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 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 GC 1Ferlay 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
GATE Study Design Randomization Part I 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 TE (q3w) T 75 mg/m2 D1 E 100 mg/m2 D1 Level 1 N=10 each arm IDMC Review TE (q3w) T 75 mg/m2 D1 E 130 mg/m2 D1 TEF (q2w) 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 Level 2 N=10 each arm IDMC Review IDMC Review Part II TE (q3w) T 75 mg/m2 D1 E 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* N=70 each arm FINAL ANALYSIS N=240 210 pts from Part II + 30 pts from Part I *XX: optimal dose was to be recommended by the IDMC after review of safety data 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 aOne patient “missing” from the TE arm (n=78) T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Disease characteristics of randomized patients 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* *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 T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Treatment-emergent Adverse Events T, docetaxel; E, oxaliplatin, F, fluorouracil; X, capecitabine
Common Adverse Events 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.