Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors
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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.
KeywordsLBY135 Dose escalation Capecitabine DR5 Death receptor TNF-related apoptosis-inducing ligand
The authors thank Syntaxx Communications, Inc. (Laura Jung and Lisa Holle who provided manuscript development and medical writing services), with the support of Novartis Pharmaceuticals Corporation.
This work was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ. USA.
Conflicts of interest
LY, SB, KP, MG, and JWS are employees of Novartis Pharmaceuticals Corporation. SB, MG, KP, and JWS own stock in Novartis Pharmaceuticals, the sponsor of this study. SS has received clinical research support and consulting fees from Novartis Pharmaceuticals.
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