Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours (TARDOX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02181075
Recruitment Status : Completed
First Posted : July 3, 2014
Last Update Posted : August 3, 2017
Oxford University Hospitals NHS Trust
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.

Condition or disease Intervention/treatment Phase
Liver Tumour Drug: lyso-thermosensitive liposomal (LTSL) doxorubicin Phase 1

Detailed Description:

The study is split into two parts. Part I will identify 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 will be reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry. Part II, which does not require thermistor implantation, is designed to reflect how the therapy would be implemented in clinical practice. All evaluable participants from both Part I and Part II will be included in the endpoint analysis.

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.

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.

This single centre trial is sponsored by the University of Oxford. The recruiting study site will be Oxford University Hospitals NHS Trust. Both have extensive clinical FUS experience. The first extracorporeal FUS device in Europe was used for a study performed at Oxford between 2002 and 2004.

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.

Patients receive treatment for 1 day and are followed up for 30 days.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
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

Intervention Details:
  • Drug: lyso-thermosensitive liposomal (LTSL) doxorubicin
    ThermoDox® infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)
    Other Name: ThermoDox®

Primary Outcome Measures :
  1. To determine whether targeted release of doxorubicin from ThermoDox® ('drug') using mild hyperthermia generated noninvasively by focused ultrasound (FUS) is feasible in cancer patients [ Time Frame: Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1) ]
    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, in at least 50% of evaluable participants. Analytical chemistry performed on section of biopsy sample within 72 hours of intervention.

Secondary Outcome Measures :
  1. (Part I only) To determine optimal FUS exposure parameters for a range of participant Body Mass Indices (BMIs) and tumour locations within the liver [ Time Frame: Real-time thermometry monitoring during intervention, comparison of samples taken at timepoints during intervention (Day 1) and collection of AEs up to 30 days post intervention. ]
    Quantifiable measures: desired range of mild hyperthermia in the target tissue, Thermal tissue damage induced by FUS exposure in the absence of released drug, thermal tissue damage induced by FUS exposure in the absence of released drug and adverse events deemed related to FUS.

  2. (Part II Only) To assess the safety of FUS-induced mild hyperthermia for drug delivery without real-time thermometry [ Time Frame: Quantity and severity of adverse events deemed related to FUS up to 30 days post-intervention. ]
  3. To assess the local and systemic cytotoxic effects of ThermoDox® in this setting [ Time Frame: Quantity and severity of adverse events deemed related to ThermoDox® up to 30 days post-intervention and Quantity of Grade 3 and 4 laboratory results from blood tests at Day 1 and Day 15 post intervention ]

Other Outcome Measures:
  1. To determine therapeutic effect on the target tumour [ Time Frame: Scans will be performed at two timepoints within 60 days of intervention. ]
    RECIST response evaluation [1, 2] based on the follow-up pCT scan(s), MRI scan(s) and FDG PET-CT scan(s) demonstrating most significant response . The baseline scans are used as the comparator.

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

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 identifier (NCT number): NCT02181075

United Kingdom
Oxford University Hospitals NHS Trust
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
University of Oxford
Oxford University Hospitals NHS Trust
Principal Investigator: Mark R Middleton, PhD, FRCP University of Oxford

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: University of Oxford Identifier: NCT02181075     History of Changes
Other Study ID Numbers: OCTO_040
2014-000514-61 ( EudraCT Number )
First Posted: July 3, 2014    Key Record Dates
Last Update Posted: August 3, 2017
Last Verified: August 2017

Keywords provided by University of Oxford:
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:
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action