Tas-102 and Radioembolization With 90Y Resin Microspheres for Chemo-refractory Colorectal Liver Metastases

This is a phase I dose escalation study (3+3 design) with a dose expansion arm (12 patients) designed to evaluate safety of the combination of Tas-102 and radioembolization using Yttrium-90 (90Y) resin microspheres for patients with chemotherapy-refractory liver-dominant chemotherapy-refractory metastatic colorectal cancer (mCRC).

Randomized studies have demonstrated that Tas-102 has single agent activity against chemotherapy refractory colorectal cancer. A recent pre-clinical study has shown that Tas-102 may have activity as a radiation sensitizer in bladder cancer cell lines. Benefit of single agent Tas-102 against chemotherapy refractory colon cancer and the drug's promise a radiosensitizer make Tas-102 a potential candidate drug for testing in combination with radioembolization using Yttrium-90 resin microspheres in patients with liver-dominant chemotherapy-refractory mCRC. This is a phase I dose escalation study with a dose expansion arm designed to evaluate safety of the combination of Tas-102 and radioembolization using 90Y resin microspheres for patients with chemotherapy-refractory colon or rectal adenocarcinoma metastatic to the liver.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female, 18 years of age or older, and of any ethnic or racial group.
2. Diagnosis of unresectable metastatic colorectal adenocarcinoma with liver-dominant bilobar disease. Diagnosis may be made by histo- or cyto-pathology, or by clinical and imaging criteria.
3. Disease progression or intolerance to at least two prior Food and Drug Administration-approved therapeutic regimens.
4. If extrahepatic disease is present, it must be asymptomatic.
5. If a primary tumor is in place, it must be asymptomatic.
6. Measurable target tumors using standard imaging techniques (RECIST v. 1.1 criteria).
7. Tumor replacement \< 50% of total liver volume.
8. Current Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 through screening to first treatment on study.
9. Completion of prior systemic therapy at least 14 days prior to enrollment.
10. Able to understand informed consent.

Exclusion Criteria:

1. At risk of hepatic or renal failure

   * Serum creatinine \> 1.5 mg/dl
   * Serum bilirubin \> 1.3 mg/ml
   * Albumin \< 2.0 g/dL
   * Aspartate and/or alanine aminotransferase level \> 5 times upper normal limit
   * Any history of hepatic encephalopathy
   * Cirrhosis or portal hypertension
   * Clinically evident ascites (trace ascites on imaging is acceptable)
2. Contraindications to angiography and selective visceral catheterization

   * Any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device)
   * Severe allergy or intolerance to contrast agents, narcotics, or sedatives that cannot be managed medically
3. Symptomatic lung disease
4. Prior therapy with Tas-102.
5. Contraindications to Tas-102

   * Absolute neutrophil count \< 1,500/μl
   * Platelet count \< 75,000/μl
   * Allergy or intolerance to Tas-102
6. Unresolved toxicity of greater than or equal to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2 due to prior therapies.
7. Evidence of potential delivery of

   * Greater than 30 Gy absorbed dose of radiation to the lungs during a single 90Y resin microsphere administration; or
   * Cumulative delivery of radiation to the lungs \> 50 Gy over multiple treatments.
8. Evidence of any detectable Tc-99m macro aggregated albumin flow to the stomach or duodenum, after application of established angiographic techniques to stop such flow.
9. Previous radiation therapy to the lungs and/or to the upper abdomen
10. Any prior arterial liver-directed therapy, including chemoembolization, bland embolization, and 90Y radioembolization
11. Any intervention for, or compromise of the ampulla of Vater
12. Active uncontrolled infection. Presence of latent or medication-controlled HIV and/or viral hepatitis is allowed.
13. Significant extrahepatic disease

    * Symptomatic extrahepatic disease (including primary tumor, if unresected).
    * Greater than 10 pulmonary nodules (each \< 20 mm in diameter) or combined diameter of all pulmonary nodules \> 15 cm.
    * Peritoneal carcinomatosis
14. Life expectancy less than 3 months
15. Pregnant or lactating female
16. In the investigator's judgment, any co-morbid disease or condition that would place the patient at undue risk and preclude safe use of radioembolization or Tas-102.