Liver Tumour Clinical Trial
Official title:
A Proof of Concept Study to Investigate the Feasibility of Targeted Release of Doxorubicin From Lyso-thermosensitive Liposomal (LTSL) Doxorubicin (ThermoDox®) Using Focused Ultrasound in Patients With Primary or Secondary Liver Tumours
This proof of concept study proposes targeted delivery of a broad-spectrum cytotoxic agent
(doxorubicin), via a specially formulated LTSL (ThermoDox®) activated by mild hyperthermia,
by using focused ultrasound (FUS), to achieve enhanced intra-tumoural doxorubicin
concentrations for the same systemic dose.
Adult patients with incurable confirmed hepatic primary or secondary tumours received a
single cycle of LTLD, followed by ultrasound-mediated hyperthermia to a single target liver
tumour. The primary endpoint relates to evidencing enhanced delivery of doxorubicin from LTLD
at the target tumour site, by comparing intratumoural concentrations of the drug before and
after focused ultrasound (FUS) exposure.
To date, purely pharmacological approaches have failed to address what is essentially a
threefold challenge: (i) to deliver therapeutically significant concentrations of active
agents to the tumour vasculature while minimizing off target effects; (ii) to release the
therapeutic agent 'on-demand' at the target site; and, (iii) to improve the distribution and
spread of the therapeutic agent against the intra-tumoural pressure gradient in order to
achieve a therapeutically relevant concentration throughout the tumour.
Recent pre-clinical studies performed at Oxford using ThermoDox® released using FUS has shown
that increased uptake at the target site is achievable. Hence there is great promise in using
this combination therapy to achieve increased tumour uptake and local dose for the equivalent
dose of doxorubicin used in systemic chemotherapy for human subjects, which has a well
established and safe toxicity profile. The first extracorporeal FUS device in Europe was used
for a study performed at Oxford between 2002 and 2004.
This single centre trial was sponsored by the University of Oxford. The recruiting study site
was Oxford University Hospitals NHS Trust, where there is extensive clinical FUS experience.
The study is split into two parts. Part I identified optimal FUS exposure parameters for a
range of patient BMIs and tumour locations within the liver using real time thermometry data
from an implanted thermistor. After at least 5 and no more than 14 participants have had the
intervention using real-time thermometry, data was reviewed by the Trial Management Group
(TMG) to confirm readiness to proceed without real-time thermometry. Part II, which did not
require thermistor implantation, is designed to reflect how the therapy would be implemented
in clinical practice.
Participants received treatment for 1 day and are followed up for 30 days. All evaluable
participants from both Part I and Part II were included in the endpoint analysis. Doxorubicin
concentrations were directly determined from tissue biopsies of the target tumour, using a
Good Laboratory Practice-validated high performance liquid chromatography (HPLC) assay, based
on previously published methods.
If this study demonstrates successful targeted drug delivery in human subjects using LTSLs
released by mild-hyperthermia, this could potentially transform the future of chemotherapy in
clinical practice; targeted therapy using LTSLs containing other chemotherapeutic agents
triggered non-invasively by mild hyperthermia could be applied to any solid organ cancer.
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