A Phase 2 Trial of RANKL Antibody, Denosumab, in Two Cohorts of Patients with Recurrent / Refractory Osteosarcoma, A Report from the Children's Oncology Group (COG).
Academic Article
Overview
abstract
BACKGROUND: Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single arm open label phase 2 trial was to determine if denosumab, a RANKL monoclonal antibody, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historical COG clinical trial data. PATIENTS AND METHODS: Skeletally mature patients 11-49 years old with measurable disease were eligible for cohort 1 or those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. RESULTS: Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event free at 12 months. The pre-defined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11% respectively). At steady state, mean serum denosumab trough concentrations were 23.7-31 ug/mL in cycle 2-7. Serum c-telopeptides and urine n-telopeptides decreased on treatment. CONCLUSIONS: Denosumab was well tolerated with anticipated side effects, and PK and PD parameters but had insufficient activity for further development in osteosarcoma.
