Tas-102 and Radioembolization With 90Y Resin Microspheres for Chemo-refractory Colorectal Liver Metastases
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tas-102 and radioembolization Combination therapy with Tas-102 and radioembolization using 90Y resin microspheres |
Drug: Tas-102
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.
Other Names:
Device: SIR-Sphere
20-60mm resin microspheres containing Yttrium-90 (90Y, Y90) radioisotope
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Determine dose limiting toxicities (DLT) [56 days]
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
- Maximum tolerated dose (MTD) [Up to 4 years]
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.
Secondary Outcome Measures
- Overall response rate (ORR) [Up to 4 years]
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.
- Progression-free survival (PFS) [Up to 4 years]
PFS will be defined as a time period that started at enrollment, during which a patient neither progressed nor died based on radiographic response.
- Hepatic progression-free survival (HPFS) [Up to 4 years]
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.
- Extrahepatic progression free survival (EHPFS) [Up to 4 years]
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
- Overall survival (OS) [Up to 12 months]
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
- Biomarker response [Up to 4 years]
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.
Eligibility Criteria
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.
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Disease progression or intolerance to at least two prior Food and Drug Administration-approved therapeutic regimens.
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If extrahepatic disease is present, it must be asymptomatic.
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If a primary tumor is in place, it must be asymptomatic.
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Measurable target tumors using standard imaging techniques (RECIST v. 1.1 criteria).
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Tumor replacement < 50% of total liver volume.
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Current Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 through screening to first treatment on study.
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Completion of prior systemic therapy at least 14 days prior to enrollment.
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Able to understand informed consent.
Exclusion Criteria:
- At risk of hepatic or renal failure
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Serum creatinine > 1.5 mg/dl
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Serum bilirubin > 1.3 mg/ml
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Albumin < 2.0 g/dL
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Aspartate and/or alanine aminotransferase level > 5 times upper normal limit
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Any history of hepatic encephalopathy
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Cirrhosis or portal hypertension
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Clinically evident ascites (trace ascites on imaging is acceptable)
- Contraindications to angiography and selective visceral catheterization
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Any bleeding diathesis or coagulopathy that is not correctable by usual therapy or hemostatic agents (e.g. closure device)
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Severe allergy or intolerance to contrast agents, narcotics, or sedatives that cannot be managed medically
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Symptomatic lung disease
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Prior therapy with Tas-102.
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Contraindications to Tas-102
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Absolute neutrophil count < 1,500/μl
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Platelet count < 75,000/μl
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Allergy or intolerance to Tas-102
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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
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Greater than 30 Gy absorbed dose of radiation to the lungs during a single 90Y resin microsphere administration; or
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Cumulative delivery of radiation to the lungs > 50 Gy over multiple treatments.
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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.
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Previous radiation therapy to the lungs and/or to the upper abdomen
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Any prior arterial liver-directed therapy, including chemoembolization, bland embolization, and 90Y radioembolization
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Any intervention for, or compromise of the ampulla of Vater
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Active uncontrolled infection. Presence of latent or medication-controlled HIV and/or viral hepatitis is allowed.
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Significant extrahepatic disease
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Symptomatic extrahepatic disease (including primary tumor, if unresected).
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Greater than 10 pulmonary nodules (each < 20 mm in diameter) or combined diameter of all pulmonary nodules > 15 cm.
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Peritoneal carcinomatosis
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Life expectancy less than 3 months
-
Pregnant or lactating female
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California San Francisco | San Francisco | California | United States | 94143 |
Sponsors and Collaborators
- University of California, San Francisco
- Sirtex Medical
- Taiho Pharmaceutical Co., Ltd.
Investigators
- Principal Investigator: Nicholas Fidelman, MD, University of California, San Francisco
- Principal Investigator: Katherine Van Loon, MD, University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 16452
- NCI-2017-01321