Abstract A260: A phase 1 study of sorafenib (BAY 43-9006) in combination with S-1 plus cisplatin in patients with advanced gastric cancer
Authors: Yamada Yasuhide , Minami Hironobu , Fuse Nozomu , Ohtsu Atsushi , Kato Ken , Kiyota Naomi , Shimada Yasushiro , Doi Toshihiko , Nakajima Takako , Hamaguchi Tetsuya , Fujiwara Yutaka , Ito Yuichiro , Mera Kiyomi 
Published: June 2012

Abstract
Background: Sorafenib (BAY 43-9006) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-. S-1, an oral fluoropyrimidine, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase 1 study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP in patients (pts) with AGC.
Methods: Pts with histologically confirmed previously untreated AGC were enrolled in the study. Treatment of pts in 3 cohorts was planned. Cohort 1: sorafenib (400 mg bid, day 1–35), S-1 (40 mg/m2 bid, day 1–21) and CDDP (60 mg/m2, day 8); cohort 2: sorafenib (400 mg bid, day 1–28), S-1 (25 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1); cohort 3: sorafenib (400 mg bid, day 1–28), S-1 (40 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1). Treatment schedule and dosages for cohort 1 were set based on the SPIRITS study (Koizumi, et al. Lancet Oncol. 9, 2008), and for cohorts 2 and 3 on the FLAGS study (Ajani, et al. ASCO, 2009). Treatment was continued until disease progression or unacceptable toxicity occurred.
Results: Between May/2008 and Jan/2009, 13 Japanese pts were enrolled in cohort 1 and received at least one dose of the study treatment. Cohorts 2 and 3 were canceled because of negative results of the FLAGS study reported during our study of cohort 1. Pt characteristics were: 10 male and 3 female, median age 61 years (range 41–72), ECOG PS 0 in 9 pts and 1 in 4 pts. At the data cut off (30/Jun/2009), 12 of 13 pts had discontinued the study treatment (7 due to adverse events (AEs) and 5 due to disease progression) and 1 remained under treatment. The most common AEs occurring in ≥10 pts were neutropenia (92%), thrombocytopenia (92%), rash/desquamation (100%), anorexia (100%), hand-foot skin reaction (85%), nausea (85%), fatigue (77%), and lipase increase (77%). The grade 3/4 AEs occurring in ≥3 pts were neutropenia (54%), anemia (23%), lipase increase (62%), hand-foot skin reaction (23%), fatigue (23%), and amylase increase (23%). AEs resulted in treatment discontinuation included neutropenia (Gr 3) and anemia (Gr 2) that persisted for more than 4 weeks, AST/ALT increase (Gr 4), diarrhea (Gr 3), gastric perforation (Gr 3), hand-foot skin reaction (Gr 3), and auditory disturbance (Gr 1) attributed to CDDP. A total of ≥5 cycles of the study treatment was delivered in 6 pts. Two pts did not complete the 1st cycle due to Gr 1 auditory disturbance and Gr 4 AST/ALT increase, respectively. No treatment-related death was observed. Five pts had partial response and 7 had stable disease as the best response.
Conclusions: Hematological, skin-related, and gastrointestinal events were the main toxicities of sorafenib plus S-1 and CDDP combination. The regimen demonstrated antitumor activity in untreated AGC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A260.