Background: Hsp27 (heat shock protein 27) is over-expressed in a variety of tumor types causing initiation, growth, and metastasis of cancer cells. OGX-427 (apatorsen) is an antisense oligonucleotide that binds to Hsp27 mRNA, inhibiting production of the Hsp27 protein. Pts with pancreatic adenocarcinoma have significantly higher levels of Hsp27 than healthy individuals. Preclinical studies with apatorsen showed inhibited proliferation, induced apoptosis, and enhancement of the effect of chemotherapy in pancreatic cancer models. This randomized, phase II trial evaluates the efficacy of gem/n-pac chemotherapy with or without apatorsen in patients with mPaCa. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, objective response rate, CA19-9 response, and safety. Archival tissue will be collected and assessed for expression of Hsp27, PTEN (protein expression by IHC), and a panel of gene mutations for correlative analyses. Methods: A total of 130 patients are planned to be randomized in a 1:1 ratio to Arm A (gem, n-pac, apatorsen) or Arm B (gem, n-pac, placebo). Three loading doses of apatorsen 600 mg or placebo are given prior to start of chemotherapy. Apatorsen 600 mg or placebo IV is then administered weekly in 28 day cycles. Gem 1000 mg/m² and n-pac 125 mg/m² are administered IV on days 1, 8, and 15. Patients will be re-staged every 2 cycles per RECIST v 1.1 and will continue treatment until disease progression or other reasons for discontinuation. Key eligibility includes: stage IV pancreatic adenocarcinoma, ECOG PS of 0 or 1, adequate bone marrow and organ function, and no known CNS metastases or clinically significant cardiac disease. Serum Hsp27 levels will be collected at screening, baseline, and during treatment. Correlative analyses of clinical outcomes and between Hsp27 expression/percentage of tumors expressing Hsp27 will be explored. This trial is currently open to enrollment. Clinical trial information: NCT01844817.