title: A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.
abstract: Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N = 3; 1400 mg, N = 3; 2000 mg, N = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib (N = 3) or gefitinib (N = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (Cmax) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
authors.forename: Toshihiko
authors.identifier: 0000-0003-2042-6829
authors.initials: T
authors.lastname: Doi
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Zenke
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
authors.affiliation: Eli Lilly Japan K. K., Kobe, Japan.
authors.forename: Sotaro
authors.initials: S
authors.lastname: Enatsu
authors.affiliation: Eli Lilly Japan K. K., Kobe, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kellie
authors.initials: K
authors.lastname: Turner
authors.affiliation: Eli Lilly Japan K. K., Kobe, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Uenaka
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C000599789:emibetuzumab; D000077156:Gefitinib
keywords: Antibodies, monoclonal; Epidermal growth factor receptor; LY2875358; MET; Pharmacokinetics; Solid tumors