TPS6090 Background: Buparlisib (AN2025) is a 2,6-dimorpholino pyrimidine derivative oral pan-class I PI3K inhibitor. The PI3K signaling pathway is one of the most frequently altered pathways in HNSCC. A previous randomized, double-blind, placebo-controlled phase II study (BERIL-1)assessed patients with recurrent/metastatic HNSCC after PD on or after platinum-based chemotherapy in the metastatic setting. Patients assigned 1:1 to receive second-line oral buparlisib or placebo, plus intravenous weekly paclitaxel in 28-day cycles. Median PFS 4.6 months buparlisib arm, 3.5 months placebo arm (hazard ratio 0.65 [95% CI: 0.45–0.95], nominal one-sided p=0.011). Median OS 10.4 months buparlisib arm, 6.5 months placebo arm (hazard ratio 0.72 [95% CI: 0.49-1.04], nominal one-sided p=0.041). Best ORR buparlisib arm 39%, placebo arm 14%. Safety in buparlisib arm was manageable and comparable to placebo arm. (Soulieres, Lancet Oncology). Results suggest that buparlisib in combination with paclitaxel could be effective treatment following failure of platinum-based chemotherapy. Methods: The treatment algorithm for HNSCC was recently modified with inclusion of anti-PD-1/PD-L1 agents that provide a survival advantage, defining an unmet need after their use. The BURAN study is initiated as a confirmatory study to define activity in this setting. Methods: A multicenter, randomized, open-label phase III trial evaluating efficacy and safety of daily buparlisib (100 mg) in combination with weekly paclitaxel (80 mg/m2), compared to weekly paclitaxel alone, in patients with refractory, recurrent, or metastatic HNSCC, progressing after prior anti PD-1/anti PDL-1 therapy either as monotherapy or with a platinum-based regimen (in combination or sequence), and no more than two prior lines of treatment. 483 patients will be randomized 2:1, to receive either buparlisib in combination with paclitaxel or paclitaxel alone, stratified according to historical HPV status. Primary Objective: OS of buparlisib in combination with paclitaxel compared to paclitaxel alone. Secondary Objectives: Comparative PFS, ORR, and DoR, by Investigator and Independent Radiological Review Committee. Efficacy in subgroups of patients by randomization strata. Effect on symptoms and health related QOL. Efficacy related to biomarkers, microbiome analysis. Pharmacokinetics (PK) of buparlisib in combination with paclitaxel. Safety Objective: Comparative safety and tolerability. Primary analysis is OS in the ITT population, once 383 events have occurred, to demonstrate a 20% reduction in risk of death. Survival follow-up is to a maximum of five years. Trial opened December 12, 2020; X patients currently enrolled. Clinical Trial registry number: NCT04338399. Clinical trial information: NCT04338399.