Contact information
Type
Public
Primary contact
Dr Sarah Johnson
ORCID ID
Contact details
Cancer Research UK Clinical Trials Unit (CRCTU)
Robert Aitken Clinical Research Building
Institute of Cancer and Genomic Sciences
The University of Birmingham
Vincent Drive
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 414 6754
seludex@trials.bham.ac.uk
Additional identifiers
EudraCT number
2016-003904-29
ClinicalTrials.gov number
NCT03705507
Protocol/serial number
33990, RG_16-186
Study information
Scientific 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
Acronym
SeluDex
Study hypothesis
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). The trialists 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.
During Phase I the trial will look at establishing what is the most suitable dose level of selumetinib in combination with dexamethasone that can be safely given to participants. The Phase II part of the trial will look at the dose level of selumetinib which has already been established in Phase I as being the most effective in combination with dexamethasone to see what effects the combination of these medications will have on participants' leukaemia.
Ethics approval
Yorkshire & The Humber - Leeds West Research Ethics Committee, 12/07/2017, ref: 17/YH/0123
Study design
Non-randomised; Interventional; Design type: Treatment, Screening, Drug
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Acute lymphoblastic leukaemia
Intervention
Current intervention as of 15/11/2019:
Patients will receive selumetinib on cycle 1 day 1, then continuously from cycle 1 day 4 onwards. Combined with pulsed doses of dexamethasone on days 2-4, 8-11, 15-18 and 22-25 during cycle 1, then on days 1-4 of cycle two, then on days 1-5 during subsequent cycles. Dose levels will be determined throughout phase I using a statistical model, observation of dose limiting toxicities, and pharmacokinetic analysis. Phase II patients will be administered the recommended phase II dose determined from the phase I part of the trial using the same schedule. The aim is to recruit patients to both phases into both arms of the trial over a 2-year period. It is anticipated that patients will be on treatment for approximately 6 months and will be followed up for a further month after completion of treatment.
Previous intervention:
Patients will receive selumetinib on cycle 1 day 1, then continuously from cycle 1 day 4 onwards, combined with dexamethasone from days 2-28 during cycle 1, then tapered dosing for the first week of cycle two, with full doses on days 1-5 during subsequent cycles. Dose levels will be determined throughout phase I using a statistical model, observation of dose limiting toxicities, and pharmacokinetic analysis. Phase II patients will be administered the recommended phase II dose determined from the phase I part of the trial using the same schedule. The aim is to recruit patients to both phases into both arms of the trial over a two-year period. It is anticipated that patients will be on treatment for approximately six months and will be followed up for a further month after completion of treatment.
Intervention type
Drug
Phase
Phase I/II
Drug names
Selumetinib
Primary outcome measure
Phase I
Selection of the Recommended Phase II Dose using occurrence/non-occurrence of dose limiting toxicities and pharmacokinetic results during cycle 1 day 1-28
Phase II
Response to treatment is measured using morphological response and for patients with CNS involvement only clearance of CSF blasts at cycle 1 day 28
Secondary outcome measures
Phase I
1. The occurrence of adverse events (AEs) is measured using Common Terminology Criteria for Adverse Events (CTCAE) version 4 and causality assessment from cycle 1 day 1 until 28 day follow up
2. Pharmacokinetic variables of selumetinib in combination with dexamethasone are measured using the concentration time profile (area under the curve (AUC), Cmax, Tmax, t1/2) at cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1
3. Response to treatment is measured by complete remission rate using morphological and minimal residual disease (MRD) response in bone marrow (BM) and for patients with CNS involvement only clearance of Cerebrospinal Fluid (CSF) blasts at cycle 1 day 28
4. Difference in pharmacokinetics of selumetinib measured by the area under the curve (AUC) when selumetinib is administered as single agent and in combination with dexamethasone at cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1
Phase II
1. The occurrence of adverse events (AEs) measured using Common Terminology Criteria for Adverse Events (CTCAE) version 4 and causality assessment from cycle 1 day 1 until 28 day follow up
2. The occurrence/non-occurrence of DLTs measured by assessment of the DLTs defined in the trial protocol during cycle 1 day 1-28
3. Pharmacokinetic variables of selumetinib in combination with dexamethasone measured using the concentration time profile (area under the curve (AUC), Cmax, Tmax, t1/2) at cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1
4. Difference in pharmacokinetics of selumetinib measured by the area under the curve (AUC) when selumetinib is administered as single agent and in combination with dexamethasone at cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1
5. MRD response in BM is measured using the MRD level at cycle 1 day 28
Overall trial start date
09/10/2014
Overall trial end date
01/08/2022
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Morphologically proven relapsed/refractory (M2 or M3 marrow; ≥1st relapse for adults, ≥2nd relapse in paediatric group – see Appendix 5) or progressive B cell precursor or T-Acute Lymphoblastic Leukaemia (ALL) with demonstrated RAS pathway activating mutations (NRAS, KRAS, FLT3, PTPN11, cCBL) identified during the trial screening process
2. Group P (paediatric): <18 years of age; Group A (adult): ≥18 years of age
3. Adequate renal function:
3.1. Group A: Serum creatinine <1.5 x upper limit of normal (ULN)
3.2. Group P as follows:
3.2.1. ≤ 5 years: Serum creatinine <0.8 mg/dL or 70 μmol/L
3.2.2. > 5 years but ≤ 10 years: Serum creatinine <1 mg/dL or 88 μmol/L
3.2.3. > 10 years but ≤ 15 years: Serum creatinine <1.2 mg/dL or 106 μmol/L
3.2.4. > 15 years: Serum creatinine <1.5 mg/dL or 132 μmol/L
4. Patient is able to swallow selumetinib capsules whole
5. Performance status (PS): Group A - Eastern Cooperative Oncology Group (ECOG) ≤2 (Appendix 6); Group P - Lansky play scale ≥60% (Appendix 7) or Karnofsky scale ≥60% (Appendix 8)
6. Women of childbearing potential (see section 7.9.1 for definition) must have a negative pregnancy test
7. Patients who are women of childbearing potential and male patients with partners who are women of childbearing potential must agree to use appropriate contraception (see section 7.9.1 for definition) whilst on trial
8. Written informed consent
9. Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
10. Patients who relapse or progress after HSCT need to be at least at day +100, with no signs of Graft versus Host Disease and off immunosuppressive therapy for at least one week
11. Patients who relapse or progress after CAR T cell therapy should be at least 4 weeks after infusion of CAR T cells.
12. Patients must have a body surface area (BSA) ≥ 0.55 m2
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 42; UK Sample Size: 31
Participant exclusion criteria
1. ALL without presence of RAS-pathway activating mutations
2. Mature B-cell leukaemia and Philadelphia positive ALL
3. Prior exposure to MEK, RAS or RAF inhibitors
4. Any unresolved toxicity > = CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia
5. Cardiac conditions as follows:
Group A and P
5.1. Prior or current cardiomyopathy including but not limited to the following:
5.1.1. Known hypertrophic cardiomyopathy
5.1.2. Known arrhythmogenic right ventricular cardiomyopathy
5.2. Even if full recovery has occurred, previous moderate or severe impairment of left ventricular systolic function (LVEF < 45% on ECHO in Group A; SF < 29% in Group P but excluding transient impairments due to e.g. anaemia/sepsis or results not thought to represent a true reflection of cardiac function)
5.3. Severe valvular heart disease
5.4. Severe congential heart disease
5.5. Uncontrolled hypertension:
Group A: BP > = 150/95 mmHg despite medical therapy;
Group P: BP > = 95th percentile for age, height and gender (please refer to Blood Pressure by Age and Height Percentiles tables in (Appendices 8 and 9)
Group A
5.6. Baseline (LVEF) below the lower limit of normal (LLN) or < 55% measured by ECHO
5.7. Acute coronary syndrome within 6 months prior to trial registration
5.8. Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy (Appendix 11)
5.9. Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix 12)
5.10. Prior or current cardiomyopathy including but not limited to the following:
5.10.1. Known hypertrophic cardiomyopathy
5.10.2. Known arrhythmogenic right ventricular cardiomyopathy
5.11. Atrial fibrillation with a ventricular rate > 100 bpm on Electrocardiogram (ECG) at rest
5.12. QTcF > 450ms in male patients or > = 460ms in female patients, or other factors that increase the risk of QT prolongation
Group P
5.13. Baseline SF < 29%
5.14. Atrial fibrillation with a ventricular rate > 130 bpm on Electrocardiogram (ECG) at rest
5.15. QTcF > 450ms in patients < 12 years or > = 460ms in patients > = 12 but < 18 years
6. Ophthalmological conditions as follows:
6.1. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion
6.2. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of IOP)
7. Pregnant and breast feeding females
8. Known severe hypersensitivity to selumetinib, dexamethasone or combination medications or any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
9. Have received or are receiving an IMP or other systemic anti-cancer treatment (not including dexamethasone or hydroxycarbamide) within 4 weeks (6 weeks for nitrosoureas, mitomycin, and suramin) prior to trial registration, or within a period during which the IMP or systemic anticancer treatment has not been cleared from the body (e.g. a period of 5 ‘half-lives’), whichever is the most appropriate and as judged by the investigator
10. Have had recent major surgery within a minimum 4 weeks prior to trial registration, with the exception of surgical placement of vascular access
11. Have received radiation therapy within 4 weeks prior to trial registration, or limited field of radiation for palliation within 7 days of the first dose of trial treatment
12. Laboratory values as listed below (SI units):
12.1. Serum bilirubin > 1.5 x ULN (unless due to Gilbert’s syndrome)
13. Have evidence of any other significant clinical disorder or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the trial
14. Have any evidence of a severe or uncontrolled systemic disease (e.g. unstable or uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including hepatitis B, hepatitis C, HIV), active bleeding diatheses, or renal transplant)
15. Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would adversely affect the absorption/bioavailability of the orally administered trial medication
16. Any other active malignancy which, in the opinion of the investigator would limit the ability of the patient to complete the study
Recruitment start date
17/04/2018
Recruitment end date
01/11/2021
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Freeman Hospital
Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Trial participating centre
Great North Children's Hospital
Royal Victoria Infirmary
Queen Victoria Rd
Newcastle upon Tyne
NE1 4LP
United Kingdom
Trial participating centre
Birmingham Children's Hospital
Steelhouse Ln
Birmingham
B4 6NH
United Kingdom
Trial participating centre
Queen Elizabeth Hospital Birmingham
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Alder Hey Children's Hospital Liverpool
East Prescot Road
Liverpool
L14 5AB
United Kingdom
Trial participating centre
Royal Marsden Hospital
Downs Rd
Sutton
SM2 5PT
United Kingdom
Trial participating centre
University College London Hospital
Gower St
Bloomsbury
London
WC1E 6BT
United Kingdom
Trial participating centre
Christie Hospital
Wilmslow Rd
Manchester
M20 4BX
United Kingdom
Trial participating centre
Royal Hallamshire Hospital
Glossop Rd
Sheffield
S10 2JF
United Kingdom
Trial participating centre
Great Ormond Street Hospital
Great Ormond Street
Holborn
London
WC1N 3JH
United Kingdom
Trial participating centre
Hammersmith Hospital
Du Cane Rd
White City
London
W12 0HS
United Kingdom
Trial participating centre
King’s College Hospital
Denmark Hill
Camberwell
London
SE5 9RS
United Kingdom
Trial participating centre
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom
Sponsor information
Organisation
University of Birmingham
Sponsor details
-
Birmingham
-
United Kingdom
+44 (0)121 414 6754
seludex@trials.bham.ac.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Industry
Funder name
AstraZeneca
Alternative name(s)
AstraZeneca PLC
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United Kingdom
Funder name
Cancer Research UK; Grant Codes: C27943/A22304
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Planned publication in a peer reviewed journal.
IPD sharing statement
The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository (https://www.cancertrials.bham.ac.uk/SeluDexLive). Type of data that will be shared: case report form data. When the data will become available and for how long: from trial entry registration until the end of the trial. Access to the eRDC system will be granted to authorised individuals via the UK Coordinating Centre, for analysis of outcome measures, Phase I dose escalation continual reassessment method, Phase II Bayesian design. Consent from participants was obtained prior to trial entry,
Intention to publish date
01/08/2023
Participant level data
Stored in repository
Basic results (scientific)
Publication list