Simvastatin + Cetuximab/Irinotecan in K-ras Mutant Colorectal Cancer (CRC)

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.

Inclusion criteria

• Histologically-confirmed, advanced/metastatic colorectal carcinoma Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (last regimen has to be irinotecan-based chemotherapy; To be eligible, patients must also have received one of several qualifying, irinotecan regimens for at least 6 weeks and must have had documented progression of disease during receipt of this regimen or within six months thereafter.
• Ras mutation (+) (checked at the central lab)
• At least one measurable tumor mass according to RECIST 1.1
• Expected survival for approximately 12 weeks or longer
• Karnofsky Performance Score (KPS) ≥ 70
• Age ≥ 18 years
• WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3
• ANC ≥ 1,500 cells/mm3
• Hemoglobin ≥ 10 g/dL (transfusion allowed)
• Platelet count ≥ 100,000 plts/mm3
• Total bilirubin ≤ 1.5ULN
• AST, ALT ≤ 2.5 ULN (if liver metastases(+): AST,ALT ≤5.0 x ULN)
• Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic or have a screening random glucose > 160 mg/dL, a fasting glucose must be done and patients must be WNL or Grade 1 in order to be eligible for the study.
• Written informed consent

Exclusion criteria

• Prior simvastatin therapy within 1-year from the date of study entry
• Severe or unstable cardiac disease, including (for example) coronary artery disease requiring increased doses of anti-anginal mediation and/or coronary angioplasty (including stent placement) within the preceding 24 months
• Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed)
• Patients with CPK > 5 x ULN at baseline
• Patients with alcohol abuse
• Uncontrolled hypothyroidism
• Concomitant use with clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, telithromycin
• Concomitant use of gemfibrozil, cyclosporine, danazol, amiodarone, verapamil