Chemosaturation Therapy Percutaneous Hepatic Perfusion (PHP) Compared with Best Available Care (BAC)...
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Chemosaturation TherapyPercutaneous 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
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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
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CHEMOSATURATION Therapy (CS-PHP)
IsolationSaturation
Filtration
A PERCUTANEOUS ALTERNATIVE to IHP
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Filtration Procedure Chemo Filtration
CircuitChemo Isolation &
Delivery Circuit
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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
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Drug Levels During Therapy
Pingpank JF, et al. J Clin Oncol 2005;23:3465–74
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• 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
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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
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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
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PHASE III
PRELIMINARY RESULTS*
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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
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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 Randomization
Patient Demographics
Pingpank JF, et al. ASCO 2010
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Therapy CS-PHP N=44 (%)
BACN=49 (%)
AllN=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
*Fisher’s Exact Test. Two-sided PR <= P
No differences between two groupsNo differences between two groups
Therapy Prior to Randomization
Pingpank JF, et al. ASCO 2010
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PH-III Randomized US Trial
Primary End Point
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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
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PH-III Randomized US Trial
Secondary End Points
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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
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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 2011
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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
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Secondary Endpoint: Hepatic Response Rate
Disease Control Rate (CR+PR+SD): CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%)
Disease Control Rate (CR+PR+SD): CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%)
Pingpank JF, et al. ECCO-ESMO 2011
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Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments)
Hematologic Grade 3-4, n(%) Grade 5, n(%) Neutropenia 71 (61) 1 (<1) Thrombocytopenia 86 (74) 1 (<1) Anemia 54 (47)
Hepatic Elevated AST 14 (12) Elevated ALT 6 (5) Hyperbilirubinemia 8 (7) 1 (<1) Increased alk. phos. 6 (5)
*Percentages Per Cycle
Phase III: Treatment Related Toxicities of CS-PHP
Pingpank JF, et al. ASCO 2010
44 Patients, 116 Treatments44 Patients, 116 Treatments
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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 hyper-bilirubinemia (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=1o pancytopenia, n=1
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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
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Thank you