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
Acute lymphoblastic leukaemia
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.
Current inclusion criteria as of 23/12/2021: 1. Morphologically proven relapsed/refractory (M2 or M3 marrow; ≥1st relapse for adults, ≥2nd relapse in paediatric group) or progressive B cell precursor or T-Acute Lymphoblastic Leukaemia (ALL) with demonstrated RAS pathway activating mutations (NRAS, KRAS, FLT3, PTPN11, cCBL, NF1, BRAF, IKZF2, IKZF3, IL7Rα or JAK1) identified during the trial screening process 2. B cell precursor patients must either: 2.1 Have received CAR-T cell therapy, or 2.2. Be awaiting CAR-T cell therapy, or 2.3. Be considered ineligible for CAR-T cell therapy 3. Group P (paediatric): <18 years of age; Group A (adult): ≥18 years of age 4. Adequate renal function: 4.1. Group A: Serum creatinine <1.5 x upper limit of normal (ULN) 4.2. Group P as follows: 4.2.1. ≤5 years: Serum creatinine <0.8 mg/dL or 70 μmol/L 4.2.2. >5 years but ≤ 10 years: Serum creatinine <1 mg/dL or 88 μmol/L 4.2.3. >10 years but ≤ 15 years: Serum creatinine <1.2 mg/dL or 106 μmol/L 4.2.4. >15 years: Serum creatinine <1.5 mg/dL or 132 μmol/L 5. Patient is able to swallow selumetinib capsules whole 6. Performance status (PS): Group A - Eastern Cooperative Oncology Group (ECOG) ≤2; Group P - Lansky play scale ≥60% or Karnofsky scale ≥60% 7. Women of childbearing potential must have a negative pregnancy test 8. Patients who are women of childbearing potential and male patients with partners who are women of childbearing potential must agree to use appropriate contraception whilst on trial 9. Written informed consent 10. 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 11. 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 12. Patients who relapse or progress aft
Current exclusion criteria as of 23/12/2021: 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 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 5.9. Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease 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