Background: The standard of care in locally advanced rectal cancer (T3, T4, or N1) is preoperative treatment with fluoropyrimidine-based chemotherapy. Sorafenib works synergistically with radiation (RT), and inhibits ras/raf, PDFGR and VEGFR. 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 confirmed stage II or III rectal cancer 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 (45 Gy) day 1-5 at all dose levels. 6-10 weeks following neoadjuvant therapy, patients underwent surgery. Results: 17 patients were enrolled at Moffitt Cancer Center, including 10 females and 7 maleswith a median age of 54years (range: 31-72).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, the primary G3 toxicity was hypertension, in 2 patients at 200 mg adjusted DL (day 1-5) and 1 patient at the 400 mg PO BID DL. 1 patient had G3 ALT elevation at the 400 mg PO BID DL, and no grade IV toxicities were observed. G1 and G2 toxicities included diarrhea, mucositis, nausea, fatigue, proctitis, and thrombocytopenia. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery.The pCR rate was 35.7% and downstaging was observed in 85.7% of patients.KRAS status was available for 12 patients. The pCR was 40% in those with KRASmutant tumors (2/5 pts). Median NAR (neoadjuvant rectal cancer) score was 8.4. Conclusions: This regimen was very well tolerated after changing the dosing schedule. The pCR and downstaging rate is encouraging, and supports further clinical investigation of this regimen. Clinical trial information: NCT01376453