Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer–related bone metastases

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 ≥ 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 ≤ 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 ≤ 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. ( Cancer Sci 2008; 99: 1237–1242)