Neoadjuvant radiotherapy (RT) combined with capecitabine (Cape) and sorafenib (Sor) in patients with locally advanced, K-ras-mutated rectal cancer (LARC): A phase I/II trial (SAKK 41/08).

Abstract

3595 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. [Table: see text]