Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is the standard of care in locally advanced rectal cancer (T3, T4 or N1). Sorafenib inhibits of ras/raf, PDFGR and VEGFR with synergistic activity with radiation (RT). This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound (EUS) and CT scan, were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45Gy) day 1-5 at all dose levels. Patients underwent surgery 6-10 weeks following neoadjuvant therapy. Results: 14 patients were enrolled at Moffitt Cancer Center, including 8 females and 6 males with a median age of 55 years (range: 40-72). After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. Following this, hypertension was the only G3 toxicity seen. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at the 400 mg PO BID dose level, and no grade IV toxicities were observed. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery. KRAS status was available for 10 patients. The pCR rate was 36% and downstaging was observed in 81.8% of patients. The pCR was 50% in those with KRAS mutant tumors (2/4 pts). Conclusions: After changing the dosing schedule, this regimen was very well tolerated. The pCR and downstaging rate of the tumor is encouraging. Accrual to the expansion cohort is ongoing. Clinical trial information: NCT01376453.