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

Background: Previous 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.

Methods: We 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.

Findings: Between 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.

Interpretation: The 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.

Funding: Oxford Biomedical Research Centre, National Institute for Health Research.

Figure 1

Trial profile

Figure 2

Total doxorubicin concentration in plasma and tumour samples analysed by high-performance liquid chromatography (HPLC) (A) Lyso-thermosensitive liposomal doxorubicin (LTLD) plasma pharmacokinetic data by HPLC. Data for patient I.01 are omitted from the plot, because concentrations were much greater than the top standard, resulting in a ten-fold dilution step for plasma analysis subsequently being introduced to the assay. (B) Intratumoural pharmacokinetic data by HPLC. The post-LTLD values for patient I.02 and I.06, and the post-LTLD plus focused ultrasound (FUS) values for patient I.06 are worst-case estimates.

Figure 3

Illustrative controlled hyperthermia by focused ultrasound Real-time thermometry data (trace) captured after infusion of lyso-thermosensitive liposomal doxorubicin (LTLD) and during focused ultrasound exposure in moving beam (linear) mode for patient I.05. This trace was acquired at a 10 ms resolution by use of a calibrated Medtronic thermocouple, with custom LabView data-acquisition setup. Shaded regions represent the period when focused ultrasound was being applied. From approximately 30 s to 33 min, a 90·9 cm³ prescribed target tumour volume was exposed to focused ultrasound at 115 W (8·7 MPa peak rarefactional in situ pressure) at 70% duty cycle in linear mode. Although the release threshold was reached within 5 min of focused ultrasound exposure, heating in the first 30 min was deemed slightly suboptimal because of prolonged cooling periods between treatment cycles. Subsequently, by removing the outermost slices from the prescribed treatment volume, resulting in a smaller 68·3 cm³ tumour volume, and increasing power to 125 W (9·0 MPa derated) and duty cycle to 77%, optimal hyperthermia was achieved for 35–80 min. Once focused ultrasound stopped, the tumour was allowed to cool before the thermocouple was removed from the patient at 85 min, and a tumour biopsy sample was subsequently taken. The dotted curve is a fourth order polynomial fit, which is probably more representative of the bulk temperature in the prescribed tumour volume than the rapidly fluctuating point temperature recorded by the sensitive region of the intratumoural thermometry device (trace).