This phase II clinical trial will enroll patients with newly-diagnosed locally-advanced pancreatic adenocarcinoma and adopt the Simon's two-stage optimum design. After 4 cycles of SIROX regimen, patients will proceed to curative resection.

This phase II clinical trial will enroll patients with newly-diagnosed locally-advanced pancreatic adenocarcinoma and adopt the Simon's two-stage optimum design. After 4 cycles of SIROX regimen, patients will proceed to curative resection. The primary endpoint of this study is resection rate after neoadjuvant chemotherapy. The first stage will enroll 18 patients. We will go into the second stage if at least 2 patients in stage I become resectable after treatment. There will be at most 35 patients enrolled. Based on this trial, we anticipate that the SIROX regimen has comparable response rate and resection rate but lower toxicities comparing to FOLFIRINOX.

Inclusion Criteria:

1. histologically or cytologically proven pancreatic adenocarcinoma
2. newly diagnosed, unresectable, locally-advanced pancreatic cancer
3. no potential of R0 resection at diagnosis
4. presence of measurable pancreatic lesion, which must meet the criteria of being ≥ 10 mm in at least one dimension by conventional CT/MRI
5. age between 20 and 79 years at registration
6. ECOG performance status (PS) of 0 or 1
7. adequate major organ functions
8. ability to take the oral study medication (S-1)
9. no clinically significant abnormal ECG findings within 28 days (4 weeks) prior to registration
10. voluntarily signed the written informed consent form

Exclusion Criteria:

1. pulmonary fibrosis or interstitial pneumonitis diagnosed within 28 days prior to registration
2. presence of diarrhea ≥ CTCAE v.4.03 grade 2
3. concomitant active infection
4. significant co-morbid medical conditions, including, but not limited to , heart failure, renal failure, hepatic failure, hemorrhagic peptic ulcer, mechanical or paralytic ileus, or poorly controlled diabetes
5. moderate or severe ascites or pleural effusion that requires drainage
6. prior or concurrent malignancies within the last 3 years, with the exception of carcinoma in situ of the cervix, or basal type skin cancer
7. concomitant treatment with flucytosine, phenytoin or warfarin
8. peripheral neuropathy grade of 2 or higher
9. known Gilbert syndrome or homozygosity for UGT1A1 promoter TA repeats prone to high risk of drug toxicity (screening of UGT1A1 genotype will NOT performed routinely before study)
10. pregnant women or nursing mothers, or positive pregnancy test for women of childbearing potential. Patients of childbearing age should have effective contraception for both the patient and his or her partners during the study period
11. severe mental disorder
12. judged ineligible by physician for participation in the study due to safety concern