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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

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Summary

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.

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Acknowledgments

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.

Funding

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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Authors and Affiliations

  1. Huntsman Cancer Institute, Division of Medical Oncology, University of Utah, 2000 Circle of Hope Drive, Suite 3380, Salt Lake City, UT, 84112, USA

    Sunil Sharma

  2. University Medical Center Groningen, Groningen, The Netherlands

    Elisabeth G. de Vries, Corina N. Oldenhuis & Jourik A. Gietema

  3. Sarah Cannon Research Institute/ Tennessee Oncology, PLLC (Drug Development Unit), Nashville, TN, USA

    Jeffrey R. Infante & Howard A. Burris III

  4. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Lin Yang, Sanela Bilic, Katie Parker, Michael Goldbrunner & Jeffrey W. Scott

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  1. Sunil Sharma
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  2. Elisabeth G. de Vries
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  4. Corina N. Oldenhuis
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Correspondence to Sunil Sharma.

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Sharma, S., de Vries, E.G., Infante, J.R. et al. Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors. Invest New Drugs 32, 135–144 (2014). https://doi.org/10.1007/s10637-013-9952-9

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  • DOI: https://doi.org/10.1007/s10637-013-9952-9

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