Background: OGXE427 is an antisense oligonucleotide (ASO) designed to bind to Hsp27 (heat shock protein 27) mRNA, resulting in the inhibition of production of Hsp27 protein. Hsp27 is over-expressed in many cancers including lung, prostate, breast, and bladder. Increased expression has been associated with inhibition of chemotherapy-induced apoptosis, increased tumor cytoprotection, and the development of treatment resistance. OGX-427 is an inhibitor of Hsp27 that effectively targets and down-regulates Hsp27 mRNA and has been shown to increase apoptosis, inhibit tumor growth, and sensitize cells to various chemotherapy regimens in a variety of malignancies. Based on this preclinical data, addition of an Hsp27 inhibitor to standard chemotherapy may improve the efficacy of treatment. In this randomized phase II study, OGX-427 will be added to a standard carboplatin/pemetrexed regimen, with the goal of improving progression-free survival when compared to carboplatin and pemetrexed alone in the first-line treatment of non-squamous NSCLC patients. Methods: A total of 155 patients will be randomized in a 1:1 ratio. Randomization will be stratified by histology (adenocarcinoma vs. large cell carcinoma) and smoking status (smoker vs. non-smoker). Treatment will include a loading dose period with OGX-427 600 mg or placebo. On day one of each 21 day cycle, patients will receive OGX-427 1000 mg or placebo, pemetrexed 500 mg/m², and carboplatin AUC 6, all administered IV. On days 8 and 15, OGX-427 or placebo will also be administered. Key eligibility criteria include; untreated recurrent or stage IV predominantly non- squamous NSCLC, measureable disease by RECIST v 1.1, ECOG PS 0 or 1, adequate organ function, and no known CNS disease. Serum Hsp27 levels will be assessed at screening, baseline and during treatment. In addition, archival tissues will be collected and assessed for PTEN (protein expression by IHC) and a panel of gene mutations for correlative analyses.