Age
Adult
Eligibility
Well-differentiated aggressive G2 (Ki-67 between 15 and 20, both inclusive) and G3 (Ki-67 above 20 up to 55, inclusive), SSTR+ GEP-NETsInclusion
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.
Exclusion
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, .
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,
