Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours

Abstract

Background: TARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox®) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC).

Methods/design: The study is conducted in two parts: Part 1 includes minimally-invasive thermometry via a thermistor or thermocouple implanted through the biopsy co-axial needle core, to confirm ultrasound-mediated hyperthermia, whilst Part 2 is carried out without invasive thermometry, to more closely mimic the ultimately intended clinical implementation of the technique. Whilst under a general anaesthetic, adult patients with incurable confirmed hepatic primary or secondary (metastatic) tumours receive a single cycle of ThermoDox®, immediately followed by ultrasound-mediated hyperthermia in a single target liver tumour. For each patient in Part 1, the HPLC-derived total doxorubicin concentration in the ultrasound-treated tumour is directly compared to the concentration before ultrasound exposure in that same tumour. For each patient in Part 2, as the tumour biopsy taken before ultrasound exposure is not available, the mean of those Part 1 tumour concentrations is used as the comparator. Success of the study requires at least a two-fold increase in the total intratumoural doxorubicin concentration, or final concentrations over 10 μg/g, in at least 50% of all patients receiving the drug, where tissue samples are evaluable by HPLC. Secondary outcome measures evaluate safety and feasibility of the intervention. Radiological response in the target tumour and control liver tumours are analysed as a tertiary outcome measure, in addition to plasma pharmacokinetics, fluorescence microscopy and immunohistochemistry of the biopsy samples.

Discussion: If this early phase study can demonstrate that ultrasound-mediated hyperthermia can effectively enhance the delivery and penetration of chemotherapy agents intratumorally, it could enable application of the technique to enhance therapeutic outcomes across a broad range of drug classes to treat solid tumours.

Trial registration: ClinicalTrials.gov Identifier: NCT02181075, Edura-CT Identifier: 2014-000514-61.Ethics Number: 14/NE/0124.

Keywords: FUS; Focused ultrasound; HIFU; Liver tumour(s); Lyso-thermosensitive liposomal doxorubicin (LTLD); Targeted drug delivery; Therapeutic ultrasound; ThermoDox®; Triggered release.

Conflict of interest statement

Ethics approval and consent to participate

The study received competent authority from the Medicine and Healthcare products Regulatory Agency (MHRA) on 12th May, 2014. Ethical approval by the North East (York) National Research Ethics Service (NRES) Committee, UK was achieved 13th May, 2014, leading to the trial being opened to recruitment on 4th July, 2014, and closing on the 31st of March, 2017. Patients are followed up for 30 days clinically and up to 60 days radiologically; the Last Patient Last Visit is therefore expected to be April or May, 2017.

Written and verbal versions of the participant information sheets and informed consent are presented to the participants by the attending investigator, and necessarily include: the exact nature of the study; the implications and constraints of the protocol; the known side effects and any risks involving in taking part. The participant is free to withdraw from the study at any time for any reason without prejudice to future care, and with no obligation to give the reason for withdrawal. The investigator will not undertake any study specific procedures until valid consent is obtained.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Study recruitment, screening, intervention, recovery and follow-up flow diagrams. (a) Flow diagrams for recruitment, screening and preparation for intervention. (b) Flow diagrams contrasting Part 1 and Part 2 interventions, and for recovery and follow-up

Fig. 2

Schematics of the Part 1 (a) and Part 2 (b) study interventions highlighting the key differences between both parts of the study. The patient lies over the degassed water bath of the FUS device (JC200), which contains an ultrasound-guided therapeutic transducer, such that the focus of the transducer is aligned with the target tumour through the relevant intercostal space. (a) Part 1 of the study involves insertion of a co-axial needle into the target liver tumour under ultrasound guidance. This needle is used to take core biopsies of the tumour before and immediately after ThermoDox® infusion, and finally after FUS-mediated delivery, which are used in evaluation of the primary endpoint. In addition, the co-axial needle is used to pass a clinically approved thermometry device during FUS exposure, for real-time thermometry. (b) Part 2 does not require a thermistor, and FUS is applied to the target tumour following ThermoDox® infusion. Targeted drug delivery is thus performed completely non-invasively. Two serial core biopsies of the target tumour are taken following the FUS exposure, and tissue is used in evaluation of the primary endpoint. Part 2 affords more flexibility in patient positioning, and the supine position shown is illustrative only

Fig. 3

Timeline of the Part 1 (a) and Part 2 (b) interventions. Timings are appropriate and are for illustrative purposes. The pharmacokinetic curve was obtained from previous published data in patients given ThermoDox® prior to radio-frequency ablation [24]. Note that in Part 2, drug delivery is performed non-invasively and the post-delivery co-axial needle and biopsy are required purely to evaluate the primary endpoint