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

Purpose

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	Intervention	Phase
Metastatic Colorectal Cancer	Drug: cetuximab/irinotecan/simvastatin	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Colorectal Cancer

Drug Information available for: Simvastatin Irinotecan Irinotecan hydrochloride Cetuximab

U.S. FDA Resources

Further study details as provided by Samsung Medical Center:

Primary Outcome Measures:

response rate [ Time Frame: 12 months ] [ Designated as safety issue: No ]


Enrollment:	52
Study Start Date:	November 2010
Study Completion Date:	December 2012
Primary Completion Date:	September 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01281761

Locations


Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of, 135-710

Sponsors and Collaborators

Samsung Medical Center

Investigators


Principal Investigator:	Won Ki Kang, MD	Samsung Medical Center

More Information


Responsible Party:	Won Ki Kang, Professor, Samsung Medical Center
ClinicalTrials.gov Identifier:	NCT01281761 History of Changes
Other Study ID Numbers:	SMC IRB 2010-08-006
Study First Received:	January 20, 2011
Last Updated:	June 12, 2013
Health Authority:	Korea: Food and Drug Administration

Additional relevant MeSH terms:


Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases Simvastatin Irinotecan	Camptothecin Cetuximab Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors Antineoplastic Agents, Phytogenic Antineoplastic Agents Topoisomerase I Inhibitors Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on September 26, 2016