Targeted Alpha-Particle Therapy for Advanced Somatostatin Receptor Type 2 (SSTR2) Positive Neuroendocrine Tumors

Inclusion Criteria:

1. Adult (ages ≥18) PRRT-naïve 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, e.g. [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 ≤ 1.

7. Subjects with HIV positivity are allowed if CD4 Count > 350 cells/μL.

8. Concurrent Somatostatin Analog (SSA) Therapy use while on protocol therapy isallowed provided that the subject the subject must be able to tolerate withholdinglong-acting SSA therapy for a minimum of 28 days and short-acting SSA therapy for aminimum of 24 hours before the first and subsequent administrations of [203Pb]VMT-α-NET or [212Pb]VMT-α-NET

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

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

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

12. Life expectancy > 3 months.

13. Satisfactory organ function as determined by laboratory testing.

14. For females of reproductive potential: agree to use of highly effectivecontraception and refrain from donating eggs (ova, oocytes) for the purpose ofreproduction starting from screening, during treatment, and for at least 6 monthsafter the last dose of [212Pb]VMT-α-NET

15. For males of reproductive potential: agree to use of condoms or other methods toensure effective contraception with partner and refrain from donating sperm startingfrom screening, during treatment, and for at least 6 months after the last dose of [212Pb]VMT-α-NET

Exclusion Criteria:

1. Known hypersensitivity to SSA, SSTR imaging agents 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 medicinal product within 30 days ofanticipated treatment.

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

7. Prior treatment with 90-Yttrium radioembolization must be completed at least 6months prior 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 before the of first scheduleddose of [212Pb]VMT-α-NET despite adequate 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 MedicinalProduct or excipients.

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.