Chemosaturation Therapy
Percutaneous Hepatic Perfusion (PHP)
Compared with
Best Available Care (BAC) for
Metastatic Melanoma in the Liver
Exploratory Survival Analysis
of BAC Cross-over
Versus
Non-Cross-over Patients
For the
PH-III Randomized US
Multi-Center Trial
Investigators
APCCVIR 2012; Abstract #00131
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
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
Well-balanced for Prior Therapies
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
3/31/11
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
EFFICACY (PATIENTS RANDOMIZED TO
CS-PHP VERSUS RANDOMIZED TO BAC)
CS-PHP
(N=44)
BAC
(N=49)
HR
(95% CI)
Median hPFS, months
8.0
1.6
0.35
(0.23–0.54)
p<0.0001
Median OS, months
9.8
9.9
1.08
(0.69–1.68)
p=0.7403
ORR, %
32
2
–
p=0.0001
Endpoint
ITT population
Data as of 31 March 2011
P value
EFFICACY (CS-PHP AND BY BAC SUBSET)
Endpoint
Median hPFS, months
CS-PHP
randomized
(N=44)
BAC only
(N=21)
BAC-to-PHP
crossover
(n=28)
8.0
1.6
8.8
HR (crossover vs BAC-only)
Median overall survival, months
0.32
9.8
4.1
HR (crossover vs BAC-only)
Still alive as of 31 March 2011
13.1
0.33
4
3*
Follow-up: 9.7–53.5 months
*1 patient crossed over but never received PHP
BAC-only patients: chemoembolization, HAI nab-paclitaxel, temozolomide
ITT population
Data as of 31 March 2011
7
Overall survival (ITT population)
PHP randomized v PHP crossover v BAC only
1.0
PHP randomized
BAC crossover*
0.9
Proportion of subjects surviving
BAC only*
0.8
Censored observations
0.7
0.6
0.5
0.4
0.3
0.2
0.1
4.1
9.8
13.1
0.0
0
12
36
24
48
Time (months)
* Similar patient characteristics and demographics between BAC crossover and BAC only
60
Overall survival (ITT population)
Total PHP versus BAC only
1.0
Total PHP incl. crossover
BAC only
0.9
Proportion of subjects surviving
Censored observations
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
4.1
11.4
0.0
0
12
36
24
Time (months)
Overall Survival Tail For Treated Patients
48
60
PHASE III RESULTS & CONCLUSIONS*

Primary endpoint exceeded,
o P = 0.0001, Hazard Ratio = 0.35
o CS/PHP median hPFS of 8.0 months compared to 1.6
months for BAC
o Five times gain in hPFS
o 86% overall clinical benefit (CR + PR + SD)

Gen 1 Safety profile – consistent with currently approved US
labeling for IV melphalan
o 30-day deaths on PHP: 3/44 patients (6.8%)
 1 Neutropenic Sepsis; 1 Hepatic Failure (95% T.B. +
allopurinol); 1 Pancytopenia
o 30-day deaths on BAC: 3/49 patients (6.1%)
o 116 PHP procedures were performed (3/116 = 2.6%)
* Updated Investigator results presented at 2011 ECCO/ESMO Annual Meeting.
PHASE III RESULTS & CONCLUSIONS*

Secondary endpoints
o OS Secondary endpoint – No difference in Kaplan-Meier
curves due to cross over
o 9.8 months compared to 10.0 months
o CS/PHP median overall PFS of 6.7 months vs. 1.6
months for BAC

OS exploratory analysis
o Median survival of 9.8 months for treatment arm
compared to 4.1 months non-crossover BAC patients
o Median survival of 11.4 months for all patients treated
with melphalan, including crossover
o 8 CS/PHP-treated patients and 2 BAC-treated patients
still alive as of 4/2012
* Updated Investigator results presented at 2011 ECCO/ESMO Annual Meeting.
Thank you