Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Sorafenib and Cetuximab in Treating Patients With Metastatic Colorectal Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Biomarker/Laboratory analysis, Treatment Temporarily closed 18 and over NCI NCI-06-C-0164 NCI-7416, NCI-P6821, 7416, NCT00343772

Special Category: NCI Web site featured trial

Objectives

Primary

1. Determine the response rate (partial and complete) in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer and wild type or mutant KRAS tumor treated with sorafenib and cetuximab.
2. Determine the safety and tolerability of this regimen in these patients.

Secondary

1. Examine the biochemical modulation of EGFR, Ras-Raf-mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor receptor (VEGFR) signal transduction pathways in tumors after treatment and correlate these results with response to treatment and tumor KRAS status in these patients.
2. Evaluate dynamic contrast-enhanced (DCE)-MRI and fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scan to determine early changes in tumor vascularity.
3. Determine the progression-free survival, defined as the duration of time from start of treatment to time of progression, of patients treated with this regimen.
4. Evaluate the pharmacokinetics of this regimen in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed metastatic colorectal cancer
  • Evidence of disease recurrence or progression after ≥ 1 prior chemotherapy regimen administered for the treatment of metastatic disease



• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan



• At least 1 lesion amenable to biopsy that is not a target lesion being followed on imaging studies to evaluate response to treatment



• Expression in tumor cells of epidermal growth factor receptor (EGFR)



• Must have tumor blocks or unstained slides from an archival pathological specimen suitable for isolation of genomic DNA



• Must have received OR been offered and declined ≥ 1 prior fluorouracil-containing combination chemotherapy regimen for metastatic disease unless available chemotherapy regimens were contraindicated



• Not eligible for or refused tumor resection



• No known brain metastases unless stable for ≥ 6 months without anticonvulsant or steroid therapy

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
• At least 4 weeks since prior chemotherapy, biologic therapy, radiotherapy, or surgery
• At least 4 weeks since prior investigational agents
  • At least 2 weeks since prior investigational agents administered as part of a phase 0 study
• At least 4 weeks since prior and no concurrent ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital, rifampin, Hypericum perforatum (St. John's wort), or prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
• No prior sorafenib or cetuximab
• No concurrent products containing grapefruit juice
• No concurrent therapeutic anticoagulation
  • Concurrent prophylactic anticoagulation (e.g., low-dose warfarin) of venous or arterial access devices allowed provided the requirements for PT, INR, or PTT are met
• No other concurrent investigational or anticancer therapies or agents
• Concurrent antihypertensive medication to achieve control of blood pressure allowed

Patient Characteristics:

• ECOG performance status 0-1
• Life expectancy > 3 months
• Platelet count ≥ 100,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• PT/PTT ≤ 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception before, during, and for at least 2 months after completion of study treatment
• Systolic blood pressure ≤ 150 mm Hg and diastolic blood pressure ≤ 90 mm Hg
• Able to swallow tablets
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib (e.g., other multitargeted kinase inhibitors, such as sunitinib) or cetuximab (e.g., other drugs containing murine proteins, such as bevacizumab)
• No evidence of bleeding diathesis
• No uncontrolled illness including, but not limited to, any of the following:
  • Ongoing or active serious infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled hypertension
  • Psychiatric illness or social situation that would preclude compliance with study requirements
• No known HIV positivity
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer, superficial bladder cancer, or in situ cervical cancer

Expected Enrollment

A total of 66 patients will be accrued for this study.

Outcomes

Response rate, safety, and toxicity measured by two sample t-test or Wilcoxon rank sum test

Progression-free survival measured by Kaplan-Meier curve

Outline

Patients receive oral sorafenib twice daily on days 1-28 and cetuximab IV over 1-2 hours once on days 1, 8, 15, and 22. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients are stratified according to tumor KRAS status (wild type vs codon 12/13 mutation in KRAS).

Blood samples are collected periodically and examined for biomarkers by enzyme immunoassay. These include angiogenesis markers (vascular endothelial growth factor [VEGF], basic fibroblast growth factor [b-FGH], and hepatocyte growth factor [FGH]), cytokines (interleukin-6 and -8), and carcinoembryonic antigen (CEA). Pharmacokinetic and pharmacogenomic (CYP3A4*1B and CYP3A5*3C polymorphisms) analyses are also conducted.

Tumor tissue collected prior to and during study treatment and at disease progression is analyzed for KRAS and BRAF mutations. Tissue is examined by pharmacoproteomic analysis and immunohistochemistry.

After completion of study treatment, patients are followed for 4 weeks.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Shivaani Kummar, MD, Principal investigator		Ph: 301-435-5402 Email: kummars@exchange.nih.gov

Related Information

Web site for additional information
Featured Trial Article

Registry Information
Official Title		A Phase II Study of BAY 43-9006 (Sorafenib) in Combination With Cetuximab (Erbitux) in EGFR Expressing Metastatic Colorectal Cancer
Trial Start Date		2006-05-19
Trial Completion Date		2007-10-31 (estimated)
Registered in ClinicalTrials.gov		NCT00343772
Date Submitted to PDQ		2006-05-12
Information Last Verified		2008-09-02

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