Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

• Register: ClinicalTrials.gov
• Last refreshed on: 15 April 2024
• Main ID: NCT03326388
• Date of registration: 08/09/2017
• Prospective Registration: Yes
• Primary sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Public title: Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours INSPECT
• Scientific 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
• Date of first enrolment: September 26, 2019
• Target sample size: 14
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/ct2/show/NCT03326388
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United Kingdom

Contacts

• Name: Darren Hargrave, MB Bch
• Affiliation: Great Ormond Street Hospital NHS Foundation Trust

Key inclusion & exclusion 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>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
ob


Age minimum: 3 Years
Age maximum: 18 Years
Gender: All

Health Condition(s) or Problem(s) studied

Neurofibromatosis Type 1

Plexiform Neurofibroma

Optic Nerve Glioma

Intervention(s)

Drug: Selumetinib

Primary Outcome(s)

Phase 2: Objective response rate in NF1 inoperable plexiform neurofibroma and optic pathway glioma [Time Frame: 2 years]

Best Objective response rate in NF1 related optic pathway gliomas [Time Frame: 2 years]

Phase 1: To evaluate the Maximum Tolerated Dose [Time Frame: 6 months]

Secondary Outcome(s)

Time to progression - plexiform neurofibromas [Time Frame: 5 years]

Functional Outcome of patients with Plexiform Neurofibromas affecting the airway - PFT [Time Frame: 3 years]

Functional outcome of participants with plexiform neurofibromas affecting the airway - sleep studies [Time Frame: 3 years]

Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength - grooved pegboard test [Time Frame: 3 years]

Evaluation of effect on disfigurement [Time Frame: 3 years]

Functional Outcome of patients with plexiform neurofibromas which affect mobility. [Time Frame: 3 years]

Pain Evaluation - self reported changes [Time Frame: 3 years]

Retinal detachment. [Time Frame: 5 years]

Treatment related Adverse Events [Time Frame: 5 years]

Functional Outcome of patients with plexiform neurofibromas which affect bladder and bowel function. [Time Frame: 3 years]

Pharmacokinetics of selumetinib. Phase 1 only [Time Frame: 6 months]

Time to progression - optic pathway gliomas [Time Frame: 5 years]

Evaluation of clinically stable NF1 related optic pathway glioma [Time Frame: 5 years.]

Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength.- MRC grading of strength [Time Frame: 3 years]

Cardiac Function - fractional shortening [Time Frame: 5 years]

Evaluation of Visual Function in NF1 related optic pathway glioma [Time Frame: 3 years]

Functional Outcome of patients with Plexiform Neurofibromas affecting motor strength. [Time Frame: 3 years]

Pain Evaluation- Medication [Time Frame: 3 years]

Physical functioning endurance [Time Frame: 3 years]

Cardiac Function - QTc [Time Frame: 5 years]

Quality of Life Evaluation [Time Frame: 3 years]

Secondary ID(s)

15Hi53

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

AstraZeneca