Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours
Condition: Liver Tumour
MeSH terms: Liver Neoplasms
Intervention: 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; Thermometry of Target Tumour
Intervention description: ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1); 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.; A clinically approved thermistor or thermocouple was placed in the target liver tumour for real-time thermometry.
Intervention MeSH terms: Doxorubicin; Liposomal doxorubicin; Liver Extracts
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
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)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ThermoDox; High Intensity Focused Ultrasound; Lyso thermosensitive Liposomal; Non invasive drug delivery; Hepatic metastatic disease; Liver tumour(s); Targeted Release of Chemotherapy

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.
    

Eligibility 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.