TY - JOUR
T1 - Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex)
T2 - study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial
AU - Menne, Tobias
AU - Slade, Daniel
AU - Savage, Joshua
AU - Johnson, Sarah
AU - Irving, Julie
AU - Kearns, Pamela
AU - Plummer, Ruth
AU - Shenton, Geoff
AU - Veal, Gareth J.
AU - Vormoor, Britta
AU - Vormoor, Josef
AU - Billingham, Lucinda
N1 - © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
PY - 2022/3/4
Y1 - 2022/3/4
N2 - 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.
AB - 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.
KW - adult oncology
KW - clinical trials
KW - leukaemia
KW - paediatric oncology
KW - Dexamethasone
KW - Humans
KW - Benzimidazoles/therapeutic use
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Adolescent
KW - Bayes Theorem
KW - Adult
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Child
KW - Clinical Trials, Phase I as Topic
KW - Clinical Trials, Phase II as Topic
KW - adult oncology
KW - clinical trials
KW - leukaemia
KW - paediatric oncology
UR - http://www.scopus.com/inward/record.url?scp=85125775792&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/572018f7-4945-3771-ab4b-46a70261f747/
U2 - 10.1136/bmjopen-2021-059872
DO - 10.1136/bmjopen-2021-059872
M3 - Article
C2 - 35246426
AN - SCOPUS:85125775792
SN - 2044-6055
VL - 12
SP - e059872
JO - BMJ Open
JF - BMJ Open
IS - 3
ER -