BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer
Status:
Completed
Trial end date:
2014-11-07
Target enrollment:
Participant gender:
Summary
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.