A Phase II Study of Induction Systemic mFOLFIRINOX Followed by Hepatic Arterial Infusion of Floxuridine and Dexamethasone Given Concurrently With Systemic mFOLFIRI as a First-Line Therapy in Patients With Unresectable Liver-Dominant Intrahepatic Cholangiocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Incidence of abnormal liver function
研究概览
简要总结
This phase II trial studies the efficacy and safety of systemic induction of mFOLFIRINOX, followed by hepatic arterial infusion (HAI) floxuridine-dexamethasone administered concurrently with systemic mFOLFIRI in treating patients with liver-dominant intrahepatic cholangiocarcinoma (ICC) that cannot be removed by surgery (unresectable). Drugs used in chemotherapy regimens, such as mFOLFIRINOX and mFOLFIRI (Oxaliplatin, Irinotecan, Fluorouracil, Folinic acid, Floxuridine) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Delivering chemotherapy via HAI (hepatic arterial infusion) can allow for liver-directed treatment while limiting toxic side effects typically seen with traditional chemotherapy.
详细描述
PRIMARY OBJECTIVES:
I. Assess the toxicity, safety and tolerability of hepatic arterial infusion (HAI) floxuridine therapy.
II. Evaluate the efficacy of systemic induction of oxaliplatin, leucovorin calcium (folinic acid), irinotecan hydrochloride, and fluorouracil (modified [m] FOLFIRINOX), followed by HAI of floxuridine-dexamethasone (DEX) administered concurrently with systemic irinotecan hydrochloride, leucovorin calcium (folinic acid), and fluorouracil (mFOLFIRI).
SECONDARY OBJECTIVES:
I. To evaluate tumor response to treatment and participant survival. II. Assess rate of post-operative complications. III. Evaluate serious post-operative complications following surgical placement of the HAI pump.
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
- •Histologically confirmed intrahepatic cholangiocarcinoma (ICC; also variously reported as peripheral cholangiocarcinoma, cholangiolar carcinoma or cholangiocellular carcinoma) with confirmation of the pathologic diagnosis at Oregon Health & Science University (OHSU)
- •Surgically unresectable liver-dominant ICC, or multifocal ICC considered surgically unresectable or resection is contraindicated
- •For liver-dominant ICC, disease must comprise < 70% of the liver parenchyma, as defined by computed tomography (CT) liver segmental volumetrics
- •Limited extrahepatic disease
- •Clinical or radiographic evidence of metastatic disease to regional lymph nodes and limited extrahepatic disease to the lungs is permitted at the discretion of the principal investigator (PI)
- •Radiographically measurable hepatic disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria
- •Disease must be considered technically unresectable at the time of preoperative evaluation or radiographically multifocal as determined by hepatobiliary surgical oncologists
- •Participants should be treatment naive. Those previously treated with systemic chemotherapy (e.g., gemcitabine, cisplatin, or other investigational agents) may be eligible at the discretion of the PI
- •Participants with an Eastern Cooperative Oncology Group (ECOG) 0 or 1 status (Karnofsky >= 60), and can be considered candidates for general anesthesia, abdominal exploration and hepatic artery pump placement
- •Participants with treated chronic hepatitis (e.g., treated hepatitis B virus [HBV], treated hepatitis C virus [HCV]) are eligible, but must be Child-Pugh class A
- •White blood cell (WBC) >= 3000 cells/mm^3
- •Absolute neutrophil count (ANC) >= 1500 cells/mm^3
- •Platelet count >= 100,000/mm^3
- •International normalized ratio (INR) =< 1.5
- •Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 ml/min (> 0.675 ml/sec) using Cockcroft-Gault equation
- •Total bilirubin < 1.5 mg/dL
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- •Participants must be able to read, understand, and sign informed consent
- •Participants must be willing and able to fully comply with required post-operative visits associated with HAI chemotherapy
排除标准
- •Presence of extensive or multifocal metastatic extrahepatic or peritoneal disease. Clinical or radiographic evidence of metastatic disease to regional lymph nodes will be allowed, as will limited pulmonary disease at the discretion of the OHSU PI
- •Prior treatment with floxuridine, oxaliplatin, or irinotecan
- •Prior treatment with hepatic arterial infusion therapy
- •Known to have experienced an allergic reaction or other signs of intolerance to implanted devices
- •Body size that is insufficient to accommodate the physical size of the pump
- •Diagnosis of sclerosing cholangitis
- •Diagnosis of hepatic encephalopathy
- •Clinical evidence of portal hypertension (ascites, gastroesophageal varices, or portal vein thrombosis) or hepatic venous wedge pressures > 8 mmHg if available
- •History of multiple abdominal operations that would preclude HAI pump placement
- •Active infection
- •Current biliary obstruction requiring placement of endoscopic or transhepatic stents for biliary decompression
- •Presence of aberrant or replaced hepatic arterial anatomy not amenable to placement of a hepatic arterial infusion pump catheter as judged by the operating surgeon
- •History of peripheral neuropathy > grade 1
- •Allergies to iodine contrast medium, that cannot be premedicated with steroids per institutional radiology guidelines (e.g., dexamethasone)
- •Uncontrolled severe coagulation disorders (INR > 1.5 in patients not on warfarin therapy)
- •Pregnant or lactating women
- •History of malignancy other than cholangiocarcinoma within 5 years prior to screening, with the exception of:
- •Malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, melanoma in situ, localized prostate cancer, ductal carcinoma in situ, or
- •Stage I uterine cancer or a malignancy whose natural history or treatment has, in the opinion of the principal investigator, the potential to interfere with the safety or efficacy assessment of the intervention under investigation
- •Life expectancy =< 12 weeks
- •Inability to comply with study and/or follow-up procedures
- •Emotional or psychiatric problems that would preclude successful participation in the hepatic arterial infusion program as judged by the one of the study investigators, and further corroborated by the mandatory interview and assessment with medical oncology social worker
- •EXCLUSION CRITERIA FOR TREATMENT PERIOD 2
- •Participants with radiographic evidence of extrahepatic disease
- •Evidence of extrahepatic disease found at laparoscopy during open surgical exploration for HAI pump implantation. Participants with extrahepatic disease found at time of laparoscopy or laparotomy will not undergo surgical placement of HAI pump
研究组 & 干预措施
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Dexamethasone (Drug)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Oxaliplatin (Drug)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Implanted Medical Device (Device)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Quality-of-Life Assessment (Other)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Irinotecan (Drug)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Leucovorin (Drug)
mFOLFIRINOX, Floxuridine-DEX, mFOLFIRI
Treatment Period 1 - mFOLFIRINOX for 4 cycles (cycle = 14 days) Cycle 1
- Oxaliplatin 85 mg/m2 intravenously (iv) over 2 hours
- Folinic acid 400 mg/m2 iv over 2 hours
- Irinotecan 144 mg/m2 iv over 90 minutes
- Fluorouracil 2,400 mg/m2 continuous infusion over 46 hours
Dosages on Cycle 2, 3, and 4 will be reduced by 25%
Treatment Period 2 - HAI delivery of floxuridine + mFOLFIRI for 2 cycles (cycle = 28 days)
- Floxuridine-DEX (with heparin and saline) - 0.12 mg/kg/day; via HAI pump, adjusted for weight and flow rate
- mFOLFIRI on Day 15
- Irinotecan 150 mg/m2 iv over 30 minutes to 1 hour
- Folinic acid 400mg/m2 iv over 30 minutes to 1 hour
- 5-FU 1200 mg/m2 continuous infusion over 46 hours
干预措施: Floxuridine (Drug)
结局指标
主要结局
Incidence of abnormal liver function
时间窗: Up to 2 years
Defined by unacceptable elevation in liver enzymes, or radiographic evidence of biliary sclerosis on computed tomography (CT)/magnetic resonance imaging (MRI) (as measured following the completion of 2 cycles of hepatic arterial infusion \[HAI\] in Treatment Period 2).
Disease control rate (DCR) - during HAI+SYS
时间窗: Up to 2 years
DCR is defined as the percentage of patients who have achieved complete response (CR), partial response (PR), or stable disease (SD). Measured from beginning of Treatment Period 2 to end of Treatment Period 2 during treatment with HAI + systemic chemotherapy (SYS).
次要结局
- DCR - FOLFIRINOX(Up to 1 year)
- PFS(Up to 2 years)
- Overall response rate (ORR)(Up to 2 years)
- Proportion of liver toxicity in participants receiving HAI floxuridine + dexamethasone therapy(Up to 1 year)
- Incidence of serious post-operative complications(Up to 9 weeks after surgery)
- DCR - entire treatment(Up to 2 years)
- Progression free survival (PFS) - FOLFIRINOX(Up to 1 year)
- Overall survival (OS)(Up to 2 years)
研究者
Skye C Mayo
Principal Investigator
OHSU Knight Cancer Institute