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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00492999
First received: June 25, 2007
Last updated: December 17, 2013
Last verified: December 2013
  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. Giving floxuridine and dexamethasone directly into the arteries around the tumor together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well hepatic arterial infusion with floxuridine and dexamethasone works when given together with combination chemotherapy in treating patients with colorectal cancer that has spread to the liver.


Condition Intervention Phase
Colorectal Cancer
Metastatic Cancer
Drug: dexamethasone
Drug: floxuridine
Drug: fluorouracil
Drug: irinotecan hydrochloride
Drug: leucovorin calcium
Drug: oxaliplatin
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Resectability rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Antitumor activity [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Response rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Median time to progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 64
Study Start Date: May 2007
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
Patients receive hepatic arterial infusion (HAI) therapy comprising floxuridine and dexamethasone continuously on days 1-14. Patients also receive oxaliplatin IV over 2 hours and irinotecan hydrochloride IV over 30 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: dexamethasone
Given by hepatic arterial infusion
Drug: floxuridine
Given by hepatic arterial infusion
Drug: irinotecan hydrochloride
Given IV
Drug: oxaliplatin
Given IV
Experimental: Group 2
Patients receive HAI therapy as in group 1. Patients also receive irinotecan hydrochloride IV over 30 minutes and leucovorin calcium IV over 30 minutes on days 1 and 15 and fluorouracil IV continuously over 48 hours on days 1, 2, 15, and 16. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: dexamethasone
Given by hepatic arterial infusion
Drug: floxuridine
Given by hepatic arterial infusion
Drug: fluorouracil
Given IV
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 and either oxaliplatin or leucovorin calcium/fluorouracil.

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.
  • Assess the expression pattern of tissue factor (TF) and explore its correlation with the TF receptors PAR-1, PAR-2, TF regulators PTEN, k-ras, b- raf, p53, and outcome.(Closed as of 11/30/10)
  • Assess the prognostic and predictive role of preoperative, pretreatment, and during treatment serum TF in regards to outcome (progression-free survival and overall survival) and response to treatment with this regimen and to salvage treatments such as EGFR-inhibitors.(Closed as of 11/30/10)

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 and irinotecan hydrochloride IV over 30 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 and leucovorin calcium IV over 30 minutes on days 1 and 15 and fluorouracil IV continuously over 48 hours on days 1, 2, 15, and 16. 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.

Some 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 levels.

After completion of study treatment, patients are followed every 3 months for 2 years, every 4 months for 3 years, and then annually thereafter.

  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
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Physically able to tolerate major partial hepatectomy
  • No active infection
  • No concurrent active malignancies, except potentially resectable primary colorectal tumor
  • 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 stroke or transient ischemic attack within the past 6 months
  • No concurrent obstruction of the gastrointestinal or genitourinary tract

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
  • 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
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: NCT00492999

Locations
United States, New Jersey
Memoral Sloan Kettering Cancer Center
Basking Ridge, New Jersey, United States
United States, New York
Memorial Sloan-Kettering Cancer Center @ Suffolk
Commack, New York, United States, 11725
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Memorial Sloan-Kettering at Mercy Medical Center
Rockville Centre, New York, United States
Memoral Sloan Kettering Cancer Center@Phelps Memorial Hospital
Sleepy Hollow, New York, United States
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
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:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00492999     History of Changes
Other Study ID Numbers: 06-075, MSKCC-06075
Study First Received: June 25, 2007
Last Updated: December 17, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
adenocarcinoma of the colon
adenocarcinoma of the rectum
liver metastases

Additional relevant MeSH terms:
Colorectal Neoplasms
Neoplasm Metastasis
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Irinotecan
Oxaliplatin
Camptothecin
Fluorouracil
Floxuridine
BB 1101
Levoleucovorin
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on October 19, 2014