Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors.

PURPOSE: We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 ± capecitabine. EXPERIMENTAL
DESIGN: Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors.
RESULTS: In Arm1 (n = 40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 ± capecitabine at saturation of clearance (≥10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses.
CONCLUSIONS: LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 ± capecitabine was defined. Clearance was saturated at doses ≥10 mg/kg.