SUMMARY
Purpose: This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266, a novel agonistic tetravalent Nanobody® targeting the DR5 receptor.
Experimental design: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle.
Results: Grade ≥ 3 elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels occurring during cycle 1 in 3 of 4 patients enrolled at the 3 mg/kg dose level were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade ≤ 1 following TAS266 discontinuation. Evidence of antidrug antibodies, indicating pre-existing immunogenicity to TAS266, was found in the 3 patients who experienced these dose-limiting toxicities (DLTs). Immunogenic responses remained elevated and strengthened at the end of treatment. In the 1 patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 doses of TAS266; however, incipient positive immunogenicity was observed at the end of treatment visit. TAS266 had a mean total systemic clearance of 0.47 L/hr and a median terminal phase half-life of 14.29 hours.
Conclusion: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, immunogenicity to TAS266 may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis
