Trial Outcomes & Findings for Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours (NCT NCT02181075)

Last Updated: 2019-07-22

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

10 participants

Primary outcome timeframe

Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1)

Results posted on

2019-07-22

Participant Flow

10 patients were recruited (6 to Part I of the study and 4 to Part II of the study). Patients required at least one liver tumour accessible to ultrasound. Full screening criteria are available from ClinicalTrials.gov or the published protocol summary, both detailed in the References section.

Participant milestones

Participant milestones
Measure	Part I (Patients Enrolled Between March 2015-April 2017) 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) 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).
Overall Study STARTED	6	4
Overall Study COMPLETED	6	4
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part I n=6 Participants Arm I Patients	Part II n=4 Participants Arm II Patients	Total n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United Kingdom	6 participants n=5 Participants	4 participants n=7 Participants	10 participants n=5 Participants
Body Mass Index	24.73 kg/m^2 STANDARD_DEVIATION 1.60 • n=5 Participants	29.13 kg/m^2 STANDARD_DEVIATION 5.52 • n=7 Participants	26.49 kg/m^2 STANDARD_DEVIATION 4.09 • n=5 Participants

PRIMARY outcome

Timeframe: Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1)

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 Participants 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) Pre-FUS Intratumoural Doxorubicin Concentration	2.34 ug/g of total doxorubicin(tumour biopsy) Standard Deviation 0.93	2.34 ug/g of total doxorubicin(tumour biopsy) Standard Deviation 0.93
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) Post-FUS Intratumoural Doxorubicin Concentration	7.74 ug/g of total doxorubicin(tumour biopsy) Standard Deviation 4.09	9.8 ug/g of total doxorubicin(tumour biopsy) Standard Deviation 8.12

PRIMARY outcome

Timeframe: Post-LTLD+FUS sample (Day 1) compared to Post-LTLD sample (Day 1)

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.

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 Participants 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).
Patients Demonstrating >Two-fold Increase in the Amount of Intratumoural Doxorubicin Before and After Focused Ultrasound	4 Participants	3 Participants

SECONDARY outcome

Timeframe: Real-time thermometry monitoring during intervention (Day 1)

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

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.

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) 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).
(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 Participants	—

SECONDARY outcome

Timeframe: Tissue obtained on day of intervention (Day 1). All CK8 cell viability staining was performed within 2 months of sampling.

Population: 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).

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).

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=5 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 Participants 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).
Persistence of Cell Viability Stain Post-LTLD+FUS	5 Participants	3 Participants

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 Participants 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).
Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to ThermoDox (LTLD)	3 Participants	4 Participants

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 Participants 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).	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 Participants 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).
Patients With Significant (Grade 3-5) Adverse Event(s) Deemed Related to FUS Procedure	0 Participants	0 Participants

Adverse Events

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

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

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

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 participants at risk Arm 1 - see above	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 participants at risk Arm 2 - see above
Blood and lymphatic system disorders Neutropenia	50.0% 3/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	50.0% 2/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Confusion	0.00% 0/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.

Other adverse events

Additional Information

Sarah Pearson, Trial Management Director

Oncology Clinical Trials Group

Phone: 01865 227160

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Part I (Patients Enrolled Between March 2015-April 2017) n=6 participants at risk Arm 1 - see above	Part II (Patients Enrolled Between June 2016-Feb 2017) n=4 participants at risk Arm 2 - see above
Surgical and medical procedures Dysphonia	0.00% 0/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Blood and lymphatic system disorders Neutropenia	0.00% 0/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Fatigue or Lethargy	66.7% 4/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	50.0% 2/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Nausea	33.3% 2/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	50.0% 2/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Abdominal Pain	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	50.0% 2/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Decreased appetite	33.3% 2/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Malaise	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Gastrointestinal disorders Vomiting	33.3% 2/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
General disorders Constipation	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Hepatobiliary disorders Hepatic pain	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Skin and subcutaneous tissue disorders Alopecia	66.7% 4/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	100.0% 4/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Skin and subcutaneous tissue disorders Erythema	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Skin and subcutaneous tissue disorders Skin discolouration	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Back pain	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Musculoskeletal pain or discomfort	83.3% 5/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Pain in extremity	33.3% 2/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Musculoskeletal and connective tissue disorders Peripheral swelling	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Infections and infestations Urinary tract infection	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Infections and infestations Candida infection	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Infections and infestations Respiratory tract infection	16.7% 1/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	0.00% 0/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.
Blood and lymphatic system disorders Anaemia	0.00% 0/6 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.	25.0% 1/4 • Safety and toxicity reported according to NCI CTCAE v4. Adverse events were recorded at day 1 and at approximately 2 and 4 weeks post-intervention following a clinical review.