Clinical Trial Finder

Inclusion Criteria:

• - Patients with confirmed diagnosis of histologic grade 2 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 serum βHCG for women of child-bearing age)

  Exclusion Criteria:

  - Contraindications to capecitabine 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 trial.

• - 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, - Pregnant and lactating women are ineligible

Embolotherapy of Neuroendocrine Hepatic Metastases Embolization of symptomatic or progressive hepatic neuroendocrine metastases has been performed for decades with a response rate on the order of 60%. NCCN, NANETs, and ENETs guidelines all endorse embolotherapy in this setting. Practice in the U.S. is roughly evenly divided among the four methods of embolotherapy: bland embolization with microspheres alone, conventional chemoembolization with Lipiodol-drug emulsions, embolization with drug-eluting microspheres, and radioembolization with yttrium-90 microspheres. In the absence of prospective clinical trials, outcomes with each of the four methods appear similar. Y90 Radioembolization From the patient perspective, radioembolization is appealing because of its low toxicity profile relative to the other forms of embolotherapy. Since the technique involves instillation of 25-35 micron microspheres into the tumor interstitium via the hepatic artery, rather than occlusion of tumor feeding vessels as in the other methods of embolization, the post-embolization syndrome is minimized and most patients can be treated on an outpatient basis with minimal toxicity. A multi-center retrospective analysis of 148 patients reported an objective response rate of 63%, 95% disease control rate, and 70 months median overall survival. A series of 48 patients from Australia had 55% objective response, 77% disease control, and a median survival of 35 months for the entire cohort, but median survival time was not reached among the responders. A similar US single-center series of 40 patients found an objective response rate of 64%, 96% disease control, and a median overall survival of 34 months. Use of Capecitabine-Temozolomide (CapTem) for NETs In 2005, Fine described a regimen of capecitabine for 14 days with twice-daily temozolomide on days 10-14 of the two-week cycle. This combination was shown in the laboratory to have far greater activity against NET cells than either agent alone or given in other combinations. This was followed by two clinical reports of 30 and 18 patients from the same center showing 60%-70% objective response rates, 22% stable disease, and median TTP of 18 and 14 months in heavily pre-treated patients who had failed somatostatin analog therapy, many also progressing after other systemic therapy and/or embolotherapies. There were no grade 4 toxicities, and only thrombocytopenia at grade 3. This was confirmed in a recent update on 143 patients who had 54% PR and 35% SD by RECIST 1.1. 61% had >50% reduction in an initally elevated CgA level. Median PFS was 17 months [95% CI, 15-24 mo] for G1 and 14.5 mo [10-14.5] for G2. The ECOG 2211 trial compared CapTem to temozolomide alone in metastatic pancreatic NETS and reported a significant improvement in PFS with the combination, from 14.4 mo for temozolomide alone to 22.7 months with CapTem, HR 0.58[0.36-0.93], p = 0.023 without a statistical difference between Grade 1 and 2 tumors. Fluoropyrimidines are radiosensitizers, often used with radiation therapy in the treatment of gastrointestinal malignancies. Temozolomide is used synergistically with radiation for glioblastoma. Capecitabine has been used in combination with Y-90 radioembolization to treat advanced hepatic malignancies at standard doses with acceptable additive toxicities. Clinical Data to Date The safety and feasibility of combining of CapTem and Y90 radioembolization was evaluated at the University of Pennsylvania. The Penn Neuroendocrine Tumor Board identified patients with progressive grade 2 tumors with liver-dominant metastases and extrahepatic disease. A multidisciplinary treatment plan was created with CapTem given according to the Fine protocol, and lobar radioembolizations on day 7 of the 2nd and 4th cycles. 21 patients were treated. 19 completed the planned therapy; one patient who had received a prior cycle of radioembolization developed grade 2 bilirubin elevation after the first lobar treatment and did not have the other lobe treated, the other decline a 2nd embolization because of post-embolization pain. There were no unexpected toxicities. There were six grade 3/4 thrombocytopenias, one each of grade 3 fatigue, nausea, and hand-foot skin reaction, and one case of REILD. Among patients evaluable for response at median 22 months (range, 10-52 mo), ORR was 74% with three complete responses. Median chromogranin A reduction was 87%. Median PFS was not reached, with mean PFS of 38.5 months. This preliminary experience suggests that CapTemY90 can be employed as a safe and active combination regimen integrating systemic and liver-directed therapies in grade 2 NETs. Toxicities were similar to those reported for CapTem or radioembolization alone. The next step is a prospective Phase 2 evaluation of the efficacy of therapy to confirm safety and to assess if disease control is improved relative to expectation from either therapy alone.

Arms

Experimental: CapTemY90

Capecitabine 600 mg/m2 twice daily for 14 days and temozolomide 150-200 mg/m2 in two divided doses on Days 10-14, with 14 days between cycles, to be continued until 1) disease progression or 2) intolerable toxicities. During the initial cycle of CapTem, simulation angiography for Y-90 radioembolization planning will be performed. Once the patient has successfully completed the first cycle of CapTem and undergone simulation demonstrating eligibility for Y-90 radioembolization, the dominant lobe will be treated on Day 7 of the 2nd cycle of CapTem. Resin microspheres will be prescribed according to the BSA method per the manufacturer's Instructions for Use. If the other hepatic lobe needs to be treated, this will be done on Day 7 of the 3rd or 4th cycle of CapTem.

Interventions

Combination Product: - Capecitabine tablets + temozolomide tablets + SIR-Spheres

see arm description