Trial Information

A Phase II Study of S-1 in Combination With Gemcitabine and Erlotinib in Patients With Advanced or Metastatic Pancreatic Cancer

Pancreatic ductal adenocarcinoma, also known as pancreatic cancer, is an eighth cause of
cancer-related deaths in the world. The estimated worldwide incidence of pancreatic cancer
was 277,000 cases and an estimated 266,000 patients died from the disease in 20081.

Pancreatic cancer is more common in elderly persons than in younger persons, and
characterised by early locoregional spread and distant metastasis. As a result, less than
20% of patients are diagnosed with localized, potentially curable disease, and the median
survival is no longer than 3-4 months without effective treatment2.

Single-agent chemotherapy with gemcitabine was considered as standard of care for patients
with advanced pancreatic cancer, since Burris et al. demonstrated superiority of gemcitabine
over 5-fluorouracil (5-FU) in respect of a survival benefit as well as an improvement in
disease related symptoms in a randomized study3.

Nevertheless, the activity of gemcitabine monotherapy in pancreatic cancer was modest, and
there was a clear need to improve its efficacy by combining it with other anticancer drugs.

Multiple agents such as 5-FU4, capecitabine5,6, cisplatin7,8, oxaliplatin9, pemetrexed10,
irinotecan11, cetuximab12, and bevacizumab13, in combination with gemcitabine have been
tested in clinical trials, however, they have failed to improve the outcome.

The only agent that, in combination with gemcitabine, has shown a small, but statistically
significant improvement, with a hazard ratio (HR) of 0.82, the absolute improvement in
median overall survival (OS) of 5.9 months with gemcitabine versus 6.2 months with the
combination, is erlotinib, a small-molecule inhibitor of the epidermal growth factor
receptor (EGFR)14. Considering the modest improvement in survival by adding erlotinib to
gemcitabine, new combination therapy that have a great impact is urgently needed.

S-1 is an oral fluoropyrimidine derivative that combines tegafur (FT) with two modulators;
5-chloro-2, 4-dihydroxypyridine (CDHP) and oteracil potassium (Oxo) in a 1:0.4:1 molar
concentration ratio. The phase II trials of a combination of gemcitabine and S-1 have
demonstrated objective response rates of 32-48% and median survival of 8-12 months 15-17.

Therefore, we will conduct a phase II study of gemcitabine, erlotinib, and S-1 as first-line
chemotherapy in patients with advanced pancreatic cancer and evaluate the EGFR expression,
KRAS mutation, and BRAF mutation as predictive or prognostic markers.