The study evaluated the safety, PK, PD and efficacy of sEphB4 in pts with advanced solid tumors in a 3+3 design with expansion at the RP2D in 7 solid tumors including HCC and CCA. 29 pts were treated: 17 HCC and 12 biliary cancers (8 CCA and 4 gallbladder). Median PFS in months was 5.0 (1.9-7.8) in HCC and 3.0 (1.6-9.2) in CCA. Median OS in months was 11.9 (5.6-27.1) in HCC and 12.0 (3.0-28.2) in CCA. Disease control rate was 70% in HCC and 42% in CCA including 1 PR in HCC. 8 out of 9 pts with 2-3+ EphrinB2 by IHC had disease control ≥ 4 months. 1 out of 7 pts with negative EphrinB2 had disease control ≥ 4 months. sEphB4 has a manageable safety profile with preliminary evidence of anti-tumor activity in pretreated pts with HCC and biliary cancers.