To determine the optimal second line treatment strategy in patients with metastatic pancreatic cancer who underwent a therapy with gemcitabine.

The 5-year survival of patients with pancreatic cancer is less than 5%. Despite improvements over the past years with the introduction of FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin and leucovorin) and gemcitabine and nab-paclitaxel, the vast majority will have disease recurrence or progression within 6 months. Single-arm phase II studies have been conducted after gemcitabine-based therapy. Randomized clinical trial data are limited in this setting, but the conclusion up to recently was that there is no superior chemotherapeutic regimen after gemcitabine failure. However, the NAPOLI trial altered the treatment landscape. In this trial, patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy received liposomal irinotecan (nal-IRI) either as single agent or in combination with 5-fluorouracil/ leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with the combination of nal-IRI plus 5-FU/LV experienced a median survival of 6.1 months versus 4.2 months for the 5-FU/LV group.

Recently, two studies on the clinical use of S-1 for pancreatic cancer have been reported from Japan. In the first study, S-1 demonstrated non-inferiority to gemcitabine in overall survival (OS) for advanced pancreatic cancer. In the second study, S-1 showed superiority to adjuvant chemotherapy with gemcitabine in OS. In addition to gemcitabine, S-1 is now regarded as the key drug in the management of pancreatic cancer in Japan. Phase II studies of S-1 in patients with gemcitabine-resistant pancreatic cancer have demonstrated moderate activity with acceptable toxicity. Although there has been no confirmed evidence based on phase III trials, S-1 would be a feasible treatment option in this patient population.

Objective:

To determine the optimal second line treatment strategy in patients with metastatic pancreatic cancer, whereby the hypothesis is, based on studies conducted in the Asian population, that the combination of S-1 and nal-IRI will be superior compared to 5-FU/ LV and nal-IRI, in terms of progression free survival. Therefore, patients will be randomized, after the optimal dose of S-1 and nal-IRI has been determined in the run in phase, between S-1 in combination with nal-IRI and 5-FU/LV in combination with nal-IRI during the phase II part of the study.

Inclusion Criteria:

Subjects must satisfy all of the following inclusion criteria to be enrolled in the study.

1. Able to understand and provide written informed consent
2. ≥ 18 years of age
3. Histologically or cytologically confirmed adenocarcinoma of pancreas
4. Documented metastatic disease, according to RECIST 1.1.
5. Previously treated with gemcitabine or gemcitabine containing therapy, or progression within 6 months of adjuvant gemcitabine based treatment
6. Adequate hepatic, renal and hematological function

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

1. Serum total bilirubin ≥1.5 x ULN (biliary drainage is allowed for biliary obstruction)

2. Severe renal impairment (CLcr ≤ 30 ml/min)

3. Inadequate bone marrow reserves as evidenced by:

   1. ANC ≤ 1,5 x 10 9 /L; or
   2. Platelet count ≤ 100 x 10 9 /L;

4. WHO/PS 0-1

5. Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment

6. Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 1

7. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months

8. NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure. Or known abnormal ECG with clinically significant abnormal findings

9. Active infection or an unexplained fever >38.5°C (excluding tumor fever), which in the physician's opinion might compromise the patient's health

10. Current use or any use in last two weeks of strong CYP3A-enzyme inducers/inhibitors and/or strong UGT1A inhibitors

11. Known hypersensitivity to any of the components of liposomal irinotecan (Nal-IRI) other liposomal irinotecan formulations, irinotecan, fluoropyrimidines, or leucovorin.

12. Hypersensitivity to any of the active substances (tegafur, gimeracil, and oteracil)

13. Previous treatment with fluoropyrimidine therapy

14. Known dihydropyrimidine dehydrogenase (DPD) deficiency

15. Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of liposomal irinotecan (Nal-IRI).

Treatment within 4 weeks with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine.