A randomized Phase II study of second line treatment with liposomal irinotecan and S1 versus liposomal irinotecan and 5-fluorouracil in patients with metastatic pancreatic cancer who failed on first line gemcitabine-based chemotherapy

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 +
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 was up to recently 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. However, given the lack of data from prospective
studies on S-1 in combination with nal-IRI as second line treatment in
metastatic pancreatic cancer in the Western population, this study is designed
to compare nal-IRI combined with S-1 and nal-IRI combined with 5-FU/LV in terms
of safety and efficacy, in metastatic pancreatic cancer patient

This study has been transitioned to CTIS with ID 2023-509463-24-01 check the CTIS register for the current data.

The main objective of this study is to determine the optimal second line
treatment strategy in Caucasian 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 S1 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.

This is a multi-center, open label, randomized phase I/II trial

Arm 1:
S1 will be given for 14 consecutive days, twice daily, followed by 2 weeks
rest. Nal-IRI will be administered as an intravenous infusion on day 1 and 15.
Courses of treatment will be repeated every 4 weeks.

Arm 2:
Nal-IRI 80 mg/m2 will be administered first, followed by LV 400 mg/m2, followed
by 5-FU 2400 mg/m2 as an IV infusion over 46-hours on days 1. Each cycle
consists of 14 days. Courses of treatment will be repeated every 2 weeks.

The burden for the patient is 3 extra blood samples that will be taken on the
same day of, but additive to routine blood samples. Risks include side effects
related to chemotherapy, which include (depending on the chemotherapy) nausea,
diarrhoea, low blood cell counts, hand foot syndrome, loss of appetite, fatigue
and anorexia.
*