title: Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  Conatumumab is a fully human monoclonal agonist antibody against human death receptor 5 (DR5). The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients with advanced solid tumors.
  
  
  METHODS
  This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 and 20 mg/kg were planned. Six patients were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single agent. No conatumumab was administered on day 43 to allow the assessment of terminal PK parameters. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and assessment of PK parameters of conatumumab.
  
  
  RESULTS
  Eighteen patients received at least 1 dose of conatumumab. There were no DLTs observed as defined in the protocol. No patients had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics. A best response of stable disease was reported in nine patients. Monocytes were found to express DR5 and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels.
  
  
  CONCLUSIONS
  Conatumumab administered up to 20 mg/kg once every 2 weeks was well tolerated in Japanese patients with advanced solid tumors. Adverse events and PK in these patients were similar to those in the first in human (FIH) study.
authors.affiliation: Gastrointestinal/Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. todoi@east.ncc.go.jp
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: A
authors.initials: A
authors.lastname: Ohtsu
authors.forename: N
authors.initials: N
authors.lastname: Fuse
authors.forename: T
authors.initials: T
authors.lastname: Yoshino
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: N
authors.initials: N
authors.lastname: Boku
authors.forename: Y
authors.initials: Y
authors.lastname: Onozawa
authors.forename: C-P
authors.initials: CP
authors.lastname: Hsu
authors.forename: K S
authors.initials: KS
authors.lastname: Gorski
authors.forename: G
authors.initials: G
authors.lastname: Friberg
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000032:analysis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C554537:conatumumab