Background: MGCD265 is a spectrum-selective and ATP-competitive inhibitor with MET and Axl as clinically relevant RTK targets. In nonclinical studies, MGCD265 demonstrated anti-tumor activity in cancer models exhibiting dysregulation of MET or Axl RTKs. Methods: Phase I objectives were to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of MGCD265. Eligible pts with advanced solid tumors received MGCD265 on Cycle 1 Day 1, then continuous dosing starting on Cycle 1 Day 3 for 21-day cycles. PK/PD were evaluated after single dose and repeated administration. Results: 12 pts (6 males; median age 57 years; range 48-75) with advanced malignancies were treated with 600, 1200 or 1050 mg BID of MGCD265 in non-aqueous suspension capsules. At 1200 mg BID, 2 out of 6 evaluable pts experienced DLT (G3 fatigue; G3 diarrhea). 1050 mg BID was defined as the MTD with no DLTs in 3 pts. Treatment-related AEs ( > 20% all grades) included diarrhea, nausea, vomiting, fatigue, AST increase, ALT increase and lipase increase. Stable disease of at least 6 weeks was observed (n = 2). At MTD, preliminary data show that steady state average and maximum concentrations were 501 and 562 ng/mL, respectively; the area under the concentration-time curve for the dosing interval was 6010 ng•h/mL.Preliminary data show that plasma concentrations exceeded levels projected for near complete inhibition of both MET and Axl for the full dosing interval. Maximal increase of plasma soluble MET ectodomain (sMET) was observed at each dose level including those associated with sustained steady state plasma concentrations (C_min) as low as 200 ng/mL, suggesting that the MET pathway was inhibited at all 3 dose levels and concentrations achieved in this study. Conclusions: MGCD265 is well tolerated at the MTD of 1050 mg BID. Based on safety, PK data and PD data suggesting robust inhibition of MET and Axl, the expansion phase of the study began recruitment in December 2014. Patients with NSCLC and other solid tumors with specific genetic alterations for MET and AXL will be enrolled. Clinical trial information: NCT00697632