| Eligibility |
PART 1:
Inclusion Criteria:
1. Age: > 1 (>12 months) and =8 years of age at the time of study enrollment.
2. Diagnosis: Participants with a diagnosis of NF1 based on the 2021 revised consensus
criteria [52] and
3. No known PN (prior to enrollment on Part 1). Participants for whom there is clinical
suspicion for a PN (e.g., subtle facial asymmetry or large overlying hyperpigmented
area) may be included in the study after discussion with the Study Chair so long as
they have not previously had an MRI of the region of concern and are otherwise
asymptomatic.
4. Physical exam at your institution within 1 year prior to consent.
5. Written informed consent must be obtained from the legal guardians of all participants
<18 years of age.
Exclusion Criteria:
1. Presence of a known, symptomatic PN with or without previous MRI imaging.
2. Patients who have had previous whole-body MRI (WBMRI) are excluded from the study.
However, patients who have had regional MRI(s) for an indication other than a PN and
did not have a PN identified on previous MRI may still be eligible for the study.
3. Inability to undergo MRI and/or contraindication for MRI examinations following the
MRI protocol.
4. Prior treatment with selumetinib or another specific MEK1/2 inhibitor.
5. Evidence of an optic pathway or other low-grade glioma, high grade glioma, malignant
peripheral nerve sheath tumor, or other cancer/tumor requiring treatment with
chemotherapy, biologic therapy or radiation therapy.
6. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at a tumor,
immunotherapy, or biologic therapy.
7. Clinical judgement by the investigator that the patient should not participate in the
study.
PART 2:
Inclusion Criteria:
1. Enrolled on Part 1 of this study and completed baseline WBMRI within 6 weeks of
planned enrollment on Part 2.
2. A measurable (=3 mL) PN in a high-risk location as defined below (this must be
confirmed by Study Chair or a member of the Study Committee prior to enrollment on
Part 2).
- In the head or neck (with the exception of isolated scalp lesions) OR
- Within the brachial or lumbosacral plexus OR
- Adjacent to high-risk structure(s), defined as:
1. Major ("named") blood vessel OR
2. Major ("named") airway OR
3. Hollow viscus OR
4. Spinal cord and foramina OR
5. Vital Organs (including heart, lungs, liver, spleen, etc.)
3. Body Surface Area (BSA): BSA = 0.55 m2 [pending availability of granule formulation].
4. Performance status: Lansky performance =70%. Participants who are wheelchair bound
because of paralysis or immobility secondary to a non-PN related manifestation of NF1
(such as tibial pseudarthrosis or severe scoliosis) should be considered ambulatory
when they are in their wheelchair.
5. Able to swallow whole capsules [Pending availability of granule formulation].
6. Hematologic Function: Absolute neutrophil count =1200/µL, hemoglobin =9g/dL, and
platelets =100,000/µL (without transfusions).
7. Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with the
exception of those with Gilbert syndrome, and AST/ALT within = 3 x upper limit of
normal.
8. Renal Function: 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)
=5 0.8 >5 to =10 1.0 >10 to =15 1.2 >15 1.5
9. Cardiac Function:
1. Normal ejection fraction (ECHO or cardiac MRI) = 53% (or the institutional
normal; if a range is given then the upper value of the range will be used).
2. EKG with QTC or 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 medication for treatment of hypertension.
Participants must be on stable antihypertensive regimen for at least 30 days prior to
study entry.
11. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated.
12. 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, as these may affect selumetinib metabolism.
Exclusion Criteria:
1. Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignant
peripheral nerve sheath tumor, or other cancer/tumor requiring treatment with
chemotherapy, biologic therapy or radiation therapy.
2. Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or biologic
therapy directed at a tumor.
3. Prosthesis, orthopedic implant, or dental braces that would interfere with volumetric
analysis of target PN on MRI.
4. Use of an investigational agent within the past 30 days.
5. 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) will be excluded.
6. Participants who, in the opinion of the investigator, may not be able to comply with
the safety monitoring requirements of the study.
7. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.
8. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to initiation of therapy.
9. Participants not achieving adequate blood pressure despite antihypertensive therapy
for control of blood pressure.
10. Cardiac conditions:
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
11. Ophthalmologic conditions:
1. Current or past history of central serous retinopathy or retinal pigment
epithelial detachment (RPED).
2. Current or past history of retinal vein occlusion.
3. History of radiation therapy that included the orbit in the field of treatment.
4. Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP). Participants with 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 Study Chair.
5. Participants with any other significant abnormality on ophthalmic examination
should be discussed with the Study Chair for potential eligibility.
6. Ophthalmological findings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor or strabismus) will NOT be considered a
significant abnormality for the purposes of the study.
12. 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.
13. Recent major surgery within a minimum of 4 weeks prior to starting study treatment.
14. Any unresolved chronic toxicity with CTCAE grade = 2 from previous therapy, except for
alopecia.
15. Receiving herbal supplements or medications known to be strong or moderate inhibitors
or inducers of the cytochrome P450 (CYP)2C19 and CYP3A4 enzymes or fluconazole unless
such products can be safely discontinued at least 14 days or 5 half-lives (whichever
is longer) before the first dose of study medication.
PART 3:
Inclusion Criteria:
1. Enrolled on Part 2 of this study and had PN growth >20% OR development of PN related
symptom(s) while on observation portion of Part 2 (including the first 2 years for the
observation arm OR during first year of observation after treatment with selumetinib).
2. Body Surface Area (BSA): BSA = 0.55 m2 [pending availability of granule formulation].
3. Performance status: Lansky performance =70%. Participants who are wheelchair bound
because of paralysis or immobility secondary to a non-PN related manifestation of NF1
(such as tibial pseudarthrosis or severe scoliosis) should be considered ambulatory
when they are in their wheelchair.
4. Able to swallow whole capsules [Pending availability of granule formulation].
5. Hematologic Function: Absolute neutrophil count =1200/µL, hemoglobin =9g/dL, and
platelets =100,000/µL (without transfusions).
6. Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with the
exception of those with Gilbert syndrome, and AST/ALT within = 3 x upper limit of
normal.
7. Renal Function: 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)
=5 0.8 >5 to =10 1.0 >10 to =15 1.2 >15 1.5
8. Cardiac Function:
1. Normal ejection fraction (ECHO or cardiac MRI) = 53% (or the institutional
normal; if a range is given then the upper value of the range will be used).
2. EKG with QTC or QTcF =450 msec.
9. Adequate Blood Pressure defined as:
A blood pressure (BP) = the 95th percentile for age, height, and gender. Adequate
blood pressure can be achieved using medication for treatment of hypertension.
Participants must be on stable antihypertensive regimen for at least 30 days prior to
study entry.
10. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated.
11. 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, as these may affect selumetinib metabolism.
Exclusion Criteria:
1. Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignant
peripheral nerve sheath tumor, or other cancer/tumor requiring treatment with
chemotherapy, biologic therapy or radiation therapy.
2. Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or biologic
therapy directed at a tumor.
3. Prosthesis, orthopedic implant, or dental braces that would interfere with volumetric
analysis of target PN on MRI.
4. 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) will be excluded.
5. Participants who, in the opinion of the investigator, may not be able to comply with
the safety monitoring requirements of the study.
6. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.
7. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to initiation of therapy.
8. Participants not achieving adequate blood pressure despite antihypertensive therapy
for control of blood pressure.
9. Cardiac conditions:
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
10. Ophthalmologic conditions:
1. Current or past history of central serous retinopathy or retinal pigment
epithelial detachment (RPED).
2. Current or past history of retinal vein occlusion.
3. History of radiation therapy that included the orbit in the field of treatment.
4. Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP). Participants with 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 study chair.
5. Participants with any other significant abnormality on ophthalmic examination
should be discussed with the Study Chair for potential eligibility.
6. Ophthalmological findings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor or strabismus) will NOT be considered a
significant abnormality for the purposes of the study.
11. 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.
12. Recent major surgery within a minimum of 4 weeks prior to starting study treatment.
13. Any unresolved chronic toxicity with CTC AE grade = 2 from previous therapy, except
for alopecia.
14. Receiving herbal supplements or medications known to be strong or moderate inhibitors
or inducers of the cytochrome P450 (CYP)2C19 and CYP3A4 enzymes or fluconazole unless
such products can be safely discontinued at least 14 days or 5 half-lives (whichever
is longer) before the first dose of study medication.
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