Know Cancer

forgot password

Phase II Simvastatin + Cetuximab/Irinotecan in K-ras Mutant Colorectal Cancer Patients Who Have Failed Irinotecan and Oxaliplatin-based Chemotherapy

Phase 2
18 Years
Not Enrolling
Metastatic Colorectal Cancer

Thank you

Trial Information

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.

Inclusion Criteria:

1. 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.

2. Ras mutation (+) (checked at the central lab)

3. At least one measurable tumor mass according to RECIST 1.1

4. Expected survival for approximately 12 weeks or longer

5. Karnofsky Performance Score (KPS) ≥ 70

6. Age ≥ 18 years

7. WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3

8. ANC ≥ 1,500 cells/mm3

9. Hemoglobin ≥ 10 g/dL (transfusion allowed)

10. Platelet count ≥ 100,000 plts/mm3

11. Total bilirubin ≤ 1.5ULN

12. AST, ALT ≤ 2.5 ULN (if liver metastases(+): AST,ALT ≤5.0 x ULN)

13. 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.

14. Written informed consent

Exclusion Criteria:

1. Prior simvastatin therapy within 1-year from the date of study entry

2. 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

3. Current, known CNS malignancy (history of completely resected or irradiated brain
metastases by WBRT or stereotactic radiosurgery allowed)

4. Patients with CPK > 5 x ULN at baseline

5. Patients with alcohol abuse

6. Uncontrolled hypothyroidism

7. Concomitant use with clarithromycin, erythromycin, itraconazole, ketoconazole,
nefazodone, telithromycin

8. Concomitant use of gemfibrozil, cyclosporine, danazol, amiodarone, verapamil

Type of Study:


Study Design:

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

Outcome Measure:

response rate

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Won Ki Kang, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Samsung Medical Center


Korea: Food and Drug Administration

Study ID:

SMC IRB 2010-08-006



Start Date:

November 2010

Completion Date:

December 2012

Related Keywords:

  • Metastatic Colorectal Cancer
  • Colorectal Neoplasms