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, Daniel Slade, Joshua Savage, Sarah Johnson, Julie Irving, Pamela Kearns, Ruth Plummer, Geoff Shenton, Gareth J Veal, Britta Vormoor, Josef Vormoor, Lucinda Billingham, Tobias Menne, Daniel Slade, Joshua Savage, Sarah Johnson, Julie Irving, Pamela Kearns, Ruth Plummer, Geoff Shenton, Gareth J Veal, Britta Vormoor, Josef Vormoor, Lucinda Billingham

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.

Keywords: adult oncology; clinical trials; leukaemia; paediatric oncology.

Conflict of interest statement

Competing interests: JI has received research funding from F. Hoffmann-La Roche.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
SeluDex trial schema SeluDex trial schema showing the patient pathway highlighting screening, trial entry, treatment and follow-up. ALL, acute lymphoblastic leukaemia; BD, two times a day; PD, pharmacodynamic; PIS, patient information sheet; PK, pharmacokinetic.

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