*C HARITÉ ONKO LOGIE: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. RiessCharitè - 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

Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum

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)


CONKO-001 Study Design

Resected pancreatic cancer368 patients

Stratification: R; T; N

Follow up every 8 weeks

Gemcitabinefor 6 months

Observationfor 6 months


CONKO-001 Disease Monitoring

Gem

Obs

Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks

Observation: d1; q 4 weeks

Randomisati

on

Follow up every 8weeks

Gem

Ultrasoundafter week 8

Ultrasoundafter week 16

CT Scanafter week 32

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9

4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks

CA 19-9


CONKO-001 Endpoints

Primary 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: 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 RecruitmentP

atie

nts

Patients per m

onth


CONKO-001 Patient Disposition

368 patients enrolled7/98 - 12/04

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

186 pts. for Gemcitabine


CONKO-001 Patient Characteristic

Characteristic Chemotherapy(N=179)

Observation(N=177)

Days to randomisation

Median (interquartile range) 22 (15 - 32) 24 (15 - 34)

Age - years

Median (range) 62 (32 - 84) 61 (36 - 81)

Sex – no. (%)

Female 74 (41%) 79 (45%)

Male 105 (59%) 98 (55%)


CONKO-001 Tumor Characteristic

Characteristic Chemotherapy(N=179)

Observation(N=177)

<T3 25 (14%) 25 (14%)T

3 + 4 154 (86%) 152 (86%)

negative 52 (29%) 48 (27%)N

positive 127 (71%) 129 (73%)

1 10 (5%) 9 (5%)

2 103 (58%) 95 (54%)

3 62 (35%) 69 (39%)G

unknown 4 (2%) 4 (2%)

R0 145 (81%) 149 (84%)R

R1 34 (19%) 28 (16%)


CONKO-001 Toxicities WHO Grade III+IV

Chemotherapyn (%) of cycles

Observationn (%) of cycles

WHO Grading III IV III IV

Leucopenia 19 (2.6) 0 0 0

Anemia 7 (0.9) 0 1 (0.2) 0

Thrombocytopenia 5 (0.7) 2 (0.3) 0 0

Bleeding 0 0 0 0

Infection 2 (0.3) 0 2 (0.3) 0






Bilirubin 1 (0.1) 0 1 (0.2) 1 (0.2)

Transaminases 6 (0.8) 1 (0.1) 4 (0.7) 1 (0.2)

Alk. Phosphatases 1 (0.1) 0 4 (0.7) 0

Serum Creatinine 0 0 1 (0.2) 0

Proteinuria 0 0 0 0

Hematuria 0 0 0 0






Nausea 12 (1.6) 0 1 (0.2) 0

Diarrhea 9 (1.2) 0 3 (0.5) 0

Oedema 4 (0.5) 1 (0.1) 1 (0.2) 0

Pulmonary Function 2 (0.3) 0 0 0

Pain 3 (0.4) 0 10 (1.7) 0

Diverse 1 (0.1) 1 (0.1) 0 0


months

847260483624120

cum

ula

tive

dis

ea

se f

ree

su

rviv

al

100%

75%

50%

25%

0%

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

Chemotherapymedian (months)

Observationmedian (months)

P – value(log rank)

Negative 19.3 11.2 < 0.05N

Positive 13.1 7.0 < 0.05

R0 14.0 7.9 < 0.05R

R1 14.5 5.5 < 0.05


CONKO-001 Kaplan Meier Survival

months

847260483624120

cum

ula

tive

su

rviv

al

100%

75%

50%

25%

0%

Chemotherapy with gemcitabine53 % patients censored (+)

Observation45 % 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

*C HARITÉ ONKO LOGIE:Clinical studies in GI cancers

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