Condition category
Cancer
Date applied
22/01/2018
Date assigned
23/05/2018
Last edited
23/05/2018
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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

Protocol/serial number

33990

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

Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissu

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

17/03/2021

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

17/05/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Freeman Hospital
Freeman Rd High Heaton
Newcastle upon Tyne
NE7 7DN

Trial participating centre

Great North Children's Hospital
Royal Victoria Infirmary Queen Victoria Rd
Newcastle upon Tyne
NE1 4LP

Trial participating centre

Belfast City Hospital
51 Lisburn Rd
Belfast
BT9 7AB

Trial participating centre

Birmingham Children's Hospital
Steelhouse Ln
Birmingham
B4 6NH

Trial participating centre

Queen Elizabeth Hospital Birmingham
Mindelsohn Way
Birmingham
B15 2TH

Trial participating centre

Bristol Royal Hospital for Children
Upper Maudlin St
Bristol
BS2 8BJ

Trial participating centre

Bristol Royal Infirmary
Upper Maudlin St
Bristol
BS2 8HW

Trial participating centre

University Hospital of Wales
Heath Park Way Health Park
Cardiff
CF14 4XW

Trial participating centre

Beatson West of Scotland Cancer Centre
1053 Great Western Rd
Glasgow
G12 0YN

Trial participating centre

St James University Hospital
Beckett St
Leeds
LS9 7TF

Trial participating centre

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW

Trial participating centre

Alder Hey Children's Hospital Liverpool
East Prescot Road
Liverpool
L14 5AB

Trial participating centre

The Royal Liverpool University Hospital
Prescot St
Liverpool
L7 8XP

Trial participating centre

Great Ormond Street Hospital
Great Ormond St
London
WC1N 3JH

Trial participating centre

King's College Hospital
Denmark Hill Brixton
London
SE5 9RS

Trial participating centre

Royal Marsden Hospital
Downs Rd
Sutton
SM2 5PT

Trial participating centre

University College London Hospital
Gower St Bloomsbury
London
WC1E 6BT

Trial participating centre

Christie Hospital
Wilmslow Rd
Manchester
M20 4BX

Trial participating centre

Nottingham City Hospital
Hucknall Rd
Nottingham
NG5 1PB

Trial participating centre

Royal Hallamshire Hospital
Glossop Rd
Sheffield
S10 2JF

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)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

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

17/03/2022

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes