Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Abstract

SummaryBackgroundPrevious preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.MethodsWe did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.FindingsBetween March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.InterpretationThe combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.FundingOxford Biomedical Research Centre, National Institute for Health Research.

Nanoparticles in the clinic: An update

“…NCT02181075 (Ph I): Published results highlight how ThermoDox in combination with externally induced mild hyperthermia increase intratumoral concentration of dox by 3.7 times as compared to ThermoDox without hyperthermia induction …”

Towards a multiphysics modelling framework for thermosensitive liposomal drug delivery to solid tumour combined with focused ultrasound hyperthermia

“…Localised heating can be achieved by HIFU, which is favoured for its non-invasive nature and accuracy in clinical thermal therapy (Hynynen 2011). The safety and feasibility of the combined HIFU-TSL system have been reported in a very recent clinical trial, demonstrating enhanced intratumoural drug delivery for targeted treatment of liver tumours (Lyon et al 2018). However, there is still a lack of understanding on the drug transport mechanism and tumour drug uptake in response to temperature variation upon HIFU heating.…”

Ultrasound- and microbubble-mediated targeted delivery of therapeutic microRNA-loaded nanocarriers to deep liver and kidney tissues in pigs

“…The results showed enhanced miRNA delivery in the liver and kidney, with an increase in quantified miRNA for cardiac gene transfection in pigs [35]. Importantly, US therapy was recently used in clinical trials combined with drug-loaded MBs to investigate its feasibility in the treatment of pancreatic or liver cancer patients [19], [36]. Here, we use PLGA-NPs as a delivery vector rather than encapsulating the therapeutic miRNAs directly into the MBs to increase the miRNA circulation half-life and improve the drug release profile.…”