Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

  • End date
    Dec 18, 2023
  • participants needed
  • sponsor
    Great Ormond Street Hospital for Children NHS Foundation Trust
Updated on 18 June 2021
renal function
absolute neutrophil count
ejection fraction
measurable disease
tumor resection
neutrophil count
gilbert disease
plexiform neurofibroma


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.


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.

Condition Optic Nerve Glioma, Neurofibromatosis, Plexiform Neurofibroma, von Recklinghausen's Disease, Glioma, Peripheral Neuropathy, Gliomas, optic gliomas
Treatment Selumetinib
Clinical Study IdentifierNCT03326388
SponsorGreat Ormond Street Hospital for Children NHS Foundation Trust
Last Modified on18 June 2021


Yes No Not Sure

Inclusion Criteria

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
\. 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
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 caf-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/l, haemoglobin 9g/dl, and platelet 100,000/l. 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<age10: 1.0 10<age15
2 age>15: 1.5
\. 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
\. 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
\. 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
\. Willingness to avoid excessive sun exposure and use adequate sunscreen
protection if sun exposure is anticipated
\. 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

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
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
Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access
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-
\. An investigational agent within the past 28 days
\. Any unresolved chronic toxicity with toxicity CTCAE Grade 2 from previous
anti-cancer therapy, except for alopecia
\. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the
tumour, immunotherapy, or biological therapy
\. 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)
\. Patients who in the opinion of the investigator may not be able to comply
with the safety monitoring requirements of the study
\. Inability to swallow capsules, since capsules cannot be crushed or
\. 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
\. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g
inflammatory bowel disease), or significant bowel resection that would
preclude adequate absorption
\. Prior treatment with selumetinib or another specific MEK1/2 inhibitor
\. 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
\. Patients should not take any supplementation with Vitamin E
\. Patients not achieving adequate blood pressure in spite of
antihypertensive therapy for control of blood pressure
\. Cardiac Function
Known inherited coronary disease
Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease)
Prior or current cardiomyopathy
Severe valvular heart disease
History of atrial fibrillation
Ophthalmologic conditions
Current or past history of central serous retinopathy
Current or past history of retinal vein occlusion
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
Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the PI for potential eligibility
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
Clinical judgement by the investigator that the patient should not participate in the study
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
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