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Namodenoson for Second-Line Treatment of HCC Patients with CPB Cirrhosis: A Phase 2 Trial

This study evaluates the safety and efficacy of namodenoson in advanced HCC patients with CPB cirrhosis. Results show promising outcomes with potential as a second-line therapy.

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Namodenoson for Second-Line Treatment of HCC Patients with CPB Cirrhosis: A Phase 2 Trial

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  1. The Safety and Efficacy of Namodenoson in the Second-Line Treatment of Advanced Hepatocellular Carcinoma (HCC) Patients with Underlying Child-Pugh B (CPB) Liver Cirrhosis: A Phase 2 , Randomized, Double-Blind, Placebo-Controlled Trial Salomon M. Stemmer1, Nebojsa S. Manojlovic2, Mihai Vasile Marinca3, Petar Petrov4, Nelly Cherciu5, Doina Ganea6, Tudor-Eliade Ciuleanu7, Ioana Adriana Puscas8, Muhammad Shaalan Beg9, William T. Purcell10, Adina-Emilia Croitoru11, RumyanaNedyalkova Ilieva12, Sladjana Natošević13, AmedeiaLavinir Nita14, DimitarNikolaev Kalev15, Zivit Harpaz16, Motti Farbstein16, Michael H. Silverman16, David Bristol16, Inbal Itzhak16, Pnina Fishman16, and Josep M Llovet1 1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Military Medical Academy, Belgrade, Serbia; 3Institutul Regional de Oncologie Iasi – SectiaOncologie Medical, Iasi, Romania; 4Complex Oncology Center–Plovdiv, EOOD, Plovdiv, Bulgaria; 5Clinica Onco-Life, Craiova, Romania; 6Spitalul Judetean de UrgentaSfantulIoancelNouSuceava, Suceava, Romania; 7Institute of Oncology/University of Medicine and Pharmacy, Cluj-Napoca, Romania; 8S.C. Pelican Impex S.R.L. - SecţiaOncologieMedicală, Oradea, Romania; 9The University of Texas Southwestern Medical Center, Dallas, TX; University of Colorado Comprehensive Cancer Center, Aurora, CO; 10Fundeni Clinical Hospital, Bucharest, Romania; Multiprofile Hospital for Active Treatment Central Onco Hospital OOD Department of Medical Oncology, Plovdiv, Bulgaria; 11Zdravstveni CentarKladovoSlužbaOnkologije, Kladovo, Serbia; County Hospital Pratova, Ploiesti, Romania; 12Sveta Marina University Hospital, Varna, Bulgaria; 16Can-Fite BioPharma, Petach Tiqwa, Israel; 17Mount Sinai School of Medicine, New York University, New York, NY.

  2. Background • The incidence of HCC is increasing worldwide • Liver and intrahepatic bile duct cancer are the 5th and 7th leading causes of cancer deaths in males and females, respectively • For the majority of HCC patients, their Child Pugh (CP) score is not in class A • In selecting drugs to treat cirrhotic patients with HCC, there is a delicate balance due to limited liver reserve • No systemic therapies have shown clinical benefit in CPB patients with advanced HCC, and thus this population represents an unmet medical need

  3. Background (cont.) • Namodenoson (CF102), is an A3AR agonist, currently in clinical development as a treatment for patients with advanced HCC and CPB cirrhosis • The drug target, A3AR, is a Gi protein-associated cell surface receptor • A3AR expression is high in liver tumor cells and low in adjacent normal cells • Namodenoson demonstrated promising preliminary results in this population (as 1st and 2nd line therapy) in an open-label phase 1/2 clinical study (NCT00790218), with median OS of 8.1 months

  4. Namodenoson • Nucleoside derivative • Molecular weight: 544.73 Da • Water insoluble • Orally bioavailable • t1/2: 12 hours • Very stable, hardly metabolized in the liver 4 Namodenoson MOA: down regulation of the Wnt and NF-kB signaling pathways • A3AR 4

  5. Study Design and Endpoints • Study type: Phase 2, double blind, randomized, placebo-controlled, international multi-center study (NCT02128958) • Objective: Assessing the efficacy and safety of namodenoson as 2nd-line therapy in advanced HCC and CPB cirrhosis • Patients and treatment: Patients were randomized 2:1 to continuous treatment with oral BID 25 mg namodenoson or placebo • Endpoints: • Primary: OS • Secondary: Safety, PFS, OR, and DCR (response was assessed locally by RECIST and centrally by mRECIST) • Exploratory: WBC A3AR at baseline and over time • Statistical analysis: Log rank test was used to assess OS/PFS 5

  6. Patient Disposition and Treatment Exposure • Excluded (n=58) • Did not meet inclusion criteria (n=55) • Withdrew ICF (n=2) • Lost to F/U (n=1) • Patients screened (n=136) • Randomization (n= 78) • Randomized to namodenoson (n=50) • Received namodenoson 25 mg BID (n=50) • Randomized to placebo (n=28) • Received placebo (n=28) • Discontinued treatment (n= 28) • Died (n= 25) • Pt discontinued treatment (n=2) • Lost to F/U (no F/U ICF) (n=1) • Discontinued treatment (n=48) • Died (n=45) • Pt discontinued treatment (n=1) • Lost to F/U (no F/U ICF) (n=2) Analysis (ITT, n=50) • Analysis (ITT, n= 28) 6

  7. Baseline Patient and Tumor Characteristics

  8. Results: OS and PFS (ITT, All Patients) OS PFS Primary endpoint was not met (no statistically significant OS difference) 8

  9. Results: OS and PFS in Patients with CPB7 • Pre-planned subgroup analysis OS PFS Numerical but not statistically significant OS/PFS differences 9

  10. Results: 12-Month OS by Treatment (CPB7 Patients) (15/34 pts) P = 0.028 (4/22 pts) (n=34) (n=22) 10

  11. Results: Subgroup Analysis (OS, ITT) N (%) HR (95% CI) Neither EHS/PVT Either EHS/PVT 20 (25.6)0.78 (0.30, 2.00) 58 (74.4)0.77 (0.42, 1.40) • No subgroup with a statistically significant difference between the arms PVT No PVT 38 (48.7)0.90 (0.42, 1.89) 40 (51.3)0.67 (0.34, 1.33) EHS No EHS 43 (55.1)0.60 (0.29, 1.22) 35 (44.9)0.99 (0.48, 2.04) Locoregional Therapy No Locoregional Therapy 21 (26.9) 1.21 (0.43, 3.44) 57 (73.1) 0.73 (0.41, 1.30) Hepatitis C - Positive Hepatitis C - Negative 33 (44.0) 1.19 (0.52, 2.71)1 42 (56.0) 0.72 (0.37, 1.43) Hepatitis B - Positive Hepatitis B - Negative 37 (49.3) 0.90 (0.43, 1.87)2 38 (50.7) 0.86 (0.42, 1.73) ECOG = 1 ECOG = 0 58 (79.5) 0.69 (0.39, 1.22)3 15 (20.5) 1.99 (0.60, 6.62) 1 Three patients with responses of 'missing' are excluded from analysis 2 Three patients with responses of 'missing' are excluded from analysis 3 Five patients with ECOG=2 are excluded from analysis 4 Six patients do not have AFP values at baseline or screening visits 35 (48.6) 0.54 (0.25, 1.16)4 37 (51.4) 0.97 (0.47, 2.01) AFP > 400 AFP ≤ 400 57 (73.1) 0.92 (0.50, 1.68) 21 (26.9) 0.70 (0.28, 1.74) Sex - Male Sex - Female Favors Namodenoson Favors Placebo 11

  12. Results: Response Rates * Patients who had at least one assessment post baseline. • DCR for namodenoson treatment was superior to that of placebo after 4/6 cycles of treatment (ITT analysis): • 4 cycles: 18.0% (9/50) vs 7.1% (2/28), P=0.013 • 6 cycles: 14.0% (7/50) vs 7.1% (2/28), P=0.038 12

  13. Results: CT Imaging Nov 28, 2016 Jan 3, 2018 Nov 28, 2016 Jan 3, 2018 Venous phase Arterial phase 13

  14. Results: A3AR Expression • A3AR expression level at baseline was 1.98±0.36 in comparison to 1 unit in healthy subjects • Comparable A3AR expression levels were found in the different CPB subpopulations • A3AR expression did not change substantially during the treatment period, demonstrating that continuous treatment with namodenoson does not result in desensitization or loss of the target 14

  15. Treatment-related Adverse Events

  16. Conclusions • Namodenoson demonstrated a favorable safety profile in patients with advanced HCC and moderate liver dysfunction • Although the primary endpoint was not met, the subgroup analysis showed a positive efficacy signal (OS) in patients with CPB7 • The favorable safety profile and lack of liver toxicity, together with the clinical activity observed in the CPB7 subpopulation, supports further clinical development of namodenoson

  17. The Safety and Efficacy of Namodenoson in the Second Line Treatment of Advanced Hepatocellular Carcinoma (HCC) Patients with Underlying Child-Pugh B (CPB) Liver Cirrhosis: A Phase 2 , Randomized, Double-Blind, Placebo-Controlled Trial Salomon M. Stemmer1, Nebojsa S. Manojlovic2, Mihai Vasile Marinca3, Petar Petrov4, Nelly Cherciu5, Doina Ganea6, Tudor-Eliade Ciuleanu7, Ioana Adriana Puscas8, Muhammad Shaalan Beg9, William T. Purcell10, Adina-Emilia Croitoru11, RumyanaNedyalkova Ilieva12, Sladjana Natošević13, AmedeiaLavinir Nita14, DimitarNikolaev Kalev15, Zivit Harpaz16, Motti Farbstein16, Michael H. Silverman16, David Bristol16, Inbal Itzhak16, Pnina Fishman16, and Josep M Llovet1 1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Military Medical Academy, Belgrade, Serbia; 3Institutul Regional de Oncologie Iasi – SectiaOncologie Medical, Iasi, Romania; 4Complex Oncology Center–Plovdiv, EOOD, Plovdiv, Bulgaria; 5Clinica Onco-Life, Craiova, Romania; 6Spitalul Judetean de UrgentaSfantulIoancelNouSuceava, Suceava, Romania; 7Institute of Oncology/University of Medicine and Pharmacy, Cluj-Napoca, Romania; 8S.C. Pelican Impex S.R.L. - SecţiaOncologieMedicală, Oradea, Romania; 9The University of Texas Southwestern Medical Center, Dallas, TX; University of Colorado Comprehensive Cancer Center, Aurora, CO; 10Fundeni Clinical Hospital, Bucharest, Romania; Multiprofile Hospital for Active Treatment Central Onco Hospital OOD Department of Medical Oncology, Plovdiv, Bulgaria; 11Zdravstveni CentarKladovoSlužbaOnkologije, Kladovo, Serbia; County Hospital Pratova, Ploiesti, Romania; 12Sveta Marina University Hospital, Varna, Bulgaria; 16Can-Fite BioPharma, Petach Tiqwa, Israel; 17Mount Sinai School of Medicine, New York University, New York, NY.

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