Transcript Phase III Study: Gemcitabine and 5

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
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
- 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
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum


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:
Low Toxicity


H. Riess
9.3 (0.5; 26.5+) months
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
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
Stratification:
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
KPS
(60-80 % vs. 90-100 %)

Tumor stage
(III vs. IVa vs. IVb)
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GEM:

5-FU:


1000 mg/m2/wk
750 mg/m2/wk
x 4 wks,
q 6 wks
FA:

200 mg/m2/wk
Centralized Randomisation

GEM:

H. Riess
1000 mg/m2/wk x 7 wks
1000 mg/m2/wk x 3 wks,
q 4 wks
CONKO-002 Study endpoints
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
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Primary:


H. Riess
Overall survival (mOS)
Secondary:

Time to tumor progression
(TTP)

Toxicity

Quality of Life (not yet analysed)
CONKO-002 Statistical considerations
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
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Hypothesis: 33% improvement in median survival

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Statistics:

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Kaplan-Meier estimates and two-tailed log-rank test
with significance level of 0.05 and a power of 80%
Sample size:
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
H. Riess
Expected median OS:
 GEM arm: 6 months
 GFF arm: 8 months
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
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
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Histologically or cytologically proven locally advanced or
metastatic, inoperable pancreatic carcinoma
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Measurable disease

Karnofsky performance status  60%
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No prior chemo- or radiotherapy

Adequate hematologic, renal and hepatic function

Written informed consent
H. Riess
CONKO-002 Patient disposition
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
Randomized patients
n=473
GFF
235 pts.
GEM
238 pts.
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Time of recruitment: 08/00 - 11/03
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Final data-cut: 11/04
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recruiting centres: 98
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deaths observed at data-cut: 451
(95.3 %)
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median time on study: 18.2 months
(for patients living at data-cut)
Non-eligible patients:
Evaluable patients
n=466
GFF
230 pts.
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GEM
236 pts.
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3 pts. with other tumors (2 ovarialca, 1 colon-ca)
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2 pts. after surgical resection
without recurrent disease
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1 pt. with MTX comedication
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1 pt. without histologically confirmed
diagnosis
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
CONKO-002
Results
CONKO-002 Patients` characteristics
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
H. Riess
GFF
GEM
n
230
236
median age
62.7
63.7
sex (m/f) [%]
52/48
54/46
KPS (60-80/90-100) [%]
56/44
52.5/47.5
Stage [%]
 III/IVa
 IVb (metastatic)
5/18
77
4/19
77
CONKO-002 Second-line therapies
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
Regimen
GFF
n=88
Oxaliplatin/5-FU/FA
15 (17 %)
Oxaliplatin/Capecitabine 29% 4 (5 %) 39%
Gemcitabine/Oxaliplatin
6 (7 %)
Gemcitabine/5-FU/FA
27% 11 (13 %) 42%
Gemcitabine mono
6 (7 %)
5-FU/FA
2 (2 %)
5-FU mono
2 (2 %)
Paclitaxel
21 (23 %)
Doxo/MMC/5-FU/FA
7 (8 %)
Others
14 (16 %)
H. Riess
GEM
n=86
25 (29 %)
4 (5 %)
4 (5 %)
12 (14 %)
20 (23 %)
5 (6 %)
2 (2 %)
0
2 (2 %)
12 (14 %)
CONKO-002 Tumor response rates
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
GFF (%)
GEM (%)
CR
0
0
PR
4.8
7.2
SD
29.6
30.1
PD
54.3
50.0
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 %)
H. Riess
CONKO-002 Time to tumor progression
Time to Progression - Kaplan-Meier estimates
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
100
mTTP
GFF: 3.5 months [ 3.0; 4.1]
80
GEM: 3.5 months [3.0; 4.2]
60
40
Treatment arm
GEM
20
GFF
0
0
100
200
300
400
Log rank:
= 0.4360
Timep [days]
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500
600
700
days
CONKO-002 Overall survival
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
Overall Survival - Kaplan Meier estimates
100
mOS
GFF: 5.85 months [ 5.1; 7.3]
80
GEM: 6.2 months [5.4; 8.0]
60
40
Treatment arm
GEM
20
GFF
0
0
200
400
600
800
Log rank:
= 0.6830
Timep[days]
H. Riess
1000
1200
days
CONKO-002 Subgroup analysis for
overall survival: stage IVb patients
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
KPS
= 60-80
Overall Survival
- Stage IVb Patients
KPS
= 90-100
Overall survival
- Stage IVb Patients
KPS = 60-80
KPS = 90-100
100
100
mOS
80
mOS
80
Cumulative Distribution
GFF: 3.35 months [ 2.4; 4.8]
GEM: 4.9 months [3.1; 5.7]
60
40
20
GFF: 8.5 months [7.3; 11.2]
GEM: 6.2 months [5.4; 9.3]
60
40
Treatment arm
Treatm
GEM
GEM
20
GFF
GFF
0
0
0
200
400
600
800
days
Time [days]
Log rank: p = 0.6153
H. Riess
1000
1200
0
200
400
600
800
1000
days
Time [days]
Log rank: p = 0.1719
1200
CONKO-002 Toxicities
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
Adverse event
(per patient)
Leukopenia
H. Riess
GFF
GEM
n=220
n=225
Grade 3/4 [%] Grade 3/4 [%]
11.3/0.5
11.1/0.8
Thrombocytopenia
9.5/3.1
6.2/0.4
Anemia
5.9/2.3
6.2/0.4
Diarrhea
3.6/0
3.1/0.8
Nausea
10.4/3.1
6.7/0.4
Infection
3.6/1.8
5.8/2.6
Bleeding
1.3/0.9
1.3/1.8
CONKO-002 Summary
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
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Acceptable toxicities in both arms
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No difference in response rate
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No difference in time to tumor progression
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No difference in overall survival
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Trend towards better survival with combination
therapy for patients with good KPS 90-100%
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Weak trend towards better survival with standard
gemcitabine therapy for patients with KPS 60-80%
H. Riess
CONKO-002 Conclusions
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum

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
H. Riess
CONKO-002
Top recruiting centres (>6 pts.)
Charité - Universitätsmedizin Berlin - Campus Virchow-Klinikum
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Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum - Germany
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Klinikum Mannheim gGmbH, Universitätsklinikum, Fakultät für Klinische Medizin Mannheim - Germany
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SRH Wald-Klinikum Gera gGmbH - Germany
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Gemeinnützige Salzburger Landeskliniken Betriebsgesellschaft mbH - Austria
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Universitätsklinikum Bonn, Medizinische Fakultät der Rheinischen Friedrich-Wilhelms-Universität - Germany
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Humaine Klinikum Bad Saarow - Germany
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Paritätisches Krankenhaus Lichtenberg, Oskar-Ziethen-Krankenhaus, Berlin - Germany
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Praxis Dr. Stauch, Kronach - Germany
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Klinikum Nürnberg Nord - Germany
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Praxis Dr. Schlag, Würzburg - Germany
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Praxis Dr. Müller, Leer - Germany
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Klinikum Bremen Mitte gGmbH - Germany
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Marienkrankenhaus Hamburg - Germany
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Krankenhaus St. Elisabeth u. St. Barbara Halle - Germany
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Klinikum der Stadt Stralsund Krkh. West - Germany
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DRK Krankenhaus Luckenwalde - Germany
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Eberhard-Karls-Universität Tübingen, Universitätsklinikum Tübingen - Germany
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Kreiskrankenhaus Leer (Ostfriesland) - Germany
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Katharinenhospital Stuttgart - Germany
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Katholisches Klinikum Mainz St. Vincenz- und Elisabeth-Hospital - Germany
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Allgemeines Krankenhaus der Stadt Hagen - Germany
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Praxis Drs. med. Schimke/Jacobs, Saarbrücken - Germany
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Klinikum Ernst-von-Bergmann Potsdam - Germany
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Charité, Universitätsmedizin Berlin, Campus Berlin-Buch - Germany
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Praxis Dr. Müller-Hagen, Hamburg - Germany
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Ev. Waldkrankenhaus Spandau, Berlin - Germany
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Klinikum Neubrandenburg - Germany
H. Riess