BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

Phase 2

Completed

Conditions: Metastatic Colorectal Cancer

Interventions: Drug: Cetuximab
Drug: BAY 43-9006

Registration Number: NCT00326495

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 51

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BAY 43-9006 & Cetuximab	BAY 43-9006	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
BAY 43-9006 & Cetuximab	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

Primary Outcome Measures

Name	Time	Method
Overall Rate of Response	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.

Secondary Outcome Measures

Name	Time	Method
Count of Participants With Adverse Events	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.