tas-102 and radioembolization with 90y resin microspheres for chemo-refractory colorectal liver metastases

Conditions: Colon Cancer; Rectal Cancer; Liver Metastases

Summary: 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 \ 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.

Keywords: radioembolization yttrium-90 90y resin microspheres tas-102 lonsurf sir-sphere