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 (²²³RaCl₂) 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. Experimental Design: A 3+3 phase I, dose-escalation trial of ²²³RaCl₂ (50, 75, and 100 kBq/kg) was designed in recurrent/metastatic osteosarcoma patients aged ≥15 years. Objective measurements included changes in SUV of PET (18FDG and/or NaF-18) and single-photon-emission-computed-tomography-computed tomography (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, mid-study, 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 ²²³RaCl₂; 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 ²²³RaCl₂ in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.

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