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Treatment of Uveal Melanoma
Metastatic to the Liver
David J. Eschelman, M.D., FSIR
Professor of Radiology,
Sidney Kimmel Medical College of Thomas Jefferson University
Co-Director of Interventional Radiology,
Thomas Jefferson University Hospital
Disclosures
• I will discuss unapproved uses of
commercial products.
• I am a not a consultant for anyone!
MUM Treatments
(Metastatic Uveal Melanoma)
Liver-Directed Therapies
• Immunoembolization
• Radioactive microspheres
• Chemoembolization,
Drug-eluting beads
• Fotemustine infusion
• IHP/PHP
• Ablation
Chemoembolization
Carin F. Gonsalves, M.D.
Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS
Mavligit ’88 30 Cisplatin 14 6 11
Cantore ’94 8 Carboplatin -- -- 15
Bedikian ’95 44 Cisplatin 14.5 5 6
Sato ’95 14 Cisplatin -- -- 6.6
Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2
Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5
Vogl ’07 12 Mitomycin C 21 16.5 21
Dayani ’09 21 Mitomycin C, Cisplatin,
Doxorubicin
12.7 3.7 7.6 (mean)
Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7
Immunoembolization at Jefferson
Takami Sato, M.D., Ph.D.
Kevin L. Sullivan, M.D.
Michael J. Mastrangelo, M.D.
Immunoembolization
Rationale
• Destruction of tumor by embolization would control
tumor progression locally and provide tumor antigens to
the local immune system
• Concurrent use of biological response modifier(s) induces
an inflammatory response in the tumor and surrounding
tissue which may improve the antigen presentation to the
local immune system
• Local stimulation of the immune system may result in the
development of a systemic immune response against
tumor cells which may suppress the growth of untreated
tumors
• IE could potentially create an in situ tumor vaccine.
Immunoembolization
Granulocyte-Macrophage Colony-Stimulating Factor
• Glycoprotein secreted by activated T cells
• LEUKINE (sargramostim) is a recombinant yeast-
derived human GM-CSF
• Increases myeloid cell production
• Stimulates macrophages
• Increases cytotoxicity of monocytes toward tumor
cell lines
• Promotes maturation of dendritic cells
Immunoembolization
Selection of GM-CSF
Vaccination was performed with 10 tumor cell
lines engineered to secrete different cytokines
Proc Natl Acad Sci 1993; 90: 3539-3543
Immunoembolization
Phase 1 Study – Intro
• Purpose was to investigate feasibility and safety
• 2000 – 2004, single institution
• 34 of 39 patients had MUM
• <50% tumor involvement, unresectable
• Lobar hepatic artery embolization every 4 weeks using
escalating dose of GM-CSF (25-2000 mcg) emulsified
with Ethiodol followed by Gelfoam, for 6 treatments
• Imaging (CT, MRI) and clinical assessment after
every other treatment to assess response (RECIST)
• Primary end-points were dose-limiting toxicity and
maximum tolerated dose
J Clin Oncol 2008; 26:5436-5442
Immunoembolization
Phase 1 Study – Results (n=34)
• 6 procedures/patient (median, range 1-14)
• 32% responded (2 CR, 8 PR)
• 32% stable disease
• OS: 14.4 months (median)
(33.7 months for CR/PR, 12.4 months SD/PD)
• Survival: 1 yr. 62%, 2 yr. 26%
• PFS-liver: 4.8 months (median)
• PFS-systemic: 10.4 months (median)
J Clin Oncol 2008; 26:5436-5442
Immunoembolization
Initial 2 months later
Immunoembolization
Initial 2 months later
Immunoembolization
Dose-Related Response (n=31)
Patients undergoing high-dose IE (>1500 mcg) vs.
low-dose IE (<1000 mcg):
• Longer OS (20.4 vs. 13.0 months, median)
• Longer PFS-L (9.3 vs. 4.2 months, median)
• Longer PFS-S (12.4 vs. 5.6 months, median)*
* P < .05
Radiology 2009; 252:290-298
Immunoembolization
Comparison to BCNU TACE
Patients undergoing high-dose IE (>1500 mcg) vs.
TACE with BCNU (TJUH Phase II study, excluding
patients with >50% tumor burden in liver):
• Longer OS (20.4 vs. 9.8 months, median)*
• Longer PFS-L (9.3 vs. 6.4 months, median)
• Longer PFS-S (12.4 vs. 4.8 months, median)*
* P < .05
Radiology 2009; 252:290-298
Immunoembolization
Comparison to BCNU TACE
• No significant difference in overall or progression-free
survival between patients who received BCNU TACE
and lower dose IE
• Stabilization of hepatic metastases was most likely
achieved by the ischemic effects of embolization rather
than by the administered medication
• Systemic progression was delayed in the high-dose IE
group, suggesting an induction of a systemic immune
response against the melanoma cells
Immunoembolization
Additional observations -
• Tumor regression was sustained after discontinuation of
immunoembolization in several patients
• Response can take as long as 4 months (4 IE procedures)
• Evidence of activation of the memory cell arm of the
immune system (T cells), suggesting a tumor vaccine
Repeated immune stimulation has been shown to be
necessary to overcome tolerance and induce a vigorous
response (J Exp Med 1997; 186: 645-653 & J Clin Invest 1998; 101:2406-2414)
Immunoembolization of the Hepatic Artery with
Granulocyte-Macrophage Colony Stimulating Factor
• R21 study
• Randomized, double blind, phase II clinical study for
MUM patients
• Primary endpoint – regression of liver mets
• Secondary endpoint – time to progression, overall survival,
and development of local/systemic immune response
• 52 patients – randomized to receive embolization using
Ethiodol, with or without 2000 mcg GM-CSF, followed by
Gelfoam
• Stratified by liver involvement (<20% vs. 20-50%) and
HLA-A2 status
Immunoembolization of the Hepatic Artery with
Granulocyte-Macrophage Colony Stimulating Factor
• Excludes patients with >50% tumor involvement,
extrahepatic mets, prior local liver therapies
• Lobar treatments every 4 weeks with imaging (CT, MRI)
and clinical assessment every 8 weeks (RECIST)
• Investigation of biopsy specimens before/after treatment
• Analysis of peripheral blood mononuclear cells and serum
to assess systemic immune response
• 52 patients enrolled beginning June 2005
• Last treatment under protocol April 2010
• 2 completed (24 months)
• 51 patients (98%) are deceased
Immunoembolization of the Hepatic Artery with
Granulocyte-Macrophage Colony Stimulating Factor
Results – Phase II Trial
• Both immunoembolization (IE) and bland embolization were
well tolerated with acceptable toxicity
• Both approaches induced cytokine productions, more
prominent in patients treated with IE
• IE showed a potential overall survival benefit in patients with
20-50% tumor replacement
• Trend towards longer PFS-S following IE
• Unexpectedly, PFS-L was shorter following IE in patients
with <20% tumor involvement, suggesting a suppressive
(paradoxical) response to high dose GM-CSF
JVIR 2015; 26:523-532
Immunoembolization of the Hepatic Artery with
Granulocyte-Macrophage Colony Stimulating Factor
Phase II Trial
JVIR 2015; 26:523-532
Immunoembolization
Phase II Trial - Results
• Not powered to determine survival benefit; designed as proof
of concept study to investigate hypothesis that adding GM-CSF
to embolization would increase release of pro-inflammatory
cytokines and delay development of extrahepatic metastases
• Plain embo – increases in IL-6 and IL-8 > 18 hrs.
• Immunoembo – significant (P<0.001) and rapid increase in
TNF-a, IL-6, and IL-8 at 1 and 18 hrs post treatment,
suggesting faster and more robust inflammatory response
• Increased IL-6 level at 1 hr and IL-8 level at 18 hrs correlated
with delay in onset of extrahepatic metastases with a dose-
response pattern
• Double-blind, randomized clinical trial comparing bland
embolization to drug + embolization, showing a benefit of
adding the drug
Immunoembolization
1500 mcg GM-CSF
JVIR 2014; 25: S26
• 68 patients treated 3/2004 – 6/2013, retrospective
• 37 (54%) had < 20% tumor burden
31 (46%) had 20-50% tumor burden
• 42 patients (62%) with stable disease
• Median OS 18.9 months (range 2.1 – 52.2)
28 patients (41%) remain alive at time of analysis
It took us 14 years to figure out the
appropriate dose of GM-CSF!
Immunoembolization + Ipilimumab
• 27 patients initially treated with IE and Ipi
9/2012 – 9/2015, retrospective
• Median OS 20.1 months:
1 yr. 74% 2 yr. 33% 3 yr. 26%
• 16/18 patients without extrahepatic metastases at
baseline developed extrahepatic metastases
• Safe to perform this combination, but added Ipi toxicities
(diarrhea, rash, hypothyroidism, increased LFTs)
JVIR 2019; 30: S141
Immunoembolization - Lipiodol Distribution
MRI pre-treatment CT scan post-treatment
Prolonged Survival Following Immunoembolization
10/2010
3/2018
Prolonged Survival Following Immunoembolization
Work in Progress . . . . .
• 174 patients treated 6/2005 – 12/2014, retrospective
• Median OS: 17 months (range 2 – 102)
• 28 (16%) patients have prolonged survival (> 3 yr.)
and treatment breaks
Of these 28 “Superstars” . . . . .
• At least 68% lived > 4 years (11% of 174)
• At least 21% lived > 6 years (5.2% of 174)
JVIR 2019; 30: S140
Progression Despite Immunoembolization
Initial 2 months later
Additional MUM Treatments
(Metastatic Uveal Melanoma)
• Radioactive microspheres
• Chemoembolization
(Drug-eluting beads)
• IHP/PHP
Transarterial Catheter-Directed
Treatment of Liver Tumors
• Radioembolization (RE)
• 20-60 micron-sized particles loaded with a radioactive isotope
(Yttrium-90) are injected into the hepatic artery
• Radioactive particles lodge within arteries supplying tumors,
emit radiation and destroy cancer cells
Radioactive Microspheres
Y-90 Embolization for MUM
Jefferson Experience, Salvage Therapy
• 32 MUM patients
• Single institution, retrospective
• Jan 2007 – Apr 2009; follow-up to Sept 2009
• 14 M, 18 F; median age 61
• All patients had progressed followed IE or TACE
(median 9, 1-23 prior embolization procedures)
• Pre-treatment tumor burden:
< 25% (n=25)
25-50% (n=5)
>50% (n=2)
AJR 2011; 196:468-473
Y-90 Embolization for MUM
Jefferson Experience, Salvage Therapy
Results
• OS 1 – 29 months (median 10)
• Median survival longer for patients with pretreatment tumor
burden of < 25% vs. >25% (10.5 vs. 3.9 months)*
• Best radiologic response (RECIST):
CR 1
PR 1
SD 18
PD 12
• Median survival longer for patients with CR, PR, or SD vs.
PD (14.7 vs. 4.9 months)*
*P < .05
AJR 2011; 196:468-473
Y-90 Embolization for MUM
Jefferson Experience, Updated
• 71 patients, 82% salvage
• Median PFS-L 5.9 months
• Median OS after treatment 12.3 months
• Median OS following diagnosis of liver mets
23.9 months (range, 6.2 – 69 months)
• Low pre-treatment TGA (total glycolic
activity) was associated with a significantly
longer median OS (17.2 vs. 9.7 months,
p=0.01)
American Journal of Clinical Oncology 2016; 39:189-195
Y-90 Embolization for MUM
Phase II, Single Institution, Prospective Trial
• 48 patients, November 2011 – January 2017:
• 24 treatment naïve
• 24 progressed after immunoembolization
Journal of Clinical Oncology 2018; 36: 9535s
Y-90 Embolization for MUM
Phase II, Single Institution, Prospective Trial
Group A (treatment naïve) –
• 75% < 20% tumor replacement, 25% had 20 - <50%
• 39% partial response, 48% stable disease (n=23)
• Median PFS-L: 8.1 months (3.3 – 33.7)
• Median OS: 18.5 months (6.5 – 73.7)
• Survival: 1 yr. 61%, 2 yr 26%, 3 yr 13%
• All patients developed new liver metastases
Journal of Clinical Oncology 2018; 36: 9535s
Y-90 Embolization for MUM
Phase II, Single Institution, Prospective Trial
Group B (progression after immunoembolization) –
• 92% < 20% tumor replacement, 8% had 20 - <50%
• 33% partial response, 42% stable disease (n=24)
• Median PFS-L: 5.2 months (2.9 – 22.0)
• Median OS: 19.2 months (4.8 – 76.6)
• Survival: 1 yr. 70%, 2 yr 30%, 3 yr 9%
• 91% patients developed new liver metastases at time
of progression
• Median OS from initiation of IE treatment:
24.6 months (11.5 – 90.5)
Journal of Clinical Oncology 2018; 36: 9535s
Y-90 Embolization + Immunotherapy
MGH –
• 11 patients, 3/2013 – 12/2017, retrospective
• 2 patients initial treatment with Y90
9 patients received Y90 after progression on
immunotherapy; 6 received additional immunotherapy
• Median PFS-L: 15 months
• Median OS: 17 months
• CR 9%, PR 18%, SD 36%, PD 36%
JVIR 2018; 29:11369 - 1375
SIRspheres
Prior to Treatment 11 months after Treatment
Rapid Tumor Progression
Prior to SIRspheres 2 months after SIRspheres
Chemoembolization
Carin F. Gonsalves, M.D.
Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS
Mavligit ’88 30 Cisplatin 14 6 11
Cantore ’94 8 Carboplatin -- -- 15
Bedikian ’95 44 Cisplatin 14.5 5 6
Sato ’95 14 Cisplatin -- -- 6.6
Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2
Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5
Vogl ’07 12 Mitomycin C 21 16.5 21
Dayani ’09 21 Mitomycin C, Cisplatin,
Doxorubicin
12.7 3.7 7.6 (mean)
Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7
Chemoembolization
MD Anderson
Am J Clin Oncol 2010; 33:474-480
• 125 patients (Jan 1992 – Dec 2005)
• 122 patients received cisplatin; 65 also received
arterial infusion of vinblastine (n=54) or
vinblastine/dacarbazine (n=11) afterwards
• Tumor burden:
< 25% 36 patients (32%)
25-50% 41 (36%)
>50-75% 25 (22%)
>75% 11 (10%)
• Relatively high rate of complications (14%),
many severe
Chemoembolization
MD Anderson
Am J Clin Oncol 2010; 33:474-480
• Overall Survival 6.7 months (median, n=113):
< 25% 14 months
25-50% 5.1
>50-75% 5.5
>75% 2.4
• Overall Survival based on LDH:
Normal 20 months
>1 but <2 x normal 11
> 2 x normal 3.6
• Recommend against treatment when >75%
tumor replacement
Chemoembolization
BCNU
• 50 patients with >50% tumor replacement
at presentation (Jan 2004 – Nov 2011)
• 200 mg BCNU
• Median survival 7.1 months
• 22% 1 yr. survival (12.2 – 32.3 months)
• 72% had stable disease or a treatment response
• Neither pre-treatment LDH (> or < 500) nor
tumor burden (50-59%, 60-75%, > 75%) had
effect on survival
AJR 2015; 205:429-433
BCNU Chemoembolization
First Treatment 13 months later
BCNU Chemoembolization
First Treatment Second Treatment
DEBDOX
Drug-Eluting Beads for MUM
Irinotecan
in vivo 2009; 23:131-138
• 10 patients in 2 institutions (Ferrara, Florence)
• Jan 2007 – June 2008
• 8 M, 2 F; mean age 65
• All patients had prior systemic chemo/immunotherapy
• Pre-treatment tumor burden:
< 25% (n=3)
25-50% (n=4)
50-75% (n=3)
• Assessment by 3-phase CT pre/post treatment
• 100-200 mg Irinotecan administered in 2-4 ml of
100-300/300-500 micron DC Beads
• Half had one treatment, other half had 2 treatments
Drug-Eluting Beads for MUM
Irinotecan
in vivo 2009; 23:131-138
• All 10 patients obtained an objective response!
• Tumor reduction by imaging:
90% (n=3)
80% (n=3)
60-70% (n=4)
• Median follow-up 6.5 (range 4 – 9) months
• 8 patients alive at time of report; 2 died at 4 and 6 months
• Response related to degree of initial tumor involvement
• Side effects similar to TACE, no alopecia or bone
marrow toxicity
Drug-Eluting Beads for MUM
Irinotecan
Annals of Gastroenterology and Hepatology 2012; 3:9-14
• Single arm, phase II clinical trial
• Jan 2007 – Feb 2010, 52 patients
• All patients had prior systemic chemo/immunotherapy
• Pre-treatment tumor burden:
< 25% (n=30, 58%)
25-50% (n=20, 38%)
50-75% (n=4, 8%)
• 85 procedures (median 1.6/patient)
• No complications, limited toxicity, + abdominal pain
• 100 mg IRI x 10 patients, remainder 200 mg IRI
Drug-Eluting Beads for MUM
Irinotecan
Annals of Gastroenterology and Hepatology 2012; 3:9-14
• No complications, limited toxicity, + abdominal pain
• Tumor reduction by imaging (“necrosis and reduction of
contrast enhancement”):
> 90% (n=17)
80-90% (n=30)
60-80% (n=3)
• PFS-L 7.5 months, OS 13.9 months (both median)
DEBDOX/BCNU for MUM
JVIR 2014; 25: S45
• 19 patients, no prior treatments
• July 2011 – January 2013, retrospective review
• Poor candidates for other liver-directed therapies
(Tumors > 5 cm, > 50% tumor burden, rapid growth)
• < 4 ml 100-300 micron LC Beads/150 mg adriamycin
(14/36 treatments received full dose)
• 13/19 patients proceeded to BCNU chemoembolization
(73 treatments)
• Based on disparate response, patients divided into
“nodular” vs. “infiltrative” pattern, based on MRI
appearance
DEBDOX/BCNU for MUM
Size of Largest Tumor
JVIR 2014; 25: S45
DEBDOX/BCNU for MUM
Results
JVIR 2014; 25: S45
Nodular vs Infiltrative Disease
Nodular
Infiltrative
Time (months)
SurvivalProbability(%)
Nodular (n=11): 3 PR, 7 SD, 1 PD
Infiltrative (n=8): 1 PR, 3 SD, 4 PD
JVIR 2014; 25: S45
Survival Mean (mos) 95% CI
Median
(mos) 95% CI
Nodular 22.8 15.7 - 29.8 16 ---
Infiltrative 4.7 1.6 - 7.9 2.9 1.8 -7.9
Overall 16.0 11.6 - 20.4 9.1 2.9 -12.8
Chi-square = 8.4
p value = 0.0037
DEBDOX/BCNU for MUM
Results
• 2008 study includes cutaneous and uveal melanoma
• Do not report tumor burden or size
• Nodular/infiltrative pattern is determined by angiography (we use
MRI.) Infiltrative pattern significantly more likely to be ciliary
body tumors with extrascleral extension, and loss of tumor
suppressor gene (LZTS1 on 8p).
Survival (mos)
#
pts
Tx Nodular Infiltrative
Sharma KV, et
al (2008)
20 CAM 20 3.8
Dayani PN, et
al (2009)
21 CAM 12.7 3.7
Chemoembolization: Nodular vs. Infiltrative
DEBDOX/BCNU for MUM
Work in progress . . . .
• added 7 more patients, no prior treatments
• July 2011 – December 2014, retrospective review
• Poor candidates for other liver-directed therapies
(Tumors > 5 cm, > 50% tumor burden, rapid growth)
• OS (patients with NODULAR pattern):
- 18.2 months (median), range 2.7 – 87.4 months
- 2/16 patients still alive
(6 & 7 years after starting treatment!)
DEBDOX
Initial 10 months later
DEBDOX
Pre-Treatment 2 months later
DEBDOX
Pre-Treatment 12 months later
Drug-eluting Beads + Adriamycin, Followed by Chemoembolization
Initial 4 months later
Drug-eluting Beads + Adriamycin, Followed by Chemoembolization
Initial 15 months later
61 DELCATH SYSTEMS, INC
Percutaneous Hepatic Perfusion
• PHP utilizes 3 primary principles:
o ISOLATION – isolates hepatic blood flow
o INFUSION – Melphalan agent delivered to liver via hepatic artery
o FILTRATION – blood from the liver is filtered to reduce Melphalan concentration prior to returning the blood
to systemic circulation
INTERNAL-CONFIDENTIAL
Percutaneous Hepatic Perfusion
Percutaneous Hepatic Perfusion
J Surgical Oncology 2018; 117:1170-1178:
• Moffitt (FL) + Southampton (UK)
• 51 patients, 12/2008 – 10/2016, retrospective
• 15 completed planned course (4 or 6 treatments)
• 7 still undergoing treatment
• 29 patients discontinued early:
- 9 treatment-related toxicity
- 17 disease progression
- 3 patient preference
• Median of 2 treatments in UK, 3 in FL
Percutaneous Hepatic Perfusion
J Surgical Oncology 2018; 117:1170-1178:
• 6% CR + 43% PR
• 33% SD at 3 months, 22% at 6 months
• Median OS 15.3 months; 1 yr. survival 65%, 2 yr. 37%
• No treatment-related fatalities, but . . . . . .
- 3 VT, 1 SVT
- 5 myocardial ischemia (1 MI, 1 pulmonary edema)
- 3 major bleeding (DIC, abdominal, cerebral)
- 2 pulmonary edema, 2 pulmonary emboli
- DVT: LE x 2, IVC, IJ, access site
- Transfusions: 47% PRBCs, 78% platelets
- 4 episodes neutropenic sepsis with 31% experiencing
severe neutropenia
65 DELCATH SYSTEMS, INC
Phase 3 Trial for Ocular Melanoma: FOCUS Trial
A Single-arm, Multi-Center, Open-Label Study to Evaluate the Efficacy,
Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients
with Hepatic-Dominant Ocular Melanoma
• Objectives
oPrimary
▪Objective Response Rate (ORR)
oSecondary
▪Duration of Response (DOR)
▪Disease Control Rate (DCR)
▪Overall Survival (OS)
▪Progression Free Survival (PFS)
• Patients
o50 patients planned
• Sites
oApproximately 35 sites in US and Europe
66 DELCATH SYSTEMS, INC
Additional Treatments
• Treatment Frequency
In Delcath’s current clinical trials, treatment with Chemosat is
administered every 6-8 weeks.
Patients are receiving up to six cycles.
The exact interval and number of treatments should be determined by
the treating physician.
O
67 DELCATH SYSTEMS, INC
FOCUS Trial – Key Inclusion Criteria
Key Inclusion Criteria
• 50% or less ocular melanoma metastases in the liver
• Evidence of limited extrahepatic disease is acceptable if the life threatening component of
disease is in the liver. Limited extrahepatic disease is defined as follows: metastasis in bone,
subcutaneous, lung or lymph nodes that is amenable to resection or radiation and has a defined
treatment plan. Patients with extra-hepatic tumor burden which does not have a defined
treatment plan (i.e. monitor or is unable to be resected or radiated) must not be included in the
trial.
• Patients must not have had chemotherapy, radiotherapy, chemoembolization,
radioembolization, or immunoembolization for their malignancy within 30 days prior to treatment.
• Patients receiving anti-PD-1 immunotherapy such as pembrolizumab or nivolumab, or CTLA 4
blocking antibody such as ipilimumab must have completed treatment 8 weeks prior to study
enrollment.
• ECOG PS of 0-1 at screening.
• Adequate hepatic function as evidenced by total serum bilirubin ≤1.5 x the upper limit of normal
(ULN) and a prothrombin time (PT) within 2 seconds of the ULN. AST/ALT must be ≤ 2.5 x ULN.
• Platelet count > 100,000/μL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) >
2,000/uL, absolute neutrophil count ≥ 1.5 x 109/L, and a serum creatinine ≤ 1.5 mg/dL.
68 DELCATH SYSTEMS, INC
• Thomas Jefferson University Philadelphia, Pennsylvania
• Moffitt Cancer Center Tampa, Florida
• Duke University Durham, North Carolina
• Stanford University Stanford, California
• Emory University Atlanta, Georgia
• Ohio State University Columbus, Ohio
• University of Tennessee Memphis, Tennessee
• Roswell Park Cancer Institute Buffalo, New York
• University of Arizona Tucson, Arizona
• UCLA Los Angeles, California
PARTICIPATING CENTERS – US
Percutaneous Hepatic Perfusion
AnesthesiaVenovenous
Bypass
Perfusionist
2 IR Attendings
IR Nurses and
Technologists
Research
Coordinators
Microwave Ablation
• Microwave needle is placed
directly into the liver tumor
• Using CT or US guidance
• Generates heat to destroy
tumor cells
• Reserved for patients with a
solitary metastasis or for a
single “rogue” tumor that
won’t respond to
transarterial liver-directed
therapies
Microwave
needle
Microwave Ablation
Oligometastasis –
• 7 patients, median 1.7 cm diameter
• 4 with no intrahepatic progression, 11-37 months
• 3 with intrahepatic progression 1-8 months
(2 died at 23-24 months)
“Rogue Tumor” –
• 6 patients, median 2 cm diameter
• 1 patient no progression at 36 months
• 5 patients intrahepatic progression at median 5
months (1 – 11), 1 died at 27 months
JVIR 2019; S84
Microwave Ablation
IE treatments starting 10-16-2012. All tumors
responded except for one.
7/12/17 MRI shows completely necrotic tumor
Microwave ablation 4/20/16
performed by Dr. Adamo
Currently enjoying a long treatment break, 5.5
years after initiating treatment at TJUH.
Current Jefferson Treatment Algorithm
for Liver Metastases in MUM Patients
Following consideration of resection/ablation (rare):
If < 50% liver involvement, limited extrahepatic mets:
• Immunoembolization (especially minimal disease)
• SIRspheres
If < 50% liver involvement, limited extrahepatic mets,
largest tumor > 5-6 cm:
• DEBDOX followed by BCNU Chemoembolization
If > 50% liver involvement with liver dominant disease:
• Chemoembolization (BCNU, DEBDOX)
Progression following immunoembolization:
• SIRspheres (<50% tumor burden)
• Chemoembolization (BCNU, DEBDOX)
Clinical Trials (including Delcath/PHP)! gp100!!!
Future Considerations when Evaluating
Treatment of Liver Metastases in MUM Patients
Comparison of Treatments and Stratification of
Results based on –
• Tumor Burden
• Tumor Genetics
• Pattern of Disease in the Liver
(nodular vs. infiltrative)
Adjust for delay in treatment of one lobe of the
liver when using liver-directed treatments in
clinical trials (allow repeat baseline MRI)
From a grateful patient who also donated/raised > $600,000 for the MUM program.

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Metastatic Uveal Melanoma Treatment - 2019 CURE OM Symposium

  • 1. Treatment of Uveal Melanoma Metastatic to the Liver David J. Eschelman, M.D., FSIR Professor of Radiology, Sidney Kimmel Medical College of Thomas Jefferson University Co-Director of Interventional Radiology, Thomas Jefferson University Hospital
  • 2. Disclosures • I will discuss unapproved uses of commercial products. • I am a not a consultant for anyone!
  • 3. MUM Treatments (Metastatic Uveal Melanoma) Liver-Directed Therapies • Immunoembolization • Radioactive microspheres • Chemoembolization, Drug-eluting beads • Fotemustine infusion • IHP/PHP • Ablation
  • 4. Chemoembolization Carin F. Gonsalves, M.D. Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS Mavligit ’88 30 Cisplatin 14 6 11 Cantore ’94 8 Carboplatin -- -- 15 Bedikian ’95 44 Cisplatin 14.5 5 6 Sato ’95 14 Cisplatin -- -- 6.6 Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2 Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5 Vogl ’07 12 Mitomycin C 21 16.5 21 Dayani ’09 21 Mitomycin C, Cisplatin, Doxorubicin 12.7 3.7 7.6 (mean) Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7
  • 5. Immunoembolization at Jefferson Takami Sato, M.D., Ph.D. Kevin L. Sullivan, M.D. Michael J. Mastrangelo, M.D.
  • 6. Immunoembolization Rationale • Destruction of tumor by embolization would control tumor progression locally and provide tumor antigens to the local immune system • Concurrent use of biological response modifier(s) induces an inflammatory response in the tumor and surrounding tissue which may improve the antigen presentation to the local immune system • Local stimulation of the immune system may result in the development of a systemic immune response against tumor cells which may suppress the growth of untreated tumors • IE could potentially create an in situ tumor vaccine.
  • 7. Immunoembolization Granulocyte-Macrophage Colony-Stimulating Factor • Glycoprotein secreted by activated T cells • LEUKINE (sargramostim) is a recombinant yeast- derived human GM-CSF • Increases myeloid cell production • Stimulates macrophages • Increases cytotoxicity of monocytes toward tumor cell lines • Promotes maturation of dendritic cells
  • 8. Immunoembolization Selection of GM-CSF Vaccination was performed with 10 tumor cell lines engineered to secrete different cytokines Proc Natl Acad Sci 1993; 90: 3539-3543
  • 9. Immunoembolization Phase 1 Study – Intro • Purpose was to investigate feasibility and safety • 2000 – 2004, single institution • 34 of 39 patients had MUM • <50% tumor involvement, unresectable • Lobar hepatic artery embolization every 4 weeks using escalating dose of GM-CSF (25-2000 mcg) emulsified with Ethiodol followed by Gelfoam, for 6 treatments • Imaging (CT, MRI) and clinical assessment after every other treatment to assess response (RECIST) • Primary end-points were dose-limiting toxicity and maximum tolerated dose J Clin Oncol 2008; 26:5436-5442
  • 10. Immunoembolization Phase 1 Study – Results (n=34) • 6 procedures/patient (median, range 1-14) • 32% responded (2 CR, 8 PR) • 32% stable disease • OS: 14.4 months (median) (33.7 months for CR/PR, 12.4 months SD/PD) • Survival: 1 yr. 62%, 2 yr. 26% • PFS-liver: 4.8 months (median) • PFS-systemic: 10.4 months (median) J Clin Oncol 2008; 26:5436-5442
  • 13. Immunoembolization Dose-Related Response (n=31) Patients undergoing high-dose IE (>1500 mcg) vs. low-dose IE (<1000 mcg): • Longer OS (20.4 vs. 13.0 months, median) • Longer PFS-L (9.3 vs. 4.2 months, median) • Longer PFS-S (12.4 vs. 5.6 months, median)* * P < .05 Radiology 2009; 252:290-298
  • 14. Immunoembolization Comparison to BCNU TACE Patients undergoing high-dose IE (>1500 mcg) vs. TACE with BCNU (TJUH Phase II study, excluding patients with >50% tumor burden in liver): • Longer OS (20.4 vs. 9.8 months, median)* • Longer PFS-L (9.3 vs. 6.4 months, median) • Longer PFS-S (12.4 vs. 4.8 months, median)* * P < .05 Radiology 2009; 252:290-298
  • 15. Immunoembolization Comparison to BCNU TACE • No significant difference in overall or progression-free survival between patients who received BCNU TACE and lower dose IE • Stabilization of hepatic metastases was most likely achieved by the ischemic effects of embolization rather than by the administered medication • Systemic progression was delayed in the high-dose IE group, suggesting an induction of a systemic immune response against the melanoma cells
  • 16. Immunoembolization Additional observations - • Tumor regression was sustained after discontinuation of immunoembolization in several patients • Response can take as long as 4 months (4 IE procedures) • Evidence of activation of the memory cell arm of the immune system (T cells), suggesting a tumor vaccine Repeated immune stimulation has been shown to be necessary to overcome tolerance and induce a vigorous response (J Exp Med 1997; 186: 645-653 & J Clin Invest 1998; 101:2406-2414)
  • 17. Immunoembolization of the Hepatic Artery with Granulocyte-Macrophage Colony Stimulating Factor • R21 study • Randomized, double blind, phase II clinical study for MUM patients • Primary endpoint – regression of liver mets • Secondary endpoint – time to progression, overall survival, and development of local/systemic immune response • 52 patients – randomized to receive embolization using Ethiodol, with or without 2000 mcg GM-CSF, followed by Gelfoam • Stratified by liver involvement (<20% vs. 20-50%) and HLA-A2 status
  • 18. Immunoembolization of the Hepatic Artery with Granulocyte-Macrophage Colony Stimulating Factor • Excludes patients with >50% tumor involvement, extrahepatic mets, prior local liver therapies • Lobar treatments every 4 weeks with imaging (CT, MRI) and clinical assessment every 8 weeks (RECIST) • Investigation of biopsy specimens before/after treatment • Analysis of peripheral blood mononuclear cells and serum to assess systemic immune response • 52 patients enrolled beginning June 2005 • Last treatment under protocol April 2010 • 2 completed (24 months) • 51 patients (98%) are deceased
  • 19. Immunoembolization of the Hepatic Artery with Granulocyte-Macrophage Colony Stimulating Factor Results – Phase II Trial • Both immunoembolization (IE) and bland embolization were well tolerated with acceptable toxicity • Both approaches induced cytokine productions, more prominent in patients treated with IE • IE showed a potential overall survival benefit in patients with 20-50% tumor replacement • Trend towards longer PFS-S following IE • Unexpectedly, PFS-L was shorter following IE in patients with <20% tumor involvement, suggesting a suppressive (paradoxical) response to high dose GM-CSF JVIR 2015; 26:523-532
  • 20. Immunoembolization of the Hepatic Artery with Granulocyte-Macrophage Colony Stimulating Factor Phase II Trial JVIR 2015; 26:523-532
  • 21. Immunoembolization Phase II Trial - Results • Not powered to determine survival benefit; designed as proof of concept study to investigate hypothesis that adding GM-CSF to embolization would increase release of pro-inflammatory cytokines and delay development of extrahepatic metastases • Plain embo – increases in IL-6 and IL-8 > 18 hrs. • Immunoembo – significant (P<0.001) and rapid increase in TNF-a, IL-6, and IL-8 at 1 and 18 hrs post treatment, suggesting faster and more robust inflammatory response • Increased IL-6 level at 1 hr and IL-8 level at 18 hrs correlated with delay in onset of extrahepatic metastases with a dose- response pattern • Double-blind, randomized clinical trial comparing bland embolization to drug + embolization, showing a benefit of adding the drug
  • 22. Immunoembolization 1500 mcg GM-CSF JVIR 2014; 25: S26 • 68 patients treated 3/2004 – 6/2013, retrospective • 37 (54%) had < 20% tumor burden 31 (46%) had 20-50% tumor burden • 42 patients (62%) with stable disease • Median OS 18.9 months (range 2.1 – 52.2) 28 patients (41%) remain alive at time of analysis It took us 14 years to figure out the appropriate dose of GM-CSF!
  • 23. Immunoembolization + Ipilimumab • 27 patients initially treated with IE and Ipi 9/2012 – 9/2015, retrospective • Median OS 20.1 months: 1 yr. 74% 2 yr. 33% 3 yr. 26% • 16/18 patients without extrahepatic metastases at baseline developed extrahepatic metastases • Safe to perform this combination, but added Ipi toxicities (diarrhea, rash, hypothyroidism, increased LFTs) JVIR 2019; 30: S141
  • 24. Immunoembolization - Lipiodol Distribution MRI pre-treatment CT scan post-treatment
  • 25. Prolonged Survival Following Immunoembolization 10/2010 3/2018
  • 26. Prolonged Survival Following Immunoembolization Work in Progress . . . . . • 174 patients treated 6/2005 – 12/2014, retrospective • Median OS: 17 months (range 2 – 102) • 28 (16%) patients have prolonged survival (> 3 yr.) and treatment breaks Of these 28 “Superstars” . . . . . • At least 68% lived > 4 years (11% of 174) • At least 21% lived > 6 years (5.2% of 174) JVIR 2019; 30: S140
  • 28. Additional MUM Treatments (Metastatic Uveal Melanoma) • Radioactive microspheres • Chemoembolization (Drug-eluting beads) • IHP/PHP
  • 29. Transarterial Catheter-Directed Treatment of Liver Tumors • Radioembolization (RE) • 20-60 micron-sized particles loaded with a radioactive isotope (Yttrium-90) are injected into the hepatic artery • Radioactive particles lodge within arteries supplying tumors, emit radiation and destroy cancer cells Radioactive Microspheres
  • 30. Y-90 Embolization for MUM Jefferson Experience, Salvage Therapy • 32 MUM patients • Single institution, retrospective • Jan 2007 – Apr 2009; follow-up to Sept 2009 • 14 M, 18 F; median age 61 • All patients had progressed followed IE or TACE (median 9, 1-23 prior embolization procedures) • Pre-treatment tumor burden: < 25% (n=25) 25-50% (n=5) >50% (n=2) AJR 2011; 196:468-473
  • 31. Y-90 Embolization for MUM Jefferson Experience, Salvage Therapy Results • OS 1 – 29 months (median 10) • Median survival longer for patients with pretreatment tumor burden of < 25% vs. >25% (10.5 vs. 3.9 months)* • Best radiologic response (RECIST): CR 1 PR 1 SD 18 PD 12 • Median survival longer for patients with CR, PR, or SD vs. PD (14.7 vs. 4.9 months)* *P < .05 AJR 2011; 196:468-473
  • 32. Y-90 Embolization for MUM Jefferson Experience, Updated • 71 patients, 82% salvage • Median PFS-L 5.9 months • Median OS after treatment 12.3 months • Median OS following diagnosis of liver mets 23.9 months (range, 6.2 – 69 months) • Low pre-treatment TGA (total glycolic activity) was associated with a significantly longer median OS (17.2 vs. 9.7 months, p=0.01) American Journal of Clinical Oncology 2016; 39:189-195
  • 33. Y-90 Embolization for MUM Phase II, Single Institution, Prospective Trial • 48 patients, November 2011 – January 2017: • 24 treatment naïve • 24 progressed after immunoembolization Journal of Clinical Oncology 2018; 36: 9535s
  • 34. Y-90 Embolization for MUM Phase II, Single Institution, Prospective Trial Group A (treatment naïve) – • 75% < 20% tumor replacement, 25% had 20 - <50% • 39% partial response, 48% stable disease (n=23) • Median PFS-L: 8.1 months (3.3 – 33.7) • Median OS: 18.5 months (6.5 – 73.7) • Survival: 1 yr. 61%, 2 yr 26%, 3 yr 13% • All patients developed new liver metastases Journal of Clinical Oncology 2018; 36: 9535s
  • 35. Y-90 Embolization for MUM Phase II, Single Institution, Prospective Trial Group B (progression after immunoembolization) – • 92% < 20% tumor replacement, 8% had 20 - <50% • 33% partial response, 42% stable disease (n=24) • Median PFS-L: 5.2 months (2.9 – 22.0) • Median OS: 19.2 months (4.8 – 76.6) • Survival: 1 yr. 70%, 2 yr 30%, 3 yr 9% • 91% patients developed new liver metastases at time of progression • Median OS from initiation of IE treatment: 24.6 months (11.5 – 90.5) Journal of Clinical Oncology 2018; 36: 9535s
  • 36. Y-90 Embolization + Immunotherapy MGH – • 11 patients, 3/2013 – 12/2017, retrospective • 2 patients initial treatment with Y90 9 patients received Y90 after progression on immunotherapy; 6 received additional immunotherapy • Median PFS-L: 15 months • Median OS: 17 months • CR 9%, PR 18%, SD 36%, PD 36% JVIR 2018; 29:11369 - 1375
  • 37. SIRspheres Prior to Treatment 11 months after Treatment
  • 38. Rapid Tumor Progression Prior to SIRspheres 2 months after SIRspheres
  • 39. Chemoembolization Carin F. Gonsalves, M.D. Author Pt # Drug (s) OS Resp* OS Non-Resp Median OS Mavligit ’88 30 Cisplatin 14 6 11 Cantore ’94 8 Carboplatin -- -- 15 Bedikian ’95 44 Cisplatin 14.5 5 6 Sato ’95 14 Cisplatin -- -- 6.6 Patel ’05 24 BCNU (100mg) 21.9 3.3 5.2 Huppert ’09 14 Cisplatin/Carboplatin 14.5 10 11.5 Vogl ’07 12 Mitomycin C 21 16.5 21 Dayani ’09 21 Mitomycin C, Cisplatin, Doxorubicin 12.7 3.7 7.6 (mean) Gupta ’10 125 Mostly Cisplatin 15.8 6.1 6.7
  • 40. Chemoembolization MD Anderson Am J Clin Oncol 2010; 33:474-480 • 125 patients (Jan 1992 – Dec 2005) • 122 patients received cisplatin; 65 also received arterial infusion of vinblastine (n=54) or vinblastine/dacarbazine (n=11) afterwards • Tumor burden: < 25% 36 patients (32%) 25-50% 41 (36%) >50-75% 25 (22%) >75% 11 (10%) • Relatively high rate of complications (14%), many severe
  • 41. Chemoembolization MD Anderson Am J Clin Oncol 2010; 33:474-480 • Overall Survival 6.7 months (median, n=113): < 25% 14 months 25-50% 5.1 >50-75% 5.5 >75% 2.4 • Overall Survival based on LDH: Normal 20 months >1 but <2 x normal 11 > 2 x normal 3.6 • Recommend against treatment when >75% tumor replacement
  • 42. Chemoembolization BCNU • 50 patients with >50% tumor replacement at presentation (Jan 2004 – Nov 2011) • 200 mg BCNU • Median survival 7.1 months • 22% 1 yr. survival (12.2 – 32.3 months) • 72% had stable disease or a treatment response • Neither pre-treatment LDH (> or < 500) nor tumor burden (50-59%, 60-75%, > 75%) had effect on survival AJR 2015; 205:429-433
  • 46. Drug-Eluting Beads for MUM Irinotecan in vivo 2009; 23:131-138 • 10 patients in 2 institutions (Ferrara, Florence) • Jan 2007 – June 2008 • 8 M, 2 F; mean age 65 • All patients had prior systemic chemo/immunotherapy • Pre-treatment tumor burden: < 25% (n=3) 25-50% (n=4) 50-75% (n=3) • Assessment by 3-phase CT pre/post treatment • 100-200 mg Irinotecan administered in 2-4 ml of 100-300/300-500 micron DC Beads • Half had one treatment, other half had 2 treatments
  • 47. Drug-Eluting Beads for MUM Irinotecan in vivo 2009; 23:131-138 • All 10 patients obtained an objective response! • Tumor reduction by imaging: 90% (n=3) 80% (n=3) 60-70% (n=4) • Median follow-up 6.5 (range 4 – 9) months • 8 patients alive at time of report; 2 died at 4 and 6 months • Response related to degree of initial tumor involvement • Side effects similar to TACE, no alopecia or bone marrow toxicity
  • 48. Drug-Eluting Beads for MUM Irinotecan Annals of Gastroenterology and Hepatology 2012; 3:9-14 • Single arm, phase II clinical trial • Jan 2007 – Feb 2010, 52 patients • All patients had prior systemic chemo/immunotherapy • Pre-treatment tumor burden: < 25% (n=30, 58%) 25-50% (n=20, 38%) 50-75% (n=4, 8%) • 85 procedures (median 1.6/patient) • No complications, limited toxicity, + abdominal pain • 100 mg IRI x 10 patients, remainder 200 mg IRI
  • 49. Drug-Eluting Beads for MUM Irinotecan Annals of Gastroenterology and Hepatology 2012; 3:9-14 • No complications, limited toxicity, + abdominal pain • Tumor reduction by imaging (“necrosis and reduction of contrast enhancement”): > 90% (n=17) 80-90% (n=30) 60-80% (n=3) • PFS-L 7.5 months, OS 13.9 months (both median)
  • 50. DEBDOX/BCNU for MUM JVIR 2014; 25: S45 • 19 patients, no prior treatments • July 2011 – January 2013, retrospective review • Poor candidates for other liver-directed therapies (Tumors > 5 cm, > 50% tumor burden, rapid growth) • < 4 ml 100-300 micron LC Beads/150 mg adriamycin (14/36 treatments received full dose) • 13/19 patients proceeded to BCNU chemoembolization (73 treatments) • Based on disparate response, patients divided into “nodular” vs. “infiltrative” pattern, based on MRI appearance
  • 51. DEBDOX/BCNU for MUM Size of Largest Tumor JVIR 2014; 25: S45
  • 52. DEBDOX/BCNU for MUM Results JVIR 2014; 25: S45 Nodular vs Infiltrative Disease Nodular Infiltrative Time (months) SurvivalProbability(%)
  • 53. Nodular (n=11): 3 PR, 7 SD, 1 PD Infiltrative (n=8): 1 PR, 3 SD, 4 PD JVIR 2014; 25: S45 Survival Mean (mos) 95% CI Median (mos) 95% CI Nodular 22.8 15.7 - 29.8 16 --- Infiltrative 4.7 1.6 - 7.9 2.9 1.8 -7.9 Overall 16.0 11.6 - 20.4 9.1 2.9 -12.8 Chi-square = 8.4 p value = 0.0037 DEBDOX/BCNU for MUM Results
  • 54. • 2008 study includes cutaneous and uveal melanoma • Do not report tumor burden or size • Nodular/infiltrative pattern is determined by angiography (we use MRI.) Infiltrative pattern significantly more likely to be ciliary body tumors with extrascleral extension, and loss of tumor suppressor gene (LZTS1 on 8p). Survival (mos) # pts Tx Nodular Infiltrative Sharma KV, et al (2008) 20 CAM 20 3.8 Dayani PN, et al (2009) 21 CAM 12.7 3.7 Chemoembolization: Nodular vs. Infiltrative
  • 55. DEBDOX/BCNU for MUM Work in progress . . . . • added 7 more patients, no prior treatments • July 2011 – December 2014, retrospective review • Poor candidates for other liver-directed therapies (Tumors > 5 cm, > 50% tumor burden, rapid growth) • OS (patients with NODULAR pattern): - 18.2 months (median), range 2.7 – 87.4 months - 2/16 patients still alive (6 & 7 years after starting treatment!)
  • 59. Drug-eluting Beads + Adriamycin, Followed by Chemoembolization Initial 4 months later
  • 60. Drug-eluting Beads + Adriamycin, Followed by Chemoembolization Initial 15 months later
  • 61. 61 DELCATH SYSTEMS, INC Percutaneous Hepatic Perfusion • PHP utilizes 3 primary principles: o ISOLATION – isolates hepatic blood flow o INFUSION – Melphalan agent delivered to liver via hepatic artery o FILTRATION – blood from the liver is filtered to reduce Melphalan concentration prior to returning the blood to systemic circulation INTERNAL-CONFIDENTIAL
  • 63. Percutaneous Hepatic Perfusion J Surgical Oncology 2018; 117:1170-1178: • Moffitt (FL) + Southampton (UK) • 51 patients, 12/2008 – 10/2016, retrospective • 15 completed planned course (4 or 6 treatments) • 7 still undergoing treatment • 29 patients discontinued early: - 9 treatment-related toxicity - 17 disease progression - 3 patient preference • Median of 2 treatments in UK, 3 in FL
  • 64. Percutaneous Hepatic Perfusion J Surgical Oncology 2018; 117:1170-1178: • 6% CR + 43% PR • 33% SD at 3 months, 22% at 6 months • Median OS 15.3 months; 1 yr. survival 65%, 2 yr. 37% • No treatment-related fatalities, but . . . . . . - 3 VT, 1 SVT - 5 myocardial ischemia (1 MI, 1 pulmonary edema) - 3 major bleeding (DIC, abdominal, cerebral) - 2 pulmonary edema, 2 pulmonary emboli - DVT: LE x 2, IVC, IJ, access site - Transfusions: 47% PRBCs, 78% platelets - 4 episodes neutropenic sepsis with 31% experiencing severe neutropenia
  • 65. 65 DELCATH SYSTEMS, INC Phase 3 Trial for Ocular Melanoma: FOCUS Trial A Single-arm, Multi-Center, Open-Label Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Melphalan/HDS Treatment in Patients with Hepatic-Dominant Ocular Melanoma • Objectives oPrimary ▪Objective Response Rate (ORR) oSecondary ▪Duration of Response (DOR) ▪Disease Control Rate (DCR) ▪Overall Survival (OS) ▪Progression Free Survival (PFS) • Patients o50 patients planned • Sites oApproximately 35 sites in US and Europe
  • 66. 66 DELCATH SYSTEMS, INC Additional Treatments • Treatment Frequency In Delcath’s current clinical trials, treatment with Chemosat is administered every 6-8 weeks. Patients are receiving up to six cycles. The exact interval and number of treatments should be determined by the treating physician. O
  • 67. 67 DELCATH SYSTEMS, INC FOCUS Trial – Key Inclusion Criteria Key Inclusion Criteria • 50% or less ocular melanoma metastases in the liver • Evidence of limited extrahepatic disease is acceptable if the life threatening component of disease is in the liver. Limited extrahepatic disease is defined as follows: metastasis in bone, subcutaneous, lung or lymph nodes that is amenable to resection or radiation and has a defined treatment plan. Patients with extra-hepatic tumor burden which does not have a defined treatment plan (i.e. monitor or is unable to be resected or radiated) must not be included in the trial. • Patients must not have had chemotherapy, radiotherapy, chemoembolization, radioembolization, or immunoembolization for their malignancy within 30 days prior to treatment. • Patients receiving anti-PD-1 immunotherapy such as pembrolizumab or nivolumab, or CTLA 4 blocking antibody such as ipilimumab must have completed treatment 8 weeks prior to study enrollment. • ECOG PS of 0-1 at screening. • Adequate hepatic function as evidenced by total serum bilirubin ≤1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of the ULN. AST/ALT must be ≤ 2.5 x ULN. • Platelet count > 100,000/μL, hemoglobin ≥ 10.0 gm/dL, white blood cell count (WBC) > 2,000/uL, absolute neutrophil count ≥ 1.5 x 109/L, and a serum creatinine ≤ 1.5 mg/dL.
  • 68. 68 DELCATH SYSTEMS, INC • Thomas Jefferson University Philadelphia, Pennsylvania • Moffitt Cancer Center Tampa, Florida • Duke University Durham, North Carolina • Stanford University Stanford, California • Emory University Atlanta, Georgia • Ohio State University Columbus, Ohio • University of Tennessee Memphis, Tennessee • Roswell Park Cancer Institute Buffalo, New York • University of Arizona Tucson, Arizona • UCLA Los Angeles, California PARTICIPATING CENTERS – US
  • 69. Percutaneous Hepatic Perfusion AnesthesiaVenovenous Bypass Perfusionist 2 IR Attendings IR Nurses and Technologists Research Coordinators
  • 70. Microwave Ablation • Microwave needle is placed directly into the liver tumor • Using CT or US guidance • Generates heat to destroy tumor cells • Reserved for patients with a solitary metastasis or for a single “rogue” tumor that won’t respond to transarterial liver-directed therapies Microwave needle
  • 71. Microwave Ablation Oligometastasis – • 7 patients, median 1.7 cm diameter • 4 with no intrahepatic progression, 11-37 months • 3 with intrahepatic progression 1-8 months (2 died at 23-24 months) “Rogue Tumor” – • 6 patients, median 2 cm diameter • 1 patient no progression at 36 months • 5 patients intrahepatic progression at median 5 months (1 – 11), 1 died at 27 months JVIR 2019; S84
  • 72. Microwave Ablation IE treatments starting 10-16-2012. All tumors responded except for one. 7/12/17 MRI shows completely necrotic tumor Microwave ablation 4/20/16 performed by Dr. Adamo Currently enjoying a long treatment break, 5.5 years after initiating treatment at TJUH.
  • 73. Current Jefferson Treatment Algorithm for Liver Metastases in MUM Patients Following consideration of resection/ablation (rare): If < 50% liver involvement, limited extrahepatic mets: • Immunoembolization (especially minimal disease) • SIRspheres If < 50% liver involvement, limited extrahepatic mets, largest tumor > 5-6 cm: • DEBDOX followed by BCNU Chemoembolization If > 50% liver involvement with liver dominant disease: • Chemoembolization (BCNU, DEBDOX) Progression following immunoembolization: • SIRspheres (<50% tumor burden) • Chemoembolization (BCNU, DEBDOX) Clinical Trials (including Delcath/PHP)! gp100!!!
  • 74. Future Considerations when Evaluating Treatment of Liver Metastases in MUM Patients Comparison of Treatments and Stratification of Results based on – • Tumor Burden • Tumor Genetics • Pattern of Disease in the Liver (nodular vs. infiltrative) Adjust for delay in treatment of one lobe of the liver when using liver-directed treatments in clinical trials (allow repeat baseline MRI)
  • 75. From a grateful patient who also donated/raised > $600,000 for the MUM program.