1 Menne T, et al. BMJ Open 2022;12:e059872. doi:10.1136/bmjopen-2021-059872 Open access 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 Tobias Menne, 1 Daniel Slade, 2 Joshua Savage , 2 Sarah Johnson, 2 Julie Irving, 3 Pamela Kearns, 2 Ruth Plummer, 1,3 Geoff Shenton, 4 Gareth J Veal, 3 Britta Vormoor, 5 Josef Vormoor, 3,5 Lucinda Billingham 2 To cite: Menne T, Slade D, Savage J, et al. 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. BMJ Open 2022;12:e059872. doi:10.1136/ bmjopen-2021-059872 ► Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (http://dx.doi.org/10.1136/ bmjopen-2021-059872). TM, DS and JS contributed equally. JV and LB contributed equally. TM, DS and JS are joint first authors. JV and LB are joint senior authors. Received 03 December 2021 Accepted 27 January 2022 For numbered affiliations see end of article. Correspondence to Professor Lucinda Billingham; l.j.billingham@bham.ac.uk Protocol © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. ABSTRACT 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%. Many patients with newly diagnosed and relapsed ALL harbour somatic RAS-signalling activation mutations. Induction therapy for ALL involves steroids, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886) has a synergistic anticancer 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; Münster, Germany; Paris, France; and Utrecht, Netherlands. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-cell 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%. Phase I primary objective is the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method; phase II will evaluate preliminary antileukaemic activity of the combination, as defined by morphological response 28 days post-treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum 13 and maximum 21 per group), depending the number of phase I patients included in phase II. Ethics and dissemination Medical ethical committees of all the participating countries have approved the study protocol; initial (UK) ethics approval (17/YH/0123) was granted by Yorkshire & The Humber—Leeds West Research Ethics Committee. Participants are required to provide written informed consent/assent. Results will be disseminated through national and international presentations and peer-reviewed publications. Trial registration number ISRCTN92323261. INTRODUCTION Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, repre- senting 26.8% of all childhood malignancies. 1 While the overall cure rate for newly diag- nosed paediatric ALL is approaching 90%, children with relapsed ALL (rALL) are still Strengths and limitations of this study ► Novel combination of the MEK1/2 inhibitor, selume- tinib, with dexamethasone. ► Seamless phase I/II Bayesian trial design with a con- tinual reassessment method for dose escalation in phase I. ► Parallel cohort trial design of adult and paediatric patients within one protocol. ► Availability of CAR T-cell therapy since this trial started recruitment has competed for the same pa- tient population, however, SeluDex offers a bridging treatment option for patients awaiting CAR T-cell therapy outside clinical studies or at relapse after CAR-T treatment. on October 17, 2022 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2021-059872 on 4 March 2022. Downloaded from