HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first line treatment.
Authors: Harada Kazuaki , Nakano Shintaro , Kawamoto Yasuyuki , Sawada Kentaro , Miyagishima Takuto , Sogabe Susumu , Kobayashi Yoshimitsu , Ito Ken , Sato Atsushi , Yu Chen , Dazai Masayoshi , Yuki Satoshi , Yokota Isao , Komatsu Yoshito 
Published: January 2024

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Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs patient’s quality of life. In other gastrointestinal cancer, infusion pump free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen by its convenience. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for metastataic pancreatic cancer. Methods: HGCSG1803 study has conducted as a multicenter, non-randomized, single arm, phase II study in Japan. The chemotherapy-naïve patients with metastatic pancreatic cancer were eligible. S-1 (40 mg/m2) orally intake twice daily for 14-day followed by a 14-day rest, and intravenous 65 mg/m2 of L-OHP and 100 mg/m2 of IRI on day 1 and day 15 every four weeks were continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST ver1.1, with a threshold of 10% and an expected value of 30%. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Results: Between Jan 2020 and May 2022, forty patients were enrolled and 39 patients were included in full analysis set (one patient were excluded because of consent withdrawal). Median age was 66 (range, 41-75), female/male were 16/23, ECOG PS 0/1; 32/7, UGT1A1 wild /heterozygous for *6 or *28 allele 27/12, liver/lung/peritoneal metastasis 28/9/11, respectively. The median relative dose intensities of S-1, irinotecan, and oxaliplatin were 76%, 72%, and 70%, respectively. Objective response rate and disease control rate were 43.6% (95%CI 27.8-60.4%) and 76.9% (95%CI 60.4-89.1%), respectively. In the median follow-up time was 13.7 months, median progression free survival and overall survival were 4.3 months (95%CI 2.5-6.2 months) and 11.1 months (95%CI 7.2-14.9 months), respectively. Four patients discontinued protocol therapy due to adverse events (AE) without disease progression. Grade 3 or higher AE that occurred in more than 5% of patients were leucopenia (21%), hypokalemia (21%), neutropenia (18%), anemia (15%), hyponatremia (15%), ALT elevation (10%), anorexia (8%), nausea (5%), and febrile neutropenia (5%). One patient died due to protocol therapy (drug induced pneumonitis). Conclusions: OX-IRIS showed high response rate with manageable safety, and the primary endpoint was met. This new triplet regimen could be a useful first line treatment option for patients with metastatic pancreatic cancer. Clinical trial information: jRCTs011190008 .