This study is currently recruiting participants.
Neurofibromatosis 1 (NF1) is a disease that causes deformities in tissues and bones. Many children with NF1 also develop plexiform neurofibromas (PN). These are benign tumors that grow along nerves. The tumors can cause problems if they limit range of motion, lead to blindness, or block airways, for example. A drug called selumetinib can shrink PN, but effects such as blindness may not be reversible.
To find out if selumetinib can stop problems from developing in children with PN.
Children aged 1 to 8 years with NF1 but no known PN.
Part 1: Participants will have 1 clinic visit that includes a blood test and an imaging scan: They will lie on a table that slides into a large tube. The scan will look for PN that have not yet caused problems.
Part 2: Participants who are found to have PN may continue in the study. Selumetinib is a capsule taken by mouth twice a day, every day. Half of participants will take the drug for 1 year; half will not. All participants will have up to 17 clinic visits in 3 years. They will have imaging scans; some may also have other tests.
Part 3: Participants whose PN responded to the study drug may continue in the study. The goal is to see if the PN continues to respond on a lower dose of the drug. Participants will take selumetinib twice daily for 1 year. Then they will take the drug for 5 days on, 2 days off. They will have 14 study visits in 2 years.
All clinical and laboratory data for determining eligibility of a participant enrolled on this trial must be available in the participant s medical or research record which will serve as the source document for verification at the time of audit/monitoring.
Patient Eligibility for Part 1:
INCLUSION CRITERIA for Part 1:
An individual who meets all the following criteria will be considered eligible to participate in Part 1 of this study:
- Age: > 1 (>12 months) and <=8 years of age at the time of study enrollment.
- Diagnosis: Patients with a diagnosis of NF1 based on the 2021 revised consensus criteria [52] and
- No known PN (prior to enrollment on Part 1). Patients 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 otherwiseasymptomatic.
- Physical exam at your institution within 1 year prior to consent.
- Written informed consent must be obtained from the legal guardians of all participants <18 years of age.
EXCLUSION CRITERIA for Part 1:
An individual who meets any of the following criteria will be excluded from participation in Part 1 of this study:
- Presence of a known, symptomatic PN with or without previous MRI imaging.
- 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.
- Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol.
- Prior treatment with selumetinib or another specific MEK1/2 inhibitor.
- 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.
- Ongoing radiation therapy, chemotherapy, hormonal therapy directed at a tumor, immunotherapy, or biologic therapy.
- Clinical judgement by the investigator that the patient should not participate in the study.
Patient Eligibility for Part 2:
Participants who enroll on Part 1 and are found to have a PN in a high-risk location will be eligible to screen and enroll on Part 2. Participants that wish to proceed with Part 2 must enroll in the screening portion within 6 weeks of the baseline WBMRI obtained on Part 1.
For Part 2, a baseline regional MRI of the target PN must be performed, unless the Study Chair or study committee member confirms that whole body MRI is adequate for target tumor volumetric assessment. The baseline MRI of target PN, ophthalmology evaluation, echocardiogram, and EKG are required within 4 weeks prior to beginning treatment with selumetinib. All laboratory studies to determine eligibility must be performed within 2 weeks prior to start of treatment (unless otherwise specified in the Schedule of Activities). All clinical and laboratory data required for determining eligibility of a participant enrolled on this trial must be available in the participant's medical or research record, which will serve as the source document for verification at the time of audit/monitoring. Participants who enroll on part 2 must be randomized to either treatment or observation within 12 weeks of baseline WBMRI obtained on Part 1.
INCLUSION CRITERIA for Part 2:
- Enrolled on Part 1 of this study and completed baseline WBMRI within 6 weeks of planned enrollment on Part 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:
--- Major ( named ) blood vessel OR
--- Major ( named ) airway OR
--- Hollow viscus OR
--- Spinal cord and foramina OR
--- Vital Organs (including heart, lungs, liver, spleen, etc.)
- Body Surface Area (BSA): BSA >= 0.55 m^2 [pending availability of granule formulation].
- Performance status: Lansky performance >= percent. 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.
- Able to swallow whole capsules [Pending availability of granule formulation].
- Hematologic Function: Absolute neutrophil count >=1200/microL, hemoglobin >=9g/dL, and platelets >=100,000/microL (without transfusions).
- 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.
- Renal Function: Creatinine clearance or radioisotope GFR >=60ml/min/1.73 m^2 or a normal serum creatinine based on age, described below.
--Age (years) <=5, 0.8 Serum Creatinine (mg/dL)
--Age (years) >5 to <=10,1.0 Serum Creatinine (mg/dL)
--Age (years) >10 to <=15, 1.2 Serum Creatinine (mg/dL)
--Age (years) >15, 1.5 Serum Creatinine (mg/dL)
-Cardiac Function:
-- Normal ejection fraction (ECHO or cardiac MRI) >= 53 percent (or the institutional normal; if a range is given then the upper value of the range will be used).
-- EKG with QTc or QTc F <=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 medication for treatment of hypertension. Participants must be on stable antihypertensive regimen for at least 30 days prior to study entry.
- 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, as these may affect selumetinib metabolism
.
EXCLUSION CRITERIA for Part 2:
An individual who meets any of the following criteria will be excluded from participation in Part 2 of this study:
-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.
-Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or biologic therapy directed at a tumor.
- Prosthesis, orthopedic implant, or dental braces that would interfere with volumetric analysis of target PN on MRI.
- Use of an investigational agent within the past 30 days.
- Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any participant known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded.
- Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
- Supplementation with vitamin E greater than 100 percent of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy.
- Participants not achieving adequate blood pressure despite antihypertensive therapy for control of blood pressure.
- Cardiac conditions:
-- Known inherited coronary disease
-- Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy,
--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 or retinal pigment epithelial detachment (RPED).
-- Current or past history of retinal vein occlusion.
-- History of radiation therapy that included the orbit in the field of treatment.
-- 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.
-- Participants with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility.
-- 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.
- 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.
- Any unresolved chronic toxicity with CTCAE grade >= 2 from previous therapy, except for alopecia.
- 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.
Patient Eligibility for Part 3
INCLUSION CRITERIA for Part 3:
-Enrolled on Part 2 of this study and had PN growth >20 percent 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).
-Body Surface Area (BSA): BSA >= 0.55 m^2 [pending availability of granule formulation].
-Performance status: Lansky performance >=70 percent. 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.
- Able to swallow whole capsules [Pending availability of granule formulation].
- Hematologic Function: Absolute neutrophil count >=1200/microL, hemoglobin >=9g/dL, and platelets >=100,000/microL (without transfusions).
-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.
- Renal Function: Creatinine clearance or radioisotope GFR >=60mL/min/1.73 m^2 or a normal serum creatinine based on age, described below.
--Age (years) <=5, 0.8 Serum Creatinine (mg/dL)
--Age (years) >5 to <=10, 1.0 Serum Creatinine (mg/dL)
--Age (years) >10 to <=15, 1.2 Serum Creatinine (mg/dL)
--Age (years) >15, 1.5 Serum Creatinine (mg/dL)
-Cardiac Function:
-- Normal ejection fraction (ECHO or cardiac MRI) >= 53 percent (or the institutional normal; if a range is given then the upper value of the range will be used).
-- EKG with QTC or 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 medication for treatment of hypertension. Participants must be on stable antihypertensive regimen for at least 30 days prior to study entry.
- 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, as these may affect selumetinib metabolism.
EXCLUSION CRITERIA for Part 3:
An individual who meets any of the following criteria will be excluded from participation in Part 3 of this study:
- 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.
- Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or biologic therapy directed at a tumor.
- Prosthesis, orthopedic implant, or dental braces that would interfere with volumetric analysis of target PN on MRI.
- Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any participant known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded.
- Participants who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
- Supplementation with vitamin E greater than 100 percent of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy.
- Participants not achieving adequate blood pressure despite antihypertensive therapy for control of blood pressure.
- Cardiac conditions:
-- 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 or retinal pigment epithelial detachment (RPED).
- Current or past history of retinal vein occlusion.
- History of radiation therapy that included the orbit in the field of treatment.
- 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.
- Participants with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility.
- 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.
- 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.
- Any unresolved chronic toxicity with CTC AE grade (Bullet) 2 from previous therapy, except for alopecia.
- 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.