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

Phase 1

Terminated

• Conditions: Cholangiocarcinoma; Liver Neoplasms
• Interventions: Drug: Floxuridine; Drug: Dexamethasone; Drug: Gemcitabine; Drug: Oxaliplatin

• Registration Number: NCT01525069
• Lead Sponsor: Washington University School of Medicine

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-01-25
• Study First Submitted QC: 2012-01-30
• Study First Posted: 2012-02-02
• Study Start: 2012-04-03
• Primary Completion: 2018-08-08
• Status Verified: 2022-08
• Study Completion: 2022-08-02
• Last Update Submitted: 2022-08-08
• Last Update Posted: 2022-08-10

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 27

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (HAI FUDR alone)	Floxuridine	* 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.
Arm B (HAI FUDR + gemcitabine)	Floxuridine	* 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.
Arm A (HAI FUDR alone)	Dexamethasone	* 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.
Arm B (HAI FUDR + gemcitabine)	Dexamethasone	* 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.
Arm C (HAI FUDR + gemcitabine + oxaliplatin)	Gemcitabine	* 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.
Arm B (HAI FUDR + gemcitabine)	Gemcitabine	* 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.
Arm C (HAI FUDR + gemcitabine + oxaliplatin)	Floxuridine	* 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.
Arm C (HAI FUDR + gemcitabine + oxaliplatin)	Dexamethasone	* 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.
Arm C (HAI FUDR + gemcitabine + oxaliplatin)	Oxaliplatin	* 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.

Primary Outcome Measures

Name	Time	Method
Dose-limiting toxicities (DLTs)	Completion of 2 cycles of treatment by all patients (approximately 4 years)	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

Secondary Outcome Measures

Name	Time	Method
Overall survival	Up to 5 years
Number and grade of adverse events	Beginning with pump placement and continuing for 30 days following the last day of study treatment (median length of treatment 3 months)	Determine safety, tolerability and toxicities based on the number and grade of adverse events associated with this regimen.
Time to progression (TTP)	24 months	Describe median time to progression with a 95% confidence interval for each cohort.
Response rates	8 weeks	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
Imaging biomarkers of tumor response	Pre-treatment and then every 8 weeks during treatment (median length of treatment 3 months)	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

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States