A phase I/I b study of GSK1120212 (trametinib) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

Abstract

e20004 Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as monotherapy and in combination with various agents including gemcitabine in the studies with pancreatic cancer, melanoma and other 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 monotherapy, and as 2.0 mg QD for both in combination with gemcitabine. The objectives of this study are to assess its tolerability and 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 (RECIST) of trametinib alone (part 1) and in combination with gemcitabine (1000 mg/m2on Days 1, 8, and 15 of each 28-day cycle) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability and 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 including melanoma were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in part 1 in a subject at the 2.0 mg dose. The most common AE was Grade 1/2 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 gemcitabine. Although there was no DLT in the first 28 days (DLT observation period), 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 patients as monotherapy. In combination with gemcitabine, although trametinib was tolerated in the short term and showed promising antitumor efficacy, it is required to closely monitor patients for ILD while the combination is administered to patients. Clinical trial information: NCT01324258.