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

NCT ID: NCT00410956

Last Updated: 2024-12-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-05-09
• Study Completion Date: 2024-05-07

Brief Summary

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.

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.

Conditions

Liver Cancer

Keywords

adult primary hepatocellular carcinoma; localized unresectable adult primary liver cancer; advanced adult primary liver cancer; recurrent adult primary liver cancer; adult primary cholangiocellular carcinoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

bevacizumab

Intervention Type: BIOLOGICAL

dexamethasone

Intervention Type: DRUG

floxuridine

Intervention Type: DRUG

protein expression analysis

Intervention Type: GENETIC

flow cytometry

Intervention Type: OTHER

immunoenzyme technique

Intervention Type: OTHER

immunohistochemistry staining method

Intervention Type: OTHER

immunologic technique

Intervention Type: OTHER

laboratory biomarker analysis

Intervention Type: OTHER

dynamic contrast-enhanced magnetic resonance imaging

Intervention Type: PROCEDURE

Interventions

bevacizumab

Intervention Type: BIOLOGICAL

dexamethasone

Intervention Type: DRUG

floxuridine

Intervention Type: DRUG

protein expression analysis

Intervention Type: GENETIC

flow cytometry

Intervention Type: OTHER

immunoenzyme technique

Intervention Type: OTHER

immunohistochemistry staining method

Intervention Type: OTHER

immunologic technique

Intervention Type: OTHER

laboratory biomarker analysis

Intervention Type: OTHER

dynamic contrast-enhanced magnetic resonance imaging

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Memorial Sloan Kettering Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

William R. Jarnagin, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Locations

New York Weill Cornell Cancer Center at Cornell University

New York, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Countries

United States

References

Kemeny NE, Schwartz L, Gonen M, Yopp A, Gultekin D, D'Angelica MI, Fong Y, Haviland D, Gewirtz AN, Allen P, Jarnagin WR. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results? Oncology. 2011;80(3-4):153-9. doi: 10.1159/000324704. Epub 2011 Jun 14.

Reference Type: RESULT

PMID: 21677464 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

MSKCC-06114

Identifier Type: -

Identifier Source: secondary_id

GENENTECH-MSKCC-06114

Identifier Type: -

Identifier Source: secondary_id

06-114

Identifier Type: -

Identifier Source: org_study_id