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

Colorectal Cancer Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01110785
• Other study ID #: CDR0000671002
• Secondary ID: DUT-LUMC-3001200
• Status: Recruiting
• Phase: Phase 2
• First received: April 23, 2010
• Last updated: September 16, 2013
• Start date: April 2010

Study information

• Verified date: April 2011
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 46
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• panitumumab

Drug:
• simvastatin

Other:
• laboratory biomarker analysis

Locations

Country	Name	City	State
Netherlands	Reinier de Graaf Group - Delft	Delft
Netherlands	HagaZiekenhuis - Locatie Leyenburg	Den Haag
Netherlands	Diaconessenhuis Leiden	Leiden
Netherlands	Leiden University Medical Center	Leiden

Sponsors (1)

Lead Sponsor	Collaborator
Leiden University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients free from progression and alive at 11 weeks after the first dose of panitumumab measured by RECIST v 1.1			No
Secondary	Toxicity measured by NCICTC v 3.0			Yes
Secondary	Median and mean overall survival			No
Secondary	Median and mean progression-free survival			No
Secondary	Objective response rate			No
Secondary	Correlation between skin toxicity and response to treatment			No
Secondary	Serum cholesterol and subsequent treatment response			No
Secondary	Correlation between PTEN, PIK3CA, b-raf, ERK, and MEK status and objective response rate			No
Secondary	Correlation between single nucleotide polymorphisms and objective response rate			No
Secondary	Correlation between proteomics and objective response rate			No