BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer
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|ClinicalTrials.gov Identifier: NCT00326495|
Recruitment Status : Completed
First Posted : May 17, 2006
Results First Posted : August 7, 2015
Last Update Posted : July 24, 2017
- 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.
- 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.
- 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.
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: Cetuximab Drug: BAY 43-9006||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||51 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study of BAY 43-9006 (Sorafenib) in Combination With Cetuximab (Erbitux ) in EGFR Expressing Metastatic Colorectal Cancer (CRC)|
|Actual Study Start Date :||May 10, 2006|
|Actual Primary Completion Date :||November 5, 2014|
|Actual Study Completion Date :||November 7, 2014|
Experimental: BAY 43-9006 & Cetuximab
BAY 43-9006: Administered orally at a dose of 400 mg twice a day (BID). Cetuximab will be given intravenously (IV) at a dose of 400 mg/m^2 initially as a loading dose on week 2, followed by 250 mg/m^2 weekly starting on week 3
Cetuximab is a recombinant human/mouse chimeric monoclonal antibody which binds specifically to the extracellular domain of the epidermal growth factor receptor (epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 1 (HER1), c-ErbB) in normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.
Other Name: Erbitux
Drug: BAY 43-9006
Is a potent inhibitor of proto-oncogene c-Raf (c-raf), and wild-type and mutant proto-oncogene b-Raf (b-raf) in vitro
Other Name: Sorafenib
- Overall Rate of Response [ Time Frame: 4 months ]Rate of response is defined as the percentage of participants with a complete response (CR) + partial response (PR) + stable disease (SD) for 4 months. Response is defined by the Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Complete response is a disappearance of all target lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease), taking as reference the smallest sum LD since the treatment started. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
- Count of Participants With Adverse Events [ Time Frame: 96 months, 26 days ]Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00326495
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Shivaani Kummar, M.D.||National Cancer Institute (NCI)|