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

Sponsor

Leiden University Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT01110785

Collaborator

(none)

Enrollment

Locations

11.5

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Biological: panitumumab Drug: simvastatin Other: laboratory biomarker analysis	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

46 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

Apr 1, 2010

Anticipated Primary Completion Date :

Apr 1, 2012

Outcome Measures

Primary Outcome Measures

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

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Reinier de Graaf Group - Delft	Delft	Netherlands	2625 AD
2	HagaZiekenhuis - Locatie Leyenburg	Den Haag	Netherlands	2545 CH
3	Leiden University Medical Center	Leiden	Netherlands	2333 ZA
4	Diaconessenhuis Leiden	Leiden	Netherlands	2334 CK