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LBA9094

LBA9094. The ultra-low-molecular-weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in cancer patients receiving chemotherapy: SAVE-ONCO study.

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LBA9094

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  1. LBA9094 The ultra-low-molecular-weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in cancer patients receiving chemotherapy: SAVE-ONCO study Giancarlo Agnelli, University of Perugia, Perugia, Italy; Daniel George, Duke University Medical Center, Durham, USA; William Fisher, Department of Orthopedic Surgery, McGill University Health Centre, Montreal, Canada; Ajay Kakkar, Thrombosis Research Institute and University College London, London, UK; Michael R. Lassen, Hørsholm Hospital, Hørsholm, Denmark; Patrick Mismetti, Clinical Pharmacology Unit, University Jean Monnet, Saint-Etienne, France; Patrick Mouret, Klinikum Frankfurt, Höchst, Germany; Umesh Chaudhari, sanofi-aventis, Bridgewater, NJ, USA; Alexander G.G. Turpie, McMaster University, Hamilton, Canada; on behalf of the SAVE-ONCO Investigators Presented by Daniel George on behalf of Giancarlo Agnelli

  2. Relevant Disclosures • Giancarlo Agnelli • Consultant or Advisory Role: Bayer; BoehringerIngelheim • Honoraria: Bayer; Boehringer Ingelheim; GlaxoSmithKline; sanofi-aventis • Daniel George • Consultant or Advisory Role - Astellas, Bayer, CentocorOrthobiotech, Dendreon, Genentech/Roche, Ipsen, Medivation, Novartis, Pfizer, Sanofi, Viamet • Honoraria - sanofi-aventis • Speakers Bureau: CentocorOrthobiotech, Dendreon, Genentech/Roche, GSK, Novartis, Pfizer, sanofi-aventis • Research support: BMS, CentocorOrthobiotech, Dendreon, Exelixis, GSK, Ipsen, Novartis, Pfizer, Viamet

  3. What is the true burden of VTE? From 60 to 70% of fatal PE detected post-mortem are not suspected or diagnosed1,2 70% The incidence of asymptomatic VTE is twice the incidence of symptomatic VTE3 Picture modified from Ralph A. Clevenger 1Stein PD et al. CHEST.1995;110:978-981. 2Sandler DA, et al. J R SocMed. 1989;82:203-205. 3Kakkar VV et al. Lancet. 1969; August 2:230-33.

  4. Study rationale • Patients with cancer are at increased risk for VTE1,2 • Chemotherapy represents an additional risk factor for VTE3,4 • Certain tumor types and late-stage disease are associated with even higher VTE risk2,3,5,6 • Currently, routine thromboprophylaxis in ambulatory patients with cancer receiving chemotherapy is not recommended 7,8,9,10 due to several randomized controlled trials reporting inconclusive results11 • Large, randomized, placebo-controlled, VTE-prevention trials are needed 1Heit JA, et al. Arch Intern Med. 2000;160:809-15; 2Khorana AA, et al. Cancer. 2007;110:2339-46; 3Blom JW, et al. J ThrombHaemost. 2006;4:529-35; 4Kröger K, et al. Ann Oncol. 2006;17:297-303; 5Chew HK, et al. Arch Intern Med. 2006;166:458-64; 6Stein PD, et al. Am J Med. 2006;119:60-8; 7Lyman G, et al. J ClinOncol. 2007;34:1-16; 8Geerts WH, et al. Chest. 2008;133:381S-453S; 9Mandalà M, et al. Ann Oncol. 2010;21 Suppl 5:v274-6; 10National Comprehensive Cancer Network (2010)‍ http://www.nccn.org/professionals/physician_gls/f_guidelines.asp 11 Kuderer N, et al. J ClinOncol. 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition); 27(15S): 9537.

  5. Semuloparin • Ultra-low-molecular-weight heparin (ULMWH): • Molecular weight 2000–3000 Da • High anti-Factor Xa activity with anti-Factor IIa activity • Half-life 16–20 hours • 98% bioavailability after subcutaneous injection • Cmax reached at 3 hours • Excretion mainly renal

  6. Study objectives In patients with locally advanced or metastatic solid tumor receiving chemotherapy to: • Compare the efficacy of semuloparin with placebo for the prevention of VTE • Evaluate the safety of semuloparin

  7. Study design Multinational, randomized, double-blind, parallel-group study Post-treatment follow-up Standard of care chemotherapy Placebo sc once daily N = 3200 1:1 Randomization Stratified by: - Cancer type - Cancer stage - Geographical location Standard of care chemotherapy Semuloparin 20mg sc once daily End of treatment End of treatment + 1 month Treatment Duration: Patients were treated for the length of chemotherapy If chemotherapy changed prior to 3 months, patients were allowed to continue semuloparin or placebo treatment If chemotherapy changed or stopped after 3 months then semuloparin or placebo treatment was discontinued clinicaltrials.gov: NCT00694382

  8. Eligibility Criteria • Main inclusion criteria • Metastatic or locally advanced solid tumor of lung, pancreas, stomach, colon/rectum, bladder or ovary • Initiating a chemotherapy regimen with a minimum intent of 3 months* • Main exclusion criteria • ECOG (Eastern Cooperative Oncology Group) Performance status of 3 or 4 • Estimated creatinine clearance < 30mL/min • Contraindication to anticoagulation • Requirement for systemic anticoagulation or thrombolysis *Prior chemotherapy was allowed

  9. Study endpoints • Primary efficacy endpoint: • Time to first occurrence of: • Any symptomatic DVT • Any PE • Non-fatal • VTE-related deaths (fatal PE or unexplained death) • Primary safety endpoint • Clinically relevant bleeding, composite of • Major bleeding* • Clinically relevant non-major bleeding (CRNM)** *Major bleeding defined as any of the following: fatal bleeding, bleeding in a critical area or organ, or clinically overt and causing a drop in hemoglobin ≥2 g/dL, or requiring ≥2 units of blood transfusion1 **CRNM defined as bleeding requiring medical intervention and not meeting criteria for major bleeding 1ISTH criteria DVT = deep-vein thrombosis, PE = pulmonary embolism

  10. Statistical assumptions • VTE event rate ~4% in placebo group • Risk reduction (RR) with semuloparin ~50% • Power = 90% • Alpha = 0.05 • Intent-to-treat analysis of primary efficacy endpoint

  11. Analysis populations Randomized n = 3212 Placebo n = 1604 (100%) Semuloparin n = 1608 (100%) Efficacy population Intent-to-treat Treated n = 1583 (98.7%) Treated n = 1589 (98.8%) Safety population

  12. Baseline characteristics BMI = Body Mass Index, CVL = central venous line

  13. Treatment duration • Treatment duration was approximately 3.5 months, with no difference between the semuloparin and placebo groups

  14. Primary efficacy endpointComposite of symptomatic DVT and any PE Placebo : 3.4% (55/1604) Semuloparin 1.2% (20/1608) HR : 0.36 [0.21 – 0.60]; p < 0.0001 5.0% Placebo 4.0% RR 64% 3.0% Cumulative incidence (%) 2.0% Semuloparin 1.0% 0.0% 0 1 2 3 4 5 6 7 Time (Months) Number at Risk Placebo 1604 1375 1212 985 689 403 201 92 Semuloparin 1608 1410 1227 986 681 384 197 77 HR = hazard ratio

  15. Components of the primary efficacy endpoint Placebo Semuloparin OR 0.32 [0.15–0.62] OR 0.41 [0.19–0.85] 2.1 OR 0.20 [0.05–0.63] 1.5 OR 0.77 [0.27–2.13] 0.9 0.7 0.6 0.6 0.4 0.2 34/1604 10/1608 15/1604 3/1608 24/1604 9/1604 7/1608 VTE-related death Symptomatic DVT Any PE Non-fatal PE OR = odds ratio [95% CI]

  16. Bleeding Placebo Semuloparin OR 1.41 [0.89–2.25] OR 1.05 [0.55–2.04] OR 1.86 [0.98–3.68] 2.8 2.0 1.6 1.2 1.1 0.9 14/1583 26/1589 32/1583 45/1589 18/1583 19/1589 Clinically relevant Major* Non-major** *Includes 6 fatal bleedings (4 [0.3%] in placebo and 2 [0.1%] in semuloparin) ,and 5 (0.3%) non-fatal bleedings into critical area or organ in the semuloparin group **6 events in placebo and 9 in semuloparin caused study drug discontinuation; 2 events in placebo and 3 in semuloparin were serious and caused study drug discontinuation; 13events in placebo and 25 in semuloparin recovered

  17. Summary • Semuloparin, compared to placebo, showed: • 64% risk reduction in the composite of symptomatic DVT and any PE (p < 0.0001) • 59% risk reduction in any PE; OR 0.41, [0.19–0.85] • Incidence of clinically relevant bleeding of 2.8% vs 2.0% • Similar low incidence of major bleeding; 1.2% vs 1.1%

  18. Conclusions • Semuloparin 20 mg demonstrated a favorable benefit-risk profile for VTE prevention in cancer patients receiving chemotherapy • Which cancer patients should we now consider for thromboprophylaxis? • Undergoing surgery • Hospitalized/acutely ill • Receiving chemotherapy

  19. Acknowledgments We would like to thank the SAVE-ONCO investigators: Argentina: Roca E, Tatangelo M, Palazzo F, Temperley G, Medina C; Australia: Coughlin PB, Karapetis CS, McRae SJ, Keefe DMK, Atkinson VV, Leyden MJ, Brighton TA, Wong K, Yeung M, Jackson D; Austria: Samonigg H, Scheithauer W, Ulsperger E; Belgium: Deleu I, D'Hondt R, Nielander AJM, Laurent S, van Eygen KMRL, Wynendaele WLL, Polus M, Majois F, Efira A, Duck L; Brazil: Alencar V, Alvares M, Campos E, Cesário F, Fernandes H, Freitas Jr. R, Gampel O, Jendiroba D, Liberatti M, Rocha L, Andrade L, de Oliveira F, de Paula A, Tadokoro H, Filho C, Vinholes J, Wiermann E, Zereu M, Franke F, Vacaro G; Bulgaria: Guenova K, Kalev D; Belarus: Zhavrid E, Beliakouski V, Gedrevich Z, Karchmit Y; Canada: Bouchard N, Carrier M, Hirsch A, Gagnon G., Rao S, Sperlich C, Webster TM, Whitlock P, Wilson J, Yee A, Dolan S; Chile: Yañez R; China: Liu J, Liu W, Xu J, Zhang H, Zhou C, Zhuang Z, Chen L, Jia L, Wu G, Yao Y, Zhang T, Zhu Y, Bai C, Lin L, Pan H, Wang N, Xu Q, Liang J, Hu X, Li W; Taiwan: Yepes PA; Colombia: Rojas U, Lopera C, Lema M, Salazar C, Gonzalez F, Gonzalez D; Croatia: Cucevic B, Knezevic A, Kusic Z, Stimac D, Trivanovic D, Vojnovic Z, Herceg D; Czech Republic: Prausova J, Smakal M, Klepetko P; Denmark: Mellemgaard A; Finland: Paija OM-M: France: Goncalves A, Chavaillon J-M, Debourdeau P, Deplanque G, Desauw C, Farge-Bancel D, Husseini F, Lafitte J-J, Martinet Y, Miglianico L, Muir J-F, Oddou S, Prevost A, Ychou M, Adenis A, Mahé I; Germany: Baumgart D, Becker M, Behringer D, Derigs HG, Engel-Riedel W, Fenner M, Fietz T, Folprecht G, Guetz S, Harenberg F-J, Heinrich B, Held H, Jacobasch L, Karthaus M, Kretzschmar A, Kröning H, Hentrich UM, Müller L, Ostermann H, Otremba B, Pihusch M, Reichert D, Riess H, Späth-Schwalbe E, Stahl M, Südhoff T, von Pawel J, Wolf H-H, Gaska T, Stein U, Nagel S; Greece: Fountzilas G, Georgoulias V, Stergiou I; Hong Kong: Ng TY; Hungary: Bassam A, Fónay K, Kocsis J, Magyar T, Ruzsa Á, Szentpéteri I, Zsiray M, Király Z, Csöszi T, Albert I; India: Advani SH, Aggarwal S, Biswas J, Karandikar SM, Subramanian K, Lakshmaiah KC, Ross CR, Sahoo TP, Maru A, Pedapenki RM, Mukhopadhyay A, Keechilat P, Saxena R, Tuljapurkar V, Goswami C, Ramesh A, Balasubramanian S, Srinivasan K, Pathak AB, Hingmire SS, Sairam C; Indonesia: Bakta IM, Sumantri R, Gani S; Ireland: Grogan W, McDermott SR; Israel: Ben-Shahar M, Gabizon AAB. Dror Y, Stemmer S; Italy: Amadori D, Barni S, Bertolini A, Carnaghi C, Cruciani G, Faedi M, Ferraù F, Gamboni A, Gamucci T, Gasparro D, Lorusso V, Dazzi C, Pasquini E, Passalacqua R, Ravaioli A, Sacco C, Buzzi F, Crinò L; Korea: Chung HC, Kim JH, Kang J-H, Kim HK, Kim YH, Lim HY, Oh D-Y, Song HS, Kim JS; Latvia: Krievins D, Krilova A, Zvirbule Z; Lithuania: Inciura A, Jankevicius F; Malaysia: Teoh CY, Roslani AC, Chakraborty S, Thangadorai AR; Mexico: Gaytán A, Gomez V, Lopez F, Lopez H, Mejia A, Pardo T, Tellez B; Netherlands: Beeker A, de Jongh FE, Kuenen BC, Pieters WR, Sleeboom HP; Norway: Sandset P-M; Peru: Alvarez B, Auqui F, Benites M, Carracedo G, Casanova M, Chumbes S, Falcon L, Guevara J, Montenegro B, Pimentel A, Vargas Q; Poland: Badzio A, Jedrzejczak WW, Kaiser A, Koralewski P, Mruk A, Nowara E, Porzuczek-Zuziak D, Poznański J, Ramlau R, Sawrycki P, Słomian G, Tomeczko J, Palasik MG, Rogowski W, Szczęsna A; Portugal: Mellidez J, Rosales M, Sottomayor C, Coutinho C; Romania: Ciuleanu T, Croitoru A, Ganea MDE, Iacob IC, Nagy VM, Niculescu A, Volovat C; Russia: Akhmadullina L, Cheporov S, Dykhno Y, Dvorkin M, Gladkov OA, Gurina L, Kolomietz S, Uvarova S, Krikunova L, Krivorotko P, Lipatov O, Mosin I, Orlov S, Pimenov I, Elkova V, Sinyakov A, Solovyov V, Takhtamysh M, Udovitsa D, Vladimirov V, Vladimirova L, Litvinov I; Serbia: Jovanovic D, Milinic N, Rancic M, Andelkovic N; Slovakia: Dienerova M; Slovenia: Takac I, Triller N; South Africa: Jordaan JP, Landers G A; Spain: Alés J, Almenar D, Galán A, Gascón P, Alonso M, Guillot M, Pachón V, López G, Munoz A, Ortega E, Puente J, Sanchez A; Sweden: Fernebro E, Berglund A, Gustavsson B, Nestler G; Switzerland: Mueller A, Heizmann M; Ukraine: Andrusenko O, Bondarenko I, Galaychuk I, Komisarenko V, Lisovska N, Paramonov V, Senyutovych R, Shparyk Y, Vynnychenko I; United Kingdom: Awwad ST, Baumohl J, Epurescu D, Hasan J, Maraveyas A, McAdam K, McKinna F, O'Callaghan AM, Rankin E, Lord R, Sothi S, Stuart NSA, Baumohl J; USA: Siddique N, Vrindavanam NS, Dhami MS, Garcia MM, Moss RA, Slaughter MT, Young D, Kloecker GH, Galvez A, Reed RD, Guthrie TH, Ortel TL, Altomare IP, Francis C, Sethi HS, Chinnasami B, Ali MA, LeBerthon BJ, Gajra A, Starodub A, Gressot L, Scouros M, Khaira DK, Sabbath KD, Priego VM, Phooshkooru VR, Cosgriff T, Zaydan MA, Fink M, Perry DJ, Kellum AH, Brooks DJ, Rado T, Brandt D, De Shields MS, Ramachandran S, Upadhyaya G, Steis RG, Lawler W, Fiorica J, Amin D, Armenio V. We would also like to thank the patients included in the study and their families

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