Simvastatin and Panitumumab in Treating Patients With Advanced or Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Simvastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving simvastatin together with panitumumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well simvastatin given together with panitumumab works in treating patients with advanced or metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: Primary To determine if the proportion (at least 40%) of patients with K-ras mutant-type advanced or metastatic colorectal cancer are free from progression and alive based on RECIST criteria version 1.1 at 11 weeks after the first administration of panitumumab (i.e., 12.5 weeks after the scan at baseline at start of simvastatin). To determine if these results are comparable with historical results of k-ras wild-type colorectal carcinoma patients treated with panitumumab. To evaluate clinical signs of progression (according to RECIST criteria) in patients treated with this regimen. Secondary To evaluate the safety of this regimen in these patients who have failed prior treatment with fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. To evaluate the overall survival of patients who are treated with this regimen and have failed prior fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. To evaluate the progression-free survival (based on RECIST criteria version 1.1) of these patients. To evaluate the objective response rate (based on RECIST criteria version 1.1) in these patients. To evaluate the correlation between skin toxicity and anti-tumor response in these patients. Tertiary (exploratory) To evaluate the role of serum cholesterol as a biomarker during treatment with panitumumab and simvastatin. To correlate levels of serum cholesterol with treatment response and other factors, until progression of disease occurs. To investigate whether PTEN, PIK3CA, b-raf, ERK, and MEK status correlate with response to panitumumab in these patients. To investigate the role of single nucleotide polymorphisms related to the efficacy and metabolism of panitumumab as a predictor for response to panitumumab. To investigate the role of proteomics (e.g., EGF) as potential predictive markers for response to panitumumab and as potential biomarkers during treatment with panitumumab. OUTLINE: This is a multicenter study. Patients receive oral simvastatin once daily on days 1-14 and panitumumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for biomarker and other analyses. After completion of study treatment, patients are followed for 30 days and then every 3 months thereafter.

Official Title
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Safety and Efficacy of the Addition of Simvastatin to Panitumumab in K-ras Mutant Advanced or Metastatic Colorectal Cancer Patients. A Single-Arm, Multicenter, Phase II Study Using a Simon Two Stage Design.

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: panitumumab
* Drug: simvastatin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of colorectal cancer Advanced or metastatic disease Failed prior fluorouracil-, oxaliplatin- and irinotecan-containing regimens In case of progressive disease within 6 months after start of adjuvant fluorouracil-, oxaliplatin-, and irinotecan-containing regimens, the adjuvant therapy is considered to be treatment for metastatic disease Mutant-type k-ras status (mutation in codon 12, 13, or 61) on tumor material Measurable disease according to RECIST criteria version 1.1 Progressive disease in the past 3 months according to RECIST criteria version 1.1 No symptomatic brain metastases, defined as any symptoms during the past 6 months PATIENT CHARACTERISTICS: WHO performance status 0-2 WBC ≥ 2.0 x 10^9/L ANC ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Hemoglobin ≥ 9 g/dL Serum bilirubin ≤ 1.5 times upper limit of normal (ULN) AST/ALT ≤ 3 times ULN (≤ 5 times ULN in case of liver metastases) Creatinine clearance ≥ 60 mL/min Magnesium normal Calcium normal Creatine phosphokinase ≤ 2.5 times ULN Not pregnant or nursing Not planning to become pregnant within 6 months after the end of study treatment Fertile patients must use highly effective contraception during and for 6 months after completion of study therapy No noncompliance in previous studies No alcohol use > 4 units/day or unwilling to abstain from use No history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or signs of interstitial lung disease on baseline CT scan No clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, or serious uncontrolled cardiac arrhythmia) < 1 year prior to study No symptomatic hypothyroidism No history of toxicity during statin use PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior EGFr-therapy, including monoclonal antibodies (e.g., panitumumab or cetuximab) No concurrent verapamil, amiodarone, or dronedarone or unwilling to abstain from use

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: panitumumab|nan|
|Drug: simvastatin|nan|
|Other: laboratory biomarker analysis|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients free from progression and alive at 11 weeks after the first dose of panitumumab measured by RECIST v 1.1 |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity measured by NCICTC v 3.0 |  |  | 
| Median and mean overall survival |  |  | 
| Median and mean progression-free survival |  |  | 
| Objective response rate |  |  | 
| Correlation between skin toxicity and response to treatment |  |  | 
| Serum cholesterol and subsequent treatment response |  |  | 
| Correlation between PTEN, PIK3CA, b-raf, ERK, and MEK status and objective response rate |  |  | 
| Correlation between single nucleotide polymorphisms and objective response rate |  |  | 
| Correlation between proteomics and objective response rate |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent colon cancer, stage III colon cancer, stage IV colon cancer, recurrent rectal cancer, stage III rectal cancer, stage IV rectal cancer