Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial
Authors: Menne Tobias , Slade Daniel , Savage Joshua , Johnson Sarah , Irving Julie , Kearns Pamela R. , Plummer Ruth , Shenton Geoff , Veal Gareth J. , Vormoor Britta , Vormoor Josef , Billingham Lucinda 
Published: October 2021

AbstractIntroductionEvent 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 analysisThe 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; Münster, 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 disseminationMedical 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 numberThe trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.GovNCT03705507, and ITCC-063 study.Strengths and limitations of this studyNovel combination of the MEK1/2 inhibitor, selumetinib, with dexamethasoneSeamless phase I/II Bayesian trial design with a Continual Reassessment Method for dose escalation in phase IParallel cohort trial design of adult and paediatric patients within one protocolAvailability of CAR T-cell therapy since this trial started recruitment has competed for the same patient populationOffers a bridging treatment option for patients awaiting CAR T-cell therapy outside clinical studies or at relapse after CAR-T treatment