Background: 40% of patients (pts) with LARC present with K-ras mutation. Sor is an inhibitor of ras/raf and of VEGFR. Furthermore Sor has radiosensitizing effects. These facts build a strong rationale to use Sor in combination with preoperative RT and Cape in pts with K-ras mutant tumors. Methods: Pts with K-ras mutated mrT3-4 and / or mrN+, M0 disease were recruited in cohorts of 7 pts per dose level (DL). Dose limiting toxicity (DLT) was defined as any G3 or higher non hematological toxicity (tox) or haematological tox during ≥ 7 days, which are possibly, probably or definitely related to trial treatment occurring during and up to 4 weeks after last administration. If ≤ 2 out of 7 pts experienced a DLT, then the next cohort was treated at a higher dose level. If > 2 out of 7 pts suffered from a DLT, this DL would be considered too toxic and a dose level below would be tested in the next cohort. The highest dose level with ≤ 2 out of 7 pts experienced a DLT would be recommended for the phase II part. In all dose levels RT was given in 25 fractions at 1.8Gy (45Gy). Results: In 8 centers in Switzerland a total of 21 pts in 3 cohorts have been treated in the phase 1 study. After observing severe skin toxicity and diarrhea (2 pt with skin toxicity G3, one patient (pt) with diarrhea G3 plus hand-foot syndrome (HFS) (G3)) an amendment was implemented to reduce the Sor dose from 400mg BID to once daily. In DL 1 after the amendment, 2 pts experienced a DLT (enteritis G3, dermatitis G3). Two pts in DL 2 suffered from a DLT (cystitis G3 plus HFS G3, cardiac ischemia G3). Further non dose-limiting G3 toxicities after the amendment were lymphopenia (G3) (1pt, DL 2) and hypocalcaemia (G3) (1 pt, DL 2). No Grade 4 toxicity was seen. DL 2 is the recommended dose for phase II. Conclusions: After reducing the Sor dose to 400mg once daily, neoadjuvant treatment with Sor in combination with full dose Cape and RT was tolerable and the toxicities manageable.

Dose level (each with 7 pts)	Capecitabine (mg/m2) per day during 5 weeks	Sorafenib (mg) per day during 5 weeks
DL 1 before amendment	2 x 600	2 x 400
DL 1 after amendment	2 x 600	1 x 400
DL 2 after amendment	2 x 825	1 x 400