Background: The focal adhesion kinase (FAK) and MAPK pathways share common upstream activators and contribute to cell proliferation, differentiation, migration and survival. Dual inhibition of both pathways with GSK2256098 and trametinib, respectively, are synergistic in cellular growth and survival assays, especially in mesothelioma cell lines. Methods: This phase Ib study (NCT01938443, funded by GSK) evaluated GSK2256098 twice daily combined with trametinib once daily in pts with advanced solid malignancies enriching for mesothelioma. The objectives were to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 Nov 2014, 24 pts were enrolled (14 M, 10 F; median age 66 yr (range 30 to 78)). GSK2256098 at 250 or 500 mg twice-daily (BID) was orally co-administered with trametinib at 0.25, 0.375, 0.5 or 1 mg once-daily (QD) in 28-day cycles. Systemic exposure to trametinib was 2-4 X > than predicted for monotherapy causing DLTs (skin rash) and dose de-escalation. GSK2256098 PK was unchanged in the presence of trametinib. The MTD was determined to be GSK2256098 250 mg BID plus trametinib 0.5 mg QD and exposure for both agents are at concentrations that achieve antitumor activities in vitro. DLTs were observed in 6 pts (25%) at dose levels 0.5 or 1.0 mg trametinib + 500 mg GSK2256098. Median exposure was 52 days (range 17 - 181). Common adverse events (AEs), regardless of study drug relationship, were nausea (58%), diarrhea (38%), rash (33%), pruritus (33%), and vomiting (29%). Grade 3 AEs occurred in 9 individual pts (38%), and 1 (4%) Grade 4 AE occurred. One Grade 3 AE of increased CPK occurred at the MTD. Tumor biopsy PD data indicate FAK target engagement. Of 12 mesothelioma pts, 8 (67%) had stable disease lasting > 6 weeks reported as best response. Conclusions: The MTD for combined GSK2256098 and trametinib was reached, and the preliminary safety and PK/PD profile justifies further exploration. Clinical trial information: NCT01938443