BAY 43-9006 Plus Cetuximab to Treat Colorectal Cancer

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.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically documented metastatic colorectal
cancer, which has recurred or progressed following at least one prior chemotherapy
regimen administered for the treatment of metastatic disease. The diagnosis should be
confirmed by the Laboratory of Pathology at the Clinical Center, NIH (National
Institutes of Health).

- Tumor should express epidermal growth factor receptor (EGFR), defined as any membrane
staining for EGFR in tumor cells by immunohistochemistry (IHC) done on archival tumor
blocks or slides.

- Tumor blocks or unstained slides from archival pathological specimen suitable for the
isolation of genomic DNA (deoxyribonucleic acid) must be available to determine the
status of mutations in KRAS in the tumor. (For the initial 13 evaluable patients
already enrolled and treated on this study, every effort will be made to re-acquire
these blocks from patients or their referring physicians for evaluation of KRAS.)

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal to 10 mm with spiral computed tomography (CT) scan.

- Patients must have received or been offered and declined at least one prior
Fluorouracil (5FU)-containing combination chemotherapy regimen for metastatic
disease, unless available chemotherapy regimens were for some reason contraindicated
for a particular patient. Patients who have received chemotherapy and/or biologic
therapy, excluding BAY 43-9006 or cetuximab, are eligible. This therapy must have
been completed greater than or equal to 4 weeks prior to enrollment on protocol, and
the patient must have recovered to eligibility levels from prior toxicity. Prior
radiation or surgery should have been completed greater than or equal to 4 weeks
prior to study enrollment and all associated toxicities resolved to eligibility
levels.

- Age greater than or equal to18 years. Colorectal cancer does not usually occur in
patients less than 18 years of age.

- Life expectancy greater than 3 months.

- ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1.

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/ microliter

- platelets greater than or equal to 100,000/ microliter

- total bilirubin less than or equal to 1.5 times the institutional upper limits of
normal

- AST (aspartate aminotransferase) (SGOT (serum glutamic oxaloacetic transaminase))/ALT
(alanine aminotransferase) (SGPT (serum glutamic pyruvic transaminase) less than or
equal to 2.5 times the institutional upper limit of normal

- creatinine less than or equal to 1.5 times the institutional upper limits of normal

OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m^2

- PT (prothrombin time)/PTT (partial thromboplastin time) less than or equal to 1.5
times the institutional upper limits of normal

- Patients must have at least one lesion amenable to biopsy, as determined by an
associate investigator after discussion with a member of the interventional radiology
team. This lesion should be different from target lesion(s) being followed on imaging
studies to evaluate response to treatment.

- The effects of the combination of BAY 43-9006 and cetuximab on the developing human
fetus at the recommended therapeutic doses are unknown. For this reason and because
raf kinase inhibitor agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration
of study participation, and for at least 2 months following completion of study.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent document
and the ability to comply with daily oral self administration schedule.

- Patients must have systolic blood pressure less than or equal to 150 mm Hg and
diastolic blood pressure less than or equal to 90 mmHg. Concomitant antihypertensive
medications to achieve control of blood pressure are allowed.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy, biologic therapy, or radiotherapy within 4 weeks
prior to entering the study or those who have not recovered to at least eligibility
levels from adverse events due to agents administered more than 4 weeks earlier.
Patients must be greater than or equal to 2 weeks since any investigational agent
administered as part of a Phase 0 study (also referred to as an early Phase I study
or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the PIs
(principal investigator's) discretion, and should have recovered to eligibility
levels from any toxicities

- Patients who have received any other investigational agents within 4 weeks prior to
entering the study or those who have not recovered to at least eligibility levels
from adverse events due to agents administered more than 4 weeks earlier.

- Patients with known brain metastases would be excluded from this clinical trial, with
the exception of patients whose brain metastatic disease status remains stable for
greater than or equal to 6 months after treatment of the brain metastases without
steroids or anti seizure medications. These patients may be enrolled at the
discretion of the principal investigator.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BAY 43-9006 (for example, other multi-targeted kinase inhibitors, such
as sunitinib) or cetuximab (for example, other drugs containing murine proteins, such
as bevacizumab) used in the study.

- Prior therapy with cetuximab or BAY 43-9006.

- Patients on therapeutic anticoagulation are excluded. Prophylactic anticoagulation
(i.e. low dose warfarin) of venous or arterial access devices is allowed provided
that the requirements for PT, INR (International normalized ratio) or PTT are met.

- Evidence of bleeding diathesis.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
serious infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, uncontrolled hypertension, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor
agent with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the
mother is treated with BAY 43-9006.

- Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral
therapy are excluded from this study due to the possibility of pharmacokinetic
interactions between anti-retroviral medications and BAY 43-9006. HIV positive
patients not receiving antiretroviral therapy are excluded due to the possibility
that BAY 43-9006 may worsen their condition and the likelihood that the underlying
condition may obscure the attribution of adverse events with respect to BAY 43-9006.

- History of another malignancy within the past 5 years, apart from adequately treated
non-melanoma skin cancers, superficial bladder cancer or in situ cervical cancer.

- Patients with conditions that would impair their ability to swallow tablets are
excluded.

- Use of the following medications will be not be allowed within 4 weeks prior to
enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir,
cyclosporine, carbamazepine, phenytoin, phenobarbital, rifampin, St. Johns Wort, and
prophylactic use of filgrastim and sargramostim. Products containing grapefruit juice
will not be allowed while on study. BAY 43-9006 tosylate is metabolized by the P450
CYP3A enzyme; therefore, it is possible that BAY 43-9006 tosylate may interact with
the above medications. Efforts should be made to switch patients who are taking
enzyme-inducing anticonvulsant agents to other medications.

- Patients in whom resection is indicated and can be performed safely (unless surgery
is declined by the patient for other reasons).

- For the optional PET/CT imaging with (89)Zr-panitumumab correlative study,
participants with severe claustrophobia not relieved by oral anxiolytic medication or
patients weighing > 136 kg (weight limit for scanner table).

Inclusion of Women and Minorities:

Both men and women and members of all races and ethnic groups are eligible for this trial.