19030 Background: Bortezomib is a proteasome inhibitor that augments EGFR inhibitor activity. Cetuximab is a mouse-human antibody against EGFR that has been found to induce tumor responses in patients with colon cancer and head and neck cancer. The purpose of this study was to establish a maximum tolerated dose (MTD) for the combination of bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumors. Methods: A 21-day treatment cycle was given with a maximum of six cycles per patient. Bortezomib was administered intravenously on days 1 and 8. Dose escalation consisted of eight dose levels beginning with a minimum bortezomib dose of 1.3 mg/m2 and increasing in one-tenth increments to 2.0 mg/m2. Cetuximab was delivered with an initial dose of 400mg/m2 on day 1 cycle 1, followed by a dose of 250mg/ m2 on days 8 and 15. For subsequent cycles, cetuximab was delivered at a dose of 250mg/ m2 on days 1, 8 and 15. Results: Thirty-one patients (19 male and 12 female) with an ECOG PS <2 were enrolled in this study from November 2005 to September 2007. The median age was 56 (range 31–68). Median number of prior chemotherapy regimens was 3 (range 0–7). Primary tumor sites included lung (13), head and neck (6), kidney (4), pancreas (3) bladder (2), skin (1), esophagus (1) and ovary (1). A total of 88 cycles were administered, with a median number of cycles per patient of 2 (range 1–6). One dose-limiting (DLT) grade 3 gastrointestinal (CTCAE 3.0) toxicity was seen at dose level 4. No further grade 3 or 4 toxicity was observed at dose level 4 or higher doses. Grade 3 or 4 toxicities included mucositis (n=1), back pain (n=1), carotid artery hemorrhage (n=1), flu-like syndrome (n=1), fatigue (n=5), dehydration (n=3), elevated creatinine (n=1), electrolyte abnormalities (n=2), gastrointestinal (n=6), cellulitis (n=2), muscle weakness (n=1), dyspnea (n=3), pulmonary embolism(n=1), neuropathy (n=1), syncope (n=1), hypotension (n=1) and bacteremia (n=1). Conclusions: MTD for bortezomib plus cetuximab was not achieved at the highest dose levels of bortezomib tested. This regimen has shown moderate clinical activity as measured by progression free survival in extensively pretreated patients with non-small cell lung cancer and warrants further investigation. No significant financial relationships to disclose.