A study of the biological receptor activator of nuclear factor-κB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer

被引:343
作者
Body, JJ
Facon, T
Coleman, RE
Lipton, A
Geurs, F
Fan, M
Holloway, D
Peterson, MC
Bekker, P
机构
[1] Inst Jules Bordet, Dept Med, B-1000 Brussels, Belgium
[2] CHU Lille, Serv Malad Sang, F-59037 Lille, France
[3] Weston Pk Hosp, Canc Res Ctr, Sheffield, S Yorkshire, England
[4] Penn State Univ, Milton S Hershey Med Ctr, Div Hematol Oncol, Hershey, PA 17033 USA
[5] Amgen Inc, Thousand Oaks, CA 91320 USA
关键词
D O I
10.1158/1078-0432.CCR-05-1933
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Receptor activator of nuclear factor-kappa B ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. Experimental Design: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. Results: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. Conclusions: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
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页码:1221 / 1228
页数:8
相关论文
共 42 条
[1]   A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women [J].
Bekker, PJ ;
Holloway, DL ;
Rasmussen, AS ;
Murphy, R ;
Martin, SW ;
Leese, PT ;
Holmes, GB ;
Dunstan, CR ;
DePaoli, AM .
JOURNAL OF BONE AND MINERAL RESEARCH, 2004, 19 (07) :1059-1066
[2]   Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma [J].
Berenson, JR ;
Lichtenstein, A ;
Porter, L ;
Dimopoulos, MA ;
Bordoni, R ;
George, S ;
Lipton, A ;
Keller, A ;
Ballester, O ;
Kovacs, MJ ;
Blacklock, HA ;
Bell, R ;
Simeone, J ;
Reitsma, DJ ;
Heffernan, M ;
Seaman, J ;
Knight, RD .
NEW ENGLAND JOURNAL OF MEDICINE, 1996, 334 (08) :488-493
[3]   Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events [J].
Berenson, JR ;
Lichtenstein, A ;
Porter, L ;
Dimopoulos, MA ;
Bordoni, R ;
George, S ;
Lipton, A ;
Keller, A ;
Ballester, O ;
Kovacs, M ;
Blacklock, H ;
Bell, R ;
Simeone, JF ;
Reitsma, DJ ;
Heffernan, M ;
Seaman, J ;
Knight, RD .
JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (02) :593-602
[4]  
Body JJ, 2000, CANCER AND THE SKELETON, P231
[5]   A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases [J].
Body, JJ ;
Greipp, P ;
Coleman, RE ;
Facon, T ;
Geurs, F ;
Fermand, JP ;
Harousseau, JL ;
Lipton, A ;
Mariette, X ;
Williams, CD ;
Nakanishi, A ;
Holloway, D ;
Martin, SW ;
Dunstan, CR ;
Bekker, PJ .
CANCER, 2003, 97 (03) :887-892
[6]  
BODY JJ, 1995, J BONE MINER RES, V10, P1191
[7]   Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies [J].
Body, JJ ;
Diel, IJ ;
Lichinitzer, M ;
Lazarev, A ;
Pecherstorfer, M ;
Bell, R ;
Tripathy, D ;
Bergstronn, B .
BRITISH JOURNAL OF CANCER, 2004, 90 (06) :1133-1137
[8]   Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases [J].
Body, JJ ;
Diel, IJ ;
Lichinitser, MR ;
Kreuser, ED ;
Dornoff, W ;
Gorbunova, VA ;
Budde, M ;
Bergström, B .
ANNALS OF ONCOLOGY, 2003, 14 (09) :1399-1405
[9]  
BODY JJ, 2003, P ASCO, V22, P46
[10]  
BOYDE A, 1986, SCAN ELECT MICROSC, V15, P37