International Trial of Selumetinib in Combination With Dexamethasone for the Treatment of Acute Lymphoblastic Leukaemia

Exclusion Criteria

• •ALL without presence of RAS-pathway activating mutations
• •Mature B-cell leukaemia and Philadelphia positive ALL
• •Prior exposure to MEK, RAS or RAF inhibitors
• •Any unresolved toxicity ≥ CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia
• •Cardiac conditions as follows:
• •Group A and P
• •Prior or current cardiomyopathy including but not limited to the following:
• •* Known hypertrophic cardiomyopathy
• •* Known arrhythmogenic right ventricular cardiomyopathy
• •Even if full recovery has occurred, previous moderate or severe impairment of left ventricular systolic function (LVEF \<45% on Echocardiogram (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)
• •Severe valvular heart disease
• •Severe congenital heart disease
• •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 Protocol Appendices 8 and 9) Group A
• •Baseline (LVEF) below the lower limit of normal (LLN) or \<55% measured by ECHO
• •Acute coronary syndrome within 6 months prior to trial registration
• •Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy (Protocol Appendix 11)
• •Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Protocol Appendix 12)
• •Atrial fibrillation with a ventricular rate \>100 bpm on Electrocardiogram (ECG) at rest
• •QTcF \>450ms in male patients or ≥460ms in female patients, or other factors that increase the risk of QT prolongation Group P
• •Baseline SF \<29%
• •Atrial fibrillation with a ventricular rate \>130 bpm on Electrocardiogram (ECG) at rest
• •QTcF \>450ms in patients \<12 years or ≥460ms in patients ≥12 but \<18 years
• •Ophthalmological conditions as follows:
• •* Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion (RVO)
• •* Intraocular pressure (IOP) \> 21 mmHg or uncontrolled glaucoma (irrespective of IOP)
• •Pregnant and breast feeding females
• •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
• •Have received or are receiving an Investigational Medicinal Product (IMP) or other systemic anti-cancer treatment (not including dexamethasone, prednisolone 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
• •Have had recent major surgery within a minimum 4 weeks prior to trial registration, with the exception of surgical placement of vascular access
• •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
• •Laboratory values as listed below (SI units):
• •* Serum bilirubin \>1.5 x ULN (unless due to Gilbert's syndrome)
• •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
• •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)
• •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
• •Any other active malignancy which, in the opinion of the investigator would limit the ability of the patient to complete the study