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Phase II Study of Simvastatin Plus Irinotecan, Fluorouracil, and Leucovorin(FOLFIRI) for Metastatic Colorectal Cancer

Phase 2
18 Years
Not Enrolling
Colorectal Cancer, Metastasis

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Trial Information

Phase II Study of Simvastatin Plus Irinotecan, Fluorouracil, and Leucovorin(FOLFIRI) for Metastatic Colorectal Cancer

Progress in treatment for metastatic CRC has undoubtedly been achieved in the past decade.
Until 1985, 5-fluorouracil (5-FU) was the only agent available for the treatment of
metastatic CRC. Several trials have attempted to enhance the activity of bolus 5-FU, by the
addition of levamisole or interferon. Despite of these attempts, no survival advantage was
established until the introduction of the newer cytotoxic drugs. The addition of folinic
acid (FA) to 5-FU, the use of infusional rather than bolus 5-FU, and the combination of new
active agents such as irinotecan and oxaliplatin with 5-FU/FA have resulted in an increase
in activity of 5-FU. In trials of current combination regimens as first-line therapy,
response rates exceeding 30% and median survival duration longer than 16 months have been
reported. In all, despite of rapid advances in the treatment of metastatic CRC during the
last decade, the efficacy of treatment still needs to be improved. One potential way of
increasing the survival of metastatic CRC patients is the introduction of a novel targeting
agent to the standard cytotoxic regimen such as IFL (irinotecan, fluorouracil, and
leucovorin). An increasingly recognized molecular target for anticancer treatment is the
rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase. The end products of the mevalonate pathway are required for a number
of essential cellular functions such as sterols for membrane integrity, ubiquinone for cell
respiration, geranylgeranyl isoprenoids for covalent bindings to the ras family, dolichol
for glycoprotein synthesis, and isopentenyladenine for tRNA function and protein synthesis.
Fortunately, inhibitors of the key enzyme, the statins, are well established and have been
used safely in the clinic for the treatment of hypercholesterolemia for decades. Therefore,
HMG-CoA reductase may be a decent molecular target for anti-cancer therapy and statins may
be readily applicable to the clinic once its potential role as an anticancer drug is
established. The statins have recently gained attractions from medical oncologists because
large retrospective analyses for efficacy trials of statins in coronary artery disease have
shown that not only are these agents able to reduce cardiac disease-related mortality, but
cancer incidence is also reduced by 28 - 33 %.

In all, further clinical trials investigating on combining the standard treatment with these
novel molecular targeting agents, the statins, are definitely warranted.

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic colorectal cancer

2. Age ≥ 18

3. ECOG performance status 0 - 2

4. At least one measurable lesion

5. Minimum life expectancy of 12 weeks

6. Adequate bone marrow reservoir (ANC ≥ 1500/㎕, platelet ≥ 100,000/㎕)

7. Adequate renal function (serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50

8. Adequate liver functions (serum bilirubin ≤ 1.5 mg/dl, AST/ALT ≤ 3 times upper normal

9. No prior lipid-lowering therapy with statins less than 1 year before study entry

10. No prior chemo- or immunotherapy for metastatic CRC (adjuvant chemotherapy or
chemoradiation therapy more than 6 months before study entry is permitted)

11. Written informed consent

Exclusion Criteria:

1. Active infection requiring antibiotics therapy

2. Pregnancy and/or lactation

3. Other serious illness or medical condition not appropriate for chemotherapy,
especially cardiovascular disease

4. Metastatic brain lesions

5. Receipt of radiotherapy within 2 weeks before the initiation of study treatment

Type of Study:


Study Design:

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

Outcome Measure:

overall response rate

Principal Investigator

Won Ki Kang, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Samsung Medical Center


Korea: Food and Drug Administration

Study ID:

SMC IRB 2005-08-011



Start Date:

September 2005

Completion Date:

August 2007

Related Keywords:

  • Colorectal Cancer
  • Metastasis
  • colorectal cancer
  • metastatic
  • Colorectal Neoplasms
  • Neoplasm Metastasis