Trial Information

Randomized Phase II Study of FOLFOX Followed by FOLFIRI or Reverse Sequence Treatment in Patients With Advanced or Relapsed Gastric Cancer

Gastric cancer remains a major public health issue, and is the fourth most common cancer and
the second leading cause of cancer deaths worldwide. In Korea, gastric cancer is the most
common cancer in men, the second most common cancer in women, and the second leading cause
of cancer death. Despite the development of early gastric cancer detection programs, more
than two-thirds of patients diagnosed with gastric cancer will develop unresectable disease.
Even patients with operable tumors evidence high rates of both local and distant recurrence.
In cases of advanced gastric cancer, the median survival rate is 9 to 10 months.
Additionally, the overall 5-year survival rate is less than 25% in Korea and Japan.

Several combination regimens of chemotherapy for gastric cancer have been developed, but the
survival advantage appears to be marginal, and no worldwide standard regimens have yet been
established. Recently, a meta-analysis has been conducted to evaluate the efficacy and
tolerability of chemotherapy in patients with advanced gastric cancer. The analysis of
chemotherapy versus best supportive care (Hazard Ratio/HR = 0.39, confidence interval (CI)
95% 0.28-0.52) and combination versus single agent, mainly 5-Fluorouracil (5-FU), (HR =
0.83, 95% CI 0.74-0.93) demonstrated significant OS results in favour of chemotherapy and
combination chemotherapy. Several chemotherapeutic drugs, including 5-fluorouracil (5-FU),
mitomycin C, nitrosoureas, and doxorubicin have evidenced some level of efficacy against
advanced gastric cancer. However, the majority of combination chemotherapy regimens for
advanced gastric cancer have evidenced overall response rates in a range of 30 to 50% in
phase II studies. Furthermore, no new regimens including the use of taxanes or irinotecan
have improved either response or survivals in phase II or III trials other than docetaxel,
cisplatina and infusional 5-FU (DCF) combination.

Oxaliplatin, a third-generation platinum analogue, is a diaminocyclohexane platinum which
forms interstrand DNA adducts, which differ from those formed by cisplatin or carboplatin in
terms of their capability to overcome resistance mechanisms. FOLFOX-4 or FOLFOX-6
combination regimen have demonstrated response rate of 38%-50% as a first-line treatment of
gastric cancer.

Irinotecan (CPT-11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] is a semi-synthetic plant
alkaloid obtained from Camptotheca acuminate of the Nyssaceae family. After conversion to
its active metabolite, SN-38, irinotecan acts by inhibiting the eukaryotic enzyme,
DNA-topoisomerase I. Single-agent irinotecan has evidenced response rates of 13-23% in cases
of advanced gastric cancer. 5-Fluorouracil (5-FU) and Topoisomerase I inhibitor-based
regimens have demonstrated a response rate of 20-29%, and have been suggested as a
first-line treatment for advanced gastric cancer.

FOLFOX followed by FOLFIRI or reverse sequence treatment regimen have been used as a
standard treatment modality in metastatic colorectal cancer.

The study was designed to evaluate the safety and efficacy of FOLFOX followed by FOLFIRI or
reverse sequence treatment regimen as a first-line and second line therapy for patients with
relapsed or metastatic gastric cancer similar with colorectal cancer.