The Combination Chemotherapy of SIRIOX as First- or Second-Line Chemotherapy for Pancreatic Cancer
The Combination Chemotherapy of SIRIOX as First- or Second-Line Chemotherapy for Pancreatic Cancer
Pancreatic cancer represents the most lethal of the common malignancies with a 5-year
 survival rate of less than 5%. For patients who are eligible for potentially curative
 resection, despite mortality and morbidity rates after surgery have improved, the recurrence
 rate is up to 85% within 2 years. FOLFIRINOX (fluoropyrimidine/leucovorin plus irinotecan and
 oxaliplatin) has been proved to significantly improve the prognosis and is recommended as
 first line treatment in patients with advanced pancreatic cancer. However, the regimen is
 limited due to the severe adverse effects. Thus, the investigators replaced 5-FU and
 leucovorin in the FOLFIRINOX regimen with oral S-1, a new oral ﬂuoropyrimidine derivative
 which was proved to be the well-tolerated and effectively in large III phase randomized
 clinical trial, to form the SIRIOX regimen. A phase I clinical trial from Japan found that
 SOXIRI (S-1, oxaliplatin and irinotecan) works in patients with advanced pancreatic cancer.
 In this study, the researchers intend to investigate the activity and safety of the
 combination of this regimen in patients with advanced pancreatic cancer, as first- or
 second-line chemotherapy.
Pancreatic cancer (mainly pancreatic ductal adenocarcinoma, PDAC) is a disease with extremely
 poor prognosis, and is often fatal. Surgical resection is the only potentially curative
 technique for management of PDAC, but only approximately 15% to 20% of patients are
 candidates for pancreatectomy at the time of diagnosis Gemcitabine (Gem) is widely used as a
 standard chemotherapeutic agent for advanced pancreatic cancer. FOLFIRINOX
 (fluoropyrimidine/leucovorin plus irinotecan and oxaliplatin), compared with Gem, has been
 proved to significantly improve the objective response rate (31.6% VS. 9.4%, P < 0.001) and
 prolong the median survival time (11.1 months VS. 6.8 months, P < 0.001) for patients with
 metastatic pancreatic ductal adenocarcinoma(PDAC), who had a performance status of ECOG 0-1
 score. However, it is undeniable that the adverse effects of FOLFIRINOX are severe. For
 example, the incidence of 3/4 grade neutrophil decrease in patients receiving FOLFIRINOX is
 significantly higher than those with Gem (45.7% VS. 21%, P < 0.001). Thus, it is difficult
 for many patients to receive standard FOLFIRINOX and benefit from the protocol. Therefore,
 the investigators aim to explore an improvement program of FOLFIRINOX, hoping to better
 benefit patients.

 S-1 is a new oral fluoropyrimidine derivative in which tegafur is combined with two
 5-chloro-2, 4-dihydroxypyridine modulators and oteracil potassium, a potentiator of
 5-ﬂuorouracil's (5-FU's) antitumor activity that also decreases gastrointestinal toxicity.
 Combination chemotherapy with Gem and S-1 is reportedly well tolerated and benefits patients
 with advanced PDAC. Based on the results of the GEST study, S-1 is found to be non-inferior
 to Gem in patients' survival.

 Therefore, in this study, the investigators replaced 5-FU and leucovorin in the FOLFIRINOX
 regimen with oral S-1, forming a SIRIOX regimen to treat patients with advanced pancreatic
 cancer, as first- or second-line chemotherapy.
Inclusion Criteria:

 1. Patients aged 18 - 75 years old at the time of signing the ICF.

 2. Patients with pathologically proved adenocarcinoma of pancreatic cancer and diagnosed
 with inoperable/metastatic disease (previous systemic chemotherapy, neoadjuvant or
 adjuvant are acceptable without Irinotecan, Oxaliplatin, or S1).

 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

 4. Adequate hematologic function defined as: absolute neutrophil count (ANC) >= 2,000/μL;
 platelets count >= 100,000/μL; hemoglobin must be >= 10 g/dL (can be corrected by
 growth factor or transfusion).

 5. Adequate hepatic function defined as: serum bilirubin =< 1.5-fold upper limit of
 normal (ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
 alkaline phosphatase (ALP) =< 3-fold ULN (5-fold ULN if liver metastasis is observed).

 6. Adequate renal function with: serum creatinine =< 1.3 mg/dL or calculated creatinine
 clearance >= 60 mL/minute according to the Cockcroft and Gault formula.

 7. At least one measurable disease according to the Response Evaluation Criteria in Solid
 Tumors (RECIST) version 1.1.

 8. Life expectancy over 12 weeks.

 9. Women must be either of non-child bearing potential, or women with child-bearing
 potential agree to use effective a highly contraceptive method or a contraceptive
 implant, exception of hormonal contraception (estrogen/progesterone), during treatment
 from time of Screening Visit and after cessation of therapy at least 3 months.

 10. Willing and able to comply with all aspects of the treatment protocol.

 11. Provide written informed consent.

 Exclusion Criteria:

 1. Patients who are unwilling or unable to comply with the study protocol;

 2. Existing anticancer treatment-related toxicities of Grades >= 2 (except for alopecia
 and neuropathy) according to Common Terminology Criteria for Adverse Events (CTCAE
 v4.03).

 3. Simultaneously using targeted therapies, such as Erlotinib, Nimotuzumab etc;

 4. Any severe or uncontrolled systemic disease (e.g., unstable or decompensated
 breathing, heart, liver or kidney disease, HIV infection, hypertension, severe
 arrhythmia, diabetes mellitus, massive active bleeding);

 5. Large operations were performed within 14 days before entering the study, or there
 were surgical incisions that were not completely healed;

 6. Women who are pregnant or breastfeeding;

 7. Ascertained hypersensitivity to investigational product, Oxaliplatin, Irinotecan, and
 S1 or any of the excipients used in the study.

 8. History of other malignancies within 5 years, except for adequately treated basal cell
 carcinoma or squamous cell carcinoma or carcinoma in situ;

 9. Obvious gastrointestinal injury history, the researchers estimate may significantly
 affect the absorption of S1 on the whole, including the ability to swallow drugs;

 10. Other combinations of anticancer therapies (including LHRH agonists, anticancer herbs,
 immunotherapy), except steroid hormones;

 11. Patients with UGT1A1 mutations or congenital disease lack of UGT1A1 expression (e.g.
 Crigler-Najjar syndrome and Gilbert syndrome);

 12. Patients with DPD enzyme deficiency.

 13. Judged to be not applicable to this study by investigator such as difficulty of
 follow-up observation, psychiatric disorder, with any other serious diseases/medical
 history.