A Clinical Study of Lutetium[177Lu] Oxodotreotide Injection in Patients With Advanced Neuroendocrine Neoplasms

A Clinical Study to Evaluate the Safety and Efficacy of Lutetium[177Lu] Oxodotreotide Injection in Patients With Advanced Somatostatin Receptor Positive Neuroendocrine Neoplasms

This is a multicenter, single-arm, two-part study designed to evaluate the safety and efficacy of Lutetium [177Lu] Oxyoctreotide Injection in patients with inoperable, locally advanced or metastatic, progressive, advanced somatostatin receptor (SSTR) positive neuroendocrine neoplasms (NEN) other than grade G1/G2 gastroenteropancreatic neuroendocrine tumors (GEP-NET) and Neuroendocrine Carcinoma（NEC）.

This study consists of two parts, the exploratory study (Part 1) and the pivotal study (Part 2).

In both parts, participants who signs Informed consent form (ICF) and is eligible for the study will be enrolled. Participants will receive 7.4GBq (200mCi) Lutetium [177Lu] Oxyoctreotide every 8 weeks. The objective tumor response will be assessed every 12 weeks from the time of the first dose according to RECIST 1.1 until disease progression.

Inclusion Criteria:

1. Subjects who have been fully informed of this study and have voluntarily signed the Informed Consent Form (ICF).
2. Age ≥12 years; subjects aged 12-17 years must have a body weight ≥40kg. Age eligibility must be met at the time of signing the ICF.
3. Histologically confirmed, unresectable locally advanced or metastatic neuroendocrine neoplasms (NENs) [excluding well-differentiated (G1 and G2) gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and neuroendocrine carcinomas (NECs)]. The target population mainly includes:

(1)Grade 3 (G3) GEP-NET with Ki-67 index ≤ 55% (2)Other non-gastroenteropancreatic originated NEN, including pulmonary/thymic NEN, primary NEN of other sites, and NEN of unknown primary origin (3)Pheochromocytoma and paraganglioma (PPGL) Note: Histopathological specimens collected within 3 years prior to the first study drug administration are acceptable, provided that investigators confirm they can represent the pathological status at enrollment; otherwise, fresh specimens shall be collected.

4. Patients who have failed prior optimal available treatment, are intolerant to optimal available treatment, or have no access to optimal available treatment, with no restriction on the number of prior treatment lines.

Note: Optimal available treatment is determined by investigators based on individual subject conditions, including chemotherapy, targeted therapy, biologic therapy, etc.

5.Have documented disease progression within 1 year prior to the first study drug administration, and have not received any other systemic anti-tumor therapy after disease progression.

6.Have at least one measurable lesion at baseline per RECIST 1.1 criteria. 7. All baseline target lesions (per RECIST 1.1) must be confirmed as somatostatin receptor-positive via ⁶⁸Ga-Dotatate PET/CT.

Notes:

1. ⁶⁸Ga-Dotatate PET/CT images obtained within 24 weeks before the first drug administration are acceptable if investigators verify they can reflect the somatostatin receptor status at enrollment;
2. Somatostatin receptor positivity is defined as lesion uptake higher than normal liver uptake;
3. Subjects with any target lesion confirmed somatostatin receptor-negative by ⁶⁸Ga-Dotatate PET/CT shall be excluded.

8. Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at baseline.

9. Subjects of childbearing potential must voluntarily use effective contraceptive methods throughout the treatment period and for 4 months (male) or 7 months (female) after the last dose of investigational product, such as condoms, oral/injectable contraceptives, intrauterine devices, etc.

Exclusion Criteria

1. Serum creatinine > 150 μmol/L (1.7 mg/dL) or creatinine clearance rate < 50 mL/min (calculated by Cockcroft-Gault formula).

2. Hemoglobin < 100 g/L, white blood cell count < 2.0×10⁹/L, or platelet count < 100×10⁹/L.

3. Total serum bilirubin > 3 times the upper limit of normal (ULN).

4. Serum albumin < 30 g/L.

5. Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5×ULN.

6. International Normalized Ratio (INR) > 1.5 or activated partial thromboplastin time (APTT) > 1.5×ULN.

7. Positive human immunodeficiency virus (HIV) antibody.

8. Positive hepatitis B surface antigen (HBsAg) combined with positive HBV-DNA (≥1×10⁴ copies/mL or confirmed positive per local study center criteria); or positive hepatitis C virus (HCV) antibody combined with positive HCV-RNA (≥1×10³ copies/mL).

9. Pregnant or breastfeeding females.

10. Prior history of peptide receptor radionuclide therapy (PRRT).

11. Subjects receiving short-acting octreotide who cannot discontinue it within 24 hours before and after administration of Lutetium-177 Oxotreotide Injection; or subjects receiving octreotide acetate microspheres who cannot stop the treatment within 6 weeks prior to the first dose of Lutetium-177 Oxotreotide Injection.

    Note: Further evaluation is required for subjects receiving other somatostatin analog (SSA) treatments.

12. Received systemic anti-tumor therapies including targeted therapy, immunotherapy, anti-tumor traditional Chinese medicine therapy or chemotherapy within 4 weeks before the first study drug administration.

13. Enrolled in other clinical trials and received investigational drugs within 4 weeks prior to the first dose.

14. Received local anti-tumor treatments such as surgery (excluding biopsy), radical radiotherapy, hepatic arterial chemoembolization, cryoablation or radiofrequency ablation for liver metastases within 4 weeks before the first dose.

15. Received palliative radiotherapy for bone metastases within 2 weeks prior to the first dose.

16. Toxicities from previous anti-tumor therapies have not recovered to Grade 1 or lower (alopecia excluded).

17. Confirmed brain metastases (excluding those stabilized for at least 24 weeks before the first administration).

18. Uncontrolled congestive heart failure, including baseline left ventricular ejection fraction (LVEF) < 50%.

19. Uncontrolled diabetes mellitus, including baseline fasting blood glucose > 2×ULN.

20. Presence of active infections requiring intravenous antibacterial drugs or inpatient intervention.

21. History of other confirmed malignant tumors (excluding those with complete treatment and expected no recurrence within 5 years).

22. Known hypersensitivity to any ingredients or excipients of Lutetium-177 Oxotreotide Injection and octreotide acetate microspheres.

23. Contraindications to contrast-enhanced CT and MRI contrast agents due to allergic reactions or renal insufficiency.

24. Any uncontrolled diseases, mental disorders or surgical conditions that may affect study completion (including poor treatment compliance) or make subjects ineligible for the investigational product.

25. Based on the patient's disease characteristics, the investigator judges that alternative treatments such as chemotherapy and targeted therapy are more suitable for the patient than the study treatment, meaning the investigational product is not the optimal clinical treatment option.