Clinical Trials /

Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

NCT03326388

Description:

Phase I and II study of the MEK inhibitor Selumetinib given twice daily on 5 out of 7 days in children with NF1 and inoperable plexiform neurofibromas or progressive/relapsed optic pathway gliomas. This study will test the early and late toxicities of selumetinib when it is given in this intermittent schedule (in 5 out of 7 days) and will also test the effectiveness of the drug in reducing the size of plexiform neurofibromas and optic pathway gliomas in children with NF1. It will also test the effectiveness of the drug in improving the participants function in day to day life.

Related Conditions:
  • Neurofibromatosis Type 1
  • Optic Nerve Glioma
  • Plexiform Neurofibroma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours
  • Official Title: A Paediatric Phase I/II Study Of Intermittent Dosing Of The Mek-1 Inhibitor Selumetinib In Children With Neurofibromatosis Type-1 And Inoperable Plexiform Neurofibroma And/Or Progressive Optic Pathway Glioma

Clinical Trial IDs

  • ORG STUDY ID: 15Hi53
  • NCT ID: NCT03326388

Conditions

  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Optic Nerve Glioma

Interventions

DrugSynonymsArms
SelumetinibAZD6244,, ARRY-142886, AR00142886, AR-142886-XSelumetinib Intermittent Dosing

Purpose

Phase I and II study of the MEK inhibitor Selumetinib given twice daily on 5 out of 7 days in children with NF1 and inoperable plexiform neurofibromas or progressive/relapsed optic pathway gliomas. This study will test the early and late toxicities of selumetinib when it is given in this intermittent schedule (in 5 out of 7 days) and will also test the effectiveness of the drug in reducing the size of plexiform neurofibromas and optic pathway gliomas in children with NF1. It will also test the effectiveness of the drug in improving the participants function in day to day life.

Detailed Description

      Neurofibromatosis type 1 (NF1) is a common autosomal dominant, progressive disorder with an
      incidence of 1 in 3,500 of the population. NF1 is characterized by diverse, progressive
      cutaneous, neurological, skeletal and neoplastic manifestations with no standard drug
      treatment options available. Patients with NF1 have an increased risk of developing tumours
      of the central and peripheral nervous system including plexiform neurofibromas (PN) (27%) and
      optic gliomas (15-20%).

      Genetic aberrations targeting the Ras-mitogen-activated protein kinase (MAPK) signalling
      pathway are a hallmark molecular feature of Low Grade Gliomas (including optic pathway
      gliomas) and NF1 as well as some low-grade glial-neuronal tumours. The gene responsible for
      NF1 has been cloned and encodes a protein called neurofibromin. Loss of Neurofibromin is
      associated with elevated levels of Ras, and Activated Ras results in the initiation of a
      cascade of signalling events such as activation of Raf and MAPK that leads to increased cell
      proliferation. Thus MAPK inhibitors offer an attractive novel therapeutic option for both NF1
      related PN and optic pathway gliomas

      This study will comprise 2 phases. Phase 1 will be a dose escalation phase, designed to
      establish the correct dose of selumetinib. Phase 1 will be open to NF-1 participants, aged 3
      to ≤18 years with inoperable plexiform neurofibromas (PN). This phase of the study will
      investigate a new intermittent schedule of oral administration of selumetinib, (given twice
      daily on 5 out of every 7 days) to determine the maximum tolerated dose (MTD) and a
      recommended phase 2 dose. The starting dose level will be 25mg/m2/dose given twice daily.
      This was the MTD determined by the Paediatric Brain Tumour Consortium study of Selumetinib in
      children with NF1 related LGG and the National Cancer Institute study of children with NF1
      inoperable PN. In both of these trials selumetinib was given twice daily, every day. The
      purpose of this phase 1 study will allow the investigators to define the acute and chronic
      toxicities and pharmacokinetics (PK) of Selumetinib in this population and contribute to
      determining the effect of Selumetinib on the growth rate of PN.

      The Phase 2 part of the study will be a dose expansion study and will be open to 2 groups of
      participants. Those with progressive NF-1 related optic pathway gliomas (OPG), and those with
      NF1 related inoperable PN. This part of the study will only commence when the recommended
      phase 2 dose is established from part 1. The purpose of this part of the study is to
      determine the effectiveness of the 5 out of 7 day intermittent dosing schedule of
      Selumetinib, using response rates (and duration of response), appropriate MRI criteria and
      functional assessments (REINs criteria). The investigators plan to further evaluate the acute
      and chronic toxicities of selumetinib in this population and to assess the clinical status
      and quality of life in this population.
    

Trial Arms

NameTypeDescriptionInterventions
Selumetinib Intermittent DosingExperimentalPhase 1 of the study to evaluate Intermittent Dosing (Selumetinib given twice daily on 5 out of 7 days) in children with NF1 and inoperable plexiform neurofibromas. The Maximum tolerated dose will define the Recommended phase 2 dose of selumetinib.
  • Selumetinib

Eligibility Criteria

        Inclusion Criteria:

          1. Age Phase I: ≥3 years and ≤18 years of age at the time of study enrolment, if able to
             swallow whole capsules.

             Age Phase II: ≥3 years and ≤ 18 years. BSA ≥ 0.55 m2, if able to swallow whole
             capsules.

          2. Diagnosis: Phase I (Dose escalation): Patients with NF1 and inoperable PNs defined as
             PNs that cannot be surgically completely removed without risk for substantial
             morbidity due to: encasement of or close proximity to vital structures, invasiveness,
             or high vascularity of the PN. The PN has to cause morbidity or have the potential to
             cause significant morbidity, such as (but not limited to) head and neck lesions that
             could compromise the airway or great vessels, brachial or lumbar plexus lesions that
             could cause nerve compression and loss of function, lesions that could result in major
             deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the
             extremity that cause limb hypertrophy or loss of function, and painful lesions.

             Histological confirmation of tumour is not necessary in the presence of consistent
             clinical and radiographic findings, but should be considered if malignant degeneration
             of a PN is clinically suspected.

             Phase 2 (Dose expansion): Two cohorts are eligible for inclusion in the dose expansion
             cohort.

             Cohort A (10 subjects) Subjects with NF1 and inoperable PNs (as per Phase I) and
             Cohort B (10 subjects) Subjects with NF-1 related progressive optic pathway glioma are
             eligible if the subject has evidence of either clinical (e.g. worsening visual
             function as per REiNS) or MRI based significant radiological progression and has had
             at least two lines of standard therapy.

             In addition, all study subjects (phase I and II) must have either positive genetic
             testing for NF1 from a certified laboratory or have at least one other diagnostic
             criterion for NF1 listed below:

               -  Six or more café-au-lait macules (≥0.5cm in prepubertal subjects or ≥1.5 cm in
                  post pubertal subjects)

               -  Freckling in axilla or groin

               -  Optic glioma

               -  Two or more Lisch nodules

               -  A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
                  thinning of long bone cortex)

               -  A first-degree relative with NF1

          3. Measurable disease (PN): Subjects must have at least one measurable PN, defined as a
             lesion of at least 3 cm measured in one dimension. Subjects who underwent surgery for
             resection of a PN are eligible provided the PN was incompletely resected and is
             measurable. Measurable disease (OPG): Subjects must have one measurable OPG lesions
             according to RANO 1.1 i.e. Tumour ≥10 x10mm in maximal perpendicular dimensions on an
             axial image on MRI with ≤5 mm reconstruction interval.

          4. Prior Therapy: Subjects with NF1 will only be eligible if complete tumour resection is
             not considered to be feasible without substantial risk or morbidity, or if a patient
             with a surgical option refuses surgery.

               -  Since there is no standard effective chemotherapy for patients with NF1 and PN,
                  subjects may be treated on this trial without having received prior medical
                  therapy directed at their PN. For Phase 2 Cohort B in subjects with NF-1 related
                  OPGs at least two prior standard therapies need to have been received.

               -  Subjects who have received previous investigational agents or biologic therapy
                  except a prior MEK inhibitor are eligible for enrollment. At least 4 weeks must
                  have elapsed since receiving medical therapy directed at the PN. Patients who
                  received prior medical therapy for their PN must have recovered from the acute
                  toxic effects of all prior therapy to ≤ grade 1 CTCAEv4 before entering this
                  study.

               -  Growth factors that support platelet or white cell number or function must not
                  have been administered within the past 7 days.

               -  At least 6 weeks must have elapsed prior to enrollment since the patient received
                  any prior radiation therapy.

          5. Performance status: Patients ≥ 16 years of age must have a Karnofsky performance level
             of ≥70%, and children < 16 years old must have a Lansky performance of ≥70% (Error!
             Reference source not found.). Patients who are wheelchair bound because of paralysis
             secondary to a plexiform neurofibroma should be considered ambulatory when they are up
             in their wheelchair. Similarly, patients with limited mobility secondary to need for
             mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be
             considered ambulatory for the purpose of the study.

          6. Haematological Function: Patients must have an absolute neutrophil count ≥1500/µl,
             haemoglobin ≥9g/dl, and platelet ≥100,000/µl.

          7. Hepatic Function: Patients must have bilirubin within 1.5 x the upper limit of normal
             for age, with the exception of those with Gilbert syndrome, and AST/ALT within ≤ 2.5 x
             upper limit of normal.

          8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR
             ≥60ml/min/1.73 m2 or a normal serum creatinine based on age described in the table
             below.

             Age (years) Maximum Serum Creatinine (mg/dL) age ≤5: 0.8 5<age≤10: 1.0 10<age≤15: 1.2
             age>15: 1.5

          9. Cardiac Function: Normal ejection fraction (ECHO) ≥ 55%, or institutional normal value
             (if a range is given then the upper value of the range will be used); QTcF ≤450 msec.

         10. Adequate Blood Pressure defined as:

             A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequate
             blood pressure can be achieved using medications for treatment of hypertension.

         11. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine
             eligibility for this trial must only be done after obtaining written informed consent
             from all patients or their legal guardians (if the patient is <16 years old). When
             appropriate, paediatric patients will be included in all discussions and appropriate
             assent taken.

         12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
             sun exposure is anticipated.

         13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other
             products containing these fruits, e.g. grapefruit juice or marmalade) during the
             study.

        Exclusion Criteria:

          1. Pregnant or breast-feeding females are excluded due to potential risks of foetal and
             teratogenic adverse events of an investigational agent. Pregnancy tests must be
             obtained prior to enrolment on this study for girls of reproductive potential. The
             need to commence pregnancy testing will be at the discretion of the treating physician
             to facilitate taking in to account factors such as precocious puberty, endocrine
             status and medications which can affect pubertal status. Males or females of
             reproductive potential may not participate unless they have agreed to use an effective
             contraceptive method. Abstinence is an acceptable method of birth control.

          2. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or
             history of allergic reactions attributed to compounds of similar chemical or biologic
             composition to selumetinib.

          3. Recent major surgery within a minimum of 4 weeks prior to starting study treatment,
             with the exception of surgical placement for vascular access.

          4. Phase I: Patients who anticipate the need for surgical intervention within the first
             three cycles (3 months), as surgical intervention during the period of DLT evaluation
             may affect analysis of adherence and/or make the subject in-evaluable.

             Phase II: Patients who anticipate the need for surgical intervention of the target PN
             within the first eight cycles (8 months), as surgical intervention during the period
             may affect analysis of response and may make the subject in-evaluable.

          5. An investigational agent within the past 28 days.

          6. Any unresolved chronic toxicity with toxicity ≥ CTCAE Grade 2 from previous
             anti-cancer therapy, except for alopecia.

          7. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumour,
             immunotherapy, or biological therapy.

          8. Any evidence of severe or uncontrolled systemic disease, active infection, active
             bleeding diatheses or renal transplant, including any patient known to have hepatitis
             B, hepatitis C or human immunodeficiency virus (HIV)

          9. Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study.

         10. Inability to swallow capsules, since capsules cannot be crushed or broken.

         11. Inability to undergo MRI and/or contraindication for MRI examinations following the
             MRI protocol. Prosthesis or orthopaedic or dental braces that would interfere with
             volumetric analysis of target PN on MRI.

         12. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
             bowel disease), or significant bowel resection that would preclude adequate
             absorption.

         13. Prior treatment with selumetinib or another specific MEK1/2 inhibitor.

         14. Evidence of an optic glioma (progressive OPG allowed in Phase 2), malignant glioma,
             malignant peripheral nerve sheath tumour, or other cancer requiring treatment with
             chemotherapy or radiation therapy.

         15. Patients should not take any supplementation with Vitamin E.

         16. Patients not achieving adequate blood pressure in spite of antihypertensive therapy
             for control of blood pressure.

         17. Cardiac Function:

               1. Known inherited coronary disease

               2. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or
                  severe valvular heart disease)

               3. Prior or current cardiomyopathy

               4. Severe valvular heart disease

               5. History of atrial fibrillation

         18. Ophthalmologic conditions:

               1. Current or past history of central serous retinopathy

               2. Current or past history of retinal vein occlusion

               1. Patients with controlled known glaucoma and increased IOP who do not have
                  meaningful vision (light perception only or no light perception) and are not
                  experiencing pain related to the glaucoma, may be eligible after discussion with
                  the PI.

               2. Subjects with any other significant abnormality on ophthalmic examination
                  (performed by an ophthalmologist) should be discussed with the PI for potential
                  eligibility

               3. Ophthalmological findings secondary to optic pathway glioma (such as visual loss,
                  optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as
                  visual loss, strabismus) will NOT be considered a significant abnormality for the
                  purposes of the study

         19. Clinical judgement by the investigator that the patient should not participate in the
             study.

         20. While not an exclusion criterion, unless considered clinically indicated, patients
             should avoid taking other additional non-study medications that may interfere with the
             study medication. In particular, patients should avoid medications that are known to
             either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19
             and CYP3A4, as this may interfere with the metabolism of selumetinib.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: To evaluate the Maximum Tolerated Dose
Time Frame:6 months
Safety Issue:
Description:Phase 1: Definition of the maximum tolerated dose using number of participants with treatment related adverse events as assessed by CTCAEv4.0

Secondary Outcome Measures

Measure:Cardiac Function - fractional shortening
Time Frame:5 years
Safety Issue:
Description:Number of patients with changes in changes from baseline in ejection fraction as assessed by echocardiogram.
Measure:Cardiac Function - QTc
Time Frame:5 years
Safety Issue:
Description:Number of patients with changes from baseline in QTc as assessed by electrocardiogram.
Measure:Retinal detachment.
Time Frame:5 years
Safety Issue:
Description:Number of participants with evidence of treatment related retinal detachment as per CTCAE v4.
Measure:Treatment related Adverse Events
Time Frame:5 years
Safety Issue:
Description:Number of participants with Treatment- Related Adverse events as assessed by CTCAEv4.0.
Measure:Pharmacokinetics of selumetinib. Phase 1 only
Time Frame:6 months
Safety Issue:
Description:Calulation of Area Under the Curve (AUC) tests to test exposure to the drug over time. AUC will be calculated at Day 1 and at steady state (Day 27/28)
Measure:Pharmacokinetics of selumetinib. Phase 1 only
Time Frame:6 months
Safety Issue:
Description:Calculation of Time to reach peak concentration (Tmax) at day 1 and at steady state (Day 27/28)
Measure:Pharmacokinetics of selumetinib. Phase 1 only
Time Frame:6 months
Safety Issue:
Description:Calculation of Peak concentration (Cmax) at day 1 and at steady state (Day 27/28)
Measure:Pharmacokinetics of selumetinib. Phase 1 only
Time Frame:6 months
Safety Issue:
Description:Calculation of clearance of the drug from the blood after oral administration (CL/F) on day 1 and at steady state (D27/28)
Measure:Time to progression - plexiform neurofibromas
Time Frame:5 years
Safety Issue:
Description:Definition of time to progression of plexiform neurofibromas as assessed by volumetric measurement.
Measure:Time to progression - optic pathway gliomas
Time Frame:5 years
Safety Issue:
Description:Definition of time to progression as defined by changes from baseline using 2 dimensional assessment of tumour size
Measure:Pain Evaluation - self reported changes
Time Frame:3 years
Safety Issue:
Description:Number of participants with a change from baseline as assessed by Numerical Scale Rating
Measure:Pain Evaluation- Medication
Time Frame:3 years
Safety Issue:
Description:Number of participants with a change from baseline in pain medication as assessed by the pain medication survey.
Measure:Evaluation of effect on disfigurement
Time Frame:3 years
Safety Issue:
Description:Photography evaluation (imaging including standardised imaging and 3D photography where available) to provide measurement (metric system eg cm) of change from baseline in size of deformity caused by plexiform neurofibroma.
Measure:Quality of Life Evaluation
Time Frame:3 years
Safety Issue:
Description:Number of participants with a change from baseline in quality of life using the PedsQL assessment.
Measure:Evaluation of Visual Function in NF1 related optic pathway glioma
Time Frame:3 years
Safety Issue:
Description:To determine the effect of selumetinib on visual function in subjects with NF1 related optic pathway glioma using the visual function assessments outlined by the Response Evaluation in Neurofibromatosis and Schwanomatosis (REiNS) criteria
Measure:Physical functioning endurance
Time Frame:3 years
Safety Issue:
Description:Number of participants with a change in physical function as assessed using the 6 minute walk-run test.
Measure:Evaluation of clinically stable NF1 related optic pathway glioma
Time Frame:5 years.
Safety Issue:
Description:To determine the effect of selumetinib on stable NF1 related optic pathway gliomas and other gliomas for subjects whose primary indication for treatment is a progressive plexiform neurofibroma using evaluation of CNS MRI imaging
Measure:Functional Outcome of patients with Plexiform Neurofibromas affecting the airway - PFT
Time Frame:3 years
Safety Issue:
Description:Number of participants who have a change from baseline in their pulmonary function as assessed by pulmonary function testing.
Measure:Functional outcome of participants with plexiform neurofibromas affecting the airway - sleep studies
Time Frame:3 years
Safety Issue:
Description:Number of participants who have a change from baseline, in their airway function as assessed by sleep studies.
Measure:Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength - grooved pegboard test
Time Frame:3 years
Safety Issue:
Description:Number of participants who have a change from baseline in their muscle strength using grooved pegboard test.
Measure:Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength.- MRC grading of strength
Time Frame:3 years
Safety Issue:
Description:Number of participants who have a change from baseline in their muscle strength using medical research council (MRC) grading system.
Measure:Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength.
Time Frame:3 years
Safety Issue:
Description:Number of participants who have a change from baseline in their muscle strength using leg length evaluation.
Measure:Functional Outcome of patients with plexiform neurofibromas which affect mobility.
Time Frame:3 years
Safety Issue:
Description:number of participants who have a change from baseline in the patient reported outcome score (numerical scale rating) of mobility. PROMIS forms will be used.
Measure:Functional Outcome of patients with plexiform neurofibromas which affect bladder and bowel function.
Time Frame:3 years
Safety Issue:
Description:Measurement of bladder and bowel function using patient reported outcomes (tick box questionnaire) covering urgency, frequency, dysuria, constipation and incontinence

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Great Ormond Street Hospital for Children NHS Foundation Trust

Last Updated

November 1, 2017