Abstract
IntroductionEvent-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 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. 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 disseminationMedical 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 numberISRCTN92323261.
Highlights
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%
Facing a poor outlook, with reported overall event-free survival rates at 15 years of 30%–50%,2 and relapsed ALL (rALL) remains a frequent cause of death
Five-year overall survival rate remains at ~20% among adult patients aged ≥60 years, even though improvement has been observed since 1980.4
Summary
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%. 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. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-cell ALL, with demonstrated RAS pathway activating mutations are eligible. Neurofibromin (NF1) copy number variants, point mutations or intragenic deletions have been reported in approximately 4% of T-cell ALL, 14% of early T-cell precursor (ETP), ~30% of low hypodiploidy, 2% high risk of B-cell ALL and 75% of relapsed hypodiploid ALL.[6–10]. IL7Rα point mutations, deletions and in-frame alterations are found in approximately 9% of T-A LL,[12 13] and JAK1 point mutations are found in approximately 5% of T-ALL.[14]
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