Targeted Chemotherapy Using Focused Ultrasound for Liver Metastases (TARDOX)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Oxford
Sponsor:
Collaborators:
Oxford University Hospitals NHS Trust
Celsion
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT02181075
First received: July 1, 2014
Last updated: July 10, 2014
Last verified: July 2014
  Purpose

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, to achieve enhanced intra-tumoural doxorubicin concentrations for the same systemic dose.


Condition Intervention Phase
Patients With Liver Metastases From Lung, Breast or Colorectal Primary Tumours.
Drug: lyso-thermosensitive liposomal (LTSL) doxorubicin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Bio-availability Study
Intervention Model: Single Group Assignment
Masking: 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 Liver Metastases From Lung, Breast or Colorectal Primary Tumours

Resource links provided by NLM:


Further study details as provided by University of Oxford:

Primary Outcome Measures:
  • To determine whether targeted release of doxorubicin from ThermoDox® ('drug') using mild hyperthermia generated noninvasively by focused ultrasound (HIFU) is feasible in cancer patients [ Time Frame: Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1) ] [ Designated as safety issue: No ]
    A demonstrable two-fold increase in*, or value exceeding 10μg/g of, the concentration of intra-tumoural doxorubicin at the treated tumour site following HIFU-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:
  • (Part I only) To determine optimal HIFU 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. ] [ Designated as safety issue: No ]
    Quantifiable measures: desired range of mild hyperthermia in the target tissue, Thermal tissue damage induced by HIFU exposure in the absence of released drug, thermal tissue damage induced by HIFU exposure in the absence of released drug and adverse events deemed related to HIFU.

  • (Part II Only) To assess the safety of HIFU-induced mild hyperthermia for drug delivery without real-time thermometry [ Time Frame: Quantity and severity of adverse events deemed related to HIFU up to 30 days post-intervention. ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • To determine therapeutic effect on the target tumour [ Time Frame: Part I: Scans to be performed on day 15 & 30 post-intervention. Part II: Scan(s) to be performed within 30 days of intervention on day(s) to be determined by Part I. ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 28
Study Start Date: July 2014
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
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®
Detailed Description:

The study is split into two parts. Part I will identify optimal HIFU 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 HIFU experience. The first extracorporeal HIFU device in Europe was used for a study performed at Oxford from 20022004.

Recent pre-clinical studies performed at Oxford using ThermoDox® released using HIFU 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pathologically confirmed lung, breast or colorectal cancer with liver metastasis suitable for intervention (as assessed in screening ultrasound exam).
  • Will have progressed 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 previously received any doxorubicin or epirubicin.
  • Pregnant or breast-feeding. In women of childbearing potential, a negative pregnancy test (serum) is required within 14 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 radiological evidence demonstrating that the target tumour has invaded into the digestive tract, respiratory tract or compresses or invades the wall of a major vessel.
  • 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 other concurrent malignancy (patients with treated squamous cell carcinoma of the skin or basal cell carcinoma of the skin may be included) or on-going, 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. Tense ascites
    2. Suspected liver haemangioma or other vascular tumour
    3. Extra-hepatic biliary obstruction
    4. Known cystic liver disease
  • Other medical or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02181075

Contacts
Contact: Lucy Boyle 01865 227 190 TARDOX@octo-oxford.ox.ac.uk
Contact: Sylwia Kopijasz 01865 227 196 TARDOX@octo-oxford.ox.ac.uk

Locations
United Kingdom
Oxford University Hospitals NHS Trust Recruiting
Oxford, United Kingdom, OX3 7LE
Principal Investigator: Mark R Middleton, PhD, FRCP         
Sponsors and Collaborators
University of Oxford
Oxford University Hospitals NHS Trust
Celsion
Investigators
Principal Investigator: Mark R Middleton, PhD, FRCP University of Oxford
  More Information

Additional Information:
No publications provided

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02181075     History of Changes
Other Study ID Numbers: OCTO_040, 2014-000514-61
Study First Received: July 1, 2014
Last Updated: July 10, 2014
Health Authority: United Kingdom: Research Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency

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:
Neoplasm Metastasis
Liver Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 19, 2014