Floxuridine and Dexamethasone as a Hepatic Arterial Infusion and Bevacizumab in Treating Patients With Primary Liver Cancer That Cannot be Removed by Surgery

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00410956
First received: December 11, 2006
Last updated: November 25, 2013
Last verified: November 2013
  Purpose

RATIONALE: Drugs used in chemotherapy, such as floxuridine and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy directly into the arteries around the tumor together with bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving floxuridine and dexamethasone as a hepatic arterial infusion together with bevacizumab works in treating patients with unresectable primary liver cancer.


Condition Intervention Phase
Liver Cancer
Biological: bevacizumab
Drug: dexamethasone
Drug: floxuridine
Genetic: protein expression analysis
Other: flow cytometry
Other: immunoenzyme technique
Other: immunohistochemistry staining method
Other: immunologic technique
Other: laboratory biomarker analysis
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Hepatic Arterial Infusion With Floxuridine and Dexamethasone in Combination With Intravenous Bevacizumab (A Monoclonal Antibody to Vascular Endothelial Growth Factor-A), in Patients With Unresectable Primary Hepatic Malignancy

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Antitumor efficacy (complete and partial response, stable and progressive disease) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Toxicity as measured by NCI Common Toxicity Criteria [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 55
Study Start Date: May 2007
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: UNRESECTABLE PRIMARY HEPATIC MALIGNANCY
All patients enrolled in the study will receive HAI FUDR (0.16 mg/kg X pump volume / pump flow rate), Dexamethasone (1 mg/m2/day) and IV Bevacizumab at 5mg/kg. Chemotherapy with HAI FUDR/Dex will commence no sooner than 14 days post surgical placement of HAI pump; patients will receive their first treatment with Bevacizumab no sooner than 28 days post surgical placement of HAI pump.
Biological: bevacizumab Drug: dexamethasone Drug: floxuridine Genetic: protein expression analysis Other: flow cytometry Other: immunoenzyme technique Other: immunohistochemistry staining method Other: immunologic technique Other: laboratory biomarker analysis Procedure: dynamic contrast-enhanced magnetic resonance imaging

Detailed Description:

OBJECTIVES:

Primary

  • Determine the median time to progression in patients with unresectable primary hepatic malignancy treated with hepatic arterial infusion comprising floxuridine and dexamethasone in combination with systemic bevacizumab.

Secondary

  • Determine the utility of dynamic contrast-enhanced MRI (DCE-MRI) for assessing changes in tumor perfusion before and during treatment.
  • Correlate DCE-MRI findings with radiographic tumor response.

Tertiary

  • Correlate the expression patterns of vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 and their cognate ligands (including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor [PlGF]) with disease progression and survival after therapy.
  • Assess the pro-angiogenic activity of peripheral blood before and during treatment.
  • Assess tumors for immunohistochemical markers of hypoxia (e.g., hypoxia-inducible factor [HIF-1α], carbonic anhydrase IX [CA IX], and glucose transporters [Glut-1 and Glut-3]) for correlation with initial and treatment-related changes in perfusion and permeability, as determined by DCE-MRI.

OUTLINE: This is an open-label, nonrandomized study.

Patients undergo placement of the hepatic arterial infusion (HAI) pump and a cholecystectomy. Approximately 2 weeks later, patients receive floxuridine and dexamethasone by HAI continuously on days 1-14 and bevacizumab IV over 30-90 minutes on day 15 of course 1 and on days 1 and 15 of all subsequent courses. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo dynamic contrast-enhanced MRI (DCE-MRI) on days 1 and 15 of course 1 and then every 8 weeks thereafter.

Tumor and nontumor tissue is collected at the time of the HAI pump placement. Tissue is examined for the expression of vascular endothelial growth factor (VEGF)-A, -B, -C, and -D, placenta growth factor (PlGF), and VEGF receptor (VEGFR)-1, -2, and -3 by immunohistochemistry. Peripheral blood is collected at baseline and on day 1 of each course. Plasma levels of VEGF-A, -B, -C, and -D are measured by immunoenzyme techniques. Blood is also examined by flow cytometry and immunological methods and by protein extraction and analysis of VEGF and VEGFR expression (by western blot). Immunohistochemical markers of hypoxia in tissue, including hypoxia-inducible factor (HIF-1α), carbonic anhydrase IX (CA IX), glucose transporters (Glut-1 and Glut-3), and Ki-67 are assessed.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 55 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC)

    • Peripheral, cholangiolar, or cholangiocellular types
    • Mixed HCC/ICC disease allowed
    • Unresectable disease
    • Less than 70% liver involvement
  • Radiographically bidimensionally measurable disease, defined as lesion ≥ 2 cm in the greatest diameter
  • May have failed prior systemic chemotherapy or ablative therapy
  • No radiographic evidence of esophageal varices
  • No history of variceal hemorrhage
  • No occlusion of the main portal vein or the right and left portal branches
  • No clinical ascites
  • Patients ineligible for first-line MSKCC protocols for HCC are eligible for this study provided there is no clinical or radiographic evidence of extrahepatic disease
  • No metastatic disease, including CNS metastases

PATIENT CHARACTERISTICS:

  • Life expectancy ≥ 12 weeks
  • Karnofsky performance status 60-100%
  • Considered a candidate for general anesthesia and hepatic artery pump placement
  • Platelet count > 100,000/mm³
  • Albumin > 2.5 g/dL
  • Bilirubin < 1.8 mg/dL
  • WBC > 3,500/mm³
  • PTT < 1.5 times upper limit of normal
  • INR < 1.5 OR in-range INR (usually 2.0-3.0) for patients on a stable dose of therapeutic warfarin
  • Urine protein < 1+ by dipstick or urine analysis OR urine protein:creatinine ratio < 1.0

    • If proteinuria ≥ 2+ at baseline, patient must have < 1 g protein/24-hour collection
  • No concurrent disease or illness that would preclude study participation, including any of the following:

    • Hepatic encephalopathy
    • Sclerosing cholangitis
    • Gilbert's disease
    • Active infection
  • No known CNS disease
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab
  • No psychiatric illness or social situation that would preclude study compliance
  • No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
  • No serious or nonhealing active wound, ulcer, or bone fracture
  • No bleeding diathesis or coagulopathy
  • No clinically significant cardiovascular disease, including any of the following:

    • Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 100 mm Hg on antihypertensive medications
    • New York Heart Association class II-IV congestive heart failure
    • Vascular disease (e.g., aortic aneurysm, aortic dissection)
    • Myocardial infarction within the past 6 months
    • Symptomatic peripheral vascular disease
    • Unstable angina within the past 6 months
    • History of hypertensive crisis
    • Transient ischemic attack
    • Stroke
  • No other concurrent malignancy except localized basal cell or squamous cell skin cancer
  • Chronic hepatitis and/or cirrhosis allowed provided it is Child-Pugh class A disease
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • More than 4 weeks since prior and no other concurrent experimental therapy except on a Genentech-sponsored bevacizumab cancer study
  • More than 4 weeks since prior major surgical procedure or open biopsy
  • More than 1 week since prior minor surgical procedure (e.g., core biopsy), excluding placement of a vascular access device
  • No prior external-beam radiation therapy to the liver
  • No prior floxuridine
  • No chronic daily treatment with nonsteroidal anti-inflammatory medications known to inhibit platelet function
  • No chronic daily treatment with aspirin (> 325 mg/day)
  • No concurrent or recent use of a thrombolytic agent
  • No concurrent major surgery
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00410956

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
New York Weill Cornell Cancer Center at Cornell University
New York, New York, United States, 10021
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: William R. Jarnagin, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00410956     History of Changes
Other Study ID Numbers: 06-114, MSKCC-06114, GENENTECH-MSKCC-06114
Study First Received: December 11, 2006
Last Updated: November 25, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
adult primary hepatocellular carcinoma
localized unresectable adult primary liver cancer
advanced adult primary liver cancer
recurrent adult primary liver cancer
adult primary cholangiocellular carcinoma

Additional relevant MeSH terms:
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Bevacizumab
Dexamethasone
Floxuridine
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on October 19, 2014