Hepatic Arterial Infusion With Floxuridine and Dexamethasone Combined With Combination Chemotherapy and Bevacizumab in Treating Patients With Colorectal Cancer That Has Spread to the Liver - Full Text View

Sponsors and Collaborators:	Memorial Sloan-Kettering Cancer Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00492999

Purpose

RATIONALE: Hepatic arterial infusion uses a catheter to carry tumor-killing substances directly into the liver. Drugs used in chemotherapy 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 floxuridine and dexamethasone directly into the arteries around the tumor together with combination chemotherapy and bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well hepatic arterial infusion with floxuridine and dexamethasone given together with irinotecan, leucovorin, oxaliplatin or fluorouracil, and bevacizumab works in treating patients with colorectal cancer that has spread to the liver.

Condition	Intervention	Phase
Colorectal Cancer Metastatic Cancer	Biological: bevacizumab Drug: dexamethasone Drug: floxuridine Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: oxaliplatin	Phase II

MedlinePlus related topics: Cancer Colorectal Cancer

Drug Information available for: Dexamethasone Floxuridine Fluorouracil Leucovorin Citrovorum factor Dexamethasone acetate Oxaliplatin Doxiproct plus Irinotecan U 101440E Irinotecan hydrochloride Bevacizumab Leucovorin Calcium Dexamethasone Sodium Phosphate Folinic acid calcium salt pentahydrate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label
Official Title:	A Phase II Study of the Rate of Conversion to Complete Resection in Patients With Initially Inoperable Hepatic-Only Metastases From Colorectal Cancer After Treatment With Hepatic Arterial Infusion With Floxuridine and Dexamethasone in Combination With Best Systemic Chemotherapy Plus Bevacizumab

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Resectability rate [ Designated as safety issue: No ]

Secondary Outcome Measures:

Antitumor activity [ Designated as safety issue: No ]
Response rate [ Designated as safety issue: No ]
Median time to progression [ Designated as safety issue: No ]
Survival [ Designated as safety issue: No ]

Estimated Enrollment:	49
Study Start Date:	May 2007
Estimated Primary Completion Date:	May 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Group 1: Experimental Patients receive hepatic arterial infusion (HAI) therapy comprising floxuridine and dexamethasone continuously on days 1-14. Patients also receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 30 minutes, and bevacizumab IV over 10 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab Given IV on days 1 and 15 Drug: dexamethasone Given by hepatic arterial infusion Drug: floxuridine Given by hepatic arterial infusion Drug: irinotecan hydrochloride Given IV Drug: oxaliplatin Given IV
Group 2: Experimental Patients receive HAI therapy as in group 1. Patients also receive irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 30 minutes, and bevacizumab IV over 10 minutes on days 1 and 15 and fluorouracil IV continuously over 48 hours on days 1 and 2. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab Given IV on days 1 and 15 Drug: dexamethasone Given by hepatic arterial infusion Drug: floxuridine Given by hepatic arterial infusion Drug: fluorouracil Given IV on days 1 and 2 Drug: irinotecan hydrochloride Given IV Drug: leucovorin calcium Given IV

Detailed Description:

OBJECTIVES:

Primary

Assess the rate of conversion to complete resection in patients with initially unresectable colorectal cancer metastatic to the liver treated with hepatic arterial infusion comprising floxuridine and dexamethasone in combination with systemic irinotecan hydrochloride, leucovorin calcium, oxaliplatin or fluorouracil, and bevacizumab.

Secondary

Evaluate the time to progression in patients treated with this regimen.
Evaluate disease-free survival of patients treated with this regimen.
Evaluate overall survival of patients treated with this regimen.
Determine the response rate (complete, partial, and moderate response) in patients treated with this regimen.
Evaluate the safety profile and tolerability of this regimen in these patients.
Assess the expression pattern of the VEGF receptor VEGFR1, VEGFR2, and VEGFR3 and their cognate ligands (i.e., VEGF-A, VEGF-B, VEGF-C, VEGF-D, and P1GF) in patients treated with this regimen.
Correlate circulating angiogenic markers with tumor resectability, disease progression, and patient survival.
Procure normal and diseased liver tissue for evaluation of thymidylate synthase, p53 gene, p21, topoisomerase 1, dihydropyrimidine dehydrogenase, and excision repair cross-complementing gene levels.

OUTLINE: This is an open-label, nonrandomized study. Patients are assigned to 1 of 2 treatment groups according to receipt of more than 2 prior courses of oxaliplatin (no vs yes).

Group 1 (no more than 2 prior courses of oxaliplatin): Patients receive hepatic arterial infusion (HAI) therapy comprising floxuridine and dexamethasone continuously on days 1-14. Patients also receive oxaliplatin IV over 2 hours, irinotecan hydrochloride IV over 30 minutes, and bevacizumab IV over 10 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Group 2 (more than 2 prior courses of oxaliplatin): Patients receive HAI therapy as in group 1. Patients also receive irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 30 minutes, and bevacizumab IV over 10 minutes on days 1 and 15 and fluorouracil IV continuously over 48 hours on days 1 and 2. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

In both groups, patients may undergo complete resection of liver metastases after completion of at least 3 courses of therapy.

Patients undergo blood and tissue collection periodically for correlative and immunological studies. Samples are analyzed for VEGF receptor VEGFR1, VEGFR2, VEGFR3, thymidylate synthase, p53, p21, topoisomerase 1, dihydropyrimidine dehydrogenase, and excision repair cross-complementing gene via quantitative reverse-transcriptase polymerase chain reaction; VEGF receptors, their ligands, and other markers elucidated via immunohistochemistry; and the number of circulating CD133(AC133), VEGFR2, CD34, VEGFR2, endothelial progenitors, VEGFR1, and pro-angiogenic hematopoietic cells via flow cytometry.

After completion of study treatment, patients are followed every 2-3 months.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed colorectal adenocarcinoma metastatic to the liver
- Previously treated or untreated disease
- No clinical or radiographic evidence of extrahepatic disease
Primary tumor may be present at study registration provided it is not obstructing the intestinal lumen or is significantly bleeding
- If present, the primary tumor will be resected at the time of pump placement
Must have inoperable liver metastases confirmed by 2-3 hepatobiliary surgeons and the assigned radiologist
- Liver metastases < 70% of the liver parenchyma
- Inoperable liver metastases is defined by one of the following:
  - More than 6 metastases in a single lobe with one lesion ≥ 5 cm
  - At least 6 metastases distributed diffusely in both lobes of the liver
  - When a margin-negative resection would require resection of all three hepatic veins, both portal veins, or the retrohepatic vena cava
  - Requires a resection that leaves < 2 hepatic segments (not including the caudate lobe) behind with adequate arterial or portal inflow, venous outflow, and biliary drainage
No ascites or hepatic encephalopathy
No history of primary CNS tumors

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
WBC ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
INR < 1.5
Hemoglobin ≥ 9 g/dL
Creatinine ≤ 1.5 mg/dL
Total bilirubin ≤ 1.5 mg/dL
Proteinuria < 1+ OR proteinuria ≤ 1 g by 24-hour urine collection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Physically able to tolerate major partial hepatectomy
No active infection
No active concurrent malignancies, except potentially resectable primary colorectal tumor
No history of allergic reactions attributed to compounds of similar chemical or biological composition to bevacizumab
No bleeding diathesis or coagulopathy
No history of serious systemic disease, including any of the following:
- Myocardial infarction within the past 6 months
- Uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg on medication)
- Unstable angina
- New York Heart Association class II-IV congestive heart failure
- Unstable symptomatic arrhythmia requiring medication
  - Chronic atrial arrhythmia (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) allowed
- Peripheral vascular disease ≥ grade 2
No serious or nonhealing active wound, ulcer, or bone fracture
No history of seizures not well controlled with standard medical therapy
No history of stroke
No concurrent obstruction of the gastrointestinal or genitourinary tract
No significant traumatic injury within the past 28 days

PRIOR CONCURRENT THERAPY:

At least 4 weeks since prior radiotherapy to the pelvis
Prior chemotherapy allowed
No prior radiotherapy, hepatic thermal ablation, or resection (other than biopsy) to the liver
No prior floxuridine
No prior hepatic arterial infusion
More than 28 days since prior major surgical procedure or open biopsy
No concurrent chronic aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory medications known to inhibit platelet function
No other concurrent investigational agents

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00492999

Locations

United States, New York
Memorial Sloan-Kettering Cancer Center	Recruiting
New York, New York, United States, 10065
Contact: Michael D'Angelica, MD 212-639-3226

Sponsors and Collaborators

Memorial Sloan-Kettering Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Michael D'Angelica, MD	Memorial Sloan-Kettering Cancer Center
Principal Investigator:	Nancy E. Kemeny, MD	Memorial Sloan-Kettering Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Memorial Sloan-Kettering Cancer Center ( Michael D'Angelica )
Study ID Numbers:	CDR0000551709, MSKCC-06075
Study First Received:	June 25, 2007
Last Updated:	April 8, 2009
ClinicalTrials.gov Identifier:	NCT00492999 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer

adenocarcinoma of the colon
adenocarcinoma of the rectum
liver metastases

Study placed in the following topic categories:

Antimetabolites
Anti-Inflammatory Agents
Dexamethasone
Immunologic Factors
Gastrointestinal Diseases
Rectal Neoplasms
Hormone Antagonists
Colonic Diseases
Irinotecan
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Leucovorin
Bevacizumab
Hormones
Rectal Diseases

Oxaliplatin
Vitamins
Neoplasm Metastasis
Micronutrients
Dexamethasone acetate
Vitamin B Complex
Digestive System Neoplasms
Antineoplastic Agents, Hormonal
Floxuridine
Rectal Neoplasm
Trace Elements
Intestinal Diseases
Angiogenesis Inhibitors
Immunosuppressive Agents
Glucocorticoids

Additional relevant MeSH terms:

Dexamethasone
Anti-Inflammatory Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Colonic Diseases
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Bevacizumab
Rectal Diseases
Hormones
Pathologic Processes
Neoplasms by Site
Therapeutic Uses
Neoplasm Metastasis

Angiogenesis Modulating Agents
Digestive System Neoplasms
Antineoplastic Agents, Hormonal
Floxuridine
Glucocorticoids
Camptothecin
Neoplasms
Fluorouracil
Gastrointestinal Neoplasms
Antineoplastic Agents, Phytogenic
Antimetabolites
Immunologic Factors
Gastrointestinal Diseases
Antineoplastic Agents
Irinotecan

ClinicalTrials.gov processed this record on May 06, 2009