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

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

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 Well-balanced for Prior Therapies Well-Balanced Randomization Well-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: ) 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 /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

E FFICACY ( PATIENTS RANDOMIZED TO CS-PHP VERSUS RANDOMIZED TO BAC) Endpoint CS-PHP (N=44) BAC (N=49) HR (95% CI)P value Median hPFS, months (0.23–0.54) p< Median OS, months (0.69–1.68) p= ORR, %322–p= ITT population Data as of 31 March 2011

E FFICACY (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 HR (crossover vs BAC-only)0.32 Median overall survival, months HR (crossover vs BAC-only)0.33 Still alive as of 31 March *7 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

Overall survival (ITT population) Time (months) PHP randomized BAC crossover* BAC only* Censored observations PHP randomized v PHP crossover v BAC only Proportion of subjects surviving * Similar patient characteristics and demographics between BAC crossover and BAC only

Proportion of subjects surviving Overall survival (ITT population) Total PHP incl. crossover BAC only Censored observations Time (months) Total PHP versus BAC only 4.1 Overall Survival Tail For Treated Patients

P HASE III R ESULTS & C ONCLUSIONS *  Primary endpoint exceeded, o P = , 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.

P HASE III R ESULTS & C ONCLUSIONS *  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.

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