Targeted Alpha-emitter Therapy of PRRT Naïve and Previous PRRT Neuroendocrine Tumor Patients

Inclusion Criteria:

• Male or female ≥18 years old with unresectable or metastatic histologicallyconfirmed NET

• Subjects must have received and progressed following somatostatin analogadministration

• For PRRT naive subjects, documented progression of disease following previoustherapy within 12 months prior to enrollment and the presence of at least 1 site ofmeasurable disease per RECIST 1.1

• Subjects who previously received PRRT must have documented progression of diseaseand at least 1 site of measurable disease per RECIST 1.1 after receiving up to 4doses (≤ 880 mCi) of 177Lu-DOTATATE/DOTATOC and received their last dose at least 6months prior to Day 1

• Confirmed presence of somatostatin receptors on all lesions including the non-targetand measurable lesions documented by CT/MRI scans, based on positive 68Ga-DOTATATE (NETSPOT®), 64Cu-DOTATATE (Detectnet™), or other Food and Drug Administration (FDA)approved SSTR PET/CT imaging within 6 weeks prior to enrollment. Follow up imagingshould be performed with the same agent or modality used at baseline;

1. Target lesions must be positive (greater than grade 2 uptake Krenning Score) ormust have a standardized uptake value of more than the normal liver background.

2. Lytic bone lesions, with an identifiable soft tissue component, evaluated by CTor MRI, can also be considered measurable lesions if the soft tissue componentotherwise meets the definition of measurability according to RECIST 1.1.

• Eastern Cooperative Oncology Group (ECOG) status 0-2;

• Life expectancy of at least 12 weeks in the opinion of the investigator at the timeof screening;

• Sufficient bone marrow capacity and organ function in the recent blood tests within 3 weeks prior to Day 1, as defined by:

1. White blood cell (WBC) ≥2,500/ mm3;

2. Absolute neutrophil count (ANC) ≥1000/mm3;

3. Platelets ≥100,000/mm3;

4. Hemoglobin (HgB) ≥9.0 g/dL;

5. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤3 X upperlimit of normal (ULN);

6. Total Bilirubin: ≤2 X ULN;

7. Serum creatinine ≤1.7 mg/dL for PRRT naïve subjects; ≤ ULN for previous PRRTsubjects;

8. Serum albumin ≥3.0 g/L; if lower than 3.0 g/L requires normal range prothrombintime (PT) and international normalized ratio (INR), and

• Be willing to practice the following medically acceptable methods of birth control (both women of childbearing potential (WOCBP) and men who have partners ofchildbearing potential) from the Screening Visit through 3 months after the finaladministration 212Pb-DOTAMTATE

Exclusion Criteria:

• Prior whole-body radiotherapy or PRRT using 177Lu/90Y/111In-DOTATATE/ DOTATOC orTargeted Alpha Therapy (TAT).

• For subjects who previously received PRRT, prior treatment with: Prior treatmentwith 90Y- DOTATATE/ DOTATOC, 225Ac-DOTATATE/DOTATOC, and/or 111In-DOTATATE/ DOTATOC

• Prior regional hepatic radionuclide therapy within 4 months prior to enrollment orprior nonradioactive regional hepatic therapy within 6 months prior to enrollment.

• Known hypersensitivity to somatostatin analogues, Amino Acid infusion, or 212Pb-DOTAMTATE;

• Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28days) and Sandostatin® (within 1 day) prior to Cycle 1 Day 1;

• History of myelodysplastic syndrome (MDS);

• Female subjects who are pregnant or lactating;

• Indication for surgical lesion removal with curative potential;

• Known brain metastases, unless these metastases have been treated and/or stable for 6 months prior to enrollment;

• Experimental cancer treatments or other investigational therapies within 6 weeks orfive half-lives of the investigational medication prior to Day 1;

• Uncontrolled congestive heart failure (NYHA II, III, IV);

• Uncontrolled diabetes mellitus as defined by a hemoglobin A1C >10.0;

• Evidence of renal obstruction based on Tc-99m DTPA or TER for MAG3 renalscintigraphy or renal ultrasound.

• Known or active human immunodeficiency virus (HIV) or hepatitis B or C virus unlesscured;

• Known or suspected active drug or alcohol abuse;

• Participation in other interventional clinical studies within 30 days prior to Day 1;

• Other known co-existing malignancies except non-melanoma skin cancer and carcinomain situ of the uterine cervix, unless definitively treated and proven no evidence ofrecurrence for 5 years;

• Any somatic or psychiatric disease/condition or abnormal laboratory test that in theopinion of the investigator, may interfere with the objectives and assessments ofthe study; or

• Unable to comply with the requirements of the study protocol or be unsuitable forthe study for any reason, in the opinion of the investigator.