CapTemY90 for Grade 2 NET Liver Metastases

Study Overview
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Brief Summary
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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.

Detailed Description
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Patients with liver-dominant Grade 2 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.

Official Title
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UPCC 04219 Phase 2 Study of Capecitabine-Temozolomide(CapTem) With Yttrium-90 Radioembolization in the Treatment of Patients With Unresectable Metastatic Grade 2 Neuroendocrine Tumors

Conditions
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Neuroendocrine Tumor Grade 2, Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Capecitabine Oral Product
* Drug: Temozolomide Oral Product
* Combination Product: transarterial radioembolization


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral CapTem + Y90 Radioembolization<br>Capecitabine 750 mg/m2 twice daily orally for 14 days and temozolomide 200 mg/m2 orally on Days 10-14, with 14 days between cycles, to be continued until 1) disease progression or 2) intolerable toxicities. Trans-arterial radioembolization (TARE) on Day 7 of cycle 2 and, if needed for the other lobe, Day 7 of either cycle 3 or 4. | Drug: Capecitabine Oral Product<br>* Capecitabine 750 mg/m2 twice daily orally for 14 days<br>* Other names: Xeloda;Drug: Temozolomide Oral Product<br>* temozolomide 200 mg/m2 orally on Days 10-14, with 14 days between cycles<br>* Other names: Temodar;Combination Product: transarterial radioembolization<br>* Trans-arterial radioembolization (TARE) on Day 7 of cycle 2 and, if needed for the other lobe, Day 7 of either cycle 3 or 4.<br>* Other names: TARE, y90;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intra-hepatic progression-free survival | Intra-hepatic progression-free survival by RECIST 1.0 is defined as the time from initiation of study therapy until first documented intra-hepatic disease progression, death due to any cause or last scan date that documented intra-hepatic progression-free status. | 2 years. Time from initiation of study therapy until first documented intra-hepatic disease progression, death due to any cause or last scan date that documented intra-hepatic progression-free status. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Progression free survival | Overall progression-free survival is defined as the time from initiation of study therapy until first documented intra- or extra-hepatic disease progression, death due to any cause or last scan date that documented progression-free status | 2 years. time from initiation of study therapy until first documented intra- or extra-hepatic disease progression, death due to any cause or last scan date that documented progression-free status | 
| Intra-hepatic tumor responses by RECIST | Intra-hepatic tumor responses will be evaluated by RECIST. | 2 years. from time of initiation of study therapy until subject comes off of study, or study closes | 
| Intra-hepatic tumor responses by EASL | Intra-hepatic tumor responses will be evaluated by EASL criteria. | 2 years. from time of initiation of study therapy until subject comes off of study, or study closes | 
| extra-hepatic tumor responses | extra-hepatic tumor responses will be evaluated by RECIST. | 2 years. from time of initiation of study therapy until subject comes off of study, or study closes | 
| Number of participants with systemic toxicities | Systemic toxicities will be individually assessed by NCI CTCAE Version 4. | From period of enrollment to 24 months after last treatment | 
| Number of participants with hepatic toxicities | Hepatic toxicities will be individually assessed by NCI CTCAE Version 4. | From period of enrollment to 24 months after last treatment | 
| Change in CgA over time | The primary marker is CgA. Additional cancer site-specific (i.e., gastrinoma) markers may also be assayed. | Tumor markers will be assessed at baseline and then every 3 months for 24 months. | 
| Quality of Life by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Neuroendocrine tumor | Quality of Life will be measure by a validated NET-specific instrument, EORTC. Scale is 0-100, higher scores indicate worse symptoms/functioning | Quality of life will be measured at baseline and then every 3 months for 24 months . |