Phase 1B Study of Hepatic Chemoembolization Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Serious adverse event (SAE) rate
研究概览
简要总结
Liver metastases are a leading cause of death among patients with metastatic colorectal cancer. Duration of disease control is short following 2nd-line or later systemic therapy. Liver-directed therapy such as TACE has a higher response rate and improves progression-free survival (PFS), but the benefit is still limited. Cancer cells escape ischemic cell death via autophagy and hypoxia-inducible factor (HIF) activation. We hypothesize that blocking autophagy and the vascular endothelial growth factor (VEGF) pathway will improve both response and PFS following TACE.
详细描述
Subjects with liver-dominant colorectal cancer metastases failing at least one line of systemic therapy will receive 2 weeks of axitinib 5mg twice daily (BID) and HCQ 600 mg BID followed by lobar or segmental TACE monthly until the entire tumor burden is treated, then continue axitinib/HCQ until progression or intolerable toxicity. Response and hepatic progression-free survival (HPFS) will be assessed one month post-TACE, then every 3 months.
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
- •Age 18 years or more.
- •Pathologically-verified diagnosis of colorectal adenocarcinoma.
- •Measurable metastasis to liver with at least one dimension ≥ 1.0 cm.
- •Liver dominant metastases as judged by multidisciplinary team consensus review of cross-sectional imaging of the chest, abdomen and pelvis.
- •At least 2 weeks must have elapsed from the last dose of chemotherapy before starting HCQ and at least 4 weeks must have elapsed from the last dose of VEGF/VEGFR therapy prior to starting axitinib.
- •Subjects must be at least 2 weeks beyond prior radiotherapy or surgery, and have recovered from all therapy associated toxicities.
- •Eastern Cooperative Oncology Group (ECOG) Performance status must be 0-1 (see Appendix II).
- •Absolute granulocyte count > 1,500/ul, platelet count > 75,000/ul, International Normalized Ratio (INR) < 1.6
- •Serum creatinine < 2.0 mg/dl; serum bilirubin < 2.0 mg/dl.
- •Urine protein:creatinine ratio < 1 or 24-hour urine protein < 1 gm/day
- •Liver function Child-Pugh A
- •Competent and willing to provide informed consent
- •Patients of reproductive potential agree to use approved contraceptive methods per section 5.4
排除标准
- •Contraindications to angiography and selective visceral catheterization:
- •severe allergy or intolerance to contrast media not controllable with prophylaxis.
- •bleeding diathesis not correctable by usual forms of therapy.
- •severe peripheral vascular disease precluding catheterization.
- •Contraindications to hepatic artery embolization:
- •high risk of hepatic failure, indicated by the constellation of greater than 50% liver replacement by tumor, lactate dehydrogenase (LDH) >425 mU/ml, aspartate aminotransferase (AST) >100mU/ml. and bilirubin >2 mg/dl.
- •tumor volume >75% of total liver volume.
- •portal vein occlusion without hepatopetal collateral flow demonstrated by angiography; or portal hypertension with hepatofugal flow.
- •hepatic encephalopathy.
- •Prior hepatic arterial infusion chemotherapy or hepatic radiation therapy. Prior surgical resection or ablation of liver metastases is acceptable.
- •No more than two prior lines of systemic chemotherapy.
- •Pregnancy or lactation
- •Known allergic reactions to irinotecan, HCQ or axitinib
- •Allergy to contrast not mitigated by usual prophylaxis
- •Serious infection requiring intravenous therapy.
- •Known retinal disease
- •Poorly controlled hypertension, defined as a blood pressure > 150/100 at the time of enrollment. Patients with a preexisting hypertension must be on a stable anti-hypertensive regimen
- •History of abdominal fistula, gastrointestinal perforation, or serious non-healing wounds, ulcers, or bone fractures
- •Known New York Heart Association class II or greater congestive heart failure (defined as symptoms of fatigue, dyspnea, or other symptoms with ordinary physical activity)
- •Known untreated brain metastases. History of treated metastases off steroids allowed.
研究组 & 干预措施
TACE+axitinib+HCQ
2 weeks of axitinib 5mg BID and hydroxychloroquine 600 mg BID followed by lobar or segmental trans arterial chemoembolization monthly until the entire tumor burden is treated, then continue axitinib/HCQ until progression or intolerable toxicity.
干预措施: Axitinib 5 MG (Drug)
TACE+axitinib+HCQ
2 weeks of axitinib 5mg BID and hydroxychloroquine 600 mg BID followed by lobar or segmental trans arterial chemoembolization monthly until the entire tumor burden is treated, then continue axitinib/HCQ until progression or intolerable toxicity.
干预措施: Hydroxychloroquine Pill (Drug)
TACE+axitinib+HCQ
2 weeks of axitinib 5mg BID and hydroxychloroquine 600 mg BID followed by lobar or segmental trans arterial chemoembolization monthly until the entire tumor burden is treated, then continue axitinib/HCQ until progression or intolerable toxicity.
干预措施: trans arterial chemoembolization (Procedure)
结局指标
主要结局
Serious adverse event (SAE) rate
时间窗: 12 months
SAE is scored by CTCAE v5 (G3 or higher) and the 2017 revision of the Society of Interventional Radiology (SIR) Complications Classification categories 3-5.
次要结局
- Overall survival(24 months)
- axitinib treatment intensity(12 months)
- objective response rate in the liver(3 months)
- Hepatic progression-free survival(12 months)
- Progression-free survival(12 months)