TARDOX: Safety and Feasibility of Targeted Delivery of Lyso-Thermosensitive Liposomal Doxorubicin (ThermoDox®) By Focused-Ultrasound Hyperthermia for Liver Tumours

INTRODUCTION The TARDOX study (Oxford, UK, NCT02181075) is an open-label Phase I proof-of-concept study designed to demonstrate the feasibility (primary objective) and safety (secondary objective) of non-invasive targeted delivery of Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) to patients with liver tumours. Mild hyperthermia is generated by extracorporeal focused ultrasound (FUS). In Part I of the study, patients receive a single dose LTLD with a doxorubicin concentration of 50mg/m2 systemically. Immediately after infusion, a pre-identified single liver tumour target is exposed to mild hyperthermia using the ultrasound-guided extracorporeal FUS device (Model JC200 Focused Ultrasound Tumor Therapeutic System, Haifu Medical) under real-time thermometry. Part II of the study will proceed without real-time thermometry, using data from Part I, and is designed to reflect how the therapy would be implemented in routine clinical practice. METHOD Feasibility of targeted hyperthermia in the target liver tumour is assessed using an implanted thermistor or thermocouple for real-time thermometry assessment. Safety assessments are performed for 30 days post-intervention and consist of clinical, haematological and biochemical review. Adverse events are assessed for causality and expectedness and classified according to the Common Toxicity Criteria Adverse Events (NCI CTCAE, version 4.03). RESULTS We present feasibility and safety data for all the patients treated on the study to date. Presently five patients have received intervention on Part I, and optimal hyperthermia was obtained for 4/5 patients. The intervention was well tolerated and in accordance with the expected reference safety information based on data gathered from HEAT study (NCT00441376) and all clinical studies that have used ThermoDox®. A total of three serious adverse events have been reported to date and were all due to expected neutropenia. CONCLUSION Early experiences from this study have demonstrated that it is feasible and safe to combine LTLD in combination with extracorporeal focused ultrasound hyperthermia for targeted drug delivery.