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BACKGROUND. NOX-A12 is an inhibitor of the chemokine CXCL12 for treatment of solid tumors. Binding of CXCL12 by NOX-A12 prevents receptor engagement and blocks the ability of CXCL12 to form a chemotactic concentration gradient. The Opera study (NCT03168139) is a Phase I/II study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination of NOX-A12 with pembrolizumab in metastatic microsatellite-stable colorectal (CRC) and pancreatic (PaC) cancer. METHODS. Patients received 300 mg NOX-A12 twice weekly during the two-week monotherapy phase. Biopsies were taken from liver metastases before treatment and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In the combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. RESULTS. Recruitment and treatment of all patients is completed, follow-up is ongoing. Eleven of the patients had CRC and 9 PaC. Fifteen of the patients (75%) were male, with a median age of 62 (CRC) and 68 years (PaC). All patients were heavily pretreated with a median of 5 (CRC) and 3 lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for all except one patient. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. Biopsies obtained at baseline showed that the mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. However, 5 out of 20 patients (25%) achieved a stable disease, thereof 3 CRC and 2 PaC patients; 7 of the patients showed prolonged time on treatment versus the preceding line of therapy. Updated figures for progression-free survival and overall survival for the whole patient cohort will be presented. Additional characterization of immunosuppressive cells in tumor biopsies and the periphery is ongoing. CONCLUSIONS. In patients with microsatellite-stable metastatic pancreatic and colorectal cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Citation Format: Niels Halama, Ulrike Pruefer, Anna Froemming, Diana Beyer, Dirk Eulberg, Jarl Ulf Jungnelius, Aram Mangasarian. Clinical outcome and safety in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer treated with the CXCL12 inhibitor NOX-A12 in combination with PD-1 checkpoint inhibitor pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT092.