A Phase II Study of BAY 43-9006 (Sorafenib) in Combination With Cetuximab (Erbitux(Trademark)) in EGFR Expressing Metastatic Colorectal Cancer (CRC)
Colorectal cancer (CRC) is a major public health problem; 5-year survival with widespread
metastatic disease is less than 5%. Expression of epidermal growth factor (EGFR) or
up-regulation of the gene occurs in 60-80% of cases. Therapies targeting EGFR, like
cetuximab, have shown activity in the treatment of solid tumors like CRC.
Cetuximab is FDA approved for the treatment of EGFR-expressing CRC, but clinical responses
to cetuximab are seen in only 10% of EGFR-expressing CRC. Recent data strongly implicate
KRAS mutations as a mechanism of resistance to anti-EGFR antibody therapies such as
Another major pathway implicated in colon carcinogenesis is the vascular endothelial growth
factor (VEGF) pathway, which is involved in angiogenesis and is a validated target for
therapy in CRC. BAY 43-9006 is both a Raf kinase inhibitor and an inhibitor of VEGF receptor
(VEGFR2) tyrosine kinase.
We hypothesize that the combined inhibition of EGFR, VEGFR2, and the Ras-Raf pathway will
demonstrate promising clinical activity in CRC; furthermore, in patients with mutant KRAS,
combination of cetuximab with a drug that inhibits Raf kinase and acts downstream of Ras
mutations, could restore tumor sensitivity to cetuximab.
To determine the rate of response (CR+PR +SD for 4 months for patients with KRAS mutations
and CR + PR+SD for 6 months for patients with wild type KRAS) and toxicity profile of
combination of BAY 43-9006 and cetuximab in previously treated EGFR-expressing metastatic
CRC in patients with either wild type or mutant KRAS.
To evaluate BAY 43-9006 pharmacokinetics & pharmacogenomics (CYP3A4/5).
To evaluate for this combination treatment pharmacodynamics in tumor biopsies, effect on
tumor vascularity, and effect on angiogenic cytokines.
Adults with histologically or cytologically documented, measurable, EGFR-expressing
metastatic CRC, which has recurred or progressed following at least one prior 5FU-based
combination chemotherapy regimen administered for the treatment of metastatic disease.
Patients must have one lesion amenable to biopsy.
BAY 43-9006 will be administered 400 mg by mouth twice daily to patients stratified by KRAS
tumor status. Cetuximab will be administered as 400 mg/m2 loading dose (week 1) followed by
250 mg/m(2) IV weekly.
Optional PET/CT imaging with (89)Zr-labeled, EGFR-targeting antibody panitumumab may be
performed to evaluate radiation dosimetry, safety, and tumor distribution prior to and
following treatment with study agents.
Patients will be evaluated for response every 8 weeks using the RECIST criteria.
This trial uses a phase II optimal design targeting a response rate as defined above of 20%
in patients with mutant KRAS and 45% with wild type KRAS. Up to 66 patients may be treated.
Patients will be stratified by tumor KRAS status (wild type vs. codon 12/13 mutation in
Optional correlative (89)Zr-panitumumab PET/CT imaging may be performed in up to 20
participants. For the first 5 patients, (89)Zr-panitumumab will be administered at baseline
(within 10 days prior to starting cetuximab). PET/CT imaging will be performed up to 4
times: 2-6 hours following (89)Zr-panitumumab injection, 1-3 days following injection, 7-8
days following injection, and at the end of cycle 1/beginning of cycle 2, to obtain human
If uptake into tumors is shown to be measurable in these first 5 patients, up to 15
patients will be administered (89)Zr-panitumumab before cetuximab infusion (within 10 days
prior to starting cetuximab) and have one PET/CT scan prior to the initial cetuximab
infusion and a second (89)Zr-panitumumab infusion and scan at the end of cycle 1/beginning
of cycle 2 (not shown in schema).
A diary will be provided for subjects to record taking study medication and side effects.
Masking: Open Label, Primary Purpose: Treatment
Response rate, safety, and toxicity measured by two sample t-test or Wilcoxon rank sum test.
Shivaani Kummar, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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