Clinical Trials /

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

NCT03705507

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: International Trial of Selumetinib in Combination With Dexamethasone for the Treatment of Acute Lymphoblastic Leukaemia
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: RG_16-186
  • SECONDARY ID: 2016-003904-29
  • SECONDARY ID: ISRCTN92323261
  • NCT ID: NCT03705507

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Lymphoblastic Leukemia, Adult
  • Acute Lymphoblastic Leukemia, Pediatric
  • Acute Lymphoblastic Leukemia, in Relapse
  • Acute Lymphoblastic Leukemia Recurrent

Interventions

DrugSynonymsArms
SelumetinibAZD6244Selumetinib + Dexamethasone - Group A (18 years and above)
DexamethasoneSelumetinib + Dexamethasone - Group A (18 years and above)

Purpose

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 Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Selumetinib + Dexamethasone - Group A (18 years and above)ExperimentalPatients will receive the adult cohort specified dose of selumetinib by mouth, as a single dose on cycle 1 day 1, then twice daily continuously from cycle 1 day 4 onwards, combined with dexamethasone 6mg/m2/day divided into two doses (as per local practice) by mouth 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.
  • Selumetinib
  • Dexamethasone
Selumetinib + Dexamethasone - Group P (under 18 years)ExperimentalPatients will receive the paediatric cohort specified dose of selumetinib by mouth, as a single dose on cycle 1 day 1, then twice daily continuously from cycle 1 day 4 onwards, combined with dexamethasone 6mg/m2/day divided into two doses (as per local practice) by mouth 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.
  • Selumetinib
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Morphologically proven relapsed/refractory (M2 or M3 marrow; ≥1st relapse for adults,
             ≥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) identified during the trial
             screening process

          -  Group P (paediatric): <18 years of age; Group A (adult): ≥18 years of age

          -  Adequate renal function:

               -  Group A: Serum creatinine <1.5 x upper limit of normal (ULN)

               -  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
             (Protocol Appendix 6); Group P - Lansky play scale ≥60% (Protocol Appendix 7) or
             Karnofsky scale ≥60% (Appendix 8)

          -  Women of childbearing potential (see protocol 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 childbearing potential must agree to use appropriate contraception (see
             protocol 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 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) ≥ 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 ≥ 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 <45% on Echocardiogram (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)

          -  Severe valvular heart disease

          -  Severe congenital heart disease

          -  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 Protocol Appendices 8 and 9)
                  Group A

          -  Baseline (LVEF) below the lower limit of normal (LLN) or <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 >100 bpm on Electrocardiogram (ECG) at
             rest

          -  QTcF >450ms in male patients or ≥460ms in female patients, or other factors that
             increase the risk of QT prolongation Group P

          -  Baseline SF <29%

          -  Atrial fibrillation with a ventricular rate >130 bpm on Electrocardiogram (ECG) at
             rest

          -  QTcF >450ms in patients <12 years or ≥460ms in patients ≥12 but <18 years

          -  Ophthalmological conditions as follows:

               -  Current or past history of retinal pigment epithelial detachment (RPED)/central
                  serous retinopathy (CSR) or retinal vein occlusion

               -  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 Investigational Medicinal Product (IMP) or other
             systemic anti-cancer treatment (not including dexamethasone 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: The occurrence/non-occurrence of dose limiting toxicities (DLTs) in the trial defined assessment period
Time Frame:During cycle 1 (each cycle is 28 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Phase I & II: The occurrence of adverse events (AEs) as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4
Time Frame:From cycle 1 day 1 until 28 days after End of Treatment (6 cycles, each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: The occurrence of adverse events (AEs) as measured by causality assessment
Time Frame:From cycle 1 day 1 until 28 days after the last treatment (6 cycles, each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by area under the plasma concentration versus time curve (AUC)
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by the peak plasma concentration (Cmax)
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by the time to reach peak plasma concentration (Tmax)
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Pharmacokinetic variables of selumetinib in combination with dexamethasone from the concentration time profile measured by the time required for the concentration of the drug to reach half of its original value (t1/2)
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I: Response to treatment assessed by complete remission rate as measured by morphological response in bone marrow (BM)
Time Frame:At the end of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I: Response to treatment assessed by complete remission rate as measured by minimal residual disease (MRD) response in BM
Time Frame:At the end of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I: For patients with CNS involvement only response to treatment assessed by complete remission rate as measured by clearance of CSF blasts
Time Frame:At the end of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Difference in pharmacokinetics of selumetinib (ΔAUC) when selumetinib is administered as single agent
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase I & II: Difference in pharmacokinetics of selumetinib (ΔAUC) when selumetinib is administered in combination with dexamethasone
Time Frame:At cycle 1 day 1, cycle 1 day 4 and cycle 2 day 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase II: The occurrence/non-occurrence of DLTs in the trial defined assessment period
Time Frame:During cycle 1 (each cycle is 28 days)
Safety Issue:
Description:
Measure:Phase II: MRD response in BM
Time Frame:At the end of cycle 1 (each cycle is 28 days)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Birmingham

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