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BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

NCT00326495 · Status: COMPLETED · Phase: PHASE2 · Type: INTERVENTIONAL · Enrollment: 51

Last updated 2017-07-24

Study results available
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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.

Conditions

Interventions

DRUG

Cetuximab

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.

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

Sponsors & Collaborators

  • National Cancer Institute (NCI)

    lead NIH

Principal Investigators

  • Shivaani Kummar, M.D. · National Cancer Institute (NCI)

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2006-05-10
Primary Completion
2014-11-05
Completion
2014-11-07
FDA Drug
Yes

Countries

  • United States

Study Locations

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Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT00326495 on ClinicalTrials.gov