*CHARITÉ ONKOLOGIE: Clinical studies in GI cancers Phase III Study: Gemcitabine and 5-FU (24h infusion) with Folinic acid (GFF) vs. Gemcitabine alone (GEM) in the Treatment of Advanced, Inoperable Pancreatic Cancer - CONKO*-002 - H. Riess, A. Helm, M. Niedergethmann, I. Schmidt-Wolf, M. Moik, C Hammer, K. Zippel, K. Weigang-Köhler, M. Stauch, H. Oettle, Deutsche Krebsgesellschaft Charité Virchow Klinikum Berlin, Universitätsklinikum Mannheim, Universitätsklinikum Bonn, Landeskrankenhaus Salzburg, Humaine Klinikum Bad Saarow, Oskar-Ziethen-Krankenhaus Berlin, Klinikum Nürnberg Nord, Outpatient Department Stauch, Kronach Austria; Germany *CHARITÉ ONKOLOGIE: Clinical studies in GI cancers

CONKO-002 Study rationale GFF combination is active in advanced pancreatic carcinoma: phase II study* results (38 pts.) RR: 5.2% Median TTP: 7.1 (0.4; 18.1) months Median OS: 9.3 (0.5; 26.5+) months Low Toxicity grade III + IV: 19/143 cycles (13%) The phase III study was designed to evaluate GFF efficacy as compared to GEM standard treatment. *Oettle et al, Ann Oncol, 11: 1267-72

CONKO-002 GFF vs. GEM study design Stratification: KPS (60-80 % vs. 90-100 %) Tumor stage (III vs. IVa vs. IVb) GEM: 1000 mg/m2/wk 5-FU: 750 mg/m2/wk FA: 200 mg/m2/wk x 4 wks, q 6 wks Centralized Randomisation GEM: 1000 mg/m2/wk x 7 wks 1000 mg/m2/wk x 3 wks, q 4 wks

CONKO-002 Study endpoints Primary: Overall survival (mOS) Secondary: Time to tumor progression (TTP) Toxicity Quality of Life (not yet analysed)

CONKO-002 Statistical considerations Hypothesis: 33% improvement in median survival Expected median OS: GEM arm: 6 months GFF arm: 8 months Statistics: Kaplan-Meier estimates and two-tailed log-rank test with significance level of 0.05 and a power of 80% Sample size: 472 pts – 236 pts per treatment arm (1:1 ratio) with up to 20% drop-outs 392 events (deaths) needed for final analysis

CONKO-002 Inclusion criteria Histologically or cytologically proven locally advanced or metastatic, inoperable pancreatic carcinoma Measurable disease Karnofsky performance status  60% No prior chemo- or radiotherapy Adequate hematologic, renal and hepatic function Written informed consent

CONKO-002 Patient disposition Time of recruitment: 08/00 - 11/03 Final data-cut: 11/04 recruiting centres: 98 deaths observed at data-cut: 451 (95.3 %) median time on study: 18.2 months (for patients living at data-cut) Non-eligible patients: 3 pts. with other tumors (2 ovarial-ca, 1 colon-ca) 2 pts. after surgical resection without recurrent disease 1 pt. with MTX comedication 1 pt. without histologically confirmed diagnosis Randomized patients n=473 GFF 235 pts. GEM 238 pts. Evaluable patients n=466 GFF 230 pts. GEM 236 pts.

CONKO-002 Results

CONKO-002 Patients` characteristics

CONKO-002 Second-line therapies 29% 39% 27% 42%

CONKO-002 Tumor response rates 315 pts as documented 95 pts died before first staging (12 weeks) – documented as PD 56 pts missing data (GFF: 11.3 %; GEM: 12.7 %)

CONKO-002 Time to tumor progression days mTTP GFF: 3.5 months [ 3.0; 4.1] GEM: 3.5 months [3.0; 4.2] Log rank: p = 0.4360

CONKO-002 Overall survival days mOS GFF: 5.85 months [ 5.1; 7.3] GEM: 6.2 months [5.4; 8.0] Log rank: p = 0.6830

CONKO-002 Subgroup analysis for overall survival: stage IVb patients KPS = 60-80 KPS = 90-100 mOS GFF: 3.35 months [ 2.4; 4.8] GEM: 4.9 months [3.1; 5.7] mOS GFF: 8.5 months [7.3; 11.2] GEM: 6.2 months [5.4; 9.3] days days Log rank: p = 0.6153 Log rank: p = 0.1719

CONKO-002 Toxicities

CONKO-002 Summary Acceptable toxicities in both arms No difference in response rate No difference in time to tumor progression No difference in overall survival Trend towards better survival with combination therapy for patients with good KPS 90-100% Weak trend towards better survival with standard gemcitabine therapy for patients with KPS 60-80%

CONKO-002 Conclusions The combination of gemcitabine, 5-FU and folinic acid did not result in improved survival as compared to gemcitabine standard therapy Single agent gemcitabine remains the standard of care for patients with advanced pancreatic cancer

CONKO-002 Top recruiting centres (>6 pts.) Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum - Germany Klinikum Mannheim gGmbH, Universitätsklinikum, Fakultät für Klinische Medizin Mannheim - Germany SRH Wald-Klinikum Gera gGmbH - Germany Gemeinnützige Salzburger Landeskliniken Betriebsgesellschaft mbH - Austria Universitätsklinikum Bonn, Medizinische Fakultät der Rheinischen Friedrich-Wilhelms-Universität - Germany Humaine Klinikum Bad Saarow - Germany Paritätisches Krankenhaus Lichtenberg, Oskar-Ziethen-Krankenhaus, Berlin - Germany Praxis Dr. Stauch, Kronach - Germany Klinikum Nürnberg Nord - Germany Praxis Dr. Schlag, Würzburg - Germany Praxis Dr. Müller, Leer - Germany Klinikum Bremen Mitte gGmbH - Germany Marienkrankenhaus Hamburg - Germany Krankenhaus St. Elisabeth u. St. Barbara Halle - Germany Klinikum der Stadt Stralsund Krkh. West - Germany DRK Krankenhaus Luckenwalde - Germany Eberhard-Karls-Universität Tübingen, Universitätsklinikum Tübingen - Germany Kreiskrankenhaus Leer (Ostfriesland) - Germany Katharinenhospital Stuttgart - Germany Katholisches Klinikum Mainz St. Vincenz- und Elisabeth-Hospital - Germany Allgemeines Krankenhaus der Stadt Hagen - Germany Praxis Drs. med. Schimke/Jacobs, Saarbrücken - Germany Klinikum Ernst-von-Bergmann Potsdam - Germany Charité, Universitätsmedizin Berlin, Campus Berlin-Buch - Germany Praxis Dr. Müller-Hagen, Hamburg - Germany Ev. Waldkrankenhaus Spandau, Berlin - Germany Klinikum Neubrandenburg - Germany