Background: Concurrent chemoradiotherapy is the standard management approach for unresectable, non-metastatic locally advanced non-small cell lung cancer (NSCLC). However, progress has been slow in making substantial improvements in the outcomes of these patients. Preclinical data suggests that adding molecular targeted drugs affecting specific pathways could enhance radiation effects, and Kras mutated NSCLC may be particularly susceptible for MEK1/2 inhibition for radiation sensitization. This trial tests the safety of combining trametinib (GSK1120212), a potent MEK1/2 inhibitor, with standard carboplatin and paclitaxel chemoradiotherapy, for the treatment of locally advanced NSCLC. Methods: This is a multi-center, NCI UM1-sponsored, phase I clinical trial. Patients with unresectable stage II-III NSCLC with Kras mutation who can receive concurrent carboplatin (AUC 2.0) and paclitaxel (50 mg/m2) with once-daily trametinib and 60 Gy radiotherapy delivered in 30 fractions are eligible. Two additional cycles of consolidation chemotherapy (carboplatin AUC 6.0 and paclitaxel 200 mg/m2) are given after completing concurrent chemoradiotherapy. Trametinib is delivered at the starting dose level of 1.0 mg, and Time-to-Event-Continuous Reassessment Method (TiTE-CRM) is used for dose escalation at 4 levels (0.5, 1.0, 1.5, and 2.0 mg). CTCAE v4.0 is used to determine dose-limiting toxicity (DLT), with the Pr(tox) within 70 days at 0.6 for general DLTs, and 0.3 for severe DLTs. Primary objective of the trial is to determine the maximum tolerated dose (MTD) and safety of trametinib as measured by rate of grade 3 or worse non-hematologic toxicities attributed to chemoradiation within 70 days of start of therapy, as well as pharmacokinetic studies. Secondary objectives include response rate, overall survival, patterns of recurrence, dose delay and percentage of dose delivered, and biomarker exploratory endpoints. The maximum number of patients is 30. Conduct to Date: The trial was activated October 28, 2013 at MD Anderson, and recently at Ohio State University. So far 7 patients have enrolled on study. Clinical trial information NCT01912625. Clinical trial information: NCT01912625