to randomisation, as locally authorised, by:
• 68Ga-based SSTR positron emission tomography (PET) imaging ( 68Ga-edotreotide or 68Ga-DOTATATE), or
• 111In-pentetreotide SSTR SPECT/planar imaging, or
• 99mTc-octreotide SSTR SPECT/planar imaging
• 64Cu-based SSTR PET imaging (64Cu-DOTATATE), if approved, according to local regulations
All target lesions and ≥ 90% of non-target lesions need to be positive for SSTR; this relates to lesions of at least 15 mm in diameter acquired on SRI images with SPECT, and of at least 10 mm in diameter acquired on SRI images with PET systems.
7. The patient must have progressive disease based on RECIST 1.1
Criteria as evidenced by two morphological imaging examinations made with the same imaging method (either CT or MRI), within a maximum of 36 months prior to randomisation. The most recent scan must not be older than 90 days prior to randomisation date. The minimum interval
between the two scans must be ≥ 90 days.
8. Karnofsky performance status (KPS) scale ≥ 70
9. Life expectancy allows the patient to participate in the study based on the investigator's assessment
10. Glomerular filtration rate (GFR, CKD-EPI) ≥ 60 mL/min/1.73 m^2
11. For patients included in France only, verification and confirmation of their affiliation with a social security
12. Patients with functional P-NETs who require SSA for symptom
control may continue SSA treatment throughout the study, on condition
that:
a) they have been on a stable dose for at least three months prior to study enrolment
b) that progressive disease has been diagnosed while under such stable dose |
|
| E.4 | Principal exclusion criteria |
A patient will be excluded from participation in the trial if one or more of
the following criteria are met:
1. Known hypersensitivity to edotreotide or everolimus
2. Known hypersensitivity to DOTA, lutetium-177, or any excipient of edotreotide or everolimus or any other Rapamycin derivative
3. Known hypersensitivity to lysine, arginine, or any excipient of the nephroprotective amino acid solution
4. Prior exposure to any peptide receptor radionuclide therapy (PRRT), including 177Lu-edotreotide, 90Y-edotreotide or other SSTR-targeting agents (e.g. 177Lu-octreotate or high-dose 111In-pentetreotide)
5. Prior therapy with mTOR inhibitors
6. Prior EFR (external field radiation) to GEP-NET lesions within 90 days before randomization or radioembolisation therapy (e.g. 90Y microspheres, 131I-lipiodol) with administration to the liver
7. Prior therapy with chemotherapy, immunotherapy, interferon, chemo-embolisation, bland embolisation, cyclosporine-A within 4 weeks before randomisation; any new cancer treatment between screening and randomisation
8. Therapy with an investigational compound and/or medical device within 30 days or 5 half-life periods (whichever is longer) prior to randomisation
9. Subjects who have received a live vaccine up to 4 weeks prior to first dose
10. Current therapy with any prohibited medication (see 6.1.1)
11. Ongoing toxicity grade 2 according to CTCAE version 4.03 from previous standard or investigational therapies
12. Indication for surgical lesion removal with curative potential
13. Planned (for the period of study participation): chemotherapy, immunotherapy, interferon, radiation therapy, chemo-embolisation, bland embolisation, radio-embolisation, treatment with cyclosporine-A
14. Neuroendocrine tumours, not meeting the inclusion criteria:
• With known non-GEP-NET origin (e.g. pulmonary or gonadal
primaries)
• Functional GE-NET
• Explicit diagnosis of unknown primary (CUP)
• G3 neuroendocrine tumours and neuroendocrine carcinomas
• NET for which no histological specimen for secondary histological
analysis can be obtained
15. Total hepatic tumour burden > 70%
16. Brain metastases
17. Other malignancy within previous 5 years (except basal cell carcinomas and in situ squamous cell carcinomas of the skin)
18. Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic), that may interfere with the objectives of the study or with the safety or compliance of the subject, as judged by the investigator
19. Clinical relevant renal, hepatic, cardiovascular, or haematological organ dysfunction, potentially interfering with the safety of the study treatments, as follows:
• Renal
o Renal obstruction
• Hepatic
o Total bilirubin >1.5 x ULN
o AST or ALT > 2.5 x ULN
o Alkaline phosphatase > 5 x ULN
o Albumin < 3 g/dL, unless prothrombin time is within normal range
• Cardiovascular
o New York Heart Association classification III & IV
o Uncontrolled hypertension
• Haematopoietic
o Platelets ≤ 80 * 10^9/L
o Absolute neutrophil count (ANC) < 1 x 10^9 cells/L
20. Pregnant or breast-feeding women. Female patients of childbearing potential or male patients with female partners of childbearing potential, unless willing to practice full and true sexual abstinence or who are surgically/permanently sterile (bilateral tubal occlusion, hysterectomy, or vasectomy (provided the partner is the sole sexual partner of the female patient of childbearing potential), or who are note willing to practice highly effective contraception in combination with a barrier method of contraception (e.g. condom). Contraception methods that are considered highly effective are: oral or non-oral (injected or implanted) non-oestrogen progesterone-based hormonal method; oral, intravaginal, or transdermal combined oestrogen and progesterone-based hormonal methods; and/or intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS). Sexual abstinence or the contraception methods described above must be followed throughout the entire study period and for 56 days after treatment in the everolimus group and 66 days in the PRRT group (10 half-lives of 177Lu) after the last treatment cycle.
21. Subjects not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders) or any other vulnerable population to that sense (e.g. persons institutionalised,
incarcerated etc.). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression-free survival (PFS). Diagnosis of progression and liver tumour burden will be established based on radiological information from morphological imaging (MRI and/or CT) according to RECIST 1.1. Stratification will be made for primary tumour origin (GE-NET vs. P-NET) and prior medical therapy (1st line vs. 2nd line). Tumour grade (G1, G2), and baseline Karnofsky score will be used for further statistical subgroup analyses. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival (PFS) will be determined as time elapsed between randomisation, and the date of first objective report of tumour progression (evaluated by RECIST criteria, 1.1), or death. Diagnosis of Progression will be established based on radiological Information from morphological Imaging (MRI/CT) using RECIST 1.1. Status of disease will be defined as one of the following Options: Complete Response (CR), partial Response (PR), stable disease (SD), or progressive disease (PD). |
|
| E.5.2 | Secondary end point(s) |
| Secondary endpoints include parameters of morphological and functional tumour response, such as objective response rate (ORR), overall survival (OS) , disease control rates (DCR), and duration of disease control (DDC), as well as safety, health-related quality of life (HRQL).Furthermore, exploratory analyses will be performed on patient and tumour characteristics, as well as the degree of 177Lu-edotreotide uptake as possible predictors of PRRT efficacy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Dosimetry: Full dosimetry assessments of target organs and tumour lesions. Cumulative AD (in Gy) from 177Lu-edotreotide to target tumour lesions. Sub-Study A: cumulative AD to kidneys and tumour lesions at D1 compared with cumulative AD measured at the different times (i.e. D1 to D4). Sub-Study B: AD (in Gy) by 3D dosimetry compared to AD by planar (2D) and hybrid (2D/3D) dosimetry. Sub-Study C: bone marrow AD (in Gy) extrapolated from blood radioactivity. |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Switzerland |
| Australia |
| South Africa |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| 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
|
| The end of the study is defined as the last visit of the last patient or the last date of follow-up of toxicities, if required (whichever is the later). |
|
| 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 | 9 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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