Phase Ib dose-escalation study of a phase II randomized trial to assess the safety and tolerability of tigatuzumab (CS-1008) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC).

Abstract

e14617 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist and exerts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-like activity, is currently undergoing a phase Ib/II study in advanced HCC. Preclinical studies showed that sorafenib (S) can overcome TRAIL resistance in HCC cells and enhances T-induced apoptosis. In this phase Ib dose-escalation portion of a phase 2 study, safety/tolerability of T + S was evaluated in advanced HCC pts. Methods: Adult pts (≥ 18 years) with advanced HCC and measurable disease (RECIST v1.1), ECOG=0/1, and Child-Pugh A, were administered sequentially-escalating doses of T (2, 4, 6 mg/kg/week IV) in combination with S (400 mg PO BID) over 4 weeks (n = 3/cohort). If no pt had a dose-limiting toxicity (DLT), dose escalation proceeded. If 1/3 pts had DLT, the cohort was to be expanded to 6; if 2/3 or 2/6 pts had DLT, the cohort was to be expanded to 9. Dose escalation was to be stopped when ≥ 3 pts experienced DLTs in a cohort with the prior dose designated as the maximum tolerated dose (MTD). Pts received treatment until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. Results: Nine pts (3 at each dose level of T + S) were treated in this phase Ib portion. Grade 3/4 treatment-emergent AEs (> 20% incidence) were increased AST, blood amylase, and lipase and hand-foot syndrome. Serious AEs were reported in 5 pts (upper GI hemorrhage, esophageal varices hemorrhage [EVH], tumor progression, increased serum amylase, fever, and lumbar spine compression), which were considered unrelated to study medication except for EVH (T + S), increased serum amylase (T + S), and fever (S). No DLTs were observed and the MTD of T was not reached. 2 pts had a partial response, and 4 pts had disease stabilization. The trial is ongoing. Conclusions: Phase Ib data show that T in combination with S was safely administered with no DLT and demonstrated clinical activity in advanced HCC pts. T and S constitute a promising rational combination treatment for HCC.