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

 Acute lymphoblastic leukaemia (ALL) / Posted 6 months ago

Brief Summary
This trial is to investigate the combination of selumetinib and dexamethasone in the treatment of acute lymphoblastic leukaemia (ALL) in both adults and children. Phase I is to find the most suitable dose of selumetinib to safely give with dexamethasone. Phase II will use this dose to find out how well the combination works.

Detailed Summary

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer worldwide. The overall newly diagnosed ALL cure rate is approaching 90% however children with relapsed ALL often do not survive. The frequency of ALL in adults is significantly lower however more challenging to treat compared to childhood ALL. Adult ALL is more resistant to chemotherapy and patient have reduced treatment tolerance (particularly the elderly population) therefore overall survival rates are low. Therefore there is a need to develop more effective treatment which improves survival rates for this patient population.

Those eligible in the paediatric setting are in their second or further relapse, often after a previous allogeneic stem cell transplant (SCT), and usually in a palliative situation. Adult patients who are not suitable for more intensive therapy can enter the trial in first relapse. The trial offers an out-patient based treatment approach of this heavily pre-treated patient group. The trial includes patients with B-cell precursor and T-ALL irrespective of Central Nervous System (CNS) disease status.CNS positive patients and patients with T-ALL are usually excluded from other early phase clinical trials. If treatment is successful, patients could continue with other therapies/trials once complete remission achieved (e.g. Chimeric Antigen Receptor (CAR) T cell therapy).

Selumetinib is a small molecule inhibitor of MEK, a protein in the RAS-pathway. Mutations in genes in the RAS pathway have been found in a large proportion of patients with ALL. Selumetinib targets this over-activated pathway to arrest cancer cell growth. Dexamethasone is a steroid important in the treatment of leukaemia to stimulate the death of cancer cells. The SeluDex trial is for patients with relapsed or refractory RAS-pathway mutated ALL.

The primary objective of this trial in Phase I is to see what dose of selumetinib can safely be given in combination with dexamethasone in participants. During Phase II, the primary objective is to assess the preliminary information regarding the effectiveness of this combined treatment.

  • Inclusion Criteria :
    • Morphologically proven relapsed/refractory (M2 or M3 marrow; at least 1st relapse for adults, at least 2nd relapse in paediatric group - see Protocol 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, IL7Rα or JAK1) identified during the trial screening process
    • B cell precursor patients must either:
    • Have received CAR -T cell therapy, or
    • Be awaiting CAR -T cell therapy, or
    • Be considered ineligible for CAR -T cell therapy
    • Group P (paediatric): less than 18 years of age; Group A (adult): at least 18 years of age
    • Adequate renal function:
    • Group A: Serum creatinine less than 1.5 x upper limit of normal (ULN) Group P as follows:
    • 5 years: Serum creatinine less than 0.8 mg/dL or 70 μmol/L, more than 5 years but at most 10 years: Serum creatinine less than 1 mg/dL or 88 μmol/L, more than 10 years but at most 15 years: Serum creatinine less than1.2 mg/dL or 106 μmol/L, more than 15 years: Serum creatinine less than 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) at most 2 (Protocol Appendix 6); Group P - Lansky play scale at least 60% (Protocol Appendix 7) or Karnofsky scale at least 60% (Appendix 8)
    • Women of childbearing potential (see protocol section 7.9.3 for definition) must have a negative pregnancy test
    • Patients who are women of childbearing potential and male patients with partners who are women of childbearing potential must agree to use appropriate contraception (see protocol section 7.9.3 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 Haematopoetic Stem Cell Transplant (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) at least 0.55 m2.
  • 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 at least 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 less than 45% on Echocardiogram (ECHO) in Group A; SF less than 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 at least 150/95 mmHg despite medical therapy
    • Group P: BP at least 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 less than 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 more than 100 bpm on Electrocardiogram (ECG) at rest
    • QTcF more than 450ms in male patients or ≥460ms in female patients, or other factors that increase the risk of QT prolongation Group P
    • Baseline SF less than 29%
    • Atrial fibrillation with a ventricular rate more than 130 bpm on Electrocardiogram (ECG) at rest
    • QTcF more than 450ms in patients less than 12 years or at least 460ms in patients at least 12 but less than 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) more than 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
  • Study start date : May 18, 2018
  • Study end date : December 2023
  • Wales-Based Study Contact : Please speak to your clinician
  • Principal Investigator : Alice Norton
Contact details

Birmingham Children's Hospital, Birmingham Birmingham,England,B4 6NH  Show Phone Number seludex@trials.bham.ac.uk bwc.nhs.uk

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