Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Neuroendocrine Tumors

Inclusion Criteria:

1. Adult (ages ≥18) subjects with NETs by local pathology.

2. Locally advanced/unresectable or metastatic NETs.

3. Radiological evidence of measurable disease by RECIST v1.1 criteria on CT withcontrast or MRI of the areas of tumor involvement within 60 days of enrollment.

4. Lesions must have shown radiological evidence of disease progression in the 12months prior to enrollment.

5. Demonstration of lesional SSTR2 expression using an FDA-approved somatostatinreceptor PET imaging agent, i.e.[68Ga]DOTATATE, [64Cu]DOTATATE, or [68Ga]DOTATOC, (SSTR2 positivity defined as uptake > background liver) obtained and interpreted inaccordance with product labeling and appropriate clinical use criteria within 12months of enrollment.

6. ECOG Performance Status 0-2.

7. Subjects with HIV positivity are allowed if CD4 Count > 500 cells/μL.

8. Concurrent SSA use while on protocol therapy is allowed provided that the subject:

1. has a functional tumor and 2) has previously demonstrated radiographic diseaseprogression while on SSA therapy.

9. Long-acting somatostatin analogues are allowed but should be withheld within 30 daysprior to [68Ga]DOTATATE PET/CT (or another SSTR2-PET), if clinically possible. Shortacting somatostatin analogues should be withheld for 24 hours.

10. Progressive Disease on approved therapies other than radionuclide therapy.

11. Must have clinically demonstrated adequate catecholamine blockade ifcatecholamine-secreting pheochromocytoma/paraganglioma tumors are present.

12. Able to sign informed consent and comply with all study requirements.

13. Life expectancy > 3 months.

Exclusion Criteria:

1. Known hypersensitivity to Octreotate, DOTATATE, or any of the excipients of [212Pb]VMT-α-NET.

2. Active secondary malignancy.

3. Pregnancy or breastfeeding a child.

4. Febrile illness within 48 hours of any scheduled [212Pb]VMT-α-NET administrationshould be rescheduled > 48 hours after resolution of fever].

5. Treatment with another investigational drug product (therapeutic IND agents) within 30 days of anticipated treatment.

6. Prior treatment with systemic PRRT based therapies (i.e., 90Y DOTATATE/DOTATOC or 177Lu DOTATATE)

7. Prior treatment with 90-Ytrium radioembolization must be completed at least 6 monthsprior to enrollment.

8. External beam radiation therapy must be completed at least 30 days prior toenrollment.

9. Prior treatment with systemic anticancer therapy must be completed at least 30 daysprior to enrollment (except for SSAs in subjects with functional tumors).

10. Major surgery must be completed at least 30 days prior to enrollment.

11. Known brain metastases; unless these metastases have been treated and stabilized 6months prior to enrollment and the subject has been off steroid support for at least 14 days prior to enrollment.

12. Recently diagnosed and active infections requiring a time-limited course ofantifungals or antibiotics in the 3 days prior to enrollment.

13. Receipt of live attenuated vaccines in the 7 days prior to enrollment.

14. Grade 3 nausea/vomiting or diarrhea within 72 hours of first scheduled dose despiteadequate antiemetic and other supportive care

15. Known medical condition which would make this protocol unreasonably hazardous forthe subject.

16. Medical history of a condition resulting in a severe allergic reaction such asanaphylaxis or angioedema to known components of the Investigational Product orexcipients.

17. Current abuse of alcohol or illicit drugs (exclusive of use of medically prescribedcannabinoids).

18. Existence of any medical or social issues likely to interfere with study conduct orthat may cause increased risk to the subject or to others, e.g., lack of ability tofollow radiation safety precautions.

19. QTc > 450 milliseconds for males and females.

20. Abnormal laboratory values:

• Hemoglobin ≤ 9.0 g/dL

• Platelet Count ≤ 60,000/mm3

• Absolute Neutrophil Count (ANC) ≤ 1,250/mm3

• Calculated Creatinine Clearance < 60 mL/min OR Total Bilirubin ≥ 2.0 x ULN*

• Albumin ≤ 2.8 g/dL

• AST/ALT ≥ 3.0 x ULN