title: A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases.
abstract: BACKGROUND
  Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF-kappaB ligand (RANKL). RANKL/RANK interaction is important in terminal differentiation and activation of osteoclasts. In binding to RANKL, OPG blocks differentiation and activation of osteoclasts. AMGN-0007 is a recombinant OPG construct developed as a potential therapeutic agent in the treatment of bone disease.
  
  
  METHODS
  A randomized, double-blind, double-dummy, active-controlled, single-dose, dose escalation study was conducted to determine the safety and effect on bone resorption of AMGN-0007 in patients with multiple myeloma (n = 28) or breast carcinoma (n = 26) with radiologically confirmed lytic bone lesions. Patients were randomized (3:1 ratio) to receive a single dose of either AMGN-0007 (subcutaneously [SC]) or pamidronate (90 mg intravenously) and were followed for 56 days. Medications or other diseases affecting bone metabolism and chemotherapy within 28 days of dosing were exclusion criteria. Biologic activity of AMGN-0007 was assessed by measurement of the surrogate marker of bone resorption, urinary N-telopeptide of collagen (NTX).
  
  
  RESULTS
  AMGN-0007 caused a rapid, sustained, dose-dependent decrease in NTX/creatinine levels, which was at least comparable to the profile observed with pamidronate. Four serious adverse events were reported, three in breast carcinoma patients: a fracture in the left femur (pamidronate, considered unrelated), extreme fatigue (0.3 mg/kg AMGN-0007, considered unrelated), and congestive heart failure (1.0 mg/kg AMGN-0007, considered by the investigator to be probably related to doxorubicin and radiation therapy); one event occurred in a multiple myeloma patient: Herpes zoster (pamidronate, considered unrelated). Two multiple myeloma patients (1.0 mg/kg AMGN-0007) had albumin-adjusted serum calcium levels of 1.9 mmol/L on Day 8 but without clinical symptoms.
  
  
  CONCLUSIONS
  A single SC dose of AMGN-0007 suppressed bone resorption as indicated by a rapid, sustained, and profound decrease of urinary NTX/creatinine in multiple myeloma and breast carcinoma patients. Changes were comparable to those with pamidronate. AMGN-0007 was well tolerated.
authors.affiliation: Unit of Endocrinology, Institut Jules Bordet, Brussels, Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Body
authors.forename: Philip
authors.initials: P
authors.lastname: Greipp
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.forename: Thierry
authors.initials: T
authors.lastname: Facon
authors.forename: Filip
authors.initials: F
authors.lastname: Geurs
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Fermand
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Williams
authors.forename: Arline
authors.initials: A
authors.lastname: Nakanishi
authors.forename: Donna
authors.initials: D
authors.lastname: Holloway
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: Pirow J
authors.initials: PJ
authors.lastname: Bekker
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D004164:Diphosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D053244:Osteoprotegerin; D000077268:Pamidronate; D018160:Receptors, Cytoplasmic and Nuclear / Q000008:administration & dosage / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; D000077268:Pamidronate