ALPHA- EMITTER THERAPY OF OSTEOSARCOMA PROJECT SUMMARY Three-year overall survival for patients with recurrent osteosarcoma (OS) is 20%. Current therapy for metastatic osteosarcoma (OS) is largely ineffective. Over the past four decades no new therapies have been identified for OS. Our overall objective is to evaluate the potential efficacy and toxicity of targeted alpha-particle radiopharmaceutical therapy (αRPT) against OS. Targeted alpha-emitter therapy is a promising treatment modality that is not susceptible to the resistance mechanism observed for chemotherapy, traditional radiotherapy, targeted (i.e., pathway inhibition) therapy and immunotherapy. This is because alpha-particles cause massive and irreparable DNA double-strand break damage, irrespective of oxygenation, dose-rate, cell signaling or mutational burden. Osteosarcoma expresses the ganglioside GD2 receptor that can be targeted by the anti-GD2 antibody (Ab), Hu3F8. We propose to evaluate the safety and efficacy of 225Ac-Hu3F8 (A3F8) in a naturally occurring, large animal model of osteosarcoma. Actinium-225 emits 4 alpha-particles per decay and has a 10-day half-life. These experiments in client-owned dogs, which develop metastatic OS disease at a higher rate than people, would be the first evaluation of radiopharmaceutical therapy (RPT) with an alpha-emitter- conjugated Ab that targets both soft-tissue and calcified disseminated OS — a highly radioresistant disease. A two-cycle treatment scheme will be used wherein a fixed administered activity (AA) of A3F8, will be directly imaged by SPECT using a novel proprietary technique developed by Rapid, LLC (a Hopkins startup that has licensed α-particle emitter dosimetry and imaging technology) to obtain pharmacokinetics (PK) for dosimetry and treatment planning to identify the AA that balances potential toxicity with maximum anti-tumor efficacy. The specific aims are: 1. Identify the maximum tolerated absorbed dose (MTAD) to the red marrow in client-owned dogs with OS; utilizing SPECT imaging, collect PK to relate dose-limiting organ (DLO) absorbed dose (AD) to measured toxicity. 2. Determine treatment efficacy at the MTAD. 3. Evaluate how different measured or calculated quantities (e.g., tumor burden, tumor AD and DLO AD) are related to toxicity and efficacy. 4. Using data collected in Aims 1-3, develop a pharmacokinetic/dosimetry model that will help guide optimization of αRPT treatment in human OS patients. New treatments that are fundamentally different from those currently available are urgently needed for osteosarcoma. Radiopharmaceutical therapy with the highly potent alpha-emitter, 225Ac, is such a therapy. The proposed studies would yield required data to launch a clinical αRPT trial against OS in humans.