Liver TumourPhase 1TARDOXNCT02181075
Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours
A Phase 1 study testing ThermoDox® (LTLD), Focused Ultrasound of Target Liver Tumour and Pre-LTLD Biopsy of Target Liver Tumour in people with Liver Tumour, run by University of Oxford at 1 site in United Kingdom.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Tumour
- What is being tested?
- ThermoDox® (LTLD), Focused Ultrasound of Target Liver Tumour and Pre-LTLD Biopsy of Target Liver Tumour
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Jul 2014to Apr 2017
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Pathologically confirmed advanced solid tumour with liver metastasis suitable for intervention (as assessed by ultrasound or other radiological methods). In addition confirmed primary liver tumours (hepatocellular carcinoma or cholangiocarcinoma) can be included.
- Will have progressed or remained stable on conventional chemotherapy.
- Male or Female, Age ≥ 18 years.
- Have life expectancy of ≥ 3 months.
- Left Ventricular Ejection Fraction (LVEF) ≥ 50% on echocardiogram.
- Have not received radiotherapy to the target area within the preceding 12 months.
- A World Health Organisation (WHO) performance status of ≤ 1 - Able and willing to give written informed consent, indicating that they are aware of the investigational nature of this study and potential risks, and able to comply with the protocol for the duration of the study, including scheduled follow-up visits and examinations.
Who cannot join
- Have surgery or other procedure requiring general anaesthesia planned to be undertaken during the period of the study.
- Have serious illnesses including, but not limited to, congestive heart failure (NYHA class III or IV functional classification); life threatening cardiac arrhythmia; or myocardial infarction or cerebral vascular accident within the last 6 months.
- Have on going significant infection (chest, urine, blood, intra-abdominal).
- Have uncontrolled diabetes.
- Have Have received a life-time dose of doxorubicin > 450 mg/m2 or a life-time dose of epirubicin > 900 mg/m2 or any dose of both.
- Pregnant or breast-feeding. In women of childbearing potential, a negative pregnancy test (serum) is required within 30 days prior to study intervention.
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- Female participants of child bearing potential and male participants whose partner is of child bearing potential who are not willing to practice an acceptable form of contraception (i.e. oral contraceptive, diaphragm, cervical cap, condom, surgical sterility) during the study and for 6 months thereafter. Women whose partner has or men who have undergone a vasectomy must use a second form of birth control.
- Have any known allergic reactions to any of the drugs or liposomal components or intravenous imaging agents to be used in this study.
- Have portal or hepatic vein tumour invasion/thrombosis.
- Inadequate haematological and biochemical function (as listed in protocol)
- Have contraindications to receiving doxorubicin including prior sensitivity (rash, dyspnoea, wheezing, urticarial or other symptoms) attributed to anthracyclines or other liposomal drugs.
- Use of chemotherapy or of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the intervention.
- Have medically significant active infection.
- Have Child-Pugh Class C liver disease, or Class A-B with encephalopathy and/or refractory ascites.
- Documented HIV positive.
- Documented diagnosis of haemochromatosis.
- Documented history of contrast-induced nephropathy.
- Have any of the following contraindications for liver biopsy:
- Suspected liver haemangioma or other vascular tumour
- Tense ascites
- Known cystic liver disease*
- Extra-hepatic biliary obstruction*
- ( Relative contraindications only and may be non-exclusive at discretion of the study team)
- Other medical or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Oxford University Hospitals NHS Trust
Oxford, OX3 7LE
About this study
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.
Read the detailed description
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.
- Conditions
- Liver Tumour
- Being tested
- ThermoDox® (LTLD), Focused Ultrasound of Target Liver Tumour, Pre-LTLD Biopsy of Target Liver Tumour, Post-LTLD Biopsy of Target Liver Tumour, Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour
- Keywords
- ThermoDox, High Intensity Focused Ultrasound, Lyso thermosensitive Liposomal, Non invasive drug delivery, Hepatic metastatic disease, Liver tumour(s), Targeted Release of Chemotherapy
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ThermoDox® (LTLD)Drug
Also called Lyso-thermosensitive Liposomal Doxorubicin
ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)
Focused Ultrasound of Target Liver TumourDevice
Whilst the ThermoDox® was circulating in the blood stream, the JC200 Therapeutic Ultrasound device was used to induce mild hyperthermia in a single (region of) a target liver tumour.
Pre-LTLD Biopsy of Target Liver TumourDiagnostic test
Post-LTLD Biopsy of Target Liver TumourDiagnostic test
Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver TumourDiagnostic test
Thermometry of Target TumourDevice
A clinically approved thermistor or thermocouple was placed in the target liver tumour for real-time thermometry.
| Study group | Role | What they receive |
|---|---|---|
| Part I | Experimental | All participants in Part I received:
Pre-LTLD Biopsy of Target Liver Tumour ThermoDox® (LTLD) Post-LTLD Biopsy of Target Liver Tumour Focused Ultrasound of Target Liver Tumour Thermometry of Target Tumour Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour
Part I of the study was designed to identify optimal focused ultrasound (FUS) exposure parameters for a range of tumour locations within the liver, using real-time thermometry data from an implanted thermometry device (a thermistor or thermocouple). Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post-LTLD+FUS. Receives: Drug: ThermoDox® (LTLD); Device: Focused Ultrasound of Target Liver Tumour; Diagnostic Test: Pre-LTLD Biopsy of Target Liver Tumour; Diagnostic Test: Post-LTLD Biopsy of Target Liver Tumour; Diagnostic Test: Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour; Device: Thermometry of Target Tumour |
| Part II | Experimental | All participants in Part II received:
ThermoDox® (LTLD) Focused Ultrasound of Target Liver Tumour Post-LTLD Biopsy of Target Liver Tumour
Following a minimum of 5 Part I cases, and subject to Trial Management Group approval, Part II of the study was opened to run in parallel to Part I. Part II did not require implantation of a thermometry device, and instead used predictions from Part I data to set the FUS parameters. Targeted drug delivery in Part II thus proceeded completely non-invasively, and this part of the study was designed to more closely reflect how the therapy might be implemented in routine clinical practice. Plasma samples were taken pre-LTLD, post-LTLD and post-LTLD+FUS. Biopsy samples of the target liver tumour were taken only post-LTLD+FUS. Receives: Drug: ThermoDox® (LTLD); Device: Focused Ultrasound of Target Liver Tumour; Diagnostic Test: Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour |
What is being measured
The primary outcome is the main question the study is designed to answer.
Concentration of Total Intratumoral Doxorubicin in Liver Tumour (Biopsies) Following Targeted Release of Doxorubicin From ThermoDox® ('Drug') Using Mild Hyperthermia Generated Non-invasively by Focused Ultrasound (FUS)
Analytical chemistry (High Performance Liquid Chromatography) for total doxorubicin (including both released and unreleased forms) was performed on section of intratumoral biopsy samples in Good Clinical Practice Laboratory, using a validated assay.
Doxorubicin concentration was evaluated in biopsy samples both post-LTLD and post-LTLD+FUS.
Tumour samples were not analysed same day and were frozen at -80^oC for subsequent analysis. Required to evaluate the primary endpoint.
Measured: Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1)
Patients Demonstrating >Two-fold Increase in the Amount of Intratumoural Doxorubicin Before and After Focused Ultrasound
To satisfy the primary endpoint, a demonstrable two-fold increase in*, or value exceeding 10μg/g of, the concentration of intra-tumoural doxorubicin at the treated tumour site following FUS-induced mild hyperthermia, was required in at least 50% of evaluable participants.
- As per the a priori protocol design, in Part II the biopsy prior to FUS-induced mild hyperthermia is not performed and therefore the average value for all evaluable tumours receiving intervention in Part I is used as a comparison for the two-fold increase from pre-FUS to post-FUS biopsy.
Measured: Post-LTLD+FUS sample (Day 1) compared to Post-LTLD sample (Day 1)
Secondary outcomes (4)
(Part I Only) Achievement of Satisfactory Hyperthermia Within the Target Liver Tumour for a Range of Participant Body Mass Indices (BMIs) and Tumour Locations Within the Liver (Optimal FUS Exposure Parameters)
Achievement of hyperthermia in the target liver tumour, as determined by real-time thermometry obtained by an indwelling thermometry device.
For success, sustained and controlled hyperthermia is required in the target tumour, consequent with drug release (in excess of 39.5^oC). Real time thermometry plots for each Part I patient are available in the key Lancet Oncology publication, details available in the References section.
Measured: Real-time thermometry monitoring during intervention (Day 1)
Persistence of Cell Viability Stain Post-LTLD+FUS
Post-LTLD+FUS tissue from the targeted liver tumours was obtained by biopsy at the time of the intervention, between 24/03/2015 and 29/03/2017. Cytokeratin-8 (CK-8) is a cell viability marker which if present, demonstrates lack of ablative cell death by any ablative modality, including FUS.
Not all histological cell types express CK8, thus if the Post-LTLD+FUS it may either indicate:
- Non-CK8 expression ii) Thermal ablation and consequent cell death.
Note there was uncertainty about CK8 expression of individual patient tumours prior to recruitment. In this study if the Post-LTLD+FUS tissue shows specific cellular CK8 cellular staining, then it demonstrates that i) the tumour is CK8+, and, ii) the tumour was not instantaneously thermally ablated and any subsequent cell death is likely due to drug delivery/chemo-ablation.
For more information see key TARDOX Lancet Oncology publication and Cytokeratin 8 reference (both detailed in References section).
Measured: Tissue obtained on day of intervention (Day 1). All CK8 cell viability staining was performed within 2 months of sampling.
Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to ThermoDox (LTLD)
Adverse Events are listed separately in the subsequent results, but were also specified as a secondary endpoint in the a priori protocol and thus significant events are summarised here.
'Definitely' or 'Probably' related events are included.
Measured: Up to 30 days post-intervention (Day 1-30)
Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to FUS Procedure
Adverse Events are listed separately in the subsequent results, but were also specified as a secondary endpoint in the a priori protocol and thus significant events are summarised here.
'Definitely' or 'Probably' related events are included.
Measured: Up to 30 days post-intervention (Day 1-30)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jul 2014 (estimated)
- Study startJul 2014
- Primary completionMar 2017
- Study completionApr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Liver TumourStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary, detailed in References section. After a minimum of 5 patients were treated in Part 1 (Arm 1), Part 2 (Arm 2) of the study could be opened.
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Oxford University Hospitals NHS Trust, Imunon
- Responsible party
- Sponsor
- Investigators
- Mark R Middleton, PhD, FRCP, Principal investigator, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02181075
- Sponsor's protocol ID
- OCTO_040
- Other IDs
- 2014-000514-61, 2014
- Acronym
- TARDOX
- Status last verified
- Nov 2018
- First submitted
- 1 Jul 2014
- Last updated
- 22 Jul 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: Key patient data with tumour characteristics is available in the Lancet Oncology clinical paper (https://doi.org/10.1016/S1470-2045(18)30332-2).
Publications
Lyon PC, Griffiths LF, Lee J, Chung D, Carlisle R, Wu F, Middleton MR, Gleeson FV, Coussios CC. Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox(R)) using focused ultrasound in patients with liver tumours. J Ther Ultrasound. 2017 Nov 2;5:28. doi: 10.1186/s40349-017-0104-0. eCollection 2017.
PubMed 29118984Kreb DL, Bosscha K, Ernst MF, Rutten MJ, Jager GJ, van Diest PJ, van der Linden JC. Use of cytokeratin 8 immunohistochemistry for assessing cell death after radiofrequency ablation of breast cancers. Biotech Histochem. 2011 Dec;86(6):404-12. doi: 10.3109/10520295.2010.517473. Epub 2010 Oct 18.
PubMed 20950219Lyon PC, Gray MD, Mannaris C, Folkes LK, Stratford M, Campo L, Chung DYF, Scott S, Anderson M, Goldin R, Carlisle R, Wu F, Middleton MR, Gleeson FV, Coussios CC. 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. Lancet Oncol. 2018 Aug;19(8):1027-1039. doi: 10.1016/S1470-2045(18)30332-2. Epub 2018 Jul 11.
PubMed 30001990Gray MD, Lyon PC, Mannaris C, Folkes LK, Stratford M, Campo L, Chung DYF, Scott S, Anderson M, Goldin R, Carlisle R, Wu F, Middleton MR, Gleeson FV, Coussios CC. Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I Trial. Radiology. 2019 Apr;291(1):232-238. doi: 10.1148/radiol.2018181445. Epub 2019 Jan 15.
PubMed 30644817