TARDOX: Early Results of a Phase I Study of Targeted Delivery of Lyso-Thermosensitive Liposomal Doxorubicin (ThermoDox®) By Focused-Ultrasound Hyperthermia for Liver Tumours


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Paul Lyon1,Lang'O Odondi1,Lucy Boyle1,Christophoros Mannaris2,Michael Gray2,Daniel Chung3,Aarti Shah3,Robert Carlisle4,Feng Wu5,Mark Middleton4,Fergus Gleeson3,Constantin Coussios2
1University of Oxford,2Institute of Biomedical Engineering, University of Oxford, Oxford, UK,3Department of Radiology, Oxford University Hospitals, Oxford, UK,4Department of Oncology, University of Oxford, Oxford, UK,5Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford

Abstract

Background

The TARDOX study (Oxford, UK, NCT02181075) is a Phase I first-in-man proof-of-concept study which aims to demonstrate the safety and feasibility of targeted drug delivery using lyso-thermosensitive liposomal systems in combination with mild hyperthermia delivered non-invasively using focused-ultrasound (FUS). The primary endpoint of the study concerns demonstration of enhanced intratumoural delivery of Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) to liver tumours when released locally by FUS hyperthermia.

At the time of writing five patients have received intervention; a single treatment cycle of ThermoDox® combined with FUS to a single target liver tumour using the ultrasound-guided extracorporeal FUS device (Model JC200 Focused Ultrasound Tumor Therapeutic System, Haifu Medical) under real-time thermometry.

Method

Each treatment was performed under a general anaesthetic. An 18-gauge co-axial needle was placed under ultrasound-guidance into the target tumour, allowing interchange of a thermometry device or a core biopsy needle. Shortly following the intravenous ThermoDox® infusion, the FUS beam was moved transcostally through the target tumour volume, to induce bulk hyperthermia of 40-44°C. Heating strategies were optimised based upon ex vivo liver tissue experiments using the same system (presented at 3rd European Symposium on FUS Therapy, London 2015).

Core tumour biopsies were taken a) prior to drug infusion, b) following completion of drug infusion, and, c) following FUS, for analysis of intratumoral doxorubicin concentration and microscopy studies. Plasma samples were taken at simultaneous time points for pharmacokinetic analysis.

MRI, CT and PET-CT scans were performed the day prior to treatment and post-treatment with clinical review, and the target tumour was assessed for response. 

 

Results

We present safety, thermometry and pharmacokinetic data and radiological outcomes.

Conclusion

We demonstrate the use of LTLD with extra-corporeal FUS hyperthermia for targeted drug delivery in human liver tumours is feasible, safe and can enhance intratumoral delivery of doxorubicin for a given systemic dose relative to LTLD alone.