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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01281761
Recruitment Status : Completed
First Posted : January 24, 2011
Last Update Posted : June 14, 2013
Information provided by (Responsible Party):
Won Ki Kang, Samsung Medical Center

Brief Summary:
Based on the results from preclinical study, the investigators suggest that the addition of simvastatin at a dose of cardiovascular use (40 ~ 80 mg qd daily) may overcome cetuximab resistance in KRAS mutant colorectal cancer via B-Raf protein degradation and inducing Bim and Bad. Given the result of a phase II FOLFIRI plus cardiovascular dose of simvastatin (80mg qd daily) and this study, phase II study of conventional cetuximab treatment with 40 mg simvastatin is planned in metastatic colorectal cancer patients with KRAS mutation.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: cetuximab/irinotecan/simvastatin Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Simvastatin + Cetuximab/Irinotecan in K-ras Mutant Colorectal Cancer Patients Who Have Failed Irinotecan and Oxaliplatin-based Chemotherapy
Study Start Date : November 2010
Actual Primary Completion Date : September 2012
Actual Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: cetuximab/irinotecan/simvastatin

D1 Cetuximab 500mg/m2 IV stepwise shortened infusion duration- [C1D1 over 120min, C2D1 over 90min,subsequent dose over 60min] D1 Irinotecan 150-180mg/m2 + Dextrose 5% 500ml IV [over 90min] D1-14 Simvastatin 80mg P.O(continuous, daily)

  • every 2weeks
Drug: cetuximab/irinotecan/simvastatin
D1 Cetuximab 500mg/m2 IV stepwise shortened infusion duration- [C1D1 over 120min, C2D1 over 90min,subsequent dose over 60min] D1 Irinotecan 150-180mg/m2 + Dextrose 5% 500ml IV [over 90min] D1-14 Simvastatin 80mg P.O(continuous, daily) every 2weeks

Primary Outcome Measures :
  1. response rate [ Time Frame: 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01281761

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Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of, 135-710
Sponsors and Collaborators
Samsung Medical Center
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Principal Investigator: Won Ki Kang, MD Samsung Medical Center

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Responsible Party: Won Ki Kang, Professor, Samsung Medical Center Identifier: NCT01281761     History of Changes
Other Study ID Numbers: SMC IRB 2010-08-006
First Posted: January 24, 2011    Key Record Dates
Last Update Posted: June 14, 2013
Last Verified: June 2013
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological
Anticholesteremic Agents
Hypolipidemic Agents
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors