| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory acute lymphoblastic leukaemia with mutation in the RAS pathway |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/refractory acute lymphoblastic leukaemia with mutation in the RAS pathway |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
| 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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, IL7Rα 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): <18 years of age; Group A (adult): ≥18 years of age
- Adequate renal function:
o Group A: Serum creatinine <1.5 x upper limit of normal (ULN)
o Group P as follows:
≤ 5 years: Serum creatinine <0.8 mg/dL or 70 μmol/L
> 5 years but ≤ 10 years: Serum creatinine <1 mg/dL or 88 μmol/L
> 10 years but ≤ 15 years: Serum creatinine <1.2 mg/dL or 106 μmol/L
> 15 years: Serum creatinine <1.5 mg/dL or 132 μmol/L
- Patient is able to swallow selumetinib capsules whole
- 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)
- Female patients post menarche: negative pregnancy test
- Sexually active participants must agree to use appropriate contraception whilst on trial
- Written informed consent
- 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
-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.
- Patients who relapse or progress after CAR T cell therapy should be at least 4 weeks after infusion of CAR T cells.
- Patients must have a body surface area (BSA) ≥ 0.55 m2.
|
|
| E.4 | Principal 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 <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)
o Severe valvular heart disease
o Severe congential heart disease
o 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
9 and 10)
-Group A
o Baseline (LVEF) below the lower limit of normal (LLN) or <55% measured by ECHO
o Acute coronary syndrome within 6 months prior to trial registration
o Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite
medical therapy (Appendix 11)
o Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix 12)
o Prior or current cardiomyopathy including but not limited to the following:
• Known hypertrophic cardiomyopathy
• Known arrhythmogenic right ventricular cardiomyopathy
o Atrial fibrillation with a ventricular rate >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 <29%
o Atrial fibrillation with a ventricular rate >130 bpm on Electrocardiogram (ECG)
at rest
o QTcF >450ms in patients <12 years or ≥460ms in patients ≥12 but <18 years
- Ophthalmological conditions as follows:
o Current or past history of retinal pigment epithelial detachment (RPED)/central
serous retinopathy (CSR) or retinal vein occlusion
o 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 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 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
|
|
| E.5 End points |
| E.5.1 | 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
|
|
| E.5.1.1 | 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.
|
|
| E.5.2 | 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 (ΔAUC) 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 (ΔAUC) when selumetinib is
administered as single agent and in combination with dexamethasone
|
|
| E.5.2.1 | 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.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose finding and toxicity assessment |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial will be 6 months after last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The applicable NCC will notify the relevant Competent Authority and REC that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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