A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs

This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutetium\[177Lu\] Oxodotreotide Injection to high dose (60 mg) Octreotide LAR in patients with unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours.

After the screening period, participants who signed the ICF and were eligible for the study in accordance with the entry criteria were randomly assigned to treatment either Lutetium\[177Lu\] Oxodotreotide Injection or Octreotide LAR. Participant randomization was performed according to a centralized permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups, stratified by primary site of tumor (pancreatic or non-pancreatic), NET pathological grading (G1 or G2) and by the length of time that a participant was on a constant dose of Octreotide (=\< 6 versus \> 6 months). Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed: any participants with progressive disease ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety.

Eligibility Criteria:
Inclusion Criteria:

1. Ability to understand and willingness to sign a written informed consent document.
2. Aged 18 years or older.
3. Histopathologically confirmed low and moderate grade (G1 or G2) unresectable locally advanced or metastatic GEP-NET (based on the fifth edition of the WHO classification and grading criteria for neuroendocrine tumors of the digestive system in 2019, to be centrally confirmed).
4. Previously received fixed-dose Octreotide LAR (20-30 mg/3-4 weeks) for at least 12 weeks of continuous treatment with disease progression.
5. Presence of disease progression prior to randomization (time point of disease progression limited to 1 year prior to randomization and no other antitumor therapy received after progression).
6. Presence of at least 1 measurable site of disease (based on RECIST 1.1).
7. All target lesions (based on RECIST 1.1) at baseline must be confirmed as somatostatin receptor positive by 68Ga-Dotatate PET/CT .
8. ECOG score of 0 or 1.
9. Subjects of childbearing potential voluntarily use an effective method of contraception, such as condoms, oral or injectable contraceptives, IUDs, etc., during treatment and within 4 months (men) or 7 months (women) of the last use of the trial drug.

Exclusion Criteria:

1. Serum creatinine \>150 μmol/L (1.7 mg/dL) or creatinine clearance \<50 ml/min (Cockcroft Gault formula).
2. Hemoglobin \<80g/L, or white blood cell count \<2.0×10\^9/L, or platelets \<75×10\^9/L.
3. Serum total bilirubin \> 3 × upper limit of normal (ULN).
4. Serum albumin \<30g/L.
5. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5×ULN.
6. international normalized ratio (INR) \> 1.5 or partially activated prothrombin time (APTT) \> 1.5 x ULN.
7. Positive human immunodeficiency virus (HIV) antibody.
8. Positive for hepatitis B virus (HBV) surface antigen (HBsAg) and positive for HBV DNA (≥1×10\^4 copies/ml or judged positive by research center criteria), or positive for hepatitis C virus (HCV) antibodies.
9. Pregnant or lactating females.
10. Received peptide receptor radionuclide therapy(PRRT) prior to randomization.
11. Received Octreotide LAR at a dose strength \>30 mg/3-4 weeks (increasing dose or frequency) within 12 weeks prior to randomization.
12. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutetium\[177Lu\] Oxodotreotide Injection, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of Lutetium\[177Lu\] Oxodotreotide Injection.
13. Received systemic antitumor therapy such as targeted therapy, immunotherapy, antitumor herbal therapy, chemotherapy within 4 weeks prior to randomization.
14. Participated in other drug clinical trials within 4 weeks prior to randomization and received treatment with the corresponding trial drug.
15. Received the following treatments within 12 weeks prior to randomization, including but not limited to surgery (except biopsy), radical radiotherapy, hepatic artery interventional embolization, cryoablation of liver metastases, or radiofrequency ablation.
16. Received external beam radiation therapy for bone metastases within 2 weeks prior to randomization
17. Toxicity of prior antitumor therapy has not returned to ≤ grade 1 levels (except for alopecia)
18. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study.
19. Uncontrolled congestive heart failure, including baseline left ventricular ejection fraction (LVEF) \<50%.
20. uncontrolled diabetes mellitus, including baseline fasting glucose \> 2 x ULN.
21. Any clinically significant active infection.
22. Known other malignancies (except for those without recurrence within 5 years after adequate treatment)
23. Known hypersensitivity to Lutetium\[177Lu\] Oxodotreotide Injection or oxytetracycline acetate microsphere components and their excipients.
24. Known to be unsuitable for enhanced CT or MRI contrast imaging due to allergic reaction or renal insufficiency.
25. Any other disease, mental status or surgical condition that is uncontrolled, may interfere with study completion (including poor compliance) or is inappropriate for the use of the investigational drug.
26. Other treatment options (e.g., chemotherapy, targeted therapy) that, in the opinion of the investigator, are more appropriate for the patient than the treatment provided in the study based on the patient's disease characteristics, i.e., the investigational drug is not the best therapeutic agent for clinical practice.