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

P HASE 3 S TUDY I NVESTIGATORS 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

C HEMOSATURATION Therapy (CS-PHP) Isolation Saturation Filtration A PERCUTANEOUS ALTERNATIVE to IHP

Filtration Procedure Chemo Filtration Circuit Chemo Isolation & Delivery Circuit

M ELPHALAN  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

Drug Levels During Therapy Pingpank JF, et al. J Clin Oncol 2005;23:3465–74

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 P HASE III: CS-PHP VS. BAC STUDY DESIGN ELEMENTS

P HASE 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 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) Treatments 1 through 6 - Melphalan - Angiogram (Celiac, SMA) - GDA assessment (Treatment #1) 4-5 Weeks 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 *Scan Evaluation (hPFS) using RECIST Criteria

PHASE III PRELIMINARY RESULTS*

M ELANOMA M ETASTATIC TO L IVER ( N = 93) M ELANOMA M ETASTATIC TO L IVER ( N = 93) PHP A RM ( N = 44) PHP A RM ( N = 44) BAC A RM ( N = 49) BAC A RM ( N = 49) HEPATICPROGRESSIONHEPATICPROGRESSION HEPATICPROGRESSIONHEPATICPROGRESSION C HEMOSATURATIOIN PHP Cross over to C HEMOSATURATIOIN PHP (n=28, 57%) C HEMOSATURATIOIN PHP Cross over to C HEMOSATURATIOIN PHP (n=28, 57%) Randomization and Treatment Schematic R A N D O M I Z E 1:1 R A N D O M I Z E 1:1 F OLLOW - UP Total Accrual: 93 patients (PHP: 44; BAC: 49, Crossover: 28) Total Accrual: 93 patients (PHP: 44; BAC: 49, Crossover: 28) Scan Evaluation (hPFS) using RECIST Criteria Pingpank JF, et al. ECCO-ESMO 2011

Baseline Characteristic CategoryPHP N=44 (%) BAC N=49 (%) P value* Age (years)Mean55 NS GenderMale Female 23 (52) 21 (48) 22 (45) 27 (55) NS RaceWhite Non-White 44 (100) 0 (0) 48 (98) 1 (2) NS ECOGMissing (7) 37 (84) 4 (9) 4 (8) 42 (86) 3 (6) NS Primary TumorOcular Cutaneous 39 (89) 5 (11) 43 (88) 6 (12) NS *Fisher’s Exact Test. Two-sided PR <= P Well-Balanced Randomization Patient Demographics Pingpank JF, et al. ASCO 2010

TherapyCS-PHP N=44 (%) BAC N=49 (%) All N=93 (%) P Value* Radiation (primary tumor) 23 (52) 24 (49) 47 (51) NS Chemotherapy7 (16) 6 (12) 13 (14) NS Immunotherapy6 (14) 7 (14) 13 (14) NS Image Directed Local Therapy 2 (5) 3 (6) 5 (5) NS Unknown0 (0) 1 (2) 1 (1) NS *Fisher’s Exact Test. Two-sided PR <= P No differences between two groups Therapy Prior to Randomization Pingpank JF, et al. ASCO 2010

PH-III Randomized US Trial Primary End Point

Hepatic Progression-free Survival (ITT) Hazard Ratio: 0.35 (CI: ) Months CS-PHP BAC p< Survival probability Pingpank JF, et al. ECCO-ESMO /31/11

PH-III Randomized US Trial Secondary End Points

Overall Progression-free Survival (ITT) Hazard Ratio: 0.36 (CI: ) Months CS-PHP BAC p< Survival probability Pingpank JF, et al. ECCO-ESMO 2011

Overall Survival (ITT) Hazard Ratio: 1.08 (CI: ) Months CS-PHP BAC p= Survival probability % crossover Pingpank JF, et al. ECCO-ESMO 2011

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

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

Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments) Hematologic Grade 3-4, n(%)Grade 5, n(%) Neutropenia71 (61)1 (<1) Thrombocytopenia86 (74)1(<1) Anemia 54 (47) Hepatic Elevated AST 14 (12) Elevated ALT6 (5) Hyperbilirubinemia8 (7) 1 (<1) Increased alk. phos. 6 (5) Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments) Hematologic Grade 3-4, n(%)Grade 5, n(%) Neutropenia71 (61)1 (<1) Thrombocytopenia86 (74)1(<1) Anemia 54 (47) Hepatic Elevated AST 14 (12) Elevated ALT6 (5) Hyperbilirubinemia8 (7) 1 (<1) Increased alk. phos. 6 (5) *Percentages Per Cycle Phase III: Treatment Related Toxicities of CS-PHP Pingpank JF, et al. ASCO Patients, 116 Treatments

P HASE 3 M ELANOMA S TUDY : S AFETY  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 ( %)  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 < ) 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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