A Phase II Study of Continuous Hepatic Arterial Infusion With Floxuridine (FUDR) and Dexamethasone (DEX) in Patients With Unresectable Primary Hepatic Malignancy

Study Overview
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Brief Summary
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This phase II study aims to evaluate regional chemotherapy in patients with unresectable primary hepatic malignancy. Specifically, eligible patients with hepatocellular carcinoma and peripheral cholangiocarcinoma, considered unresectable after review by the Hepatobiliary Surgery service, will undergo hepatic artery pump placement and continuous infusion of FUDR. The protocol includes radiological and biological correlative studies.

Detailed Description
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This phase II study aims to evaluate regional chemotherapy in patients with unresectable primary hepatic malignancy. Specifically, eligible patients with hepatocellular carcinoma and peripheral cholangiocarcinoma, considered unresectable after review by the Hepatobiliary Surgery service, will undergo hepatic artery pump placement and continuous infusion of FUDR. The protocol includes radiological and biological correlative studies. The primary objectives of the study are 1.) to assess the efficacy of continuous hepatic arterial infusion (HAI) of FUDR and dexamethasone (DEX) in patients with unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and 2.)to assess patient tolerability of this therapy stratified by degree of underlying hepatic parenchymal disease, as determined on liver biopsy. Secondary objectives are 1.) to use dynamic MRI to evaluate changes in tumor perfusion during treatment and to correlate these findings with radiographic tumor response and 2.) to investigate molecular genetic changes associated with these tumors using comparative genomic hybridization and cDNA array from tumor and liver biopsy specimens obtained at the time of operation. All patients enrolled in the study will begin HAI FUDR at 0.16 mg/kg/day. An initial cohort of 12 patients will be enrolled and treated. Dose limiting toxicity (DLT) related to FUDR is defined by changes in liver function blood tests that are unrelated to disease progression or mechanical biliary obstruction. Modifications in the FUDR dose may be required. A patient will be considered intolerant of therapy if treatment must be stopped due to DLT at least once during the first 3 months. Treatment will continue as long as there is at least stable disease and acceptable toxicity. If, in the initial cohort, 4 or more patients (> 30%) are intolerant of therapy or if there are not at least 2 responders, then the study will be terminated. Otherwise, accrual will continue to a maximum of 35 patients.

Official Title
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A Phase II Study of Continuous Hepatic Arterial Infusion With Floxuridine (FUDR) and Dexamethasone (DEX) in Patients With Unresectable Primary Hepatic Malignancy

Conditions
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Hepatic Cancer

Intervention / Treatment
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* Drug: FLOXURIDINE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a liver mass that is radiographically consistent with HCC and a serum alpha fetoprotein (AFP) > 500 ng/dl do not require biopsy confirmation of the diagnosis. Patients with HCC or ICC undergoing exploration for a possible curative resection but found to have unresectable disease confined to the liver will be eligible, provided that no intraoperative findings would exclude them and prior informed consent has been obtained (see below). There must be <70% liver involvement by cancer, and the disease must be considered unresectable. Patients who have failed ablative therapy will be eligible. Patients must have a KPS > 60% and be considered candidates for general anesthesia and hepatic artery pump placement. Patients with chronic hepatitis and/or cirrhosis are eligible Serum albumin must be >2.5 g/dl and total serum bilirubin must be <1.8 mg/dl based on preoperative laboratory values within 14 days of registration. WBC must be >3500 cells/mm3 and platelet count must be >100,000/mm3 based on preoperative laboratory values within 14 days of registration. The international normalized ratio (INR) must be less than 1.5 in patients not on coumadin therapy, based on preoperative laboratory values within 14 days of registration. Age >_ 18 years. Female patients cannot be pregnant or lactating. Patients must be able to understand and sign informed consent. Exclusion Criteria: Patients who have received prior treatment with FUDR Patients who have had prior external beam radiation therapy to the liver. Patients who have a diagnosis of sclerosing cholangitis. Patients who have a diagnosis of Gilbert's disease. Patients who have clinical ascites Patients with hepatic encephalopathy Patients who have radiographic evidence of esophageal varices or history of variceal hemorrhage. Patients with occlusion of the main portal vein nor of the right and left portal branches Patients that have concurrent malignancies (except localized basal cell or squamous cell skin cancers). Patient with active infection. Female patients who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: FLOXURIDINE<br>* [0.16* mg/kg/day X 30 ml] / pump flow rate * If the patient is >25% above ideal body weight, the dose of FUDR will be calculated from an average of the patients actual and ideal body weights. For example, for a patient who is 5ft. 10 inches and weighs 100kg: Ideal Body Weight (kg) = 50 + (2.3 X height in inches over 5 feet) = 50 + (2.3 X 10) = 73 Weight Used for dose calculation = (100 + 73)/2 = 86.5 Therefore, FUDR Dose will be = (0.16 X 86.5 X 30)/Flow Rate If no dose modification due to toxicity is required, the dosages given above (adjusted for changes in weight and pump flow rate) will be repeated on Day 1 of Week 1 of Cycle 2 and all subsequent cycles.<br>* Other names: FUDR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Response | To assess the efficacy of continuous arterial infusion (HAI) of FUDR (Floxuridine) and dexamethasone (DEX) in patients with unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). | Up to 5 years | 
| Number of Patients With Treatment Related Toxicity | Toxicity evaluated and graded according to the National Cancer Institute, CTCAE v4.0 | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression |  | Up to 5 years | 
| Median Survival | Median Survival from Initiation of Hepatic Arterial Infusion | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FUDR, FLOXORUIDINE, DEXAMETHASONE, Hepatic, Cancer, 02-120