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Cancer Therapy: Clinical

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer

Lee S. Rosen, Jonathan W. Goldman, Alain P Algazi, P. Kellie Turner, Brian Moser, Tianle Hu, Xuejing Aimee Wang, Jay Tuttle, Volker Wacheck, James E. Wooldridge and Michaela Banck
Lee S. Rosen
Medicine, UCLA Santa Monica Hematology-Oncology
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  • For correspondence: lrosen@mednet.ucla.edu
Jonathan W. Goldman
Division of Hematology/Oncology, UCLA - Department of Medicine
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Alain P Algazi
Medicine, University of California, San Francisco
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P. Kellie Turner
Global PK/PD&Pharmacometrics, Eli Lilly and Company
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Brian Moser
Global PK/PD and Pharmacometrics, Eli Lilly and Company
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Tianle Hu
Global Statistics, Eli Lilly and Company
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Xuejing Aimee Wang
Global Statistics, Eli Lilly and Company
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Jay Tuttle
AME Clinical Services, Eli Lily and Company
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Volker Wacheck
Early Phase Oncology, Eli Lilly & Company
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James E. Wooldridge
Early Phase Oncology, Eli Lilly and Company
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Michaela Banck
Oncology, Mayo Clinic Rochester
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DOI: 10.1158/1078-0432.CCR-16-1418
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Abstract

Purpose: The MET/hepatocyte growth factor (HGF) pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here we report dose escalation results from the first-in-human phase I trial of emibetuzumab. Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered IV every two weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended Phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity. Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1400, and 2000 mg and fourteen NSCLC patients at 700, 1400, and 2000mg in combination with erlotinib 150mg daily. No dose-limiting toxicities, related serious or {greater than or equal to} grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear pharmacokinetics at doses >210mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700-2000 mg IV Q2W.

  • Received June 6, 2016.
  • Revision received September 15, 2016.
  • Accepted September 21, 2016.
  • Copyright {copyright, serif}2016, American Association for Cancer Research.
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Published OnlineFirst October 10, 2016
doi: 10.1158/1078-0432.CCR-16-1418

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A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer
Lee S. Rosen, Jonathan W. Goldman, Alain P Algazi, P. Kellie Turner, Brian Moser, Tianle Hu, Xuejing Aimee Wang, Jay Tuttle, Volker Wacheck, James E. Wooldridge and Michaela Banck
Clin Cancer Res October 10 2016 DOI: 10.1158/1078-0432.CCR-16-1418

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A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer
Lee S. Rosen, Jonathan W. Goldman, Alain P Algazi, P. Kellie Turner, Brian Moser, Tianle Hu, Xuejing Aimee Wang, Jay Tuttle, Volker Wacheck, James E. Wooldridge and Michaela Banck
Clin Cancer Res October 10 2016 DOI: 10.1158/1078-0432.CCR-16-1418
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Clinical Cancer Research
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