Introduction Event free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30-50%, with 5-year survival for adult patients only 20%. A large proportion of patients with newly diagnosed and relapsed ALL harbour somatic mutations that activate the RAS-signalling cascade. Steroids are a backbone of all induction blocks of ALL therapy, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886), results in a potent synergistic anti-cancer effect. Methods and analysis The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Munster, Germany; Paris, France; and Utrecht, Netherlands. Paediatric centres are all part of the Innovative Therapies for Children with Cancer consortium. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are >18 years old, ECOG < 2 and paediatric < 18 years old, Lansky play scale [≥]60% or Karnofsky score [≥]60%. The primary objective in phase I is to determine the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method, and phase II will evaluate preliminary anti-leukaemic activity of the selumetinib/dexamethasone combination, as defined by morphological response 28 days post treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum of 13 and maximum of 21 in each group), depending on how many phase I patients are included also in phase II. Ethics and dissemination Medical ethical committees of all the participating countries will approve the study protocol. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration number The trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.Gov NCT03705507, and ITCC-063 study.