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Digestive System Diseases

Rare Diseases

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Digestive System Neoplasms

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All Drugs and Chemicals

Technetium Tc 99m Aggregated Albumin

Patients receive routine pre-therapy technetium Tc 99m-labeled macroaggregated albumin. Patients then undergo routine radioembolization with yttrium Y 90 resin microspheres. Within 36 hours after radioembolization, patients undergo PET/CT imaging.

positron emission tomography

computed tomography

Michael Knopp, MD, PhD

This pilot clinical trial studies positron emission tomography (PET)/computed tomography (CT) in finding beads after Yttrium-90 bead therapy in patients with primary liver cancer or cancer that has spread to the liver (metastatic) that can not be removed by surgery. Imaging procedures, such as PET/CT after Yttrium-90 bead therapy, may help see if the beads are present in the lung and compare the results with the pre-therapy imaging.

PRIMARY OBJECTIVES:

I. To estimate the absolute difference in post-therapy Yttrium-90 microsphere hepatopulmonary shunt fraction and the pre-therapy Technetium-99m macroaggregated albumin hepatopulmonary shunt fraction in patients with unresectable primary hepatic malignancy and hepatic metastatic disease.

SECONDARY OBJECTIVES:

I. To quantify and compare the pre-therapy Technetium-99m macroaggregated albumin particle sizes and post-therapy Yttrium-90 microsphere sizes.

OUTLINE:

Patients receive routine pre-therapy Technetium-99m macroaggregated albumin. Patients then undergo routine radioembolization with Yttrium-90 microspheres. Within 36 hours after radioembolization, patients undergo PET/CT imaging.

Available imaging, clinical, interventional and surgical follow-up data for 2 years after completion of enrollment in the study will be obtained.

Pilot Study to Assess Lung Shunting of Yttrium-90 Microspheres Using PET/CT

PET/CT-Derived Hepatopulmonary Shunt Fraction Following Yttrium-90 Radioembolization

Non-parametric Wilcoxon signed rank testing will be used to compare the 99mTc MAA and 90Y microsphere shunt fractions. Alternatively, a natural log transformation of the hepatopulmonary shunt fractions may be used to normalize these data for subsequent parametric paired t-test analysis.

Descriptive statistical assessment of Technetium-99m macroaggregated albumin particle size and microsphere size for each patient (e.g., mean, median, standard deviation, distribution, etc.) will be performed.

University of Cincinnati

Principal Investigator

Central Nervous System Depressants

Antineoplastic Agents

Hematinics

Anti-Infective Agents

Anesthetics

Doxorubicin

Liposomal doxorubicin

Liver Extracts

Anesthetics, General

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

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.

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.

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

ThermoDox® (LTLD)

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.

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

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

Thermometry of Target Tumour

Mark R Middleton, PhD, FRCP

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.

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.

Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours

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

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

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.

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.

Achievement of hyperthermia in the target liver tumour, as determined by real-time thermometry obtained by an indwelling thermometry device.

For success, sustained and controlled hyperthermia is required in the target tumour, consequent with drug release (in excess of 39.5\^oC). Real time thermometry plots for each Part I patient are available in the key Lancet Oncology publication, details available in the References section.

Post-LTLD+FUS tissue from the targeted liver tumours was obtained by biopsy at the time of the intervention, between 24/03/2015 and 29/03/2017. Cytokeratin-8 (CK-8) is a cell viability marker which if present, demonstrates lack of ablative cell death by any ablative modality, including FUS.

Not all histological cell types express CK8, thus if the Post-LTLD+FUS it may either indicate:

i) Non-CK8 expression ii) Thermal ablation and consequent cell death.

Note there was uncertainty about CK8 expression of individual patient tumours prior to recruitment. In this study if the Post-LTLD+FUS tissue shows specific cellular CK8 cellular staining, then it demonstrates that i) the tumour is CK8+, and, ii) the tumour was not instantaneously thermally ablated and any subsequent cell death is likely due to drug delivery/chemo-ablation.

For more information see key TARDOX Lancet Oncology publication and Cytokeratin 8 reference (both detailed in References section).

Adverse Events are listed separately in the subsequent results, but were also specified as a secondary endpoint in the a priori protocol and thus significant events are summarised here.

'Definitely' or 'Probably' related events are included.

Oxford University Hospitals NHS Trust

Imunon

University of Oxford

Part I (Patients Enrolled Between March 2015-April 2017)

Part II (Patients Enrolled Between June 2016-Feb 2017)

Part I

Part II

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United Kingdom

Region of Enrollment

Body Mass Index

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

Sarah Pearson, Trial Management Director

A paired t-test was used for Part I (Arm 1) only. Analysis only applies to Part I (Arm 1) because only this study arm has matched Post-LTLD (i.e. post-drug alone) and Post-LTLD+FUS biopsy samples obtained from the same liver tumours before and after targeted drug delivery. In Part II of the study design in which drug delivery occurred completely non-invasively, no Post-LTLD tissue sample is obtained and only a single tumour biopsy is obtained following drug delivery (Post-LTLD+FUS).

Pre-FUS Intratumoural Doxorubicin Concentration

Post-FUS Intratumoural Doxorubicin Concentration

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). Patients in Part I receive a single cycle of Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) intravenously, at a dose of of 50 mg/m2. After a minimum of five patients have received the Part I intervention with real-time thermometry, data was reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry in Part II of the study. Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post-LTLD+FUS.

Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

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. Parts I and II of the study are not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

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)

Patients Demonstrating >Two-fold Increase in the Amount of Intratumoural Doxorubicin Before and After Focused Ultrasound

Part I (July 2014-July 2017)

Part II (May 2016-July 2017)

In Part II there was no real-time thermometry and this endpoint only applies to Part I patients.

(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)

5/6 Part I patients and 4/4 Part II patients had tissue which was analysable for CK-8. The Outcome Measure Data Table demonstrates the number of patients from each arm having CK-8 positive tumour biopsy samples post-LTLD+FUS, indicating lack of thermal ablation (which is consistent with desired hyperthermia rather than undesirable FUS ablation).

Persistence of Cell Viability Stain Post-LTLD+FUS

Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to ThermoDox (LTLD)

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

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). Patients in Part I receive a single cycle of Lyso- Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) intravenously, at a dose of of 50 mg/m2. After a minimum of five patients have received the Part I intervention with real-time thermometry, data was reviewed by the Trial Management Group (TMG) to confirm readiness to proceed without real-time thermometry in Part II of the study. Plasma and biopsy samples of the target liver tumour were taken pre-LTLD, post-LTLD and post- LTLD+FUS.

Parts I and II of the study were not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

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.

Parts I and II of the study are not randomised, and both Parts of the study are detailed further in the published protocol summary (https://doi.org/10.1186/s40349-017-0104-0).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pilot Study to Assess Lung Shunting of Yttrium-90 Microspheres Using PET/CT	NCT02119065	Advanced Adult ... Liver Metastase... Localized Unres... Recurrent Adult...	positron emissi... computed tomogr...	18 Years -	University of Cincinnati
Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours	NCT02181075	Liver Tumour	ThermoDox® (LTL... Focused Ultraso... Pre-LTLD Biopsy... Post-LTLD Biops... Post-LTLD+FUS (... Thermometry of ...	18 Years -	University of Oxford

Spots Global Cancer Trial Database for hepatic metastatic disease