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http://www.clevelandclinic.org/myeloma/osteoprotegerin_opg.htm 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) •
Age 18 years or older
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Diagnosis of multiple myeloma or breast cancer with lytic or mixed lyticblastic 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) •
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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. 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. 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 randomization. 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 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. 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 1998;12:1260-1268. 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; 14:14781485. 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.
Age 18 years or older
• • •
Diagnosis of multiple myeloma or breast cancer with lytic or mixed lyticblastic 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 investigator. 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 randomization. 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 85. 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: 165-176. 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 1998;12:1260-1268. 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; 14:14781485. 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.
