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

Purpose: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride (223 RaCl2 ) 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. Patients and Methods: A 3+3 phase I, dose-escalation trial of 223 RaCl2 (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. Results: Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine ( n = 12, 67%), pelvis ( n = 10, 56%), ribs ( n = 9, 50%), extremity ( n = 7, 39%), and skull ( n = 2, 11%). Patients received 1-6 cycles of 223 RaCl2 ; 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 ( N = 1) was a DLT. The median overall survival time was 25 weeks. Conclusions: The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for 223 RaCl2 in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.