Alpha Particle Radium 223 Dichloride in High-risk Osteosarcoma: A Phase I Dose Escalation Trial

The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride ( RaCl ) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers. A 3+3 phase I, dose-escalation trial of RaCl (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study. Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine ( = 12, 67%), pelvis ( = 10, 56%), ribs ( = 9, 50%), extremity ( = 7, 39%), and skull ( = 2, 11%). Patients received 1-6 cycles of RaCl ; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia ( = 1) was a DLT. The median overall survival time was 25 weeks. The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for RaCl in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.