Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours

NCT02181075 | Completed Phase 1 Results DMC

• 2 other identifiers: OCTO_0402014-000514-61
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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)

  Real-time thermometry monitoring during intervention (Day 1)

• Persistence of Cell Viability Stain Post-LTLD+FUS

  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)

  Up to 30 days post-intervention (Day 1-30)

• Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to FUS Procedure

  Up to 30 days post-intervention (Day 1-30)

Study Arms (2)

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.

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.

Drug: ThermoDox® (LTLD); Device: Focused Ultrasound of Target Liver Tumour; Diagnostic Test: Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour

Interventions

ThermoDox® (LTLD) DRUG

ThermoDox® (LTLD) infusion at a dose of 50mg/m2 whilst under general anaesthetic during intervention (Day 1)

Also known as: Lyso-thermosensitive Liposomal Doxorubicin

Part I; Part II

Focused Ultrasound of Target Liver Tumour DEVICE

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.

Part I; Part II

Pre-LTLD Biopsy of Target Liver Tumour DIAGNOSTIC_TEST

Part I

Post-LTLD Biopsy of Target Liver Tumour DIAGNOSTIC_TEST

Part I

Post-LTLD+FUS (Post-FUS) Biopsy of Target Liver Tumour DIAGNOSTIC_TEST

Part I; Part II

Thermometry of Target Tumour DEVICE

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

Part I

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead
• Oxford University Hospitals NHS Trust: collaborator
• Imunon: collaborator

Study Sites (1)

Oxford University Hospitals NHS Trust

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 29118984 BACKGROUND

• Kreb 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.

  PMID: 20950219 BACKGROUND

• Lyon 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.

  PMID: 30001990 RESULT

• Gray 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.

  PMID: 30644817 RESULT

Related Links

• Cancer Research UK Summary of TARDOX Trial \& Results

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Limitations and Caveats

Key Lancet Oncology paper (detailed in References section) addresses these limitations: 1. Laboratory limitations not detailed e.g. under/over estimates 2. Tertiary endpoints not presented

Results Point of Contact

• Title: Sarah Pearson, Trial Management Director
• Organization: Oncology Clinical Trials Group

sarah.pearson@oncology.ox.ac.uk

01865 227160

Study Officials

• Mark R Middleton, PhD, FRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 1, 2014
• First Posted: July 3, 2014
• Study Start: July 1, 2014
• Primary Completion: March 1, 2017
• Study Completion: April 1, 2017
• Last Updated: July 22, 2019
• Results First Posted: June 24, 2019

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)