Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as mono-therapy and in combination with various agents including gemcitabine (GEM) in the studies with several types of cancer. According to these studies, the recommended dose (RD) and maximum tolerated dose (MTD) were determined as 2.0 mg QD and 3.0 mg QD respectively as mono-therapy, and as 2.0 mg QD for both in combination with GEM. The objectives of this study are to assess its tolerability/safety, and to evaluate the RD and the MTD in Japanese patients (pts).Methods: This open-label dose-escalation study evaluated the tolerability/safety, pharmacokinetics (PK), and preliminary efficacy of trametinib alone (part 1) and in combination with GEM (1000 mg/m2) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability/safety in part 1, part 2 was investigated. Results: (Part 1) Thirteen pts received trametinib at doses of 1.0 mg (n=4), 2.0 mg (n=6), and 3.0 mg (n=3). Various cancer types were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in a subject at the 2.0 mg dose. The most common AE was G1/2 rash (n=12). One PR (salivary gland cancer) and 3 long SDs (appendix cancer (n=1) and melanoma (n=2)) were observed. Preliminary PK results showed no obvious ethnic difference. (Part 2) Five pts with pancreatic cancer received trametinib (2.0 mg QD) in combination with GEM. Although there was no DLT, interstitial lung disease (ILD) was observed in 3 pts after DLT observation period. Best responses were 3 PRs and 2 SDs. Conclusions: The RD (2.0 mg QD) and the MTD (3 mg QD) of trametinib that were determined in Western countries were tolerated in Japanese pts as mono-therapy. In combination with GEM, trametinib was tolerated in the short term and showed promising antitumor efficacy, however it is required to closely monitor pts for ILD while the combination is administered to pts.