New drug shows promise for treating bone cancer in dogs

Abstract

OBJECTIVE: To manufacture and characterize a modified niclosamide stearate (NS) prodrug therapeutic (mNSPT) for use in a small clinical trial in a metastatic canine osteosarcoma (OS) model. ANIMALS: 10 dogs that presented for treatment of nondetectable metastatic OS underwent resection of primary tumors prior to systemic therapy. Four cycles of IV carboplatin (300 mg/m2, IV, q 3 wk) followed by 4 cycles of the experimental mNSPT (10 mg/kg, IV, weekly). Posttreatment surveillance included physical examination and thoracic radiographs every 3 months for 2 years. Samples for pharmacokinetic analysis were taken at the end of the 0.5- to 1-hour IV infusion of the mNSPTs and followed for 2 hours. CLINICAL PRESENTATION: The NS average concentration at the end of infusion was 134.88 ± 13.32 μg/mL; the average area under the curve was 211.62 ± 27.89 h·µg/mL. The niclosamide concentration at the end of infusion was 23.11 μg/mL ± 3.77 μg/mL, and the area under the curve was 27.52 ± 5.92 h·µg/mL, well above the NSPT 0.75 μg/mL (1.27 μM) cell-effective concentrations for OS cells in culture. The average terminal half-life was 4.57 hours for NS and 3.23 hours for niclosamide. Three dogs developed metastatic disease on carboplatin and did not receive mNSPT. The median time to tumor progression and OS of the 7 treated dogs was 510 and 632 days, respectively, with 3 dogs living > 4 years. RESULTS: The results support further translational investigation of this novel therapeutic approach to OS treatment in a randomized, prospective phase III study in dogs and, if successful, ultimately in OS patients. CLINICAL RELEVANCE: These results suggest that niclosamide-when transformed into the highly bioavailable NSPT-may have potential as a novel therapeutic agent for treating OS.