Background: Regorafenib is an oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, B-RAF). Regorafenib resulted in a 74% disease control rate (PR+SD) in a phase I study in patients (pts) with refractory metastatic colorectal cancer (CRC). A phase III monotherapy trial in relapsing CRC pts is ongoing. Methods: The phase Ib study 11656 investigated the safety, PK, and efficacy of sequentially administered regorafenib in combination with mFOLFOX6 (FOLFOX) or FOLFIRI (oxaliplatin 85 mg/m² or irinotecan 180 mg/m², 400 mg/m² D/L-folinic acid, 400 mg/m² 5‑FU bolus followed by 5‑FU 2400 mg/m² for 46 h) every 2 wks as 1st or 2nd line treatment for CRC. Regorafenib 160 mg was given once daily on days 4-10 and 18-24 of every 4 wk cycle. Tumor response was evaluated per RECIST 1.0. Results: 45 pts (FOLFOX: n=25 , FOLFIRI: n=20) were enrolled. 12 pts were ongoing at data cutoff Dec 2010. Demographic variables were similar in both groups. The median treatment duration was 107 days in the FOLFOX and 112 days in the FOLFIRI group. The primary reason for discontinuation was PD (n=10), AE (n=12), consent withdrawn/other (n=8), metastasectomy surgery (n=3).The incidence of treatment related AEs is presented in the table below. Regorafenib had no significant effect on the PK of platinum and 5-FU, whereas exposure of SN-38 increased by 32%. Of the 21 pts in the FOLFOX group who were evaluable for efficacy, 4 achieved PR, 15 SD and 2 PD as best response. Of the 17 evaluable pts in the FOLFIRI group, 4 achieved PR, 11 SD and 2 PD. Conclusions: Regorafenib, when administered sequentially with standard chemotherapy, has shown acceptable tolerability and promising activity in 1st and 2nd line pts with CRC. Regorafenib increased the exposure to SN-38 in the FOLFIRI group, but was not associated with a reduced tolerability. Regorafenib combined with mFOLFOX6 or FOLFIRI will be evaluated in phase II CRC trials.