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

Study Overview
=================
Brief 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).

Detailed Description
-----------------
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.

Official Title
-----------------
Phase I Study of Tas-102 and Radioembolization With 90Y Resin Microspheres for Chemo-refractory Colorectal Liver Metastases

Conditions
-----------------
Colon Cancer, Rectal Cancer, Liver Metastases

Intervention / Treatment
-----------------
* Drug: Tas-102
* Device: SIR-Sphere


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, 18 years of age or older, and of any ethnic or racial group. 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. Disease progression or intolerance to at least two prior Food and Drug Administration-approved therapeutic regimens. If extrahepatic disease is present, it must be asymptomatic. If a primary tumor is in place, it must be asymptomatic. Measurable target tumors using standard imaging techniques (RECIST v. 1.1 criteria). Tumor replacement < 50% of total liver volume. Current Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 through screening to first treatment on study. Completion of prior systemic therapy at least 14 days prior to enrollment. Able to understand informed consent. Exclusion Criteria: 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) 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 Symptomatic lung disease Prior therapy with Tas-102. Contraindications to Tas-102 Absolute neutrophil count < 1,500/μl Platelet count < 75,000/μl Allergy or intolerance to Tas-102 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. 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. 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. Previous radiation therapy to the lungs and/or to the upper abdomen Any prior arterial liver-directed therapy, including chemoembolization, bland embolization, and 90Y radioembolization Any intervention for, or compromise of the ampulla of Vater Active uncontrolled infection. Presence of latent or medication-controlled HIV and/or viral hepatitis is allowed. 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 Life expectancy less than 3 months Pregnant or lactating female 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tas-102 and radioembolization<br>Combination therapy with Tas-102 and radioembolization using 90Y resin microspheres | Drug: Tas-102<br>* Oral nucleoside antitumor agent consisting of α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydro chloride (TPI) at a molar ratio of 1:0.5.<br>* Other names: Lonsurf;Device: SIR-Sphere<br>* 20-60mm resin microspheres containing Yttrium-90 (90Y, Y90) radioisotope<br>* Other names: Yttrium-90 (Y90; 90Y) resin microspheres;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine dose limiting toxicities (DLT) | Any adverse events grade ≥ 3 will be reviewed by the treating interventional radiologist and medical oncologist within 24 hours of being informed event. If none of the 3 patients in a cohort experiences a DLT, another 3 patients will be treated at the next higher dose level. However, if 1 of the first 3 patients experiences a DLT, 3 more patients will be treated at the same dose level. The dose escalation will continue until at least 2 patients among a cohort of 3-6 patients experience DLTs (i.e., ≥ 33% of patients with a dose-limiting toxicity at that dose level) or until 3-6 patients had been treated at TAS-102 dose of 35mg/m2 per day in 2 divided doses (up to a maximum of 80 mg per dose) administered concurrently with radioembolization cycles 1 and 2 without experiencing a DLT. DLT window will be 56 days (cycle 1, day 1 to cycle 2, day 28). Dose limiting toxicity will be reached when one of the clinical and/or laboratory parameters are met | 56 days | 
| Maximum tolerated dose (MTD) | Traditional 3+3 design will be used to determine the recommended dose for the dose expansion phase will be defined as the dose level just below this toxic dose level. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Radiographic overall response rate (measured in accordance to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) using imaging. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): 30% decrease in the sum of the longest diameter of target lesionsStable Disease (SD): Small changes that do not meet the criteria for CR, PR, or Progressive Disease (PD): 20% increase in the sum of the longest diameter of target lesions. ORR will be defined as a ratio of the number of patients who demonstrated complete response (CR) or partial response (PR) to the number of all evaluated patients. | Up to 4 years | 
| Progression-free survival (PFS) | PFS will be defined as a time period that started at enrollment, during which a patient neither progressed nor died based on radiographic response. | Up to 4 years | 
| Hepatic progression-free survival (HPFS) | HPFS will be defined as a time period that started at enrollment, during which a patient neither progressed in the liver nor died based on radiographic response. | Up to 4 years | 
| Extrahepatic progression free survival (EHPFS) | EHPFS will be defined as a time period that started at enrollment, during which a patient neither progressed outside the liver nor died based on radiographic response | Up to 4 years | 
| Overall survival (OS) | Overall Survival will be analyzed 12 months after the last patient is enrolled. Overall survival will be assessed using a two-sided, log-rank test. The survival function will be estimated using the Kaplan-Meier product limit method. In addition, two-sided 95% confidence intervals for the median overall survival will be computed | Up to 12 months | 
| Biomarker response | Proportion of patients with carcinoembryonic antigen (CEA) response with ≥ 50% decline from baseline (in patients with baseline level ≥ 3.2) post combination therapy with Tas-102 and 90Y radioembolization. Maximum percent change will be calculated. CEA level will only be followed for participants with elevated level (≥3.2) at baseline. | Up to 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SIR-Sphere, radioembolization, Yttrium-90, 90Y, Resin microspheres, Tas-102, Lonsurf