CLINICAL TRIAL: RADIATION THERAPY FOLLOWED BY SURGICAL RESECTION FOR RECTAL CANC

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the proposed study, we will combine Cetuximab (C225) with neoadjuvant chemoradiotherapy using Oxaliplatin, Capecitabine, and concomitant radiotherapy. The multiple mechanisms of antitumor activity associated with endothelial growth factor receptor (EGFR) inhibition present an opportunity for synergy with cytotoxic therapy. Cetuximab has demonstrated synergistic activity with platinums, Fluoropyrimidines and radiation in preclinical models. In addition, Cetuximab has already shown antitumor activity in colorectal cancer patients with advanced-stage disease as a single-agent as well as with Irinotecan in Irinotecan-refractory patients. While preoperative chemoradiotherapy has been studied combining Oxaliplatin with 5-FU/LV and radiotherapy, no trial has been performed to date substituting 5-FU/LV with Capecitabine in this regimen. Capecitabine provides convenient oral dosing, a favorable toxicity profile, and known activity in rectal cancer. Given the concern for potential overlapping toxicities such as diarrhea, asthenia, and skin changes, we propose a Phase I sequential dose-escalation trial of Oxaliplatin and Capecitabine with fixed-dose Cetuximab and radiotherapy to assess the safety and tolerability of this regimen. Once the maximally tolerated doses (MTD) of Oxaliplatin and Capecitabine have been established, a Phase II trial is then proposed to evaluate the antitumor activity of this regimen. During the Phase II portion of the study, patients will be randomly assigned to begin weekly Cetuximab on either day 1 (Group A) or day 8 (Group B). This stratification will allow for exploratory correlative immunohistochemical (IHC) studies to be performed to evaluate not only the effects of chemoradiotherapy, but also allow for observational analysis of the biological impact of EGFR inhibition upon chemoradiotherapy. All patients will undergo endoscopic staging with transrectal ultrasound and core-needle biopsy to obtain tissue for these IHC studies prior to beginning therapy. A repeat endoscopic core-needle biopsy will be performed on day 7 or 8 in all patients. An assessment of apoptosis and angiogenesis, the presumed mechanisms by which EGFR inhibition may enhance radiotherapy and induce tumor regression as well as downstream signaling pathways will be performed on serial biopsy specimens.