Clinical trial NCT01110785: Simvastatin and Panitumumab in Treating Patients With Advanced or Metastatic Colorectal Cancer
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: recurrent colon cancer
stage III colon cancer
stage IV colon cancer
recurrent rectal cancer
stage III rectal cancer
stage IV rectal cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-04-27
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of patients free from progression and alive at 11 weeks after the first dose of panitumumab measured by RECIST v 1.1
Secondary outcomes:
measure: Toxicity measured by NCICTC v 3.0
measure: Median and mean overall survival
measure: Median and mean progression-free survival
measure: Objective response rate
measure: Correlation between skin toxicity and response to treatment
measure: Serum cholesterol and subsequent treatment response
measure: Correlation between PTEN, PIK3CA, b-raf, ERK, and MEK status and objective response rate
measure: Correlation between single nucleotide polymorphisms and objective response rate
measure: Correlation between proteomics and objective response rate
Other outcomes:
Locations:
city: Delft
country: Netherlands
facility: Reinier de Graaf Group - Delft
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis - Locatie Leyenburg
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Leiden
country: Netherlands
facility: Diaconessenhuis Leiden
Study officials:
affiliation: Leiden University Medical Center
name: Hans Gelderblom, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: