Background: Preclinical studies suggest that intermittent dosing with selumetinib, an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life, should be evaluated in combination with durvalumab, a selective, high-affinity human IgG1 mAb, that blocks PD-L1 binding to PD-1 and CD80. Selumetinib may prime the immune response and also potentially inhibit T-cell function, thereby maximizing tumor cell damage and antigen presentation during the period of MEK inhibition; intermittent dosing with selumetinib will allow maximal relief of T-cell checkpoint blockade by durvalumab. The SELECT-4 study (NCT02586987) aims to evaluate this combination for the first time in pts. Methods: SELECT-4 is a Phase I, open-label, multicenter, dose escalation study investigating the safety and tolerability of intermittent doses of selumetinib combined with durvalumab in pts with advanced solid tumors for which no standard therapy exists. Selumetinib (starting dose 50 mg po bid, increasing until the maximum tolerated dose is reached) will be given for a 7-day monotherapy run in, then on a 1 week on, 1 week off schedule, every 4 weeks in combination with durvalumab (1500 mg, iv) administered once every 4 weeks. Approximately 20–30 evaluable pts will be enrolled, with up to 6 pts in each dose escalation cohort and 6–10 evaluable pts in a paired biopsy expansion cohort. Additional cohorts may be explored as determined by the Safety Review Committee. Pts must have a WHO performance status of 0‒1 and measurable disease at baseline (RECIST 1.1). Tumor assessments will be performed at screening, then every 8 weeks until confirmed disease progression. The primary objective is to investigate the safety and tolerability of intermittent dosing of selumetinib combined with durvalumab. Secondary objectives include defining the recommended dose for selumetinib combined with durvalumab, preliminary assessment of anti-tumor activity, characterization of population pharmacokinetics for each drug when in combination, and assessment of the immunogenicity of durvalumab. Biomarkers will be assessed as an exploratory objective. Recruitment is ongoing. Clinical trial information: NCT02586987