Relapsed/refractory acute lymphoblastic leukaemia with mutation in the RAS pathway MedDRA version: 21.0 Level: LLT Classification code 10000845 Term: Acute lymphoblastic leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: Selumetinib
Product Code: AZD6244, ARRY 142886
Pharmaceutical Form: Capsule
INN or Proposed INN: Selumetinib
CAS Number: 606143-52-6
Current Sponsor code: AZD6244, ARRY 142886
Other desc
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Morphologically proven relapsed (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, IL7Ra or JAK1) identified during the trial screening process • B cell precursor patients must either: o Have received CAR -T cell therapy, or o Be awaiting CAR -T cell therapy, or o Be considered ineligible for CAR -T cell therapy - Group P (paediatric): 5 years but = 10 years: Serum creatinine 10 years but = 15 years: Serum creatinine 15 years: Serum creatinine =65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
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 o Prior or current cardiomyopathy including but not limited to the following: • Known hypertrophic cardiomyopathy • Known arrhythmogenic right ventricular cardiomyopathy o Even if full recovery has occurred, previous moderate or severe impairment of left ventricular systolic function (LVEF 100 bpm on Electrocardiogram (ECG) at rest o QTcF >450ms in male patients or =460ms in female patients, or other factors that increase the risk of QT prolongation -Group P o Baseline SF 130 bpm on Electrocardiogram (ECG) at rest o QTcF >450ms in patients 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 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): o Serum bilirubin >1.5 x ULN (unless due to Gilber
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To define the recommended phase II dose (RP2D) of selumetinib in combination with dexamethasone in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL, and to assess the preliminary anti-leukaemic activity of the combination in those patients;Secondary Objective: To evaluate the safety and tolerability of the combination of selumetinib and dexamethasone, and to evaluate selumetinib and N-desmethyl selumitinib pharmacokinetics when given in combination with dexamethasone.;Primary end point(s): Phase I - The occurrence/non-occurrence of dose limiting toxicities (DLTs) in the trial defined assessment period Phase II - Response to treatment at 28 days as measured by morphological response (complete remission (CR), complete remission with incomplete platelet recovery (CRi), partial remission (PR), Non-response (NR) (see Appendix 2 for Response Definitions)) and MRD response in BM and clearance of CSF blasts ;Timepoint(s) of evaluation of this end point: The analysis (for each group) for the dose decision phase of the trial will take place once 12 patients have been followed for the DLT assessment period, at this stage a decision will be made as to which dose to take forward to the phase II dose expansion element of the trial. The analysis for the primary outcome of the dose expansion phase (phase II) of the trial will take place once the final patient has been followed for 28 days for response assessment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I - The occurrence of adverse events (AEs) as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4 and causality assessment - Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile (area under the curve (AUC), Cmax, Tmax, t1/2) - Response to treatment assessed by complete remission rate at 28 days (max 35 days) as measured by morphological and minimal residual disease (MRD) response in bone marrow (BM) and clearance of Cerebrospinal Fluid (CSF) blasts -Difference in pharmacokinetics of selumetinib (?AUC) when selumetinib is administered as single agent and in combination with dexamethasone Phase II - The occurrence of AEs as measured by CTCAE version 4 and causality assessment - The occurrence/non-occurrence of DLTs in the trial defined assessment period - Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile (AUC, Cmax, Tmax, t1/2) - Difference in pharmacokinetics of selumetinib (?AUC) when selumetinib is administered as single agent and in combination with dexamethasone ;Timepoint(s) of evaluation of this end point: The analysis (for each group) for the dose decision phase of the trial will take place once 12 patients have been followed for the DLT assessment period, at this stage a decision will be made as to which dose to take forward to the phase II dose expansion element of the trial. The analysis for the primary outcome of the dose expansion phase (phase II) of the trial will take place once the final patient has been followed for 28 days for response assessment. | — |
Countries
Denmark, France, Netherlands, United Kingdom
Contacts
Public ContactDeborah Bird
University of Birmingham
Outcome results
None listed