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

Primary Purpose

Metastatic Colorectal Cancer

Status

Completed

Phase

Phase 2

Locations

Korea, Republic of

Study Type

Interventional

Intervention

cetuximab/irinotecan/simvastatin

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Samsung Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

cetuximab/irinotecan/simvastatin

Arm Description

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

Outcomes

Primary Outcome Measures

response rate

Secondary Outcome Measures

Full Information

NCT ID

NCT01281761

First Posted

January 20, 2011

Last Updated

June 12, 2013

Sponsor

Samsung Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT01281761

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2013

Overall Recruitment Status

Completed

Study Start Date

November 2010 (undefined)

Primary Completion Date

September 2012 (Actual)

Study Completion Date

December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Samsung Medical Center

4. Oversight

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Colorectal Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

52 (Actual)

8. Arms, Groups, and Interventions

Arm Title

cetuximab/irinotecan/simvastatin

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

cetuximab/irinotecan/simvastatin

Intervention Description

Primary Outcome Measure Information:

Title

response rate

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Won Ki Kang, MD

Organizational Affiliation

Samsung Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Samsung Medical Center

City

Seoul

ZIP/Postal Code

135-710

Country

Korea, Republic of

12. IPD Sharing Statement

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

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