Study to Test the Combination of Fulvestrant With Lu-DOTATATE for Advanced Pancreatic Neuroendocrine Tumors

Inclusion Criteria:

• Patients must have histologically confirmed pancreatic neuroendocrine tumor, WHOgrades 1-2, Ki-67 index of <20%.

• Patients must have locally advanced disease that is ineligible for curative-intentresection, or metastatic disease.

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventionaltechniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.

• Patients must also have tumors expressing somatostatin receptor, defined asradiotracer avid lesions as assessed by a previous DOTATATE PET scan.

• Patients must have radiographically progressed (as per RECIST v1.1 criteria) on oneor more prior-lines of systemic therapy prior to enrollment in the trial. Priorsystemic therapies include but are not limited to somatostatin analogs (octreotideLAR, lanreotide), Capecitabine/Temozolomide, tyrosine kinase inhibitors (e.g.everolimus), VEGF pathway inhibitors (e.g. sunitinib, cabozantinib), and/or othersystemic chemotherapy.

• Patients should not have received any prior systemic therapy with peptide receptorradionuclide therapy (including 177Lu-DOTATATE) and/or Fulvestrant.

• Prior treatment with hepatic intra-arterial embolic therapies is allowed if there isrecovery from all toxicities, measurable lesions do not include embolized liverunless there has been clear subsequent progression, all measurable lesions aresomatostatin receptor avid, and treatment completed at least 2 months prior toregistration.

• Prior treatment with cryoablation or thermal/radiofrequency ablation of metastasesis allowed if there is recovery from all toxicities, measurable lesions do notinclude treated metastases, and treatment completed at least 2 months prior toregistration.

• Concomitant Medication: Concurrent SSA use while on protocol therapy is allowedprovided that the patient: 1) has a functional tumor (evidence of peptide hormonesand/or bioactive substances associated with a clinical hormone syndrome such ascarcinoid syndrome or Cushing's syndrome), 2) has been on a stable dose ofsomatostatin analog therapy for at least three months, and 3) has previouslydemonstrated radiographic disease progression while on SSA therapy. There should bea minimum of 28 days between long-acting SSA and 177Lu-DOTATATE dosing. Short-actingSSAs should not be administered within 24 hours of 177Lu-DOTATATE dosing. Followinglutetium 177Lu-DOTATATE dosing, long-acting SSAs may be administered between 4 and 24 hours after each dose.

• Age ≥18 years. As neuroendocrine tumors are very rare in children, patients <18years of age will be excluded from this study. Furthermore, no reliable dosing oradverse event data are currently available on the use of Fulvestrant patients <18years of age.

• ECOG performance status of 0 or 1.

• Patients must have adequate organ and marrow function as defined below:

1. Absolute Neutrophil Count ≥1,500/µL

2. Platelet Count ≥100,000/µL

3. Hemoglobin ≥ 9g/dL

4. Creatinine <1.5 mg/dL

• -OR-

1. Creatinine Clearance ≥ 50 mL/min (Cockroft- Gault calculated)

2. Total bilirubin ≤ 1.5 × institutional upper limit of normal

3. AST AND ALT ≤ 3 × institutional upper limit of normal

4. Serum Albumin ≥ 3.0 g/dL

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients should not have any other active malignancies at the time of studyenrollment or a history of myelodysplastic syndromes/acute myeloid leukemiaaccounting for the rare but serious bone-marrow toxicity of 177Lu-DOTATATE. Patientswith a remote history of other malignancies may be eligible for enrollment if themalignancy was curable, they have completed all curative-intent treatment (such assurgery, radiation and adjuvant therapy if warranted), and the malignancy has notrecurred after 3 years of initial diagnosis.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression forat least 3 months.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• Not pregnant and not nursing since the effects of 177Lu-DOTATATE on the developinghuman fetus are not well-established. For women of childbearing potential only, anegative pregnancy test done ≤ 28 days prior to registration is required.

• Patients must have a life expectancy of >12 weeks.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Patients who are unable to provide or understand written informed consent and complywith scheduled visits, drug administration plan, laboratory tests, or other studyprocedures and study restrictions.

• Patients who are receiving any other investigational agents.

• Patients with a "currently active" second malignancy other than non-melanoma skincancers. Patients are not considered to have a "currently active" malignancy if theyhave completed therapy and are free of disease for ≥ 3 years.

• Pregnant or breastfeeding.

• Clinical or laboratory signs of imminent organ failure, as determined by thetreating investigator.

• Patients with known untreated brain metastases should be excluded from this clinicaltrial because of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.