3513 Background: XL281 is a potent and selective inhibitor of wild type and mutant RAF kinases showing anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may promote sensitivity to RAF kinase inhibitors. Methods: Pts were enrolled in successive cohorts of XL281 orally once daily on a 28-day cycle. Tumor response was assessed per RECIST every 8 wks. Plasma pharmacokinetic and pharmacodynamic samples were collected. The maximum tolerated dose (MTD) was expanded to 10 pts each with colorectal (CRC), melanoma, papillary thyroid (PTC) and NSCLC. Pre- and post-dose tumor and surrogate tissues were obtained. Biomarker and genotype analyses of pathway genes were performed. Results: The dose escalation phase is complete; 30 pts were treated with XL281. DLTs of fatigue, nausea, vomiting, and diarrhea were observed at the MAD (225 mg). The MTD is 150 mg. The most common related AEs included Grade 1/2, fatigue (48%), diarrhea (35%), nausea (35%), vomiting (35%) and anorexia (30%). Three pts had related AEs ≥G3: hypokalemia, nausea, and vomiting. One pt with an ocular melanoma demonstrated a cPR of 4 mos duration. Twelve pts had SD (3 -17+ mos), including 2 with I131-refractory PTC harboring BRAF V600E mutations (15+ and 17+ mos). Nine of these pts had decreases in target lesions (5–29%), including a pt with KRAS mutant CRC on study for 20 wks with marked symptomatic improvement. At the MTD, paired biopsies from 4 pts (3 melanoma, 1 NSCLC) show an average 72 % decrease in pMEK, 68 % decrease in pERK, 24 % decrease in Ki67 (proliferation) and 64 % increase in TUNEL (apoptosis). Three of 6 evaluable pts in the MTD cohort show SD at first assessment, including 1 melanoma pt with a NRAS Q61R mutation who showed a 20% decrease in target lesions. Conclusions: XL281 was generally well tolerated and the MTD was established at 150 mg. One cPR occurred in an ocular melanoma subject, and clinical benefit (PR or SD) occurred in 43% (13/30) of pts in the dose-escalation phase. XL281 demonstrates biological activity by modulation of the RAF pathway in tumor and surrogate tissue, with decreases in cell proliferation and increases in apoptosis. [Table: see text]