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Safety, Pharmacokinetics, and Pharmacodynamics of the DR5 Antibody LBY135 Alone and in Combination with Capecitabine in Patients with Advanced Solid Tumors

Sharma, S. and deVries, E.G. and Infante, J.R. and Oldenhuis, C.N. and Gietema, J.A. and Yang, Lin and Bilic, Sanela and Parker, Kathryn and Goldbrunner, Michael and Scott, Jeffrey and Burris, H.A. (2013) Safety, Pharmacokinetics, and Pharmacodynamics of the DR5 Antibody LBY135 Alone and in Combination with Capecitabine in Patients with Advanced Solid Tumors. Investigational New Drugs. ISSN 0167-6997

Abstract

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; 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 (20mg/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 146–492 hours. 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 40mg/kg, the maximal dose administered; no MTD for LBY135 ± capecitabine was defined. Clearance was saturated at doses ≥10 mg/kg.

Item Type: Article
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Keywords: LBY135, dose escalation, capecitabine, DR5, death receptor, TNF-related apoptosis-inducing ligand
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9585

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