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Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.
- Source :
-
Cancer science [Cancer Sci] 2008 Jun; Vol. 99 (6), pp. 1237-42. Date of Electronic Publication: 2008 Apr 21. - Publication Year :
- 2008
-
Abstract
- Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade < or = 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related; other treatment-related AE were grade < or = 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose-linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N-telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from -61.9% to -90.8%. No dose-limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non-Japanese populations.
- Subjects :
- Adult
Aged
Antibodies, Monoclonal adverse effects
Antibodies, Monoclonal, Humanized
Biomarkers, Tumor urine
Bone Neoplasms drug therapy
Bone Neoplasms secondary
Bone Resorption prevention & control
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Cohort Studies
Collagen Type I urine
Creatinine urine
Denosumab
Dose-Response Relationship, Drug
Female
Humans
Injections, Subcutaneous
Japan
Middle Aged
Peptides urine
RANK Ligand adverse effects
Antibodies, Monoclonal pharmacokinetics
Antibodies, Monoclonal pharmacology
Bone Neoplasms metabolism
Breast Neoplasms metabolism
RANK Ligand pharmacokinetics
RANK Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1349-7006
- Volume :
- 99
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer science
- Publication Type :
- Academic Journal
- Accession number :
- 18429961
- Full Text :
- https://doi.org/10.1111/j.1349-7006.2008.00803.x