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.
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.
