Phase II Simvastatin + Cetuximab/Irinotecan in K-ras Mutant Colorectal Cancer Patients Who Have Failed Irinotecan and Oxaliplatin-based Chemotherapy
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor leading
to inhibition of post-translational modification of small G proteins. Mevalonate-derived
prenyl groups, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP),
facilitate essential intracellular functions of various proteins such as Ras and Rho. Owing
to its effect on post-transcriptional modifications of Ras and Rho, the anti-tumor effect of
statins has been suggested in various cancer cell lines. However, more recent studies
utilizing cancer gene signatures have systematically screened an array of drugs for
potential anti-tumor effect and have discovered statins as potential novel targeted agent
against cancer. Given the cardiovascular therapeutic dose is 1 mg/kg/day which translates
into serum level of 0.1 uM in patients, the investigators have previously tested and
reported that low dose lovastatin ranging from nanomolar to 0.3- 1 uM statin induced cell
senescence or cytostatic effect of prostate cancer cells in vitro. In addition, the
investigators previously reported on well tolerability and promising anti-tumor effect of
combination of simvastatin 40 mg daily and standard FOLFIRI (irinotecan, infusional
5-fluorouracil, leucovorin) in metastatic colorectal cancer.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
response rate
12 months
No
Won Ki Kang, MD
Principal Investigator
Samsung Medical Center
Korea: Food and Drug Administration
SMC IRB 2010-08-006
NCT01281761
November 2010
December 2012
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