Comparing Capecitabine and Temozolomide in Combination to Lutetium Lu 177 Dotatate in Patients With Advanced Pancreatic Neuroendocrine Tumors

Inclusion Criteria:

• Histologic or pathologic documentation: well-differentiated pancreaticneuroendocrine tumor (G1, G2, or well-differentiated G3) confirmed by localhistology and/or pathology

• Functional or nonfunctional tumors are allowed

• Stage: locally unresectable or metastatic disease

• Tumor Site: neuroendocrine tumor of pancreatic primary site

• Radiologic evaluation: tumor must have shown somatostatin receptor (SSTR) positivityon 68Ga-DOTATATE PET or other SSTR-PET scan in the 12 months prior to registration;however, documentation of SSTR positivity in the 6 months prior to registration ispreferred. SSTR positivity is defined as uptake greater than background liver in allmeasurable lesions

• Patients are eligible if they meet one of the following criteria:

• Previously untreated patients with grade 2 or 3 disease AND with symptoms ofeither disease bulk causing pain, anorexia, early satiety, largeeffusions/ascites, abdominal pain, abdominal fullness due to hepatomegaly,dyspnea) OR incompletely controlled symptoms of hormone excess despitesomatostatin analogue (SSA) and supportive care (including but not limited to:diarrhea, hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing'ssyndrome). Patient may have been started on SSA for up to 2 months forattempted symptom control without disease progression prior to registration

• Patients previously treated with SSA only and with disease progression byRECIST in prior 12 months

• Patients previously treated with SSA and one or more prior systemic therapymust have received prior anti-vascular endothelial growth factor (VEGF) pathwaytherapy inhibitor OR have contraindication to anti-VEGF therapy (including butnot limited to: uncontrolled hypertension [systolic blood pressure [SBP] > 150and/or diastolic blood pressure [DBP] > 90 despite medical management], stageIIB or greater heart disease, angina pectoris, prior arterial [ATE] and venousthromboembolic [VTE] events in the past 6 months, gastrointestinal [GI] bleedin the last 6 months) and disease progression by RECIST in prior 12 months

• Patients previously treated with more than 2 lines of therapy, not includinganti VEGF therapy, but with NET related symptoms as outlined in first bullet (pain, anorexia, early satiety, large effusions/ascites, abdominal pain,abdominal fullness due to hepatomegaly, anorexia, early satiety, dyspnea) ORincompletely controlled symptoms of hormone excess despite somatostatinanalogue (SSA) and supportive care (including but not limited to: diarrhea,hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing's syndrome).

• Any patient with disease progression by RECIST criteria in < 4 months

• Patients must have measurable disease per RECIST v1.1 by computer tomography (CT)scan or magnetic imaging (MRI). Any lesions which have undergone percutaneoustherapies or radiotherapy after starting protocol therapy should not be consideredmeasurable unless the lesion has clearly progressed since the procedure.

• Lesions must be accurately measured in at least one dimension (longest diameter tobe recorded) as >= 1 cm with CT or MRI (or shortest diameter >= 1.5 cm for lymphnodes). Non-measurable disease includes disease smaller than these dimensions orlesions considered truly non- measurable including: leptomeningeal disease, bonemetastases, ascites, pleural or pericardial effusion, lymphangitic involvement ofskin or lung.

• Prior treatment with tyrosine kinase inhibitors (TKIs) such as mammalian target ofrapamycin (mTOR) inhibitors (e.g. everolimus, temsirolimus, etc.) or VEGF pathwayinhibitors (e.g. sunitinib, pazopanib, cabozantinib, bevacizumab, etc.) are allowed

• 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

• Age >= 18 years

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

• Absolute neutrophil count (ANC) >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Hemoglobin >= 9.0 g/dL

• Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinineclearance >= 30 mL/min (calculated by the Cockcroft-Gault equation)

• Total bilirubin =< 1.5 x ULN (in patients with liver metastases or known Gilbert'ssyndrome, total bilirubin must be =< 3.0 x ULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN

• Albumin >= 3.0 g/dL

• Concurrent somatostatin analog use while on protocol therapy is allowed providedthat the patient:

• Has a functional tumor (evidence of peptide hormones and/or bioactivesubstances associated with a clinical hormone syndrome such as carcinoidsyndrome or Cushing's syndrome)

• Has been on a stable dose of somatostatin analog therapy for at least threemonths

• Has previously demonstrated radiographic disease progression while onsomatostatin analog therapy. For subjects receiving lutetium Lu 177 dotatate,there should be a minimum of 14 days between long-acting somatostatin analogueand lutetium Lu 177 dotatate dosing. Short-acting somatostatin analogs shouldnot be administered within 24 hours of lutetium Lu 177 dotatate dosing.Following lutetium Lu 177 dotatate dosing, long-acting somatostatin analogs maybe administered between 4 and 24 hours after each dose

Exclusion Criteria:

• Patients with poorly differentiated neuroendocrine carcinoma (large cell histologyor small cell histology) are not eligible

• No prior temozolomide, dacarbazine, capecitabine, 5-FU, or any PRRT for treatment ofthe pNET

• Not pregnant and not nursing, because this study involves an agent that has knowngenotoxic, mutagenic, and teratogenic effects

• Therefore, for women of childbearing potential only, a negative pregnancy testdone =< 14 days prior to registration is required

• No known brain metastases unless adequately treated, demonstrated to be stable, andoff all treatment (including steroids) for at least 2 months prior to registration

• No uncontrolled congestive heart failure (New York Heart Association [NYHA] II, III,IV).

• No significant medical, psychiatric, or surgical condition, currently uncontrolledby treatment, which may pose a risk to patient safety

• No "currently active" second malignancy other than non-melanoma skin cancers orcervical carcinoma in situ. Patients are not considered to have a "currently active"malignancy if they have completed therapy or are on adjuvant hormonal therapy andare free of disease for >= 3 years

• No known medical condition causing an inability to swallow and no known impairmentof gastrointestinal function that may significantly alter the absorption of an oralagent