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A Phase I study of AMGN‐0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases
Author(s) -
Body JeanJacques,
Greipp Philip,
Coleman Robert E.,
Facon Thierry,
Geurs Filip,
Fermand JeanPaul,
Harousseau JeanLuc,
Lipton Allan,
Mariette Xavier,
Williams Catherine D.,
Nakanishi Arline,
Holloway Donna,
Martin Steven W.,
Dunstan Colin R.,
Bekker Pirow J.
Publication year - 2003
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.11138
Subject(s) - medicine , osteoprotegerin , multiple myeloma , bone remodeling , bone resorption , n terminal telopeptide , rankl , breast cancer , bone disease , endocrinology , urology , oncology , gastroenterology , cancer , osteoporosis , osteocalcin , receptor , activator (genetics) , biochemistry , chemistry , alkaline phosphatase , enzyme
BACKGROUND Osteoprotegerin (OPG) is a decoy receptor for OPG ligand (OPGL), or receptor activator of NF‐κB 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. Cancer 2003;97(3 Suppl):887–92. © 2003 American Cancer Society. DOI 10.1002/cncr.11138