Background: MGCD516 is an oral, potent small molecule inhibitor of a closely related spectrum of RTKs including RET, TRK family, DDR2, MET, AXL and split RTKs (VEGFR, PDGFR and KIT). MGCD516 has demonstrated antitumor activity in nonclinical cancer models harboring genetic alterations of MGCD516 targets including rearrangement of RET or NTRK or CHR4q12 amplification. Methods: Study objectives include evaluation for safety, pharmacokinetics (PK), pharmacodynamics (PD), the maximum tolerated dose (MTD) and clinical activity of MGCD516 in patients (pts) with advanced solid tumors. Eligible pts received a single dose for PK profiling followed by continuous daily dosing (QD) in 21 day cycles. Results: 32 unselected pts (14 men/18 women; median age 62 years; range 27-85) with advanced solid tumors were treated in escalating dose cohorts of 10, 20, 40, 80, 110, 150 or 200mg MGCD516. At 80mg, 1 of 6 evaluable pts experienced a DLT (Grade 3 palmar plantar erythrodysesthesia). At 200mg, 3 DLTs were observed among 3 evaluable pts (intolerable Grade 2 neuropathy, fatigue and stomatitis in 1 pt each), demonstrating 200mg exceeded the MTD. Treatment-related AEs ( > 15% of pts; Grade1-3) included hypertension, fatigue, diarrhea, nausea and decreased appetite. One treatment-related Grade 4 AE (febrile neutropenia) was reported. Prolonged stable disease (SD) has been observed in multiple pts including 3 pts with at least 17 weeks SD and 1 pt with 35 weeks SD. Preliminary PK data show that exposure increased dose proportionally with doses up to 200mg. At 150mg, the C_avg and AUC_0-24 values at steady state (90.7 ng/mL and 2.18 μg·h/mL, resp.) exceed plasma exposure projections required for inhibition of key RTK targets and antitumor efficacy in nonclinical tumor models. Preliminary clinical PD data indicate dose dependent inhibition of the VEGF and MET pathways. Conclusions: The Phase 1b dose for MGCD516 was established at 150mg QD. MGCD516 shows favorable PK characteristics, on-target PD effects and is associated primarily with constitutional or GI-related AEs. Phase 1b enrollment began November 2015. Pts with NSCLC or other solid tumors with specific genetic alterations in MGCD516 target RTK genes are being enrolled. Clinical trial information: NCT02219711