This is a Phase 2 evaluation of hepatic-progression free survival among patients with Grade 2 liver-dominant NET metastases undergoing combination therapy with CapTem and Y90 radioembolization.The hypothesis is to confirm safety and to assess if disease control is improved relative to expectation from either therapy alone.

A Grade 3 arm was added in 2025.

Patients with liver-dominant Grade 2/3 NET metastases from any primary will start CapTem and undergo simulation angiography for radioembolization planning during the first cycle. If they tolerate CapTem and are not excluded from radioembolization, then TARE will be performed on Day 7 of Cycle 2, with additional TARE of Day 7 of cycle 3 or 4 as needed to treat the entire tumor burden. Patients will remain on CapTem until progression or intolerance.

Primary outcome measure is hepatic progression-free survival.

Inclusion Criteria:

• Patients with confirmed diagnosis of histologic grade 2 or 3 well differentiated neuroendocrine tumor with unresectable liver metastases (primary tumor or other extrahepatic disease may be present)
• Patients with at least one measurable liver metastases, with size > 1cm (RECIST criteria)
• Patients with liver dominant disease defined as ≥50% tumor body burden confined to the liver
• Liver tumor burden does not exceed 50% of the liver volume
• Patent main portal vein
• At least 4 weeks since last administration of last chemotherapy and /or radiotherapy
• Age >18 years.
• Life expectancy of greater than 6 months.
• ECOG performance status 0-2.
• Adequate liver function as measured by: Total bilirubin ≤ 2.0mg/dl, ALT, AST ≤5 times ULN, albumin ≥2.5g/dl.
• Patients must have adequate organ and marrow function as defined below:
• platelets >100,000/mcL (may be corrected by transfusion)
• serum creatinine < 2.0 mg/dl
• INR <1.6, (may be corrected by transfusion)
• Ability to understand and the willingness to sign a written informed consent document.
• Women of child bearing potential and fertile men are required to use effective contraception (negative urine or serum βHCG for women of child-bearing age)

Exclusion Criteria:

• Contraindications to capecitibine or temozolomide
• Contraindicated for both contrast-enhanced MRI and CT
• Patients previously treated with transarterial embolization (with or without chemotherapy) or with radioembolization (Y-90 microspheres)
• Contraindication for radioembolization procedures:
• excessive hepatopulmonary shunt as determined by the investigator
• inability to deliver Y90 microspheres without risk of non-target embolization of extra-hepatic structures
• Subjects consenting to the trial who fail their simulation angiography will be removed from the study and replaced.
• Patients may not be receiving any other investigational agents.
• Absolute contraindication to intravenous iodinated contrast (Hx of significant previous contrast reaction, not mitigated by appropriate pre-medication).
• Choledochoenteric anastomosis, transpapillary stent or sphincterotomy of duodenal papilla;
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and lactating women are ineligible