Phase I Study of Tas-102 and Radioembolization With 90Y Resin Microspheres for Chemo-refractory Colorectal Liver Metastases
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Determine dose limiting toxicities (DLT)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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-
- •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.
研究组 & 干预措施
Tas-102 and radioembolization
Combination therapy with Tas-102 and radioembolization using 90Y resin microspheres
干预措施: Tas-102 (Drug)
Tas-102 and radioembolization
Combination therapy with Tas-102 and radioembolization using 90Y resin microspheres
干预措施: SIR-Sphere (Device)
结局指标
主要结局
Determine dose limiting toxicities (DLT)
时间窗: 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)
时间窗: 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.
次要结局
- Overall survival (OS)(Up to 12 months)
- Overall response rate (ORR)(Up to 4 years)
- Progression-free survival (PFS)(Up to 4 years)
- Hepatic progression-free survival (HPFS)(Up to 4 years)
- Extrahepatic progression free survival (EHPFS)(Up to 4 years)
- Biomarker response(Up to 4 years)