Randomized Phase II study (GATE study) of docetaxel plus

oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent

gastric cancerVan 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 Oncology-

Tyler, 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%– Chemotherapy in this setting remains palliative

• Currently used regimens yield:– response rates of up to 50%– 4 months median time to progression (TTP)– 8–9 months overall survival (OS)2–9

• 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 GC1Ferlay 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;

4Ohtsu 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.

GATE Study Design• Phase II, multinational, randomized, three-arm,

parallel-group, stratified study

• Part 1– Pilot phase to determine optimal doses for

each regimen

• Part 2– 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

IDMC Review

GATE Study Design

TEF (q2w)T 40 mg/m² D1E 85 mg/m² D1

F 2400 mg/m² CIV 46h+ LV 400 mg/ m² D1

TEX (q3w)T 50 mg/m2 on D1E 100 mg/m² on D1X 625 mg/m² BID

TE (q3w)

T 75 mg/m2 D1E 130 mg/m2 D1

TEF (q2w)T 50 mg/m² D1E 85 mg/m² D1

F 2400 mg/m² CIV 46h+ LV 400 mg/m² D1

TEX (q3w)T 65 mg/m2 D1E 100 mg/m² D1X 625 mg/m² BID

TE (q3w)T 75 mg/m2 D1E XX mg/m2 D1*

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*

IDMC Review

Part I

Part II

Randomization

IDMC Review

TE (q3w)

T 75 mg/m2 D1E 100 mg/m2 D1

Level 1N=10each arm

Level 2N=10each arm

N=70each arm

FINAL ANALYSIS N=240210 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

*XX: optimal dose was to be recommended by the IDMC after review of safety data

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

KPSa, %

100 24 32 22 26

90 33 39 36 36

80 40 27 38 35

70 1 2 4 2aOne patient “missing” from the TE arm (n=78)

T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine

Disease characteristics of randomized patients

 % of patientsTE

(n=79)TEF

(n=89)TEX

(n=86)Total

(n=254)

Sites of cancera

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

Weight loss in previous 3 months

≤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 10aSites 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)

ORR (95% CI) 23.1(14.3–34.0)

46.6(35.9–57.5)

25.6(16.6–36.4)

Complete response 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

Not evaluable 7.7 8.0 12.2

*Response rate was assessed by WHO criteria in the full analysis populationT, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine

Overall Survival*

*Assessed in the full analysis population

Drug ExposureMean 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

Oxaliplatin

TE 631 40 92

TEF 709 33 77

TEX 569 30 91

Fluorouracil 23837 966 81

Capecitabine

130140 6501 74

T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine

Treatment-emergent Adverse Events

 No of patients, (%)

TE

(n=78)

TEF

(n=88)

TEX

(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)

Total deaths 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)

T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine

Common Adverse Events

 

TE(n=78)

TEF(n=88)

TEX(n=82)

No. of patients, (%)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)

Febrile neutropenia 11 (14) 2 (2) 7 (9)

Anorexia 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 v3.0T, 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).

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.

Disclosures