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Chemosaturation Therapy Percutaneous Hepatic Perfusion (PHP) Compared with

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.

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Chemosaturation Therapy Percutaneous Hepatic Perfusion (PHP) Compared with

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  1. 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

  2. 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

  3. Chemosaturation Therapy (CS-PHP) 3 Procedural Steps Saturation Filtration Isolation A PERCUTANEOUS ALTERNATIVE to IHP

  4. Filtration Procedure Chemo Filtration Circuit Chemo Isolation & Delivery Circuit

  5. 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

  6. Phase III: CS-PHP vs. BACSTUDY 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 • Melphalandose = 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

  7. 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

  8. 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 4-5 Weeks 4-5 Weeks 24-30 weeks *Scan Evaluation (hPFS) using RECIST Criteria

  9. PHASE III PRELIMINARY RESULTS*

  10. Randomization and Treatment Schematic Total Accrual: 93 patients (PHP: 44; BAC: 49, Crossover: 28) H E P A T I C P R O G R E S S I O N Follow-up PHP Arm (n= 44) R A N D O M I Z E 1:1 Cross over to Chemosaturatioin PHP (n=28, 57%) Melanoma Metastatic to Liver (n = 93) BAC Arm (n = 49) Follow-up Scan Evaluation (hPFS) using RECIST Criteria Pingpank JF, et al. ECCO-ESMO 2011

  11. Patient Demographics *Fisher’s Exact Test. Two-sided PR <= P Well-Balanced Randomization Well-balanced for Prior Therapies Pingpank JF, et al. ASCO 2010

  12. PH-III Randomized US Trial Primary End Point

  13. Hepatic Progression-free Survival (ITT) Survival probability CS-PHPBAC 1.0 0.8 Hazard Ratio: 0.35 (CI: 0.23-0.54) 0.6 p<0.0001 8.0 1.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 Months 3/31/11 Pingpank JF, et al. ECCO-ESMO 2011

  14. PH-III Randomized US Trial Secondary End Points

  15. Overall Progression-free Survival (ITT) Survival probability CS-PHPBAC 1.0 0.8 Hazard Ratio: 0.36 (CI: 0.23-0.57) 0.6 p<0.0001 6.7 1.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 Months Pingpank JF, et al. ECCO-ESMO 2011

  16. Overall Survival (ITT) Survival probability CS-PHPBAC 1.0 0.8 Hazard Ratio: 1.08 (CI: 0.69-1.68) 0.6 p=0.74 9.8 9.9 0.4 55% crossover 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Months 3/31/11 Pingpank JF, et al. ECCO-ESMO 2011

  17. Factors Associated with Survival Survival was Highly Associated with Use of Melphalan with CS-PHP Pingpank JF, et al. ASCO 2010

  18. Efficacy (patients randomized to CS-PHP versus randomized to BAC) ITT population Data as of 31 March 2011

  19. Efficacy (CS-PHP and by BAC subset) *1 patient crossed over but never received PHP BAC-only patients: chemoembolization, HAI nab-paclitaxel, temozolomide ITT population Data as of 31 March 2011

  20. Overall survival (ITT population) PHP randomized v PHP crossover v BAC only 1.0 PHP randomized BAC crossover* BAC only* Censored observations 0.9 0.8 0.7 0.6 0.5 Proportion of subjects surviving 0.4 0.3 0.2 0.1 9.8 13.1 4.1 0.0 Time (months) 48 0 60 12 36 24 * Similar patient characteristics and demographics between BAC crossover and BAC only

  21. Overall survival (ITT population) Total PHP versus BAC only 1.0 Total PHP incl. crossover BAC only Censored observations 0.9 0.8 0.7 0.6 0.5 Proportion of subjects surviving 0.4 0.3 0.2 0.1 4.1 11.4 0.0 48 0 60 12 36 24 Time (months) Overall Survival Tail For Treated Patients

  22. Phase III Results & Conclusions* • Primary endpoint exceeded, • P = 0.0001, Hazard Ratio = 0.35 • CS/PHP median hPFS of 8.0 months compared to 1.6 months for BAC • Five times gain in hPFS • 86% overall clinical benefit (CR + PR + SD) • Gen 1 Safety profile – consistent with currently approved US labeling for IV melphalan • 30-day deaths on PHP: 3/44 patients (6.8%) • 1 Neutropenic Sepsis; 1 Hepatic Failure (95% T.B. + allopurinol); 1 Pancytopenia • 30-day deaths on BAC: 3/49 patients (6.1%) • 116 PHP procedures were performed (3/116 = 2.6%) * Updated Investigator results presented at 2011 ECCO/ESMO Annual Meeting.

  23. Phase III Results & Conclusions* • Secondary endpoints • OS Secondary endpoint – No difference in Kaplan-Meier curves due to cross over • 9.8 months compared to 10.0 months • CS/PHP median overall PFS of 6.7 months vs. 1.6 months for BAC • OS exploratory analysis • Median survival of 9.8 months for treatment arm compared to 4.1 months non-crossover BAC patients • Median survival of 11.4 months for all patients treated with melphalan, including crossover • 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.

  24. Thank you

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