12050 Background: Despite high frequency and significant impact on quality of life, there are limited treatment options available for cancer related fatigue (CRF) in patients with advanced cancer. The primary aim of the study was to determine the feasibility (adherence, safety, and satisfaction) of the combination therapy, physical activity (PA) plus Dexamethasone (Dex); and PA plus placebo (Pl) for CRF. The secondary aim was to explore the effects of PA+Dex, and PA+Pl on CRF as assessed by Functional Assessment of Cancer Illness Therapy–fatigue (FACIT-F). Methods: In this phase 2, randomized, double blind, placebo controlled trial, patients with advanced cancer with CRF ≥ 4/10 on Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks plus either 4mg of Dex (PA+Dex arm), or Pl (PA+PL arm) BID for the first 7 days. Changes in FACIT-F scores from baseline to Day 8, and Day 29 were assessed. Other outcomes included change in quality-of-life scores. Results: A total of64 (89%) patients were evaluable. The median (IQR) changes in FACIT-F scores at Day 8 and Day 29 from baseline were 9 (2,16), P< 0.001; 5.75 (0,12.5), P=0.015 for PA+ Dex arm, and 3.5 (-2.13, 10), P=0.054; 6.50 (2.5, 15.5), P=0.006 for PA+ Pl arm respectively. Exploratory Linear Mixed Model (LMM) analysis showed significant treatment effect of PA +Dex, with treatment having improvement of 5.63 units for FACIT-F scores (95% Cl 1.74,9.52), P=0.005. Effect sizes for improvement of FACIT-F scores at Day 8 and Day 29 were -3.49, -2.43 in PA+Dex arm; and -1.93, -2.72 in PA+Pl arm, respectively. Effect sizes for change in fatigue related symptoms and quality of life scores as assessed by Patient-Reported Outcome Measurement Information System-Fatigue T-scores, Multidimensional Fatigue Symptom Inventory-Short Form total, and Functional Assessment of Cancer Therapy -General scores at Day 8, and Day 29 in PA+ Dex arm were 2.93 (P=0.005), 2.82 (P=0.005); 2.27 (P=0.023), 2.68 (P=0.007); -2.39 (P=0.017), -3.26 (P=0.001) respectively. Adherence to Dex and Pl were 91% and 92%, respectively, Satisfaction rates with PA+Dex and PA+Pl arms were 98% and 79%, respectively. There was no significant difference in grade ≥3 adverse events between the two arms (P = 0.36). Conclusions: Satisfaction, and tolerability to the combination therapy, and medication adherence was excellent.PA + Dex significantly improved CRF at day 8 and 29. The improvement was sustained 3 weeks after discontinuation of Dex. Further larger studies are justified. Clinical trial information: NCT03583255 .