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
- Conditions
- Acute Lymphoblastic Leukemia (ALL)Leukemia10024324
- Registration Number
- NL-OMON55542
- Lead Sponsor
- niversity of Birmingham
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 3
• 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, 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): <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)
• Women of childbearing potential (see section 7.9.1 for definition) must have
a negative pregnancy test
• Patients who are women of childbearing potential and male patients with
partners who are women of child bearing potential must agree to use appropriate
contraception (see section 7.9.1 for definition) 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.
• 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 8 and 9)
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 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Phase I<br /><br>Primary endpoints:<br /><br>- The selection of RP2D based on dual primary measures of dose limiting<br /><br>toxicities (DLT) and PK (ΔAUC)<br /><br><br /><br>Phase II<br /><br>Primary endpoints:<br /><br>- Response rate</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary endpoints Phase 1:<br /><br>- Toxicity evaluation; PK variables of selumetinib in combination with<br /><br>dexamethasone; response to treatment<br /><br><br /><br>Secondary endpoints Phase 2:<br /><br>- Toxicity evaluation; PK variables of selumetinib in combination with<br /><br>dexamethasone; difference in PK of selumetinib as single agent and in<br /><br>combination with dexamethasone<br /><br><br /><br>Phase I/II<br /><br>Research (tertiary) endpoints<br /><br>- Exploratory PD biomarker studies, if clinical responses are observed</p><br>