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

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.

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.