Hepatic Arterial Infusion in Treating Patients With Locally Advanced, Non-Metastatic Cholangiocarcinoma

Study Overview
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Brief Summary
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This pilot clinical trial studies the safety and effectiveness of continuous hepatic arterial infusion (HAI) of floxuridine (FUDR) alone or in combination with other chemotherapeutic drugs in treating patients with locally advanced cholangiocarcinoma that cannot be removed by surgery. HAI is a method to deliver higher concentrations of FUDR more directly to liver tumors and reduces side effects. HAI alone or in combination with oxaliplatin and/or gemcitabine may significantly improve clinical outcomes of patients with locally advanced cholangiocarcinoma.

Official Title
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Pilot Study of Hepatic Arterial Infusion Therapy in Patients With Unresectable or Borderline Resectable Intrahepatic Cholangiocarcinoma

Conditions
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Cholangiocarcinoma, Liver Neoplasms

Intervention / Treatment
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* Drug: Floxuridine
* Drug: Dexamethasone
* Drug: Gemcitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have suspected intrahepatic or hilar cholangiocarcinoma with minimal extrahepatic disease. Diagnosis must be histologically or cytologically confirmed for continued treatment on study after pump placement. Patient must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan/MRI Patient must have disease that is unresectable or borderline resectable with < 70% liver involvement by cancer Patient must be >= 18 years old. Patient's Eastern Cooperative Oncology Group (ECOG) performance status must be =< 2 (Karnofsky >= 60%) Patient must have normal organ and marrow function as defined below: Absolute neutrophil count >= 1,500/mcL Platelets >= 75,000/mcL Total bilirubin =< 2 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 5 X institutional upper limit of normal Creatinine <= institutional upper limit normal Patient must be able to understand and willing to sign a written informed consent document Exclusion Criteria: Patients must not have had prior treatment with FUDR Patient must not be receiving any other investigational agents Patient must not have a diagnosis of Gilbert's disease Patient must not have a diagnosis of hepatic encephalopathy Patient must not have had prior external beam radiation to the liver Patient must not have a diagnosis of sclerosing cholangitis Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patient must not be pregnant or breastfeeding

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (HAI FUDR alone)<br>14-42 days after surgery for insertion of the HAI pump, floxuridine (FUDR) and dexamethasone plus heparin in normal saline to a total volume of 30 ml will be administered through the HAI pump. This will be repeated on Day 1 of each 28 day cycle. FUDR administration will be a 14-day continuous infusion using the HAI pump. The pump will be emptied and refilled with heparinized normal saline and dexamethasone on Day 15 of each cycle to be infused over the next 14 days. | Drug: Floxuridine<br> <br> * Other names: 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR;Drug: Dexamethasone<br> <br> * Other names: Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM;|
| Experimental: Arm B (HAI FUDR + gemcitabine)<br>Consists of Cohort B1, B2, and B3. Enrollment to specific cohorts will depend on the number of DLTs in each cohort. Each cohort has a different dose of FUDR and gemcitabine. Gemcitabine IV will be given on Days 1, 8, and 15 of each 28 day cycle in Cohort B1 Gemcitabine IV will be given on Days 1 and 15 of each 28 day cycle in Cohort B2 & B3 14-42 days after surgery for insertion of the HAI pump, floxuridine (FUDR) and dexamethasone plus heparin in normal saline to a total volume of 30 ml will be administered through the HAI pump. This will be repeated on Day 1 of each 28 day cycle. FUDR administration will be a 14-day continuous infusion using the HAI pump. The pump will be emptied and refilled with heparinized normal saline and dexamethasone on Day 15 of each cycle to be infused over the next 14 days. | Drug: Floxuridine<br> <br> * Other names: 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR;Drug: Dexamethasone<br> <br> * Other names: Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM;Drug: Gemcitabine<br> <br> * Other names: dFdC, dFdCyd, difluorodeoxycytidine hydrochloride, gemcitabine, Gemzar, LY-188011;|
| Experimental: Arm C (HAI FUDR + gemcitabine + oxaliplatin)<br>Consists of Cohort C1, C2, C3, and C4. Enrollment to specific cohorts will depend on the number of DLTs in each cohort. Each cohort has a different dose of FUDR, gemcitabine, and oxaliplatin. Gemcitabine IV will be given on Days 1 and 15 of each 28 day cycle. Oxaliplatin IV will be given on Days 1 and 15 of each 28 days cycle. 14-42 days after surgery for insertion of the HAI pump, floxuridine (FUDR) and dexamethasone plus heparin in normal saline to a total volume of 30 ml will be administered through the HAI pump. This will be repeated on Day 1 of each 28 day cycle. FUDR administration will be a 14-day continuous infusion using the HAI pump. The pump will be emptied and refilled with heparinized normal saline and dexamethasone on Day 15 of each cycle to be infused over the next 14 days. | Drug: Floxuridine<br> <br> * Other names: 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR;Drug: Dexamethasone<br> <br> * Other names: Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM;Drug: Gemcitabine<br> <br> * Other names: dFdC, dFdCyd, difluorodeoxycytidine hydrochloride, gemcitabine, Gemzar, LY-188011;Drug: Oxaliplatin<br> <br> * Other names: 1-OHP, Dacotin, Dacplat, diaminocyclohexane oxalatoplatinum, Eloxatin, L-OHP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLTs) | Document the frequency of grades 3-5 non-hematologic toxicities (dose-limiting toxicities) associated with the treatment regimen by patient and by type of toxicity for each cohort during the first 2 cycles of treatment | Completion of 2 cycles of treatment by all patients (approximately 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression (TTP) | Describe median time to progression with a 95% confidence interval for each cohort. | 12 months | 
| Response rates | The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) Using RECIST 1.1 | 8 weeks | 
| Overall survival |  | 12 months | 
| Number and grade of adverse events | Determine safety, tolerability and toxicities based on the number and grade of adverse events associated with this regimen. | Beginning with pump placement and continuing for 30 days following the last day of study treatment (median length of treatment 3 months) | 
| Imaging biomarkers of tumor response | Using magnetic resonance diffusion-weighted imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) before and during the course of treatment with HAI therapy, validate imaging biomarkers of tumor response | Pre-treatment and then every 8 weeks during treatment (median length of treatment 3 months) | 
| Overall survival |  | Up to 5 years | 
| Time to progression (TTP) | Describe median time to progression with a 95% confidence interval for each cohort. | 24 months |