A Phase I/II Trial of Docetaxel and Oxaliplatin in Patients With Advanced Gastric Cancer (DO for AGC)

Gastric cancer is the most common malignancy in Korea. The prognosis of unresectable gastric cancer has been improved by cytotoxic chemotherapy, but median survival rarely exceeds 1 year. New agents such as taxane, irinotecan and oxaliplatin combined with old agents such as 5-FU with or without leucovorin, doxorubicin, cisplatin showed higher response rates in phase II studies. Docetaxel as a single agents showed response rates of 17-24%, and the combination of docetaxel and cisplatin has shown a response rate of 37-56% and overall survival of 9-10.4 months. Oxaliplatin in combination with 5-FU and leucovorin(FOLFOX-6) showed an objective response rate of 50%, which included a 4% complete response. The preclinical studies, oxaliplatin has shown additive or synergistic cytotoxic properties with fluoropyrimidines, thymidylate synthase inhibitors, topoisomerase I inhibitors, microtubule inhibitors and DNA modifying/alkylating agents. The combination of docetaxel and oxaliplatin has been studied previously in the phase I setting in patients with metastatic breast and non-small cell lung cancer. The combination of docetaxel and oxaliplatin is a feasible and well tolerated regimen. Recommended doses were 75mg/m2 for docetaxel on day 1 and 70mg/m2 for oxaliplatin on day 2 without G-CSF support. The aim of this trial is to determine the dose limiting toxicities, maximum tolerated dose(MTD) and efficacy of oxaliplatin and docetaxel as combination chemotherapy in patients with advanced gastric cancer.

Primary objectives : To define the dose-limiting toxicity and maximum tolerated dose in phase I study To evaluate the overall response rate in phase II study Secondary objectives : To evaluate the safety and tolerability of the treatment combination. To estimate overall survival. To estimate the time to progression and the duration of overall response.

Docetaxel,Oxaliplatin, Phase I/II study, Advanced gastric cancer, First line treatment, Advanced gastric cancer with measurable disease

Oxaliplatin will be administered in combination with docetaxel as a first-line chemotherapy in advanced gastric cancer patients. Each cycle is repeated every 3 weeks. Docetaxel Oxaliplatin Level 1 60 mg/m2/day 1 100 mg/m2/day 1 Level 2 75 mg/m2/day 1 100 mg/m2/day 1 Level 3 75 mg/m2/day 1 130 mg/m2/day 1

To define the dose-limiting toxicity and maximum tolerated dose in phase I study To evaluate the overall response rate in phase II study

1) To evaluate the safety and tolerability of the treatment combination. 2) To estimate overall survival. 3) To estimate the time to progression and the duration of overall response.

Inclusion Criteria: Histologically documented gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction 18 ≤ age ≤ 70 ECOG performance status of 0 - 2 At least one definite measurable lesion(s): ≥ 1 cm on spiral CT scan or ≥ 2 cm in physical examination Previously untreated metastatic gastric cancer patients or relapsed gastric cancer patients (patients with recurrence at least 6 months from the date of last administration of adjuvant chemotherapy and/or radiation therapy with 5-FU and/or leucovorin containing regimen will be included in the study) Written informed consent Minimum life expectancy of 12 weeks Adequate liver, renal, bone marrow functions as evidence by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; ASAT and/or ALAT < 3 UNL; serum creatinine ≤ 1.5 ULN Exclusion Criteria: Any other malignancies within the past 5 years except skin basal cell cancer or CIS of cervix Serious comorbid diseases Pregnancy or lactation Previous history of drug allergy to one of the drugs in the study regimen

Sulkes A, Smyth J, Sessa C, Dirix LY, Vermorken JB, Kaye S, Wanders J, Franklin H, LeBail N, Verweij J. Docetaxel (Taxotere) in advanced gastric cancer: results of a phase II clinical trial. EORTC Early Clinical Trials Group. Br J Cancer. 1994 Aug;70(2):380-3. doi: 10.1038/bjc.1994.310.

Roth AD, Maibach R, Martinelli G, Fazio N, Aapro MS, Pagani O, Morant R, Borner MM, Herrmann R, Honegger H, Cavalli F, Alberto P, Castiglione M, Goldhirsch A. Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO). Ann Oncol. 2000 Mar;11(3):301-6. doi: 10.1023/a:1008342013224.

Kouroussis C, Agelaki S, Mavroudis D, Kakolyris S, Androulakis N, Kalbakis K, Souglakos J, Mallas K, Bozionelou V, Pallis A, Adamtziki H, Georgoulias V. A dose escalation study of docetaxel and oxaliplatin combination in patients with metastatic breast and non-small cell lung cancer. Anticancer Res. 2003 Jan-Feb;23(1B):785-91.

Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol. 2002 Dec 1;20(23):4543-8. doi: 10.1200/JCO.2002.02.021.