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A RANDOMIZED, DOUBLE-BLIND,
ACTIVE-CONTROLLED (PAMIDRONATE), SINGLE-DOSE PHASE 1 STUDY TO EVALUATE THE
SAFETY AND TOLERABILITY OF AMG 162 IN PATIENTS WITH CANCER-RELATED BONE
METASTASES
What is AMg 162
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
metastases.
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
PRIMARY
OBJECTIVE:
¨ To evaluate the
safety and tolerability of a single subcutaneous injection of AMG 162 compared
with pamidronate in subjects with cancer-related bone metastases.
SECONDARY
OBJECTIVES:
¨
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)
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Age 18 years or older
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Diagnosis of multiple myeloma or breast cancer with lytic
or mixed lytic-blastic bone lesions. Must have at least one lytic lesion
present.
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Life expectancy of >6 months
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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)
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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.
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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 investigator.
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Administration of calcitonin, plicamycin, PTH, vitamin D
(> 1000 IU/day), or anabolic steroids within 28 days before randomization.
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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.
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Glucocorticosteroid administration within 14 days before
study drug administration or glucocorticosteroid administration scheduled
within 14 days after study drug administration.
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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.
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Weight greater than 120 kg.
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Any organic or psychiatric disorder, or abnormal EKG,
serum chemistry, or hematology that, may prevent the subject from completing
the study.
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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.
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Prior administration of any OPG construct within 180 days
before randomization.
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Surgery to bone or long-bone fracture within 90 days of
randomization.
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Local radiation to bone within 28 days before
randomization, or local radiation to bone scheduled within 28 days after
randomization.
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Wide-filed radiation within 90 days of randomization.
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Ascites, per clinical exam.
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Albumin-adjusted serum calcium 10.5mg/dl, serum Cr >
2.5mg/dL, serum bilirubin > 2.5mg/dL.
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Known sensitivity to mammalian-derived proteins, fully
human monoclonal antibodies, or bisphosphonates.
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Subject is currently enrolled or has not completed at
least 30 days since ending other investigational device or drug trial.
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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 85.
Suggested Reading
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Lacey DL, Timms
E, Tan H-L, et al. Osteoprotegerin (OPG) ligand is a cytokine that regulates
osteoclast differentiation and activation.
Cell 1998;93: 165-176.
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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.
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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.
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Bucay
N, Sarosi I, Dunstan CR, et al.
Osteoprotegerin deficient mice develop
early onset osteoporosis and arterial calcification. Genes and Development
1998;12:1260-1268.
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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; 14:1478-1485.
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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.
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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.
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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.
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