A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA).

Abstract

285 Background: EphrinB4, a receptor kinase, is associated with stage and survival in epithelial cancers. sEphB4 is a fusion protein of soluble EphB4 and albumin. sEphB4 binds to EphrinB2, a protein expressed in tumor cells and vessels, and blocks bidirectional signaling. sEphB4 downregulates the PI3K/AKT/mTOR pathway, inhibits angiogenesis, and promotes recruitment of cytotoxic T cells and NK cells. MTD was not reached during dose escalation. The RP2D was 10 mg/Kg weekly. Here we report the results of the expansion cohorts in HCC and CCA. Methods: 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. Pts received sEphB4 10 mg/kg IV weekly in 28-day cycles. Eligibility included ECOG 0-1, Child-Pugh score ≤ 7, platelets > 50,000, AST/ALT ≤ 3xULN, serum bilirubin ≤ 1.5mg/dL and no uncontrolled hypertension. Results: 29 pts were treated: 17 HCC and 12 biliary cancers (8 CCA and 4 gallbladder). Median age was 63(25-77). ECOG PS was 1 in 76%. Median prior regimens were 1 (0-6) for HCC and 2 (1-3) for biliary cancers. 2 HCC pts had prior liver transplantation, 9 had prior anti PD-1 therapy and 2 had Child-Pugh score of B7. Median number of cycles was 4 (1-21) in HCC and 2 (1-17) in CCA. No grade 4 treatment-related adverse events (TRAE). Grade 3 TRAE were hypertension (41%) and fatigue, headache, neutropenia all in 1 pt each. Disease progression was the most common reason for treatment discontinuation. Median PFS in months was 5.0 (3.0-7.5) in HCC and 3.0 (1.6-9.2) in CCA. Median OS in months was 27.1 (4.4-27.1) 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. In HCC pts, 5/5 with 3+ EphrinB2 expression in tumor had PR or SD ≥ 6 months. Only 1/4 pts with ≤2+ expression had SD ≥ 4 months. 3/3 pts with HCC showed an increase in T cell infiltration, and decrease in pS6 (PI3K pathway activity) on post-treatment biopsy. Conclusions: sEphB4 has a manageable safety profile with preliminary evidence of anti-tumor activity in pretreated pts with HCC and biliary cancers. Several trials combining sEphB4-HSA with cytotoxic chemotherapy or immunotherapy are ongoing. Clinical trial information: NCT01642342.