Clinical trial NCT00326495
Conditions: Metastatic Colorectal Cancer
Keywords: Sorafenib Cetuximab Advanced Cancer Phase II Colorectal Cancer Colon Cancer Rectal Cancer CRC Metastatic Colorectal Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2006-05-10; Completion date: 2014-11-07
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief 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.

Detailed description:
Background:

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 receptor (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 Food and Drug Administration (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 (Kirsten rat sarcoma viral oncogene homolog) mutations as a mechanism of resistance to anti-EGFR antibody therapies such as cetuximab.

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.

Objectives:

To determine the rate of response (CR (complete response) +PR (partial response) +SD (stable disease) 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).

To evaluate for this combination treatment pharmacodynamics in tumor biopsies, 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 Fluorouracil (5FU)-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 intravenous (IV) weekly.

Optional PET (positron emission tomography) /CT (computed tomography) 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 Response Evaluation Criteria in Solid Tumor (RECIST) 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.

Patients will be stratified by tumor KRAS status (wild type vs. codon 12/13 mutation in KRAS).

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 dosimetry calculations.

If uptake into tumors is shown to be measurable in these first 5 patients, up to 15 subsequent

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.

Arms: arm 1: 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
Interventions: intervention 1: Cetuximab intervention 2: BAY 43-9006
Intervention descriptions: intervention 1: 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. intervention 2: Is a potent inhibitor of proto-oncogene c-Raf (c-raf), and wild-type and mutant proto-oncogene b-Raf (b-raf) in vitro

Protocol documents: