| 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 |
| Open-label rollover post-treatment extension to enable access to lutetium (177lu) edotreotide in patients treated with best standard of care (control) drugs who discontinued due to tumor progression – France only |
|
| 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.
4. In the investigator’s opinion, eligible to receive treatment with at least one of the following: CAPTEM, everolimus or FOLFOX according to individual risk-benefit assessment, institutional protocols, the 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 68Ga-based or 64Cu-based (if approved according to local regulations) SSTR positron emission tomography (PET) somatostatin receptor imaging (SRI; 68Ga-DOTATOC, 68Ga-DOTATATE or 64Cu-DOTATATE) within 4 months prior to randomization and as close as possible to the fluorodeoxyglucose (FDG) PET.
a. The majority of the CT/MRI lesions have to be SSTR+.
b. The SSTR PET SRI should be repeated at randomization if the scan is not within 28 days of the randomization date.
7. All patients need to undergo a FDG PET scan within 4 months prior to randomization and as close as possible to the PET SRI.
a. The majority of FDG PET-positive lesions have to be SSTR+.
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 external beam radiation therapy (EBRT) to more than 25% of the bone marrow.
4. Prior selective internal radiation therapy.
5. Prior PRRT.
6. 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.
7. Any major surgery within 4 weeks prior to randomization in the trial.
8. Therapy with an investigational compound and/or medical device within 30 days or 7 half-life periods (whichever is longer) prior to randomization.
9. Patients who have received a live attenuated vaccine up to 4 weeks prior to randomization.
10. Patients with brain metastases.
11. 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.
12. Serious non-malignant disease (e.g. 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.
13. Renal, hepatic, cardiovascular, or hematological organ dysfunction, potentially interfering with the safety of the trial treatments, as follows:
a. Renal
i. Glomerular filtration rate (GFR) < 50 mL/min/1.73 m2 (calculated by the CKD-EPI formula [local laboratory])
ii. Creatinine clearance < 50 mL/min calculated by the Cockcroft Gault method
iii. Renal tract obstruction
b. Hepatic
i. Total bilirubin > 3 × upper limit of normal (ULN)
ii. Albumin < 30 g/L
iii. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 × ULN
iv. Known ascites
c. Cardiovascular
i. Heart failure (New York Heart Association [NYHA] classification III and IV)
ii. Uncontrolled hypertension
d. Hematopoietic
i. Platelets ≤ 75 × 10e9/L
ii. Absolute neutrophil count (ANC) < 1.5 × 10e9 cells/L
iii. Hemoglobin (Hb) concentration < 5.0 mmol/L (< 8.0 g/dL)
e. Any other ongoing hematological or renal Grade 2 toxicity or other Grade 3 toxicity from previous standard or investigational therapies (NCI-Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
14. Current spontaneous urinary incontinence.
15. 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, 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 progesterone-based 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.
16. 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
| 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 | 4 |
| 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 |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| 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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