Chemosaturation Therapy
Percutaneous Hepatic Perfusion (PHP)
Compared with
Best Available Care (BAC)
For Un-resectable
Metastatic Melanoma in the Liver
PH-III Randomized US
Multi-Center Trial
Investigators
APCCVIR 2012; Abstract #00136
PHASE 3 STUDY INVESTIGATORS
Marybeth Hughes, National Cancer Institute, Bethesda, MD
H. Richard Alexander, U. of Maryland School of Medicine, Baltimore, MD
Mark Faries, John Wayne Cancer Institute, Santa Monica, CA
James F. Pingpank, U. of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA
Jonathan S. Zager, Moffitt Cancer Center, Tampa, FL
Sanjiv Agarwala, St Luke’s Hospital and Health Network, Bethlehem, PA
Charles W. Nutting, Swedish Medical Center, Englewood, CO
Richard Royal, U. of Texas, MD Anderson Cancer Center, Houston, TX
Gary Siskin, Albany Medical Center Hospital, Albany NY
Eric Whitman, Atlantic Melanoma Center, Morristown, NJ
CHEMOSATURATION Therapy (CS-PHP)
Isolation
Saturation
A PERCUTANEOUS
ALTERNATIVE to IHP
Filtration
Filtration Procedure
Chemo Filtration
Circuit
Chemo Isolation &
Delivery Circuit
MELPHALAN





A bi-functional alkylating agent (nitrogen mustard)
Not cell-cycle specific – binds DNA strands
Cytotoxic effects are related to concentration and duration
of exposure
Non-toxic to normal hepatocytes
Track record with surgical IHP
Pharmacokinetic data
Bioavailability Up to 89%
Metabolism
Hydrolysis
Half-life
1.5 ± 0.8 hours
Excretion
Renal, significantly
metabolized
Drug Levels During Therapy
Melphalan (μg/ml)
20
Pre-filter
Post-filter
Systemic
Infusion
3.0 mg/kg
15
10
Hepatic
Dose
5
Systemic Dose
0
0
10
20
30
40
50
60
70
Minutes
Pingpank JF, et al. J Clin Oncol 2005;23:3465–74
PHASE III: CS-PHP VS. BAC
STUDY DESIGN ELEMENTS
•
•
•
•
•
Conducted under Special Protocol Assessment (SPA) of US-FDA:
•
Primary Endpoint: Hepatic Progression Free Survival (hPFS)
•
Cross-Over: of BAC patients at hepatic progression
•
Stratification: Cutaneous vs. Ocular
Lead Center: National Cancer Institute (NIH)
•
Accrual: 93 patients/10 Institutions
Melphalan dose = 3.0 mg/kg (from Phase 1 Trial)
Key Secondary Endpoints :
•
Response rate & Duration of Response
•
Overall Survival
•
Safety & Tolerability
Staging Scans: Evaluation by RECIST Criteria
PHASE III: PHP-CS VS. BAC
STATISTICAL ANALYIS PLAN
Sample size: 46 patients per arm
•
Alpha: p≤0.05 (2-sided )
•
Power: 80% to detect a difference of 4 months Hepatic PFS
• Expected Hepatic PFS (used for sample size determination)
•
PHP (Treatment): 7.73 months
•
Best Alternative Care (Control): 4 months
• Response Rate (CR+PR) Detection: 88% power to detect a
difference
• Analysis of Results by Intent-to-Treat (ITT)
• Statistical Significance: p < 0.05
•
PHP-CS Arm Treatment Schema
On Study
Evaluation/Randomization
Post Treatment Follow-up
Interval Evaluation* (Baseline, 6-weeks, 12 weeks, 20 weeks, 28 weeks, 36 weeks)
Treatments 1 through 6
- Melphalan
- Angiogram (Celiac, SMA)
- GDA assessment (Treatment #1)
4-5 Weeks
4-5 Weeks
4-5 Weeks
4-5 Weeks
24-30 weeks
*Scan Evaluation (hPFS) using RECIST Criteria
4-5 Weeks
4-5 Weeks
PHASE III
PRELIMINARY
RESULTS*
Randomization and Treatment Schematic
Total Accrual: 93 patients
(PHP: 44; BAC: 49, Crossover: 28)
MELANOMA
METASTATIC
TO LIVER
(N = 93)
R
A
N
D
O
M
I
Z
E
1:1
PHP ARM
(N= 44)
H
E
P
A
T
I
C
FOLLOW-UP
Cross over to
BAC ARM
(N = 49)
Scan Evaluation (hPFS) using RECIST Criteria
P
R
O
G
R
E
S
S
I
O
N
CHEMOSATURATIOIN
PHP
(n=28, 57%)
FOLLOW-UP
Pingpank JF, et al. ECCO-ESMO 2011
Patient Demographics
Baseline
Characteristic
Category
PHP
N=44 (%)
BAC
N=49 (%)
P value*
Age (years)
Mean
55
55
NS
Gender
Male
Female
23 (52)
21 (48)
22 (45)
27 (55)
NS
Race
White
Non-White
44 (100)
0 (0)
48 (98)
1 (2)
NS
ECOG
Missing
0
1
3 (7)
37 (84)
4 (9)
4 (8)
42 (86)
3 (6)
NS
Primary Tumor
Ocular
Cutaneous
39 (89)
5 (11)
43 (88)
6 (12)
NS
*Fisher’s Exact Test. Two-sided PR <= P
Well-Balanced Randomization
Pingpank JF, et al. ASCO 2010
Therapy Prior to Randomization
Therapy
CS-PHP
N=44 (%)
BAC
N=49 (%)
All
N=93 (%)
P Value*
Radiation
(primary tumor)
23
(52)
24
(49)
47
(51)
NS
Chemotherapy
7
(16)
6
(12)
13
(14)
NS
Immunotherapy
6
(14)
7
(14)
13
(14)
NS
Image Directed
Local Therapy
2
(5)
3
(6)
5
(5)
NS
Unknown
0
(0)
1
(2)
1
(1)
NS
No differences between two groups
*Fisher’s Exact Test. Two-sided PR <= P
Pingpank JF, et al. ASCO 2010
PH-III Randomized US Trial
Primary End Point
Hepatic Progression-free Survival (ITT)
Survival probability
1.0
CS-PHP
BAC
0.8
0.6
8.0
1.6
0.4
p<0.0001
Hazard Ratio: 0.35
(CI: 0.23-0.54)
0.2
0.0
0
3/31/11
5
10
15
20
25
Months
30
35
Pingpank JF, et al. ECCO-ESMO 2011
PH-III Randomized US Trial
Secondary End Points
Overall Progression-free Survival (ITT)
Survival probability
1.0
CS-PHP
BAC
0.8
0.6
6.7
1.6
0.4
p<0.0001
Hazard Ratio: 0.36
(CI: 0.23-0.57)
0.2
0.0
0
5
10
15
20
25
Months
30
35
Pingpank JF, et al. ECCO-ESMO 2011
Overall Survival (ITT)
Survival probability
1.0
CS-PHP
BAC
0.8
0.6
9.9
0.4
Hazard Ratio: 1.08
(CI: 0.69-1.68)
p=0.74
9.8
55% crossover
0.2
0.0
0
5
10
15
20
25
30
Months
35
40
45
50
55
Pingpank JF, et al. ECCO-ESMO 2011
Factors Associated with Survival
Variable
Hazard Ratio
Confidence Interval
Melphalan
0.3
0.18 – 0.50
Gender
1.1
0.70 – 1.81
>65 years old
1.3
0.66 – 2.56
Ocular/Cutaneous
0.7
0.32 – 1.71
>1 year of disease
0.8
0.45 – 1.46
Melphalan, controlling
for all of the above
0.28
0.17 – 0.47
Survival was Highly Associated with
Use of Melphalan with CS-PHP
Pingpank JF, et al. ASCO 2010
Secondary Endpoint:
Hepatic Response Rate
Best Alternative Care
CS-PHP
(N=44)
All
(n=49)
Crossover
(N=28)
CR
0 (0)
0 (0)
0 (0)
PR
13 (29.5)
1 (2.0)
8 (28.6)
SD
26 (59.1)
14 (28.6)
14 (50)
PD
2 (4.5)
32 (65.3)
1 (3.6)
NE
3 (6.8)
2 (4.1)
5 (17.9)
13 (29.5)
1 (2.0)
8 (28.6)
Overall Response: n (%)
Objective Response Rate (CR+PR)
Disease Control Rate (CR+PR+SD):
CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%)
Pingpank JF, et al. ECCO-ESMO 2011
Phase III:
Treatment Related Toxicities of CS-PHP
Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments)
Hematologic
Neutropenia
Thrombocytopenia
Anemia
Grade 3-4, n(%)
71 (61)
86 (74)
54 (47)
Hepatic
Elevated AST
Elevated ALT
Hyperbilirubinemia
Increased alk. phos.
14
6
8
6
(12)
(5)
(7)
(5)
Grade 5, n(%)
1 (<1)
1 (<1)
1
(<1)
*Percentages Per Cycle
44 Patients, 116 Treatments
Pingpank JF, et al. ASCO 2010
PHASE 3 MELANOMA STUDY: SAFETY





Most common grade 3/4 AEs (peri-procedure)
o thrombocytopenia, anemia and hypoalbuminemia
Melphalan-related neutropenia, leukopenia (in cycle)
o febrile neutropenia in 6 (15%) patients
Transient peri-procedural transaminitis and hyperbilirubinemia (10 - 30%)
Non-hematological toxicities infrequent
Three patients died of treatment-related events
o hepatic failure, n=1 (99% liver replaced with tumor
at autopsy; prophylactic allopurinol)
o neutropenia, n=1
o pancytopenia, n=1
Conclusions
• Significant improvement in hPFS (INV)
– 6.4 months at median: HR 0.35 (p < 0.0001)
• Consistent with IRC (incl. secondary endpoints)
• No difference in mOS due to cross-over (ITT)
– 55% crossover from BAC to PHP-melphalan
• Transient LFT elevations – no Rx required
• Expected & manageable toxicities of melphalan
• Patients still alive as of April 30, 2012
– 2 BAC and 8 CS-PHP
Thank you