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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. - PowerPoint PPT Presentation
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Chemosaturation TherapyPercutaneous Hepatic Perfusion (PHP)
Compared with Best Available Care (BAC) for
Metastatic Melanoma in the Liver
Exploratory Survival Analysisof BAC Cross-over
VersusNon-Cross-over Patients
For thePH-III Randomized US
Multi-Center TrialInvestigators
APCCVIR 2012; Abstract #00131
PHASE 3 STUDY INVESTIGATORSMarybeth 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)
IsolationSaturation
Filtration
A PERCUTANEOUS ALTERNATIVE to IHP
Filtration Procedure Chemo Filtration
CircuitChemo 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
• 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
• 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: CS-PHP VS. BACSTUDY DESIGN ELEMENTS
PHASE III: PHP-CS VS. BACSTATISTICAL 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
• 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
Treatments 1 through 6
- Melphalan
- Angiogram (Celiac, SMA)
- GDA assessment (Treatment #1)
4-5 Weeks
24-30 weeks
On Study Evaluation/Randomization
Interval Evaluation* (Baseline, 6-weeks, 12 weeks, 20 weeks, 28 weeks, 36 weeks)
Post Treatment Follow-up
4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks
*Scan Evaluation (hPFS) using RECIST Criteria
PHASE III
PRELIMINARY RESULTS*
MELANOMAMETASTATIC
TO LIVER(N = 93)
PHP ARM(N= 44)
BAC ARM(N = 49)
HEPATIC
PROGRESSION
Cross over to CHEMOSATURATICHEMOSATURATI
OIN PHPOIN PHP(n=28, 57%)
Randomization and Treatment Schematic
R A N D O
M I Z E
1:1
FOLLOW-UP
FOLLOW-UP
Total Accrual: 93 patients (PHP: 44; BAC: 49, Crossover: 28)
Scan Evaluation (hPFS) using RECIST CriteriaPingpank JF, et al. ECCO-ESMO 2011
Baseline Characteristic
Category PHPN=44 (%)
BACN=49 (%)
P value*
Age (years) Mean 55 55 NS
Gender MaleFemale
23 (52)21 (48)
22 (45)27 (55)
NS
Race WhiteNon-White
44 (100)0 (0)
48 (98)1 (2)
NS
ECOG Missing01
3 (7)37 (84)
4 (9)
4 (8)42 (86)
3 (6)
NS
Primary Tumor OcularCutaneous
39 (89)5 (11)
43 (88)6 (12)
NS
*Fisher’s Exact Test. Two-sided PR <= P
Well-Balanced RandomizationWell-balanced for Prior Therapies
Well-Balanced RandomizationWell-balanced for Prior Therapies
Patient Demographics
Pingpank JF, et al. ASCO 2010
PH-III Randomized US Trial
Primary End Point
Hepatic Progression-free Survival (ITT)
Hazard Ratio: 0.35 (CI: 0.23-0.54)
0 5 10 15 20 25 30 350 5 10 15 20 25 30 35Months
CS-PHP
BAC
8.01.6
p<0.0001
1.01.0Survival probabilitySurvival probability
0.80.8
0.60.6
0.40.4
0.20.2
0.00.0
Pingpank JF, et al. ECCO-ESMO 20113/31/11
PH-III Randomized US Trial
Secondary End Points
Overall Progression-free Survival (ITT)
Hazard Ratio: 0.36 (CI: 0.23-0.57)
0 5 10 15 20 25 30 350 5 10 15 20 25 30 35Months
CS-PHP
BAC
6.71.6
p<0.0001
1.01.0Survival probabilitySurvival probability
0.80.8
0.60.6
0.40.4
0.20.2
0.00.0
Pingpank JF, et al. ECCO-ESMO 2011
Overall Survival (ITT)
Hazard Ratio: 1.08 (CI: 0.69-1.68)
0 5 10 15 20 25 30 35 40 45 50 550 5 10 15 20 25 30 35 40 45 50 55Months
CS-PHP
BAC
9.89.9
p=0.74
1.01.0Survival probabilitySurvival probability
0.80.8
0.60.6
0.40.4
0.20.2
0.00.0
55% crossover
Pingpank JF, et al. ECCO-ESMO 20113/31/11
Factors Associated with Survival
Pingpank JF, et al. ASCO 2010
Survival was Highly Associated with Use of Melphalan with CS-PHP
Survival was Highly Associated with Use of Melphalan with CS-PHP
EFFICACY (PATIENTS RANDOMIZED TO CS-PHP VERSUS RANDOMIZED TO BAC)
EndpointCS-PHP(N=44)
BAC(N=49)
HR (95% CI) P value
Median hPFS, months 8.0 1.60.35
(0.23–0.54)p<0.0001
Median OS, months 9.8 9.91.08
(0.69–1.68)p=0.7403
ORR, % 32 2 – p=0.0001
ITT population
Data as of 31 March 2011
EFFICACY (CS-PHP AND BY BAC SUBSET)
Endpoint
CS-PHP randomized
(N=44)BAC only
(N=21)
BAC-to-PHP crossover
(n=28)
Median hPFS, months 8.0 1.6 8.8
HR (crossover vs BAC-only) 0.32
Median overall survival, months 9.8 4.1 13.1
HR (crossover vs BAC-only) 0.33
Still alive as of 31 March 2011 4 3* 7
Follow-up: 9.7–53.5 months
*1 patient crossed over but never received PHPBAC-only patients: chemoembolization, HAI nab-paclitaxel, temozolomide
ITT population
Data as of 31 March 2011
Overall survival (ITT population)
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
12 360 24 48 60
4.1
PHP randomized
BAC crossover*
BAC only*
Censored observations
PHP randomized v PHP crossover v BAC only
9.8 13.1
Pro
po
rtio
n o
f s
ub
jec
ts s
urv
ivin
g
* Similar patient characteristics and demographics between BAC crossover and BAC only
Pro
po
rtio
n o
f s
ub
jec
ts s
urv
ivin
gOverall survival (ITT population)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
12 360 24 48 60
11.4
Total PHP incl. crossover
BAC only
Censored observations
Time (months)
Total PHP versus BAC only
4.1
Overall Survival Tail For Treated Patients
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 melphalano 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 endpointsoOS Secondary endpoint – No difference in Kaplan-Meier
curves due to cross over o 9.8 months compared to 10.0 months
oCS/PHP median overall PFS of 6.7 months vs. 1.6 months for BAC
OS exploratory analysisoMedian survival of 9.8 months for treatment arm
compared to 4.1 months non-crossover BAC patientsoMedian survival of 11.4 months for all patients treated
with melphalan, including crossovero8 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
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