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

• Time to progression [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Describe median time to progression with a 95% confidence interval for each cohort.
• Response rates [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Describe the overall response rate and the response rate within each cohort with 95% confidence intervals.
• Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Describe median overall survival with a 95% confidence interval and estimate the overall survival rate at 12 and 24 months with 95% confidence intervals.
• Number and grade of adverse events post HAI treatment [ Time Frame: 13 months ] [ Designated as safety issue: Yes ]
  Determine safety, tolerability and toxicities based on the number and grade of adverse events associated with this regimen.
• Imaging biomarkers of tumor response [ Time Frame: 13 months ] [ Designated as safety issue: No ]
  Using magnetic resonance diffusion-weighted imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) before and early during the course of treatment with HAI therapy, validate imaging biomarkers of tumor response

• Time to progression [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Describe median time to progression with a 95% confidence interval for each cohort.
• Response rates [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Describe the overall response rate and the response rate within each cohort with 95% confidence intervals.
• Overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Describe median overall survival with a 95% confidence interval and estimate the overall survival rate at 12 and 24 months with 95% confidence intervals.
• Number and grade of adverse events post HAI treatment [ Time Frame: 13 months ] [ Designated as safety issue: Yes ]
  Determine safety, tolerability and toxicities based on the number and grade of adverse events associated with this regimen.

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.

• Cholangiocarcinoma
• Liver Neoplasms

• Drug: floxuridine, dexamethasone

  floxuridine Given HAI; 0.16mg/kg/day on Days 1-14 of each cycle

  dexamethasone, Given HAI; 20mg

  Other Names:

  • 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR
  • Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM
• Drug: floxuridine, dexamethasone, gemcitabine hydrochloride

  floxuridine Given HAI; 0.12mg/kg/day on Days 1-14 of each cycle

  dexamethasone Given HAI; 20 mg on Days 1-14 of each cycle

  gemcitabine hydrochloride Given IV; 1000 mg/m^2 on Days 1, 8 and 15 of each cycle

  Other Names:

  • 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR
  • Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM
  • dFdC, dFdCyd, difluorodeoxycytidine hydrochloride, gemcitabine, Gemzar, LY-188011
• Drug: floxuridine, dexamethasone, gemcitabine hydrochloride, oxaliplatin

  floxuridine Given HAI; 0.12mg/kg/day on Days 1-14 of each cycle

  dexamethasone Given HAI; 20mg on Days 1-14 of each cycle

  gemcitabine hydrochloride Given IV; 800 mg/m^2 on Days 1 and 15 of each cycle

  oxaliplatin Given IV; 85 mg/m^2 on Days 1 and 15 of each cycle

  Other Names:

  • 5-FUDR, FdUrD, floxuridin, fluorodeoxyuridine, fluoruridine deoxyribose, FUdR
  • Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM
  • dFdC, dFdCyd, difluorodeoxycytidine hydrochloride, gemcitabine, Gemzar, LY-188011
  • 1-OHP, Dacotin, Dacplat, diaminocyclohexane oxalatoplatinum, Eloxatin, L-OHP

• Experimental: Cohort A (HAI)
  Patients receive FUDR and dexamethasone via continuous HAI for 14 days of a 28-day treatment cycle.
  Intervention: Drug: floxuridine, dexamethasone
• Experimental: Cohort B (HAI + gemcitabine)
  Patients receive FUDR and dexamethasone as in Cohort A. Patients also receive gemcitabine
  Intervention: Drug: floxuridine, dexamethasone, gemcitabine hydrochloride
• Experimental: Cohort C (HAI + gemcitabine + oxaliplatin)
  Patients receive FUDR and dexamethasone as in Cohort A. Patients also receive gemcitabine and oxaliplatin
  Intervention: Drug: floxuridine, dexamethasone, gemcitabine hydrochloride, oxaliplatin

• De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer "Unfit" for Cisplatin-Based Chemotherapy: Phase II--Results of EORTC Study 30986. J Clin Oncol. 2009 Sep 28; [Epub ahead of print]
• Tan BR, Brenner WS, Picus J, Marsh S, Gao F, Fournier C, Fracasso PM, James J, Yen-Revollo JL, McLeod HL. Phase I study of biweekly oxaliplatin, gemcitabine and capecitabine in patients with advanced upper gastrointestinal malignancies. Ann Oncol. 2008 Oct;19(10):1742-8. Epub 2008 Jun 4.
• Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, Jarnagin WR, Patel D, D'Angelica M. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009 Jul 20;27(21):3465-71. Epub 2009 May 26.
• Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med. 2005 Feb 17;352(7):734-5. No abstract available.
• Jarnagin WR, Schwartz LH, Gultekin DH, Gönen M, Haviland D, Shia J, D'Angelica M, Fong Y, Dematteo R, Tse A, Blumgart LH, Kemeny N. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol. 2009 Sep;20(9):1589-95. Epub 2009 Jun 2.

Inclusion Criteria:

• Patient must have histologically or cytologically confirmed intrahepatic or hilar cholangiocarcinoma with minimal extrahepatic disease
• 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%)
• 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 within normal institutional limits
• 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