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Trial record 30 of 38 for:    focused ultrasound | met

Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours (TARDOX)

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ClinicalTrials.gov Identifier: NCT02181075
Recruitment Status : Completed
First Posted : July 3, 2014
Results First Posted : June 24, 2019
Last Update Posted : July 22, 2019
Sponsor:
Collaborators:
Oxford University Hospitals NHS Trust
Celsion
Information provided by (Responsible Party):
University of Oxford

Brief 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.

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.


Condition or disease Intervention/treatment Phase
Liver Tumour 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 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Study Start Date : July 2014
Actual Primary Completion Date : March 2017
Actual Study Completion Date : April 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Doxorubicin

Arm Intervention/treatment
Experimental: Part I

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.

Drug: ThermoDox® (LTLD)
ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)
Other Name: Lyso-thermosensitive Liposomal Doxorubicin

Device: Focused Ultrasound of Target Liver Tumour
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.

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
A clinically approved thermistor or thermocouple was placed in the target liver tumour for real-time thermometry.

Experimental: Part II

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.

Drug: ThermoDox® (LTLD)
ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)
Other Name: Lyso-thermosensitive Liposomal Doxorubicin

Device: Focused Ultrasound of Target Liver Tumour
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.

Diagnostic Test: Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour



Primary Outcome Measures :
  1. 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) [ Time Frame: Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1) ]

    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.


  2. Patients Demonstrating >Two-fold Increase in the Amount of Intratumoural Doxorubicin Before and After Focused Ultrasound [ Time Frame: Post-LTLD+FUS sample (Day 1) compared to Post-LTLD sample (Day 1) ]

    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.



Secondary Outcome Measures :
  1. (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) [ Time Frame: Real-time thermometry monitoring during intervention (Day 1) ]

    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.


  2. Persistence of Cell Viability Stain Post-LTLD+FUS [ Time Frame: Tissue obtained on day of intervention (Day 1). All CK8 cell viability staining was performed within 2 months of sampling. ]

    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:

    i) 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).


  3. Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to ThermoDox (LTLD) [ Time Frame: Up to 30 days post-intervention (Day 1-30) ]

    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.


  4. Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to FUS Procedure [ Time Frame: Up to 30 days post-intervention (Day 1-30) ]

    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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • 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:

    1. Suspected liver haemangioma or other vascular tumour
    2. Tense ascites
    3. Known cystic liver disease*
    4. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02181075


Locations
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United Kingdom
Oxford University Hospitals NHS Trust
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
University of Oxford
Oxford University Hospitals NHS Trust
Celsion
Investigators
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Principal Investigator: Mark R Middleton, PhD, FRCP University of Oxford
  Study Documents (Full-Text)

Documents provided by University of Oxford:
Study Protocol  [PDF] April 6, 2016
Statistical Analysis Plan  [PDF] July 22, 2016


Additional Information:
Publications of Results:
Other Publications:
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02181075     History of Changes
Other Study ID Numbers: OCTO_040
2014-000514-61 ( EudraCT Number )
First Posted: July 3, 2014    Key Record Dates
Results First Posted: June 24, 2019
Last Update Posted: July 22, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Key patient data with tumour characteristics is available in the Lancet Oncology clinical paper (https://doi.org/10.1016/S1470-2045(18)30332-2).
Keywords provided by University of Oxford:
ThermoDox
High Intensity Focused Ultrasound
Lyso thermosensitive Liposomal
Non invasive drug delivery
Hepatic metastatic disease
Liver tumour(s)
Targeted Release of Chemotherapy
Additional relevant MeSH terms:
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Liver Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Doxorubicin
Liposomal doxorubicin
Liver Extracts
Hematinics
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action