Cetuximab, 5-FU and Radiation as Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer

The epidermal growth factor receptor (EGFR) present in normal and tumor cells is involved in
signaling pathways affecting cellular growth, differentiation, proliferation and programmed
cell death. Overexpression of EGFR has been associated with poorer prognosis in colorectal
cancer. Cetuximab targets and blocks EGFR and has been shown to be safe and effective in
treating colorectal cancer and head and neck cancers.

The primary hypothesis is that cetuximab in combination with standard 5-FU and radiation as
neoadjuvant therapy would improve pathological complete response (pCR) compared to the
historical rate (30% versus 10%). The regimen would be considered promising if 5 or more of
25 evaluable participants achieve pCR. The probability of observing this outcome is 0.91 and
0.10 if the true pCR rate is 30% and 10%, respectively.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the rectum that begins within 15cm of the
anal verge as determined by sigmoidoscopy and/or colonoscopy, with no evidence of
distant metastatic disease. A complete colonoscopy to the cecum is recommended prior
to initiating protocol therapy.

- Staging with transrectal ultrasound or endorectal coil Magnetic resonance imaging
(MRI) to confirm clinical stage of T3 or T4 or lymph node positive rectal
adenocarcinoma

- Tumor is K-ras wildtype by method of choice at respective institution (testing codons
12 and 13)

- Performance status: Eastern Cooperative Oncology Group Performance Score (ECOG PS)
less than or equal to 2

- 18 years of age or older

- No evidence of metastatic disease by abdominal/pelvic (Computed tomography) CT and
chest imaging

- Adequate bone marrow, renal,and hepatic function as outlined in protocol

- All patients will be evaluated by a surgeon and considered a candidate for definitive
surgery

- Coumadin or heparin management for line care of other indications is permitted. The
International Normalised Ratio (INR) will be monitored weekly in patients taking
coumadin.

Exclusion Criteria:

- Prior treatment for this malignancy

- Prior history of pelvic radiation therapy

- Prior history of 5-FU based or EGFR receptor inhibitor therapy

- Prior history of an allergic reaction to a monoclonal antibody

- Uncontrolled serious medical or psychiatric illness

- Significant history of uncontrolled cardiac disease

- Sexually active women of childbearing potential must use an effective method of birth
control during the course of the study

- Unwilling to agree to pre and post-cetuximab sigmoidoscopy and biopsy