Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are poor prognostic markers and are associated with a low response to the combination of cetuximab (C) and irinotecan (I). Vemurafenib (V), an oral kinase inhibitor specific to mutated V600 BRAF, demonstrated a 5% response rate in a phase I trial of pts with BRAF-mutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, which is further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAF-mutated advanced malignancies have not been defined. Methods: In this 3+3 phase I study, pts with BRAF-mutated cancers received escalating doses of V in combination with C and I over a 14-day cycle. Responses were evaluated every 4 cycles by RECIST 1.1. Adverse events (AEs) were assessed by CTCAE 4.0. Results: Among 19 total pts treated on study, 18 pts have mCRC: 6 at dose level 1(DL) (V- 480mg PO BID, C-250 mg/m² weekly and I- 180mg/m² every 14 days), 6 at DL 2 (increased to V-720mg PO BID), and 6 at DL3 (V-960mg PO BID). Median age was 63 yrs (42-73yrs). One DLT was observed at each DL (arthralgia in 2 pts, diarrhea in 1 pt). The MTD was determined to be DL3 (V-960 mg PO BID, C-250 mg/m² weekly, I-180mg/m² every 14 days). The most common AEs were fatigue (94%), diarrhea (89%), nausea (83%), and rash (78%). Six of the 17 evaluable mCRC pts achieved a partial response (RR 35%). Median best response was a reduction of -20% (+21% to -100%) with median duration of response of 12.5 cycles (IQR, 5-17 cycles). Seven mCRC pts remain on study. Median PFS is 7.7 months. One pt came off study due to diarrhea before restaging. Preliminary PKs and PDs will be reported. Conclusions: The combination of V with I and C is well tolerated in pts with BRAF-mutated mCRC with the MTD at V-960 mg PO BID, C-250 mg/m² weekly, I-180mg/m² every 14 days. Responses were seen in 35% of evaluable mCRC pts. A US cooperative group randomized phase II trial of I and C with or without V in BRAF-mutated mCRC (SWOG 1406) is ongoing. Clinical trial information: NCT01787500