*CHARITÉ ONKOLOGIE:Clinical studies in GI cancers Preliminary Results: A randomised, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer - CONKO*-001- P. Neuhaus, H. Oettle, S. Post, K. Gellert, K. Ridwelski, H. Schramm, C. Zülke, G. Fahlke, J. Langrehr, L. Roll, H. Riess Charitè - Universitätsmedizin Berlin - Campus Virchow Klinikum; Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera; Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V. *CHARITÉ ONKOLOGIE:Clinical studies in GI cancers

CONKO-001 Rationale Prognosis in disease free survival with pancreatic cancer is still poor Median survival after resection is 11 - 25 months Long term survival (>5 years) is 8 - 21percent Bakkevold (1993); Klinkenbijl (1999); Gastrointestinal Study Group (1985, 1987); Neoptolemos (2004)

Resected pancreatic cancer Stratification: R; T; N CONKO-001 Study Design Resected pancreatic cancer 368 patients Stratification: R; T; N Gemcitabine for 6 months Observation for 6 months Follow up every 8 weeks

CONKO-001 Disease Monitoring Ran domi sa t i on Follow up every 8 weeks Gem Ultrasound after week 8 after week 16 CT Scan after week 32 Obs CA 19-9 4 weeks Gem Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks Obs Observation: d1; q 4 weeks

CONKO-001 Endpoints Primary Endpoint Secondary Endpoint Disease free survival (DFS) Secondary Endpoint Overall survival (OS) Toxicity

CONKO-001 Entry Criteria Histologically proven resected pancreatic carcinoma Standard operation No measurable disease No prior chemo- or radiotherapy No active infection Karnofsky performance status  50% Adequate hematologic, renal and hepatic function CA 19-9, CEA < 2.5 ULN Start with adjuvant therapy within 6 weeks after resection Written informed consent

CONKO-001 Statistics Hypothesis: Statistics: Sample size: Significant increase in disease free survival (DFS) of at least 6 months due to chemotherapy with gemcitabine Statistics: Kaplan-Meier estimates und two-tailed log-rank test with significance level of 0.05 and a power of 90% Sample size: 368 pts – 184 pts per treatment arm (1:1 ratio) including an estimated drop out rate of up to 20%

CONKO-001 Recruitment and Analysis Time of recruitment: 7/98 - 12/04 Recruited patients: 368 Recruiting centres: 88 (Germany, Austria) Date of Analysis: March 2005

CONKO-001 Recruitment Patients Patients per month

CONKO-001 Patient Disposition 368 patients enrolled 7/98 - 12/04 186 pts. for Gemcitabine 182 pts. for Observation 179 eligible* pts. (96%) 177 eligible* pts. (97%) * 7 excluded Patients: 4 pts. lost to follow up 1 pt. without histological proven pc 1 pt. with persistent disease after resection 1 pt. with another tumor disease * 5 excluded Patients: 3 pts. lost to follow up 2 pts. with another tumor disease

CONKO-001 Patient Characteristic

CONKO-001 Tumor Characteristic

CONKO-001 Toxicities WHO Grade III+IV

CONKO-001 Toxicities WHO Grade III+IV

CONKO-001 Toxicities WHO Grade III+IV

CONKO-001 Kaplan Meier Disease Free Survival Chemotherapy with gemcitabine median: 14.21 months (95% CI, 12.86; 15.57) 41 % patients censored (+) Observation median: 7.46 months (95% CI, 6.80; 8.11) 22 % patients censored (+) Log Rank: p=0.001

CONKO-001 Disease Free Survival

CONKO-001 Kaplan Meier Survival Chemotherapy with gemcitabine 53 % patients censored (+) Observation 45 % patients censored (+)

CONKO-001 Preliminary Data Summary Toxicity of gemcitabine in adjuvant therapy is low Treatment with gemcitabine results in an improvement in disease free survival Favourable overall survival with chemotherapy (no comparative calculations done; 49% of patients censored) Improved longterm (3- and 5-year) survival expected

CONKO-001 Conclusions Treatment with gemcitabine in patients with resected pancreatic cancer results in improved disease free survival as compared to observation Gemcitabine may become the standard of care for adjuvant treatment of pancreatic cancer

CONKO-001 Top recruiting centres Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum - Germany Klinikum Mannheim gGmbH, Universitätsklinikum, Fakultät für Klinische Medizin Mannheim - Germany Paritätisches Krankenhaus Lichtenberg, Oskar-Ziethen-Krankenhaus, Berlin - Germany Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät - Germany SRH Wald-Klinikum Gera gGmbH - Germany Klinikum der Universität Regensburg - Germany Eberhard-Karls-Universität Tübingen, Universitätsklinikum Tübingen - Germany Universitätsklinikum Bonn, Medizinische Fakultät der Rheinischen Friedrich-Wilhelms-Universität - Germany Klinikum Bremen Mitte gGmbH - Germany Städtisches Klinikum Magdeburg, Standort Altstadt - Germany Klinikum der Friedrich-Schiller-Universität zu Jena - Germany Klinikum Nürnberg Nord - Germany Klinikum und Fachbereich Medizin der Johann-Wolfgang-Goethe Universität Frankfurt am Main - Germany Praxis Dr. Schlag, Würzburg - Germany Universitätsklinikum Freiburg - Germany DRK Krankenhaus Luckenwalde - Germany Praxis Drs. med. Mayr & Strohbach, Berlin - Germany Praxis Drs. med. Günther & Sauer, Potsdam - Germany Praxis Dr. Hauch, Erfurt - Germany Humaine Klinikum Bad Saarow - Germany Henriettenstiftung Hannover - Germany Charité, Universitätsmedizin Berlin, Campus Berlin-Buch - Germany Diakoniekrankenhaus Rotenburg (Wümme) - Germany Gemeinnützige Salzburger Landeskliniken Betriebsgesellschaft mbH - Austria Israelitisches Krankenhaus in Hamburg - Germany Städtisches Krankenhaus Hildesheim GmbH - Germany Praxis Dr. von Grünhagen, Cottbus - Germany Städtisches Klinikum Dessau - Germany