| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Well-differentiated Aggressive Grade2 and Grade 3, Somatostatin receptor-positive (SSTR+), Neuroendocrine Tumors of GastroEnteric or Pancreatic Origin (GEP-NET) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Aggressive metastasized and / or locally advanced neuroendocrine tumours (NET) of gastroenteric or pancreatic origin |
|
| 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 lutetium (177Lu) edotreotide in the treatment of aggressive Grade 2 (G2; Ki67 between 15 and 20, both inclusive) and Grade 3 (G3; Ki-67 above 20 up to 55, inclusive) SSTR+ GEP-NETs compared to best standard of care (investigator’s choice [from the protocol comparator list]). |
|
| E.2.2 | Secondary objectives of the trial |
1. To further demonstrate the efficacy of PRRT with lutetium (177Lu) edotreotide.
2. To assess the impact of PRRT with lutetium (177Lu) edotreotide on trial patient’s health-related quality of life (HRQL) and neuroendocrine functional tumor symptoms during and after therapy in comparison to best standard of care.
3. To assess the safety and tolerability of PRRT with lutetium (177Lu) edotreotide in trial patients compared to control treatment options. |
|
| 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 |
The genetic profiling sub-study is described in the main protocol.
Objective: To assess the association of clinical/radiological outcomes with tumor gene profiling. |
|
| E.3 | Principal inclusion criteria |
1. Provided written informed consent.
2. Patients aged ≥18 years (fully mature per local regulations).
3. Histologically confirmed diagnosis of unresectable, well-differentiated GEP-NETs, with a Ki-67 index between 15 and 55, inclusive. This should be at least confirmed by a local pathological report of a biopsy specimen of the primary tumor or metastasis, or, if unavailable, willingness to undergo current biopsy for local analysis before randomization. The biopsy should not be older than 3 years.
4. In the investigator's opinion, patients recruited into the trial must be eligible to receive treatment with at least one of the following: CAPTEM,
everolimus or FOLFOX according to individual risk-benefit assessment, institutional protocols, the latest local Prescribing Information, local
regulations or the local guidelines.
5. At least 1 measurable site of disease per RECIST v1.1 using contrast computed tomography (CT)/magnetic resonance imaging (MRI). Patients who are allergic to IV contrast may be imaged without.
6. SSTR+ disease, as evidenced by locally approved 68Ga-based or 64Cubased SSTR positron emission tomography (PET) somatostatin receptor
imaging (SRI; 68Ga-DOTATOC, 68Ga-DOTATATE or 64Cu-DOTATATE) within 2 months prior to randomization and as close as possible to the fluorodeoxyglucose (FDG) PET.
a. All RECIST v1.1 selected target lesions have to be SSTR+.
b. All other lesions considered dominant by investigator must also be SSTR+ (See guidance and examples in Protocol Appendix 4).
7. All patients need to undergo a FDG PET scan within 2 months prior to randomization and as close as possible to the PET SRI.
a. FDG PET-positive RECIST v1.1 target lesions and all other FDG PETpositive lesions considered dominant by the investigator have to be
SSTR+ (See guidance and examples in Protocol Appendix 4).
8. Patients may be treatment naïve (first-line) or have a maximum of one prior line of therapy, including SSAs (second-line).
a. Patients on any prior antineoplastic therapy (including SSAs) must have radiological disease progression (according to RECIST v1.1) within
the 4 months prior to randomization, based on the investigator's assessment.
b. Patients who progress on SSAs may enter the trial continuing on the same dose if required for symptom control.
9. Karnofsky performance status scale ≥ 60. |
|
| E.4 | Principal exclusion criteria |
1. Known hypersensitivity to 177Lu, edotreotide, DOTA, any of the comparators, or any excipient or derivative (e.g. rapamycin).
2. Known hypersensitivity to lysine, arginine, or any excipient of the nephroprotective amino acid solution (AAS) given concurrently with the
lutetium (177Lu) edotreotide infusion
3. Prior EBRT to GEP-NET lesions or liver selective internal radiation therapy within 12 weeks before randomization
4. Prior PRRT
5. Received chemotherapy, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) pathway inhibitors,
immunotherapy, interferon, chemo-embolization, bland embolization, cyclosporine A, locoregional treatment (e.g. cytoreduction surgery,
radiofrequency ablation [RFA], liver directed intra-arterial intervention) or SSAs within 4 weeks prior to randomization into the trial. Patients may be treated with SSAs for symptom control, but they must have remained on the same dose of the SSA as at the time of demonstrated disease progression.
6. Any major surgery within 4 weeks prior to randomization in the trial.
7. Therapy with an investigational compound and/or medical device within 30 days or 7 half-life periods (whichever is longer) prior to randomization.
8. Patients who have received a live attenuated vaccine up to 4 weeks prior to randomization. Live attenuated vaccines should not be administered during the trial treatment and over the next 3 months after the last treatment dose.
9. Patients with known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks prior to screening.
Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable brain disease prior to randomization in the study.
10. Other known malignancies, (except non-invasive skin cancer and carcinoma of the cervix in situ), unless definitively treated and proven no evidence of recurrence for 5 years.
11. Serious non-malignant disease (e.g. CNS diseases, psychiatric, infectious, autoimmune, metabolic or dementia), that may interfere with the objectives of the trial or with the safety or compliance of the patient, as judged by the investigator.
12. Renal, hepatic, cardiovascular, or hematological organ dysfunction, potentially interfering with the safety of the trial treatments, as follows:
a. Renal
i. GFR < 50 mL/min/1.73 m2 (calculated by the Chronic Kidney Disease Epidemiology [CKD-EPI] equation (Inker et al. 2021) or
ii. Creatinine clearance < 45 mL/min calculated by the Cockcroft Gault method
iii. Renal tract obstruction
b. Hepatic
i. Total bilirubin > 3 × ULN
ii. Albumin < 30 g/L, unless prothrombin time is within normal range
iii. AST/ALT > 5 × ULN
iv. Known ascites
c. Cardiovascular
i. Heart failure (New York Heart Association [NYHA] classification III and IV)
ii. Uncontrolled hypertension
d. Hyperkalemia (in accordance with local practice) if not adequately corrected before the study treatment starts
e. Hematopoietic
i. Platelets ≤ 75 × 10e9/L
ii. ANC < 1.5 × 10e9 cells/L
iii. Hemoglobin (Hb) concentration < 5.0 mmol/L (< 8.0 g/dL)
f. Any other ongoing hematological or renal Grade 2 toxicity or other Grade 3 toxicity from previous standard or investigational therapies (NCI-CTCAE version 5.0).
13. Current spontaneous urinary incontinence preventing safe administration of the IMP, in the investigator's opinion.
14. Pregnancy and breast-feeding:
a. 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 (hysterectomy, bilateral ovariectomy or vasectomy), or female patients whose male partners have medically successful vasectomy (provided the partner is the sole sexual partner of the female patient of childbearing potential), or who are not 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:
i. Oral or non-oral (injected or implanted) non-estrogen progesteronebased hormonal method; oral, intravaginal, or transdermal combined estrogen and progesterone-based hormonal methods;
and/or
ii. Intrauterine device (IUD), and/or intrauterine hormone-releasing system (IUS).
iii. Bilateral fallopian tubal ligation.
Note: Sexual abstinence or the contraception methods described above must be followed throughout the entire trial period and for the following
durations after last trial drug administration: 6 months for CAPTEM; 8 weeks for everolimus; 6 months for FOLFOX; 66 days for PRRT (10 half lives of 177Lu).
b. Women who are breast-feeding.
15. Patients 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 institutionalized, incarcerated etc.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 12±2 Weeks from Randomization Until Adequately Documented Disease Progression. The same is also valid for the PFS follow-up period.
|
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints
1. Further demonstration of efficacy:
For all endpoints based on RECIST v1.1, main analyses will be based on blinded, central assessment. Local assessments will be presented as sensitivity analyses.
1.1 Objective response rate (ORR), defined as the proportion of randomized patients with complete response (CR) or partial response (PR) (RECIST v1.1).
1.2 Overall survival (OS), defined as the time from randomization until death.
1.3 Duration of response (DoR), defined as the time from experiencing first CR or PR until the next progressive disease (PD) (RECIST v1.1).
1.4 Disease control rate (DCR), defined as the proportion of randomized patients with CR, PR or stable disease (SD) (RECIST v1.1).
1.5. Duration of disease control (DDC), defined as the time from experiencing CR, PR or SD until the next subsequent PD (RECIST v1.1).
2. 2. HRQL (European Organization for Research and Treatment of Cancer [EORTC] quality of life questionnaire [QLQ]-C30 and –GI.NET21):
2.1.Maximum HRQL improvement in total scores relative to baseline.
2.2.Duration of maximum HRQL improvement, defined as the time from maximum improvement until subsequent deterioration.
2.3.Time to HRQL deterioration, defined as the time from randomization until first HRQL deterioration.
3. Safety and tolerability based on adverse events, laboratory data and vital signs.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. and 2. as for the primary end point.
3.:
- at day of cycle 1
- at day of cycles 2 to 4 (pre-dose and at dosing)
- at day of cycles 5 and 6 (pre-dose, at dosing and post-dose)
- at the end of treatment |
|
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Standard of Care as per investigator choice |
|
| 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 | 21 |
| 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 |
| Australia |
| India |
| United States |
| France |
| Sweden |
| Netherlands |
| Spain |
| Germany |
| Italy |
| United Kingdom |
|
| 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 Study (EOS) for each patient is defined as the date at which the patient has been followed up for 2 years after documented disease progression or has died, or is the date of last contact if the patient is lost to follow-up, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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