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Randomized Phase II study (GATE
study) of docetaxel plus oxaliplatin
with or without fluorouracil or
capecitabine in metastatic or locally
recurrent gastric cancer
Van Cutsem E,1 Boni C,2 Tabernero J,3 Massuti B,4 Richards
DA,5 Prenen H,1 Steinberg I,6 Rougier P7
1University
Hospital Gasthuisberg, Leuven, Belgium; 2S. Maria
Nuova, Reggio Emilia, Italy; 3Vall d'Hebron University
Hospital, Barcelona, Spain; 4Alicante University Hospital,
Alicante, Spain; 5US Oncology Research, Texas OncologyTyler, Tyler, TX, USA; 6Sanofi, Cambridge, MA, USA; 7UVSQ
European Hospital Georges Pompidou, APHP, Paris, France
Introduction
•
Gastric cancer (GC) is the fourth most common cancer worldwide
and the second leading cause of cancer-related death1
•
Prognosis for advanced disease is poor with a 5-year survival rate of
<10%
–
1Ferlay
Chemotherapy in this setting remains palliative
•
Currently used regimens yield:
•
There is a need for new chemotherapy protocols
•
The primary aim of this study was to evaluate the efficacy and
tolerability of docetaxel (T) plus oxaliplatin (E) with or without
fluorouracil (F) or capecitabine (X) in advanced GC
–
–
–
response rates of up to 50%
4 months median time to progression (TTP)
8–9 months overall survival (OS)2–9
J, et al. Int J Cancer 2010;127:2893–917; 2Kim NK, et al. Cancer 1993;71:3813–8;3Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57;
A, et al. J Clin Oncol 2003;21:54–9; 5Dank M, et al. ASCO GI 2005; Abstract No. 61; 6Webb A, et al. J Clin Oncol 1997;15:261–7;
7Waters JS, et al. Br J Cancer 1999;80:269–72; 8Ross P, et al. J Clin Oncol 2002;20:1996–2004; 9Van Cutsem E, et al. J Clin Oncol 2006;24(31):4991-7.
4Ohtsu
GATE Study Design
•
Phase II, multinational, randomized, three-arm,
parallel-group, stratified study
•
Part 1
•
Part 2
– Pilot phase to determine optimal doses for
each regimen
– Efficacy and safety evaluation of doses selected
in Part 1
– Patients were randomized with stratification
according to:
 Country
 Weight loss (5% vs >5%)
 Measurable vs evaluable-only lesions
GATE Study Design
Randomization
Part I
Level 1
N=10
each arm
TE (q3w)
T 75 mg/m2 D1
E 100 mg/m2 D1
TEF (q2w)
T 40 mg/m² D1
E 85 mg/m² D1
F 2400 mg/m² CIV 46h
+ LV 400 mg/ m² D1
TEX (q3w)
T 50 mg/m2 on D1
E 100 mg/m² on D1
X 625 mg/m² BID
IDMC Review
Level 2
N=10
each arm
TE (q3w)
T 75 mg/m2 D1
E 130 mg/m2 D1
T 50 mg/m² D1
E 85 mg/m² D1
F 2400 mg/m² CIV 46h
+ LV 400 mg/m² D1
TEX (q3w)
T 65 mg/m2 D1
E 100 mg/m² D1
X 625 mg/m² BID
IDMCReview
Review
IDMC
Part II
N=70
each arm
TEF (q2w)
TE (q3w)
T 75 mg/m2 D1
E XX mg/m2 D1*
*XX: optimal dose was to be recommended
by the IDMC after review of safety data
TEF(q2w)
T XX mg/m² D1*
E 85 mg/m² D1
F 2400 mg/m² CIV 46h
+ LV 400 mg/m² D1
TEX (q3w)
T XX mg/m2 D1*
E 100 mg/m² D1
X 625 mg/m² BID*
FINAL ANALYSIS N=240
210 pts from Part II + 30 pts from Part I
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine; LV, leucovorin; CIV, continuous infusion; IDMC, independent data monitoring committee; D1, day 1
Patients
•
Age 18 years
•
KPS >70
•
Histologically proven metastatic or locally recurrent gastric
adenocarcinoma (including gastroesophageal junction)
•
At least 4 weeks after prior palliative radiotherapy and 3 weeks
after surgery
•
No prior palliative chemotherapy except for
adjuvant/neoadjuvant fluorouracil, cisplatin, and epirubicin
provided that relapse occurred >12 months after the end of
chemotherapy
•
Patients were excluded for serious illnesses or medical
conditions and neurosensory symptoms NCI-CTCAE grade ≥2
Assessments and Statistics
•
•
Primary outcome
–
Time to progression (TTP); from the time of randomization to the first progression or
death from any cause
–
Cut-off date for analysis was 1 year after last patient was randomized
Secondary outcomes
–
•
•
Overall survival (OS), overall response rate (ORR), safety
Sample size calculation
–
Part I: Two dose levels were defined per treatment arm and an estimated 60 patients
were required to determine the optimal doses.
–
Based on an estimated progression-free rate at 12 months of 23%, to obtain a
precision of 10% of the 95%CI, 68 patients per arm were required. Assuming a
dropout rate of 15%, a total of 240 patients were recruited (80 per arm plus the 30
treated at the optimal dose in part I).
Analysis
–
Intention-to-treat (ITT): all randomized patients
–
Full-analysis population: all randomized and treated patients analyzed in the arm to
which they were randomly assigned
–
Safety population: received at least 1 dose of study drug
–
Survival was estimated by the Kaplan-Meier method
Patient Disposition

In Part I, 41 patients were randomized at dose level 1 and 23
patients at dose level 2
•
Part II optimal doses
–
–
–
TE /3w: T, 75 mg/m2; E, 130 mg/m2
TEF / 2w: T, 50 mg/m2; E, 85 mg/m2; F, 2400 mg/m2 CIV 46h
TEX / 3w: T, 50 mg/m2; E, 100 mg/m2; X, 625 mg/m2 BID
•
248 (98%) patients received treatment in Part II at the
optimal dose
•
Treatment was to be administered up to progression,
unacceptable toxicities, or withdrawal of consent
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine; CIV, continuous infusion; BID, twice daily
Baseline demographics of randomized patients
TE
(n=79)
TEF
(n=89)
TEX
(n=86)
Total
(n=254)
Median age, years
60
57
60
59
Male, %
65
69
74
69
100
24
32
22
26
90
33
39
36
36
80
40
27
38
35
70
1
2
4
2
KPSa, %
aOne
patient “missing” from the TE arm (n=78)
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Disease characteristics of randomized patients
TE
(n=79)
TEF
(n=89)
TEX
(n=86)
Total
(n=254)
Lymph node
59
65
62
62
Liver
51
51
44
49
Stomach
41
32
52
42
Lung
19
20
14
18
Omentum/peritoneum
10
16
14
13
Ascites
17
8
8
11
Esophagus
6
8
2
6
Pleural effusion
6
5
4
5
Retroperitoneum
1
3
6
4
Visceral cancer only
22
24
24
23
Measurable diseasea
87
87
93
89
≤5%
50
53
52
52
>5%
50
47
48
48
Prior surgeryb
30
39
47
39
Prior radiotherapyb
5
5
7
6
Prior chemotherapyb
10
7
12
10
% of patients
Sites of cancera
Weight loss in previous 3 months
aSites
of cancer in ≥5% of patients in any one group; bOne patient “missing” from the TE arm (n=78)
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Time to Progression*
*Assessed in the full analysis population
Overall Response Rate*
% of patients
TE
(n=78)
TEF
(n=88)
TEX
(n=82)
23.1
(14.3–34.0)
46.6
(35.9–57.5)
25.6
(16.6–36.4)
2.6
9.1
4.9
Partial response
20.5
37.5
20.7
No change/stable disease
47.4
35.2
46.3
Progressive disease
21.8
10.2
15.9
7.7
8.0
12.2
ORR (95% CI)
Complete response
Not evaluable
*Response rate was assessed by WHO criteria in the full analysis population
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Overall Survival*
*Assessed in the full analysis population
Drug Exposure
Mean cumulative
dose, mg/m2
Mean dose intensity,
mg/m2/week
Mean relative
dose intensity, %
Docetaxel
TE
370
23
93
TEF
464
20
81
TEX
304
16
93
TE
631
40
92
TEF
709
33
77
TEX
569
30
91
Fluorouracil
23837
966
81
Capecitabine
130140
6501
74
Oxaliplatin
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Treatment-emergent Adverse Events
TE
TEF
TEX
(n=78)
(n=88)
(n=82)
Any TEAE
76 (97)
88 (100)
79 (96)
Grade 3/4 TEAE
60 (77)
54 (61)
55 (67)
Serious TEAE
35 (45)
24 (27)
36 (44)
Serious grade 3/4 TEAE
29 (37)
22 (25)
31 (39)
TEAEs resulting in death
4 (5)
3 (3)
11 (13)
63 (81)
50 (57)
55 (67)
≤30 days from last
infusion
5 (6)
2 (2)
10 (12)
>30 days from last
infusion
58 (74)
48 (55)
45 (55)
No of patients, (%)
Total deaths
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Common Adverse Events
TE
(n=78)
TEF
(n=88)
TEX
(n=82)
All
Grade 3/4
All
Grade 3/4
All
Grade 3/4
Fatigue
52 (67)
19 (24)
62 (70)
12 (14)
54 (66)
20 (24)
Sensory neuropathy
47 (60)
11 (14)
63 (72)
15 (17)
54 (66)
8 (10)
Diarrhea
48 (62)
15 (19)
59 (67)
10 (11)
54 (66)
6 (7)
No. of patients, (%)
Febrile neutropenia
Anorexia
11 (14)
2 (2)
7 (9)
32 (41)
4 (5)
36 (41)
3 (3)
38 (46)
8 (10)
Thrombosis/thromboembolism
6 (8)
4 (5)
4 (5)
4 (5)
5 (6)
4 (5)
Hand–foot
7 (9)
2 (3)
10 (11)
2 (2)
21 (26)
6 (7)
Abdominal pain
25 (32)
4 (5)
19 (22)
4 (5)
20 (24)
2 (2)
Vomiting
37 (47)
4 (5)
31 (35)
3 (3)
33 (40)
3 (4)
Neutrophils
2 (3)
2 (3)
7 (8)
5 (6)
1 (1)
1 (1)
Constitutional symptoms
5 (6)
4 (5)
3 (3)
1 (1)
6 (7)
2 (2)
Dehydration
5 (6)
4 (5)
0
0
4 (5)
1 (1)
Assessed by NCI-CTCAE v3.0
T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Conclusions

Results of the GATE study suggest that in patients
with advanced gastric cancer, treatment with
docetaxel plus oxaliplatin and fluorouracil (TEF) was
associated with improved time to progression,
overall response rate, and overall survival with a
better safety profile compared with docetaxel plus
oxaliplatin (TE) and docetaxel plus oxaliplatin with
capecitabine (TEX).
Disclosures
The GATE study (DOCOX-C00082; NCT00382720) was
sponsored by Sanofi.
Editorial assistance for preparing the poster was provided by
Adelphi Communications Ltd. and supported by Sanofi.