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.

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.

Key patient data with tumour characteristics is available in the Lancet Oncology clinical paper (https://doi.org/10.1016/S1470-2045(18)30332-2).