SeluDex
Research type
Research Study
Full title
International phase I/II expansion trial of the MEK inhibitor selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult Acute Lymphoblastic Leukaemia
IRAS ID
203556
Contact name
Sean Jennings
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2016-003904-29
Duration of Study in the UK
3 years, 3 months, 31 days
Research summary
Research Summary:
The purpose of this trial is to test a new drug called selumetinib in combination with another drug called dexamethasone. The trial specifically targets those patients who have relapsed or refractory acute lymphoblastic leukaemia (ALL) and who have an identified mutation in a particular gene in their cancer’s DNA (in the RAS pathway). We would like to see what effect combining these two drugs has on the patient's leukaemia. This will include looking at how well this treatment works, finding out more information about how it affects the disease, and to see how safe the drugs are in participants taking the trial medication.
Lay Summary of Results:
In the SeluDex clinical trial (ISRCTN92323261), children and adults with acute lymphoblastic leukaemia (ALL) were treated with selumetinib and dexamethasone. Selumetinib is a targeted cancer drug that works by blocking the signals from the MEK protein. MEK is a protein inside cells that sends signals for them to grow and to stop growing but can be changed (mutated) in some cancers allowing cells to grow abnormally. Patients in this trial were tested to see if they had changes in the RAS pathway that controls the MEK protein. Dexamethasone is an anti-inflammatory drug called a steroid already used to treat leukaemia. From testing the combination of selumetinib with steroids in cell experiments, we have learned that the two drugs work together and reinforce each other.
This trial was trying to determine the most effective and safe dose of Selumetinib to give to patients when combined with dexamethasone. Patients were treated in groups of two, known as cohorts, and then assessed by an independent Trial Safety Committee (TSC) to decide if the dose could safely be increased, should remain the same or be reduced. This decision was based on the number of Dose Limiting Toxicities (DLTs) that were reported; DLTs are side effects or adverse events (AEs) that are specifically defined as significant in the trial protocol. The TSC also considered pharmacokinetic (PK) results obtained from patient samples which look at how the body interacts with a drug; how they are absorbed, spread around the body, metabolised and excreted.
Between 18-May-2018 and 10-Aug-2021, 12 patients were registered to SeluDex, eight were registered into Group A (Adults) and four into Group P (Paediatrics; <18 years old). One patient from Group A died before they started treatment so were not considered in the results (not evaluable).
SeluDex was closed early due to slow recruitment, which was attributed to changes in the standard of care with the introduction of CAR-T cell therapy and the challenges of academic international early-phase clinical trials in rare patient populations.
All patients in Group A received 75 mg Selumetinib (starting dose level 0) twice a day by mouth and received Dexamethasone according to the protocol; this dose was reduced in cycle 1 (a cycle is defined as 28 days) and switched to a pulsed rather than continuous dosing in response to safety concerns involving serious infections. One DLT was reported in Cohort 2.
All patients in Group P received 20mg/m2 Selumetinib (starting dose level -1) twice a day by mouth and received Dexamethasone according to the protocol; as in group A, this dose was reduced in cycle 1 and switched to a pulsed rather than continuous dosing in response to the same safety concerns than in group A. One DLT was reported in Cohort 1.
Nine patients were evaluable for response, which assessed their morphological response (percentage of leukemic cells) in the bone marrow or cerebrospinal fluid at 28 days; four patients showed a complete remission (disappearance of disease) at this point, three in group A, and one in group P. All patients eventually discontinued treatment due to resistant disease (disease that did not respond to treatment), relapse (return of disease), side effects or death.
In total, there were 561 AEs reported in 11 patients with an average (median) of 27 per patient. 16 Serious Adverse Events (SAEs) were reported in nine patients during the trial; 10 in Group A and six in Group P. Three urgent safety measures were implemented during the trial to address safety concerns that were reported regarding sepsis; these changed the dexamethasone dosing and mandated preventative antibiotics for all patients.
Whilst the study was ended early, the results support further investigation of MEK inhibitors, like selumetinib with dexamethasone in patients with RAS-pathway activated ALL.REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
17/YH/0123
Date of REC Opinion
12 Jul 2017
REC opinion
Further Information Favourable Opinion