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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Colorectal Cancer, Metastatic Cancer

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Resectability rate

Outcome Time Frame:

2 years

Safety Issue:

No

Principal Investigator

Michael D'Angelica, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

06-075

NCT ID:

NCT00492999

Start Date:

May 2007

Completion Date:

May 2013

Related Keywords:

  • Colorectal Cancer
  • Metastatic Cancer
  • recurrent colon cancer
  • stage IV colon cancer
  • recurrent rectal cancer
  • stage IV rectal cancer
  • adenocarcinoma of the colon
  • adenocarcinoma of the rectum
  • liver metastases
  • Colorectal Neoplasms
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Memoral Sloan Kettering Cancer CenterBasking Ridge, New Jersey  
Memorial Sloan-Kettering Cancer Center @ SuffolkCommack, New York  11725
Memoral Sloan Kettering Cancer Center@Phelps Memorial HospitalSleepy Hollow, New York  
Memorial Sloan-Kettering at Mercy Medical CenterRockville Centre, New York