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Osteoprotegerin (OPG) has been demonstrated to be a potent inhibitor of bone

resorption in vivo. It acts as a decoy receptor, binding and inactivating OPG Ligand
(OPGL), which is an essential factor required for osteoclast differentiation."
Transgenic over expression of OPG in mice produces an osteopetrotic phenotype due
to the inhibition of growth-related bone resorption. Disruption of the OPG gene in the
OPG knockout mouse produces osteoporosis marked by excessive bone resorption
indicating the importance of this molecule in normal bone physiology. OPG has been
shown to oppose the bone resorptive activity of parathyroid hormone (PTH), PTHrP,
1,25(OH)2D3, interleukin-1 B, TNFa and estrogen withdrawal after ovariectomy."
These factors are the main mediators of metabolic, inflammatory, and cancer-related
bone diseases. In mice inoculated with cells derived from a human breast cancer
(MDA231), OPG was effective at blocking the bone resorption and bone destruction
resulting from growth of these cells within the bone (data on file). OPG was shown to
prevent and reverse hypercalcemia in a murine model of hypercalcemia of
malignancy. OPG has been demonstrated to be present in the circulation of adult
humans and both OPG and OPGL have been found to regulate the differentiation of
osteoclasts from precursors in human peripheral blood. OPG has been shown to be
bone anti-resorptive in postmenopausal women and in patients with lytic bone

AMG 162 is the second generation of anti bone resorption compounds that are
currently being investigated. In addition to the drugs ability to stop bone destruction
by myeloma cell, and breast cancer, it appears to have anti-tumor activity against the
myeloma environment. This is a randomized single dose study to determine the
effects of the new compound relative to established bisphosphonates as Aredia, as
well as determine a safe dose to use in the next generation (Phase II/III) studies


¨ To evaluate the safety and tolerability of a single subcutaneous injection of AMG

162 compared with pamidronate in subjects with cancer-related bone metastases.


¨ To determine the following after a single SC injection of AMG 162 in subjects

with cancer-related bone metastases:

1) Pharmacokinetic profile

2) The presence or absence of an antibody response

3) Pharmacodynamic profile (bone anti-resorptive activity assessed by changes in

bone turnover markers) compared with pamidronate.

¨ To assess the optimal AMG 162 dose (in terms of adverse events and profile of
bone turnover suppression) will be estimated.

INCLUSION: (specific to this study)

• Age 18 years or older

• Diagnosis of multiple myeloma or breast cancer with lytic or mixed lytic-
blastic bone lesions. Must have at least one lytic lesion present.
• Life expectancy of >6 months
• Not currently receiving medication that affects bone metabolism and free of
any underlying condition that may result in abnormal bone metabolism (other
than cancer-related bone lesions)

EXCLUSION: (specific to this study)

• Administration of bisphosphonates, estrogens or estrogen derivatives, gallium

nitrate or fluoride within 60 days before randomization. Bisphosphonate
treatment should not be withdrawn from a subject to make the subject eligible
for the study.
• Bisphosphonate therapy scheduled within 56 days after randomization. The
investigator will be notified if the patients urinary N-Tx did not decrease
within the first 28 days after study drug administration and will allow
bisphosphonate therapy to be initiated before day 57 at the discretion of the
• Administration of calcitonin, plicamycin, PTH, vitamin D (> 1000 IU/day), or
anabolic steroids within 28 days before randomization.
• If taking anti-estrogens (e.g., tamoxifen), progesterone derivatives,
thalidomide, interferon, or aromatase inhibitors (e.g., aminogluthemide), not
on a stable dose for at lease 90 days before randomization.
• Glucocorticosteroid administration within 14 days before study drug
administration or glucocorticosteroid administration scheduled within 14 days
after study drug administration.
• Chemotherapy administration within 28 days before randomization or
chemotherapy scheduled within 28 days after randomization date.
Chemotherapy administration allowed within 28 days before randomization, if
the urinary N-Tx level is D 30 nmol BCE/mmol creatinine.
• Weight greater than 120 kg.
• Any organic or psychiatric disorder, or abnormal EKG, serum chemistry, or
hematology that, may prevent the subject from completing the study.
• Evidence of any of the following conditions: hyper or hypo parathyroidism,
hyperthyroidism, hypothyroidism (stable on thyroid replacement therapy
allowed; serum TSH level must be within normal range), Osteomalacia,
Rheumatoid arthritis, current flare-up of osteoarthritis and/or gout, Pagets
disease of the bone, Malabsorption syndrome.
• Prior administration of any OPG construct within 180 days before
• Surgery to bone or long-bone fracture within 90 days of randomization.
• Local radiation to bone within 28 days before randomization, or local radiation
to bone scheduled within 28 days after randomization.
• Wide-filed radiation within 90 days of randomization.
• Ascites, per clinical exam.
• Albumin-adjusted serum calcium 10.5mg/dl, serum Cr > 2.5mg/dL, serum
bilirubin > 2.5mg/dL.
• Known sensitivity to mammalian-derived proteins, fully human monoclonal
antibodies, or bisphosphonates.
• Subject is currently enrolled or has not completed at least 30 days since ending
other investigational device or drug trial.
• Subject will not be available for follow-up assessment.
Pamidronate must be given by IV infusion and AMG 162 will be given SC
injection, the study will be double-dummy-blinded. All subjects will receive both
a SC injection and an IV infusion (pamidronate or saline), over 4 hours. AMG
will be administered in a single injection in the abdomen.

Blood and urine samples will be obtained on Day 1,2,3,4,8,15,22,29,43,57,71 and


Suggested Reading

• Lacey DL, Timms E, Tan H-L, et al. Osteoprotegerin (OPG) ligand is a

cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:
• Kong Y-Y, Yoshida H, Sarosi I, et al. OPGL is a key regulator or
osteoclastogenesis, lymphocyte development and lymph-node organogenesis.
Nature 1999;397:315-323.
• Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: A novel secreted
protein involved in the regulation of bone density. Cell 1997, 89: 309-319.
• Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin deficient mice develop
early onset osteoporosis and arterial calcification. Genes and Development
• Morony S, Capparelli C, Lee R, et al. A chimeric form of osteoprotegerin
inhibits hypercalcemia and bone resorption induced by IL-1B TNFa, PTH,
PTHrP, and 1,25-dihydroxyvitamin D3. J Bone Mineral Res 1999; 14:1478-
• Capparelli C, Kostenuik PJ, Morony S et al. Osteoprotegerin prevents and
reverses hypercalcemia in a murine model of humoral hypercalcemia of
malignancy. Cancer Research 2000; 60:783-787.
• Yano K, Tsuda E, Washida N, et al. Immunological characterization of
circulating osteoprotegerin/osteoclastogenesis inhibitory factor: Increased
serum concentrations in postmenopausal women with osteoporosis. J Bone
Mineral Research 1999; 14:518-527.
• Shalhoub V, Faust J, Boyle WJ, et al. Osteoprotegerin and osteoprotegerin
ligand effects on osteoclast formation from human peripheral blood
mononuclear cell precursors. J Cellular Biochem 1999;72:251-261.
• Bekker PJ, Holloway D, Nakanishi A et al. The effect of a single dose of
osteoprotegerin in postmenopausal women. J Bone Min Res 2000; 16:348-360

Research Nurse: Pamela Shrewsbury-Myers R.N.