Inclusion Criteria:

• Male and female participants, aged ≥ 12 to < 18 years at the time of signing the informed consent.
• All study participants must be diagnosed with:
  • NF1 per NIH Consensus Development Conference Statement; and
  • Inoperable PN.
• In addition to PN, participants must have at least 1 other diagnostic criterion for NF1:
  • Six or more café-au-lait macules (≥ 0.5cm in prepubertal participants or ≥ 1.5cm in post pubertal participants);
  • Freckling in axilla or groin;
  • Optic glioma;
  • Two or more Lisch nodules;
  •  A distinctive bone lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex);
  •  A first degree relative with NF1.

A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches.
Inoperable PN is defined as PN that cannot be completely surgically removed without a risk of substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.

• Participants must require treatment for NF1 and inoperable PN due to actual symptoms or because of the potential to develop significant clinical complications, as judged by the Investigator, including but not limited to: head and neck lesions that could compromise the airway or great vessels; paraspinal lesions that can cause myelopathy; brachial or lumbar plexus lesions that could cause nerve compression and loss of function; lesions that would result in major deformity (eg, orbital lesions) or are significantly disfiguring; lesions that cause limb hypertrophy or loss of function; and painful lesions.
• Participants who have had prior treatment with any MEKi (including selumetinib) may be considered for inclusion in this study.
• Performance status:
  • Participants > 16 years of age must have a Karnofsky performance level of ≥ 70, and participants ≤ 16 years old must have a Lansky performance of ≥ 70;
  • Participants who are wheelchair bound because of paralysis secondary to a PN should be considered ambulatory when they are in their wheelchair. Similarly, participants with limited mobility secondary to a need for mechanical support (such as an airway PN requiring tracheostomy or continuous positive airway pressure) will also be considered ambulatory for the purpose of the study.
• Participants must have a BSA ≥ 1.3 and ≤ 2.5 m².
• All participants must be able to swallow whole capsules.
• Participants must be willing to take part in all three treatment periods (T1, T2 and T3).
  • Note that the recommendation to initiate T3 will be dependent on the results of T1 and T2.
• Female participants of childbearing potential who are not totally sexually abstinent (i.e., refraining from heterosexual intercourse during the entire period of risk associated with study interventions) and intend to be sexually active with a non-sterilised male partner must use at least one highly effective method of contraception, as defined below. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue to use it throughout the study and until at least 1 week after the last dose of selumetinib. Highly effective methods of contraception (< 1% failure rate) include:
  • Intrauterine device containing copper;
  • Bilateral tubal occlusion;
  • Vasectomised sexual partner (with participant assurance that partner received post-vasectomy confirmation of azoospermia);
  • Total sexual abstinence (evaluate in relation to the duration of the clinical study and the preferred and usual lifestyle choice of the participant);
  • Injection: Medroxyprogesterone injection (e.g., Depo-Provera®);ᵃ
  • Levonorgestrel-releasing intrauterine system (e.g., Mirena®);ᵃ
  • Implants: Etonogestrel-releasing implants (e.g., Implanon® or Norplant®);
  • Intravaginal devices: Ethinylestradiol/etonogestrel-releasing intravaginal devices (e.g., NuvaRing®);
  • Combined pill: Normal and low dose combined oral contraceptive pill;
  • Patch: Norelgestromin/ethinylestradiol-releasing transdermal system (e.g., Ortho Evra®);
  • Mini pill: Progesterone based oral contraceptive pill using desogestrel: Cerazette® is currently the only highly effective progesterone-based pill. ᵃ   Hormonal methods not prone to drug-drug interactions.
• Non-sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant. Female participants should refrain from breastfeeding throughout this period.
• All females of child bearing potential must have a negative serum pregnancy test result at Visit 1 and a negative serum or urine pregnancy test result prior to each treatment period.
• Male participants of reproductive potential must be surgically sterile by prior vasectomy with a post-vasectomy confirmation of azoospermia, or using an acceptable method of contraception (including use of condoms with spermicidal foams/gels or true abstinence, condom alone in countries where spermicides are not approved) for the duration of the study (from the time they sign consent) and for at least 1 week after the last dose of study intervention to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
• Male participants must not donate or bank sperm during this same time period.
• Female partners (of childbearing potential) of male participants must also use a highly effective method of contraception throughout this period.
• Mandatory provision of signed and dated parent/legal guardian consent for the study along with the paediatric assent form, when applicable, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP. For participants who reach the age of legal consent during the clinical study, notification will be required and a new consent form will need to be signed by the participant.

ᵃ Note that this is an example of a low fat meal – variations are allowed as long as the total calories and fat content are within the guidelines specified within the table. 
250 ml milk (1% fat) | One boiled egg | One packet flavoured instant oatmeal made with water.

Exclusion Criteria:

• Evidence or suspicion of optic glioma, malignant glioma, MPNST, or other cancer requiring treatment with chemotherapy or radiation therapy.
• Prior malignancy requiring active treatment (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the participant had been disease free for ≥ 2 years or which would not have limited survival to < 2 years).
• A life-threatening illness, medical condition, organ system dysfunction of laboratory finding which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of selumetinib, or put the study outcomes at undue risk.
• Participants with clinically significant cardiovascular disease as defined by the following:
  • Known inherited coronary disease;
  • History of angina or acute coronary syndrome;
  • Symptomatic heart failure;
  • New York Association Class II to IV;
  • Prior or current cardiomyopathy;
  • Severe valvular heart disease;
  • Current or history of atrial fibrillation ;
  • Baseline LVEF below LLN or < 55% measured by ECHO or cardiac MRI;
  • A QTcF > 450 ms;
  • Blood pressure > 95% percentile for age, height and gender measured.
• 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 HIV will be excluded. Participants with HIV who have adequate CD4 count, not requiring antiretroviral medication, may be enrolled.
• Liver function tests: bilirubin > 1.5 × the ULN for age (with the exception of those with Gilbert syndrome) or AST/ALT > 2 × upper limit of normal.
• Renal Function: Creatinine clearance or radioisotope glomerular filtration rate < 30 mL/min/1.73 m^2 or a serum creatinine > 1.2 mg/dL (for participants aged between 12 and 15 years) or > 1.5 mg/dL for participants aged > 15 years).
• Participants with the following ophthalmological findings/conditions:
  • Current or past history of RPED/CSR or RVO;
  • Intraocular pressure > 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 Medical Monitor.
  • Participants with any other significant abnormality on ophthalmic examination should be discussed with the Sponsor for potential eligibility.
  • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study.
• Have refractory nausea and vomiting, chronic GI diseases (e.g., inflammatory bowel disease), or significant bowel resection that would adversely affect the absorption/bioavailability of the orally administered study medication.
• Have any unresolved chronic toxicity, associated with previous therapy for NF1-PN:
  • Gastrointestinal toxicity of CTCAE Grade 1 or higher. − Have any other unresolved chronic toxicity with CTCAE Grade ≥ 2, except hair changes (such as alopecia or high lightening).
  • Participants who have previously been treated with a MEKi (including selumetinib) and either discontinued treatment or required a dose reduction due to toxicity
• Have had recent major surgery within a minimum of 4 weeks prior to starting study intervention, with the exception of surgical placement for vascular access. Have planned major surgery during the treatment period.
• Have inadequate haematological function: defined as an absolute neutrophil count < 1500/μL, Hb < 9g/dL, and platelets < 100,000/μL or have required a blood or platelet transfusion or received growth factors within the 7 days prior to the start of study intervention. Prior/Concomitant Therapy.
• Have received or are receiving an IMP or other systemic PN target treatment (including chemotherapy, hormonal therapy, radiation therapy, immunotherapy, biologic therapy or MEKi) within 4 weeks prior to the first dose of study intervention, or within a period during which the IMP or systemic PN target treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is the most appropriate and as judged by the Investigator. 15 Has received radiotherapy in the 6 weeks prior to start of study intervention.
• Any multivitamin containing vitamin E must be stopped at least 7 days prior to initiation of selumetinib.
• Receiving herbal supplements or medications known to be strong or moderate inhibitors or inducers of the CYP2C19 and CYP3A4 enzymes 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.
• Participation in another clinical study with an investigational product administered in the last 30 days.
• Known severe hypersensitivity to selumetinib or any excipient in the selumetinib formulation, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
• Previous treatment in the present study.
• For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding (it is allowed to discontinue lactation and participate in the study; however, resumption of lactation after study completion is not allowed).