Hepatic Perfusion (CHEMOSAT® or CS-PHP) of Melphalan vs. Best Alternative Care
#1141P (BAC) in Patients with Hepatic Metastases from Melanoma: Update of a Randomized
Phase 3 Study
H.R. Alexander Jr on behalf of Phase 3 Investigators, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD, USA
*CHEMOSAT®; Delcath Systems, Inc., NY, NY
RANDOMIZATION
BAC
(n=49)
8.0
1.6
0.35 (0.23–0.54)
p<0.0001
0.0
Median OS, months
9.8
9.9
1.08 (0.69–1.68)
p=0.7403
2
–
Follow-up
(n=21)
EXPLORATORY
ANALYSIS
● A randomized phase 3 study (n=93) compared melphalan
delivered via CS-PHP with BAC in patients with ocular or
cutaneous melanoma metastatic to the liver:
– based on an intention-to-treat analysis by the investigators
(April 2010, primary datalock), CS-PHP melphalan
significantly improved hepatic progression-free survival by
6.4 months at the median, with a hazard ratio of 0.30 (95%
CI 0.18–0.50; p<0.0001) versus BAC.5
● We performed an exploratory post-hoc analysis of BAC
patients who crossed over to CS-PHP after disease
progression:
– (BAC→CS-PHP crossover) vs. BAC only vs CS-PHPrandomized patients.
Total
(n=49)
BAC to CS-PHP
crossover (n=28)
BAC only
(n=21)
55
56
56
56
90
10
86
14
95
5
Hepatic tumor burden, %
<50%
≥50%
80
20
80
20
89
11
67
33
47
50
43
0.6
0.5
HR=0.35
(95% CI 0.23–0.54)
8.0
1.6
p<0.0001
Intent-to-treat population.
52
73
18
55
88
20
54
82
18
57
95
24
Patients (%)
20
24
28
32
36
40
44
po
al b
um
cy
to
16
48
Conclusions
BAC only
BAC to CS-PHP crossover
CS-PHP randomized
0.8
0.6
0.5
15.3
4.1
0.4
0.3
0.4
0.2
0.3
● CS-PHP significantly prolonged hPFS
compared with BAC in patients with liverdominant metastatic melanoma.
● The primary study objective was met.
● Overall survival was similar in both groups, as
expected:
– confounded by crossover
– prolonged survival observed in BAC→CSPHP crossover patients
– most long-term survivors received CS-PHP.
● Efficacy similar in BAC-crossover and CS-PHPrandomized patients.
● Hematological AEs managed effectively with
supportive care.
● CS-PHP with melphalan is a new treatment
option for unresectable metastatic melanoma in
the liver.
0.1
11.2
0.0
0
0
4
5
10
15
20
25
30
35
40
45
50
55
Study investigators
Time (months)
8
12
16
20
24
28
32
36
40
44
48
Independent Review Committee data; intent-to-treat population; data as of April 2010 (primary datalock).
Time to hepatic progression (months)
Investigator-assessed data; intent-to-treat population; data as of 31 March 2011.
Safety of CS-PHP melphalan
Median hPFS, months
CS-PHP
randomized
(n=44)
BAC
only
(n=21)
8.0
1.6
HR (crossover vs BAC-only)
Median OS, months
Previous treatment, %
Radiation therapy
Surgery/procedure
Chemotherapy
12
0.7
Endpoint
48
8
0.9
BAC
CS-PHP
Exploratory analysis
89
11
4
1.0
0.7
0.0
BAC (n=49)
CS-PHPrandomized
(n=44)
0
Time to hepatic progression (months)
hPFS
6.4
Primary tumor site, %
Ocular
Cutaneous
Extrahepatic sites, %
0
Exploratory analysis: Overall survival
0.1
Baseline characteristics
Purpose
10
p=0.0001
0.2
Median age, years
20
Investigator-assessed data; intent-to-treat population; data as of 31 March 2011.
Follow-up
(n=44)
PRIMARY
ANALYSIS
Characteristic
9.6
1.6
Independent Review Committee data; intent-to-treat population; data as of April 2010 (primary datalock).
0.8
Crossover to CS-PHP
(n=28)
40
bo
Median hPFS, months
0.9
CS-PHP
(n=44)
50
Th
ro
m
0.1
Patient flowchart
CS-PHP circuit
60
0.4
P value
32
Day 4 post-treatment to cycle end
30
7.0
0.5
HR
(95% CI)
1.0
Ocular or cutaneous
melanoma with
liver metastases
(n=93)
0.6
BAC
(n=49)
ORR, %
Post-procedural events
70
0.7
CS-PHP
(n=44)
Endpoint
Peri-procedural events
Day of treatment to day 3 post-treatment
90
0.8
0.2
● CS-PHP with melphalan:
– 3.0 mg/kg as a 30-minute intra-arterial infusion
– an additional 30 minutes of extracorporeal filtration at end
of infusion (washout)
– under general anesthesia
– allowed up to 6 treatments, repeated every 4–8 weeks.
● Best alternative care (BAC):
– investigator’s choice of systemic, regional or other
appropriate therapy
– crossover to CS-PHP permitted after hepatic progression
(if patients still met eligibility criteria).
100
80
0.3
Efficacy analysis
Study treatments
BAC only
BAC to CS-PHP crossover
CS-PHP randomized
0.9
Hy
*1 patient received a combination of systemic chemotherapy and chemoembolization.
1.0
Proportion of patients surviving
● CS-PHP with melphalan:
– median of 3 (range, 1–6) CS-PHP treatments
– median melphalan dose 187 (range, 85–220) mg/cycle.
● BAC:
– active treatment (n=40)
• temozolomide (n=20)
• chemoembolization (n=12)*
• yttrium microspheres (n=3)
• systemic chemotherapy (n=6)*
– supportive care/watchful waiting (n=9).
Most common (>10%) grade 3/4 AEs
pe
ni
An a
em
ia
i ne
AS
m
T
ia
a P i n cr
ea
TT
se
pr
d
Hy ol on
g
po
ca ed
l ce
AL
m
Hy T in
ia
cr
pe
e
rb
i l i r a se
d
ub
i ne
m
ia
Th Neu
tro
ro
m
bo pen
cy
i
to a
Le p en
ia
uk
op
e
Hy
ni
pe
An a
Fe rbilir em
ia
ub
br
Al
ile
i ne
ka
lin
ne
m
e
i
ut
ph
ro a
A
pe
os
S
nia
ph T i
n
at
a s c re
as
e
ed
in
AL crea
T
i n c se d
Hy
po
re
as
al b
um ed
i ne
m
ia
● Isolates the liver from the systemic circulation using a
system of special catheters introduced percutaneously.
● Infusion via the proper hepatic artery allows perfusion of the
entire hepatic parenchyma.
● The procedure allows for considerable dose escalation to
the affected organ and provides treatment for both
established and micrometastatic disease.
● Hepatic venous effluent is captured via a double-balloon
catheter positioned in the retrohepatic vena cava, filtered to
remove chemotherapeutic agents, and then returned to the
systemic circulation.4
● The procedure is minimally invasive and repeatable.
● Randomized, open-label, multicenter phase 3 study.
Patients
● Ocular or cutaneous metastatic melanoma predominantly in
the liver parenchyma with limited extra-hepatic disease.
Endpoints
● Primary:
– hepatic progression-free survival (hPFS) by RECIST.
● Secondary:
– hepatic objective response rate
– overall survival
– safety.
Exploratory analysis: hPFS
Proportion of patients surviving
Chemosaturation-PHP*
Treatment exposure
Proportion of patients surviving
● The prognosis for patients with liver-dominant metastatic
melanoma is dismal.
● Recently introduced drugs, i.e. ipilimumab and
vemurafenib, are limited by tolerability, long induction
periods, and/or applicability to ocular melanoma patients.
● Regional therapies deliver high doses of chemotherapy to a
cancer-burdened organ while limiting unwanted systemic
toxicity.
● Regional therapy using isolated hepatic perfusion with
melphalan has shown promising efficacy in patients with
liver metastases from ocular melanoma,1–3 but requires an
open surgical procedure and is not repeatable.
Study design
HEPATIC DISEASE PROGRESSION
Background
8.8
0.32
9.8
4.1
4
3*
HR (crossover vs BAC-only)
Still alive as of 31 March 2011
BAC to CS-PHP
crossover
(n=28)
15.3
0.33
Follow-up: 9.7–53.5 months
*1 patient crossed over but never received CS-PHP.
Investigator-assessed data; intent-to-treat population; data as of 31 March 2011.
7
● Most common grade 3/4 AEs were thrombocytopenia and
anemia.
● Neutropenia was common during in-cycle period:
– febrile neutropenia in 6 patients (15%).
● Hepatic laboratory abnormalities in 10–30% of patients:
– transient peri-procedural transaminitis
– hyperbilirubinemia.
● Non-hematological toxicities infrequent.
● Three treatment-related deaths ≤30 days of last melphalan
dose:
– hepatic failure in patient with >75% liver tumor burden, n=1
– streptococcal sepsis, n=1
– gastric perforation, n=1 (BAC-crossover).
Marybeth Hughes, National Cancer Institute, Bethesda, MD.
Charles W. Nutting, Swedish Medical Center, Englewood, CO.
Jonathan S. Zager, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
Mark Faries, John Wayne Cancer Institute, Santa Monica, CA.
Gary Siskin, Albany Medical Center Hospital, Albany NY.
Sanjiv Agarwala, St Luke’s Hospital and Health Network, Bethlehem, PA.
Eric Whitman, Atlantic Melanoma Center, Morristown, NJ.
Richard Royal, University of Texas, MD Anderson Cancer Center, Houston, TX.
James Pingpank, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA.
References
1. Alexander HR, et al. Clin Cancer Res 2000;6:3062–70.
2. Alexander HR, et al. Clin Cancer Res 2003;9:6343–9.
3. Noter SL, et al. Melanoma Res 2005;14:67–72.
4. Pingpank JF, et al. J Clin Oncol 2005;23:3465–74.
5. Pingpank JF, et al. J Clin Oncol 2010;28:18s (suppl; abstr LBA8512).
Support for third-party medical writing assistance was provided by Delcath Systems Inc.
Presented at the European Society for Medical Oncology 2012 Meeting,
September 28 to October 2 2012, Vienna, Austria.