The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma

Liver Metastases

Background §  80 new cases a year in Sweden (Cancerregistret, 2013)

§  30-50% will develop metastases (Diener-West et al 2005, Kujala 2003)

§  50-70% will have isolated liver metastases (Diener-West et al 2005)

Survival after diagnose of metastatic disease §  Systematic screening (Gragoudas 1991)

1116 patients screened yearly with LFTs and lung x-ray Overall survival 4 months (145 patienter)

§  COMS-trial (Diener-West 2005)

2320 patients screend yearly with LFTs Overall survival 6 months (739 patients)

§  MSK (Rietchel 2005)

All patients developing metastatic disease during 10 years Overall survival 12,5 months (119 patienter)

Treatments (median overall survival) §  Chemotherapeutic

§  6.7 months for temozolomide (Bedikian et al 2003)

§  10.6 months for BOLD (Kivelä et al 2003)

§  Immunotherapy - 9.6 months for ipilimumab (Luke et al 2013)

§  Targeted therapies - 10.8 months for selumetinib (Falchook 2012)

§  Chemoembolization - 9.0 months (Sharma et al 2008)

§  Intra-arterial fotemustine - 13.5 months (Leyvraz et al 2012)

§  Liver resection - 14 months (Mariani et al 2009)

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Melphalan 1 mg/kg

Retrospective study (Olofsson et al 2013)

§  2005 – 2011

§  34 patients

§  Uveal melanoma

§  Isolated liver metastases, no extra-hepatic disease

§  Age 59 years (18-77)

Morbidity/Mortality §  No postoperative mortality

§  3 major complications

§  2 respiratory insufficiency

§  1 perforated duodenal ulcer

§  Median time ICU: 1 (1-38) days

§  Median in hospital stay: 10 (3-43) days

§  (2012-2013 less than 7 days)

Response

§  RECIST-criteria

§  Independent radiologist

CR 4 (12%) PR 19 (59%) SD 5 (15%) PD 6 (18%) Overall response 23 (71%)

Uveal melanoma C69.3, C69.4

Swedish patient registry

2002-2012

Liver metastases C78.7 n=135

Uveal melanoma C69.3, C69.4

Swedish patient registry

2002-2012

Liver metastases C78.7 n=135

No IHP n=107

IHP n=28

Leverperfusion n=28

Kontroll n=107

Uveal melanoma C69.3, C69.4

Swedish patient registry

2002-2012

Liver metastases C78.7 n=135

No IHP n=107

IHP n=28

Leverperfusion n=28

Kontroll n=107

Uveal melanoma C69.3, C69.4

Swedish patient registry

2002-2012

Liver metastases C78.7 n=135

IHP n=28

Longest survivor

n=28

No IHP n=107

IHP n=28

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The SCANDIUM trial The Scandinavian Randomized Controlled Trial of

Isolated Hepatic Perfusion for Uveal Melanoma Liver Metastases

Studie

§  Randomized, multicenter (Nordic countries) §  IHP vs BAC §  No crossover to IHP allowed

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§  Randomized, multicenter (Nordic countries) §  IHP vs BAC §  No crossover to IHP allowed

§  Primary endpoint: OS at 24 months §  Secondary endpoints: PFS, HPFS, Respons, QoL

and SAE

§  78 patients (50% vs 20% survival at 24 months) §  5 year (15 pts. per year)

Studie

§  Randomized, multicenter (Nordic countries) §  IHP vs BAC §  No crossover to IHP allowed

§  Primary endpoint: OS at 24 months §  Secondary endpoints: PFS, HPFS, Respons, QoL

and SAE §  78 patients (50% vs 20% survival at 24 months) §  5 year (15 pts. per year)

§  Randomization, BAC and follow-up at local center §  IHP at Sahlgrenska, Göteborg

Studie

Inclusion Criteria 1. Male or female aged above 18 years. 2. Signed and dated written informed consent before the start of specific protocol

procedures. 3. Histologically or cytologically proven liver metastases of uveal melanoma. 4. Liver metastases measurable by CT/MRI (thorax and abdomen) according to

RECIST version 1.1 with at least one unidimensional measurable lesion ≥ 10 mm.

5. ECOG performance status of 0 or 1. 6. No previous chemotherapy, radiotherapy, or biologic therapy for uveal

melanoma metastases (ie first-line therapy) 7. Adequate hepatic function (defined as ASAT,ALAT, bilirubin <= 3*ULN and PK-

INR <= 1.5) and no medical history of liver cirrhosis or portal hypertension

Studie

Exclusion Criteria 1. More than 50% of the liver volume (measured by CT or MRI) replaced by

tumour. 2. Evidence of extrahepatic disease by PET-CT 3. Life expectancy of less than 4 months 4. Pregnant or breast-feeding. Women of childbearing potential must have a

negative pregnancy test performed within seven days prior to the start of study. 5. Active infection. 6. Ischemic cardiac disease or history of congestive heart failure with an LVEF <

40%. 7. COPD or other chronic pulmonary disease with PFT's indicating an FEV< 50%

predicted for age. 8. Reduced renal function defined as S-Creatinine >=1.5xULN or Creatinine

Clearance < 40 mL/min, calculated using the Cockroft and Gault formula. 9. Reduced blood leukocytes or platelets defined as LPK < 2.0x109/L and TPK

<100x109/L 10. Use of live vaccines four weeks before or after the start of study. 11. Body mass index above 35.

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Follow-up The subjects will be followed for 2 years. Study visits will be at each center and performed at baseline, and after 3, 6, 12, 18 and 24 months.

•  CT or MRI of liver (same modality as baseline examination) according to specified protocol

•  Laboratory tests •  EQ5D-3L Quality of Life questionnaire

Studie

Cross-over §  No cross-over from BAC to IHP allowed §  At progression, patients can cross-over from IHP to BAC

www.scandiumtrial.se

scandium online

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2014"Mar" Maj" Jul" Sep" Nov" 2015"Mar" Maj" Jul" Sep" Nov" 2016"Mar" Maj" Jul" Sep" Nov" 2017"Mar" Maj" Jul" Sep" Nov" 2018"Mar" Maj" Jul" Sep" Nov"

SCANDIUM)Accrual)status)

11/78 patienter randomiserade 7 BAC 4 IHP

Principal investigators and Sites Lars Ny Sahlgrenska University Hospital, Gothenburg

Ingrid Ljuslinder Norrlands University Hospital, Umeå Johan Hansson Karolinska University Hospital, Stockholm Ulf Lönn Linköping University Hospital, Linköping Gustav Ullenhag Uppsala University Hospital, Uppsala Sara Kinhult Skåne University Hospital, Lund Jens Folke Kiilgaard Rigshospitalet, Köpenhamn, Danmark

Protocol amendment version 2.5 1. Krav på cytologisk verifikation av levermetastaser innan

behandling startas (men inte nödvändigtvis vid randomisering).

2. MR lever är den undersökningsmodalitet som föredras, CT

lever går dock att använda för dom som inte har möjlighet. 3. MR/CT av lever ska vara maximalt 4 veckor gammal innan

randomisering.

Protocol amendment version 2.5 4. Vid baseline och uppföljning har vi lagt till analys av S-100,

efter förslag om att detta möjligen skulle kunna vara en markör för respons.

Protocol amendment version 2.5 5.  Förändring avseende rapportering av AE i IHP gruppen, där

nu endast grad III-V behöver rapporteras. 8. Förändringar i rapportering av SAE i båda grupper, där vi nu

listat undantag relaterade till cancersjukdom.

9. Att patienter om möjligt ska genomgå IHP inom 4 veckor efter randomisering.

SAE #1 Man född 1935 I bakgrunden väsentligen frisk, viss etylöverkonsumtion kan ej uteslutas. Genomgår IHP 2014-02-05. Vid perfusion noteras två relativt likstora artärer där endast den större perfunderas. Postoperativt höga transaminaser som leder till exploration som dock visar normalt kärlflöde till levern. Utvecklar njursvikt postoperativt och får hemodialys. Leverfunktionen hämtar och allmäntillståndet förbättras. Utskrives 2014-02-26 till hemsjukhus, har nu inget dialysbehov och normal urinproduktion. Senaste MR visat PR.

SAE/SUSAR #2 Kvinna 1941 Hypertoni och övervikt. Genomgår IHP 2014-03-19, tekniskt besvärligt, misstanke om intimaskada i huvudartären. En mindre artär till segment 2+3 stängs under perfusionen. Postoperativt höga transaminaser som sjunker, efter en vecka dock försämring med på nytt stigande leverprover. Exploreras pga peritonit och man finner dåligt arteriellt flöde till höger leverhalva, misstanke om dissektion. Utskrives till avdelning från IVA efter 2 dagar. Sista veckan trött och förhöjt bilirubin. Insjuknar 2014-04-04 med fekala kräkningar, aspirerar och får hjärtstillestånd som ej går att häva. Avlider.

The Scandinavian Randomized Controlled Trial of Isolated Hepatic Perfusion for Uveal Melanoma

Liver Metastases