Selumetinib for the Prevention of Plexiform Neurofibroma Growth in NF Type 1

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 consensuscriteria [52] and

3. No known PN (prior to enrollment on Part 1). Participants for whom there is clinicalsuspicion for a PN (e.g., subtle facial asymmetry or large overlying hyperpigmentedarea) may be included in the study after discussion with the Study Chair so long asthey have not previously had an MRI of the region of concern and are otherwiseasymptomatic.

4. Physical exam at your institution within 1 year prior to consent.

5. Written informed consent must be obtained from the legal guardians of allparticipants <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 anddid 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 theMRI 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, malignantperipheral nerve sheath tumor, or other cancer/tumor requiring treatment withchemotherapy, 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 inthe study.

PART 2:

Inclusion Criteria:

1. Enrolled on Part 1 of this study and completed baseline WBMRI within 6 weeks ofplanned enrollment on Part 2.

2. A measurable (≥3 mL) PN in a high-risk location as defined below (this must beconfirmed by Study Chair or a member of the Study Committee prior to enrollment onPart 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.)

6. Body Surface Area (BSA): BSA ≥ 0.55 m2 [pending availability of granuleformulation].

7. Performance status: Lansky performance ≥70%. Participants who are wheelchair boundbecause of paralysis or immobility secondary to a non-PN related manifestation ofNF1 (such as tibial pseudarthrosis or severe scoliosis) should be consideredambulatory when they are in their wheelchair.

8. Able to swallow whole capsules [Pending availability of granule formulation].

9. Hematologic Function: Absolute neutrophil count ≥1200/µL, hemoglobin ≥9g/dL, andplatelets ≥100,000/µL (without transfusions).

10. Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with theexception of those with Gilbert syndrome, and AST/ALT within ≤ 3 x upper limit ofnormal.

11. Renal Function: Creatinine clearance or radioisotope GFR ≥60ml/min/1.73 m2 or anormal 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:

10. Normal ejection fraction (ECHO or cardiac MRI) ≥ 53% (or the institutionalnormal; if a range is given then the upper value of the range will be used).

11. EKG with QTC or QTcF ≤450 msec.

12. Adequate Blood Pressure defined as: A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequateblood pressure can be achieved using medication for treatment of hypertension.Participants must be on stable antihypertensive regimen for at least 30 days priorto study entry.

13. Willingness to avoid excessive sun exposure and use adequate sunscreen protection ifsun exposure is anticipated.

14. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well asother products containing these fruits, e.g., grapefruit juice or marmalade) duringthe study, as these may affect selumetinib metabolism.

Exclusion Criteria:

1. Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignantperipheral nerve sheath tumor, or other cancer/tumor requiring treatment withchemotherapy, biologic therapy or radiation therapy.

2. Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, orbiologic therapy directed at a tumor.

3. Prosthesis, orthopedic implant, or dental braces that would interfere withvolumetric 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, activebleeding diatheses, or renal transplant, including any patient known to havehepatitis 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 withthe 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 precludeadequate absorption.

8. Supplementation with vitamin E greater than 100% of the daily recommended dose. Anymultivitamin containing vitamin E must be stopped prior to initiation of therapy.

9. Participants not achieving adequate blood pressure despite antihypertensive therapyfor control of blood pressure.

10. Cardiac conditions:

11. Known inherited coronary disease

12. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, orsevere valvular heart disease)

13. Prior or current cardiomyopathy

14. Severe valvular heart disease

15. History of atrial fibrillation

16. Ophthalmologic conditions:

17. Current or past history of central serous retinopathy or retinal pigmentepithelial detachment (RPED).

18. Current or past history of retinal vein occlusion.

19. History of radiation therapy that included the orbit in the field of treatment.

20. Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) oruncontrolled glaucoma (irrespective of IOP). Participants with known glaucomaand increased IOP who do not have meaningful vision (light perception only orno light perception) and are not experiencing pain related to the glaucoma, maybe eligible after discussion with the Study Chair.

21. Participants with any other significant abnormality on ophthalmic examinationshould be discussed with the Study Chair for potential eligibility.

22. Ophthalmological findings secondary to long-standing optic pathway glioma (suchas visual loss, optic nerve pallor or strabismus) will NOT be considered asignificant abnormality for the purposes of the study.

23. Known severe hypersensitivity to selumetinib or any excipient of selumetinib orhistory of allergic reactions attributed to compounds of similar chemical orbiologic composition to selumetinib.

24. Recent major surgery within a minimum of 4 weeks prior to starting study treatment.

25. Any unresolved chronic toxicity with CTCAE grade ≥ 2 from previous therapy, exceptfor alopecia.

26. Receiving herbal supplements or medications known to be strong or moderateinhibitors or inducers of the cytochrome P450 (CYP)2C19 and CYP3A4 enzymes orfluconazole unless such products can be safely discontinued at least 14 days or 5half-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 relatedsymptom(s) while on observation portion of Part 2 (including the first 2 years forthe observation arm OR during first year of observation after treatment withselumetinib).

2. Body Surface Area (BSA): BSA ≥ 0.55 m2 [pending availability of granuleformulation].

3. Performance status: Lansky performance ≥70%. Participants who are wheelchair boundbecause of paralysis or immobility secondary to a non-PN related manifestation ofNF1 (such as tibial pseudarthrosis or severe scoliosis) should be consideredambulatory 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, andplatelets ≥100,000/µL (without transfusions).

6. Hepatic Function: Bilirubin within 1.5 x the upper limit of normal for age, with theexception of those with Gilbert syndrome, and AST/ALT within ≤ 3 x upper limit ofnormal.

7. Renal Function: Creatinine clearance or radioisotope GFR ≥60mL/min/1.73 m2 or anormal 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:

9. Normal ejection fraction (ECHO or cardiac MRI) ≥ 53% (or the institutionalnormal; if a range is given then the upper value of the range will be used).

10. EKG with QTC or QTcF ≤450 msec.

11. Adequate Blood Pressure defined as: A blood pressure (BP) ≤ the 95th percentile for age, height, and gender. Adequateblood pressure can be achieved using medication for treatment of hypertension.Participants must be on stable antihypertensive regimen for at least 30 days priorto study entry.

12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection ifsun exposure is anticipated.

13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well asother products containing these fruits, e.g., grapefruit juice or marmalade) duringthe study, as these may affect selumetinib metabolism.

Exclusion Criteria:

1. Evidence of an optic pathway or other low-grade glioma, high-grade glioma, malignantperipheral nerve sheath tumor, or other cancer/tumor requiring treatment withchemotherapy, biologic therapy or radiation therapy.

2. Ongoing radiation therapy, chemotherapy, hormonal therapy, immunotherapy, orbiologic therapy directed at a tumor.

3. Prosthesis, orthopedic implant, or dental braces that would interfere withvolumetric analysis of target PN on MRI.

4. Any evidence of severe or uncontrolled systemic disease, active infection, activebleeding diatheses, or renal transplant, including any patient known to havehepatitis 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 withthe 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 precludeadequate absorption.

7. Supplementation with vitamin E greater than 100% of the daily recommended dose. Anymultivitamin containing vitamin E must be stopped prior to initiation of therapy.

8. Participants not achieving adequate blood pressure despite antihypertensive therapyfor control of blood pressure.

9. Cardiac conditions:

10. Known inherited coronary disease

11. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, orsevere valvular heart disease)

12. Prior or current cardiomyopathy

13. Severe valvular heart disease

14. History of atrial fibrillation

15. Ophthalmologic conditions:

16. Current or past history of central serous retinopathy or retinal pigmentepithelial detachment (RPED).

17. Current or past history of retinal vein occlusion.

18. History of radiation therapy that included the orbit in the field of treatment.

19. Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) oruncontrolled glaucoma (irrespective of IOP). Participants with known glaucomaand increased IOP who do not have meaningful vision (light perception only orno light perception) and are not experiencing pain related to the glaucoma, maybe eligible after discussion with the study chair.

20. Participants with any other significant abnormality on ophthalmic examinationshould be discussed with the Study Chair for potential eligibility.

21. Ophthalmological findings secondary to long-standing optic pathway glioma (suchas visual loss, optic nerve pallor or strabismus) will NOT be considered asignificant abnormality for the purposes of the study.

22. Known severe hypersensitivity to selumetinib or any excipient of selumetinib orhistory of allergic reactions attributed to compounds of similar chemical orbiologic composition to selumetinib.

23. Recent major surgery within a minimum of 4 weeks prior to starting study treatment.

24. Any unresolved chronic toxicity with CTC AE grade ≥ 2 from previous therapy, exceptfor alopecia.

25. Receiving herbal supplements or medications known to be strong or moderateinhibitors or inducers of the cytochrome P450 (CYP)2C19 and CYP3A4 enzymes orfluconazole unless such products can be safely discontinued at least 14 days or 5half-lives (whichever is longer) before the first dose of study medication.