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Clinical Trial Results:
The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

Summary
EudraCT number	2013-000564-29
Trial protocol	SE
Global end of trial date	11 Mar 2023

Results information
Results version number	v1(current)
This version publication date	28 Mar 2024
First version publication date	28 Mar 2024
Other versions
Summary report(s)	Study protocol Results response Final results SCANDIUM

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SUGBG-013001

ISRCTN number

US NCT number

NCT01785316

WHO universal trial number (UTN)

Sponsor organisation name

Transplant Institute, Sahlgrenska University Hospital

Sponsor organisation address

Bruna straket 5, Gothenburg, Sweden, 413 45

Public contact

Transplant institute, Sahlgrenska University Hospital, per.lindner@surgery.gu.se

Scientific contact

Transplant institute, Sahlgrenska University Hospital, 46 705548400, per.lindner@surgery.gu.se

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Jan 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Mar 2023

Global end of trial reached?

Yes

Global end of trial date

11 Mar 2023

Was the trial ended prematurely?

Main objective of the trial

To evaluate if IHP increases the Overall survival compared to BAC.

Protection of trial subjects

The original protocol and all amendments were approved by the Swedish Medical Product Agency (EudraCT number 2013-000564-29) and the Regional Ethical Review Board at the University of Gothenburg (Dnr 144-13). The study was conducted in accordance with the protocol, Good Clinical Practice guidelines, and the provisions of the Declaration of Helsinki. All patients provided written informed consent before inclusion in the trial.

Background therapy

Isolated hepatic perfusion (IHP) with melphalan is a regional treatment where the liver is completely isolated from the systemic circulation, to allow hepatic perfusion with high concentrations of chemotherapy, with minimal systemic exposure. IHP has been evaluated in several studies, mainly for liver metastases derived from colorectal cancer, melanoma, neuroendocrine tumours and primary hepatic malignancies. A retrospective study comparing patients with uveal melanoma metastases treated with IHP with the longest surviving patients in Sweden during the same time period showed a 14-month increase in survival (26 vs. 12 months) in the IHP group.

Evidence for comparator

Among patients with liver metastases from ocular melanoma, the median survival is approximately 10-12 months and only few patients survive more than five years. These disappointing outcomes reflect generally poor responses to systemic chemotherapy, which shows minimal efficacy and delivers no detectable survival benefit. In contrast to cutaneous melanoma, immune checkpoint inhibition (ICI) has been of only limited benefit in uveal melanoma patients, with combined ipilimumab and nivolumab showing an overall response rate of 10-18% and an uncertain impact on survival. As no therapy currently is established for metastasized ocular melanoma , best alternative care (BAC) was chosen as the comparator.

Actual start date of recruitment

01 Jul 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 93

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients with histologically or cytologically confirmed liver metastases from uveal melanoma were recruited to the study if they fulfilled the inclusion criteria. Recruitment was performed via the oncology clinics at the swedish university hospitals.

Screening details

From July 2013 to March 2021, 147 patients were screened, and 93 patients were enrolled at six sites.

Number of subjects started

Number of subjects completed

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Study was by its nature not blinded for either patient or investigator.

Are arms mutually exclusive

Yes

Isolated Hepatic Perfusion (IHP)

Arm description

Isolated Hepatic Perfusion means that the liver blood circulation is isolated from the rest of the body. Perfusion is performed with a target flow rate of 500-1200 ml/min with a target liver temperature of 40°C. When the perfusion circuit is established, melphalan at a dose of 1 mg/kg body weight is added to the perfusion system divided into two doses. Perfusion is continued for 60 minutes, after which the perfusion is discontinued and the liver irrigated and the normal blood flow is re-established.

Arm type

Experimental

Investigational medicinal product name

melphalan

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection/infusion

Routes of administration

Other use

Dosage and administration details

1 mg/kg was injected into the liver perfusion circuit, divided in 2 portions given with a 30 minutes interval.

Control

Arm description

Patients randomized to the control group received the investigator’s choice of treatment according to the discretion of the treating physician at each study site. All available treatments including surgery and other experimental treatments were accepted; however, no crossover to IHP was allowed.

Arm type

Best alternative care according to patient's physi

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Isolated Hepatic Perfusion (IHP)	Control
Started	46	47
Completed	43	44
Not completed	3	3
Consent withdrawn by subject	-	2
Protocol deviation	3	1

Baseline characteristics

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Reporting group title

Overall trial

Reporting group description

Reporting group values	Overall trial	Total
Number of subjects	93	93
Age categorical
Adults
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	46	46
From 65-84 years	47	47
85 years and over	0	0
Gender categorical
Male/female
Units: Subjects
Female	42	42
Male	51	51

Subject analysis set title

Overall survival at 24 months

Subject analysis set type

Intention-to-treat

Subject analysis set description

43 patients allocated to IHP, 44 patients allocated to control Additionally 3 patients were randomized to IHP-arm but excluded due to to much tuner burden or systemic metastases. In the control group 2 patients were excluded as they withdrew consent and 1 patient did not have verified metastases-

Subject analysis sets values	Overall survival at 24 months
Number of subjects	87
Age categorical
Adults
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	41
From 65-84 years	46
85 years and over	0
Age continuous
Units:
	±
Gender categorical
Male/female
Units: Subjects
Female
Male

End points

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Reporting group title

Isolated Hepatic Perfusion (IHP)

Reporting group description

Reporting group title

Control

Reporting group description

Subject analysis set title

Overall survival at 24 months

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Overall survival at 24 months

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End point title

Overall survival at 24 months

End point description

Subjects alive 24 months after randomization

End point type

Primary

End point timeframe

24 months after randomization

End point values	Isolated Hepatic Perfusion (IHP)	Control	Overall survival at 24 months
Number of subjects analysed	43	44	87
Units: Alive
Alive	20	13	33
Dead	23	31	54

Primary endpoint analysis ITT

Statistical analysis description

Two-sided Fisher's exact test

Comparison groups

Isolated Hepatic Perfusion (IHP) v Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.12 ^[1]

Method

Fisher exact

Confidence interval

Notes
[1] - There was no significant difference between the groups.

Secondary: Overall response rate

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End point title

Overall response rate

End point description

ORR was defined as the proportion of patients who had a partial or complete response to therapy. ORR was defined as the percentage of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST. Efficacy was assessed in the intention-to-treat population, with all patients included in the treatment group to which they were randomly assigned.

End point type

Secondary

End point timeframe

Radiological response within 24 months

End point values	Isolated Hepatic Perfusion (IHP)	Control
Number of subjects analysed	43 ^[2]	44 ^[3]
Units: Radiological response
Overall response (CR or PR)	17	2
No response (SD or PD)	26	42

Notes
[2] - 3 excluded after randomization due to inappropriate enrollment
[3] - 2 withdrawn due to inappropriate enrollment, 1 due to withdrawn consent

Comparison of overall response rate

Statistical analysis description

Fisher’s exact test was used to compare ORR

Comparison groups

Isolated Hepatic Perfusion (IHP) v Control

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Fisher exact

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Serious adverse events were collected during first-line therapy during the whole study period. Adverse events were not collected.

Adverse event reporting additional description

SAEs occurring after secondary line treatment were not reported.

Assessment type

Non-systematic

Dictionary name

CTC for AE

Dictionary version

4.0

Reporting group title

Isolated hepatic perfusion(IHP)

Reporting group description

Experimental group

Reporting group title

Control

Reporting group description

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: In this study we collected all Serious Adverse Events were collected, but Adverse Events were not collected.

Serious adverse events	Isolated hepatic perfusion(IHP)	Control
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 41 (19.51%)	3 / 46 (6.52%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	1	0
Vascular disorders
Arterial repair
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver artery dissection
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
thromboembolic event
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver artery thrombosis
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Wound infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypophysitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 46 (2.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Wound dehiscence
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	1 / 41 (2.44%)	0 / 46 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Isolated hepatic perfusion(IHP)	Control
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 41 (0.00%)	0 / 46 (0.00%)

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/36940407
http://www.ncbi.nlm.nih.gov/pubmed/25106493
http://www.ncbi.nlm.nih.gov/pubmed/38420778

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Clinical trials

Clinical Trial Results:
The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall survival at 24 months

Primary: Overall survival at 24 months

Secondary: Overall response rate

Secondary: Overall response rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall survival at 24 months

Primary: Overall survival at 24 months

Secondary: Overall response rate

Secondary: Overall response rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases