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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 Un-resectable Metastatic Melanoma in the Liver PH-III Randomized US Multi-Center Trial Investigators . APCCVIR 2012; Abstract #00136. Phase 3 Study 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 Un-resectable Metastatic Melanoma in the Liver PH-III Randomized US Multi-Center Trial Investigators APCCVIR 2012; Abstract #00136

  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. Drug Levels During Therapy Melphalan (μg/ml) 20 Pre-filterPost-filterSystemic Infusion3.0 mg/kg 15 10 Hepatic Dose 5 Systemic Dose 0 0 10 20 30 40 50 60 70 Minutes Pingpank JF, et al. J Clin Oncol 2005;23:3465–74

  7. 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

  8. 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

  9. 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

  10. PHASE III PRELIMINARY RESULTS*

  11. 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

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

  13. Therapy Prior to Randomization *Fisher’s Exact Test. Two-sided PR <= P No differences between two groups Pingpank JF, et al. ASCO 2010

  14. PH-III Randomized US Trial Primary End Point

  15. 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

  16. PH-III Randomized US Trial Secondary End Points

  17. 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

  18. 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 Pingpank JF, et al. ECCO-ESMO 2011

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

  20. Secondary Endpoint: Hepatic Response Rate Disease Control Rate(CR+PR+SD): CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%) Pingpank JF, et al. ECCO-ESMO 2011

  21. Phase III: Treatment Related Toxicities of CS-PHP Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments) HematologicGrade 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 44 Patients, 116 Treatments Pingpank JF, et al. ASCO 2010

  22. Phase 3 Melanoma Study: Safety • Most common grade 3/4 AEs (peri-procedure) • thrombocytopenia, anemia and hypoalbuminemia • Melphalan-related neutropenia, leukopenia (in cycle) • 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 • hepatic failure, n=1 (99% liver replaced with tumor at autopsy; prophylactic allopurinol) • neutropenia, n=1 • pancytopenia, n=1

  23. 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

  24. Thank you

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