Abstract A260: A phase 1 study of sorafenib (BAY 43‐9006) in combination with S‐1 plus cisplatin in patients with advanced gastric cancer

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/m 2 bid, day 1–21) and CDDP (60 mg/m 2 , day 8); cohort 2: sorafenib (400 mg bid, day 1–28), S‐1 (25 mg/m 2 bid, day 1–21), and CDDP (75 mg/m 2 , day 1); cohort 3: sorafenib (400 mg bid, day 1–28), S‐1 (40 mg/m 2 bid, day 1–21), and CDDP (75 mg/m 2 , 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.