A Phase II Study of BAY 43-9006 (Sorafenib) in Combination With Cetuximab (Erbitux ) in EGFR Expressing Metastatic Colorectal Cancer (CRC)

Background:

• Colorectal cancer (CRC) is a major public health problem in the U.S. and worldwide, and 5-year survival with widespread metastatic disease is less than 5%.
• Expression of epidermal growth factor receptor (EGFR) or up-regulation of the gene occurs in the majority of CRC cases (60-80%).
• Therapies targeting EGFR, like cetuximab, have shown activity in the treatment of solid tumors like CRC.
• Cetuximab is FDA (Food and Drug Administration) approved for the treatment of EGFR-expressing CRC, but clinical responses to cetuximab are seen in only 10% of EGFR-expressing CRC.
• One possible mechanism of resistance to cetuximab could be KRAS (Kirsten rat sarcoma) mutations.
• 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-(rapidly accelerated fibrosarcoma) 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.

Objectives:

• To determine the rate of response (complete response (CR) + partial response (PR) + stable disease (SD) for 4 months) and toxicity profile of combination of BAY 43-9006 and cetuximab in previously treated EGFR-expressing metastatic CRC in patients with mutant KRAS.
• To evaluate BAY 43-9006 pharmacokinetics & pharmacogenomics (CYP3A4/5 (cytochrome P450 3A4/5)).
• To evaluate for this combination treatment pharmacodynamics, effect on tumor vascularity and effect on angiogenic cytokines.

Eligibility:

• Adults with histologically or cytologically documented, measurable, EGFR-expressing metastatic CRC, which has recurred or progressed following at least one prior 5FU (Fluorouracil)-based combination chemotherapy regimen administered for the treatment of metastatic disease.
• Patients must be KRAS mutation-positive.

Design:

• BAY 43-9006 will be administered 400 mg by mouth twice daily
• Cetuximab will be administered as 400 mg/m^2 loading dose (week 1) followed by 250 mg/m^2 IV (intravenous) weekly.
• If procedure may be performed safely, tumor biopsy will be obtained prior to treatment and after 4 weeks of treatment.
• Optional positron emission tomography (PET)/computerized tomography (CT) imaging with 89Zr-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 (Response Evaluation Criteria in Solid Tumors) criteria.
• This trial uses a phase II optimal design targeting a response rate as defined above of 20% in patients with mutant KRAS. Up to 49 patients may be treated.