Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours (TARDOX)
Drug: lyso-thermosensitive liposomal (LTSL) doxorubicin
|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 Primary or Secondary Liver Tumours|
- 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.
- (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 ]
- 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.
|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)|
Drug: lyso-thermosensitive liposomal (LTSL) doxorubicin
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02181075
|Contact: Lucy Boyle||01865 227 190||TARDOX@octo-oxford.org.uk|
|Contact: Sylwia Kopijasz||01865 227 196||TARDOX@octo-oxford.org.uk|
|Oxford University Hospitals NHS Trust||Recruiting|
|Oxford, United Kingdom, OX3 7LE|
|Principal Investigator: Mark R Middleton, PhD, FRCP|
|Principal Investigator:||Mark R Middleton, PhD, FRCP||University of Oxford|