- Inclusion Criteria:

- Patients must have a documented germline NF1 mutation in a CLIA certified laboratory
or a diagnosis of NF1 based on clinical NIH consensus criteria51 of at least one
other diagnostic criterion in addition to the presence of a PN. NF1 mutation analysis
will be performed on germline DNA as described by Messiaen & Wimmer 52. Histologic
confirmation of tumor is not necessary in the presence of consistent clinical and
imaging findings, but should be considered if malignant transformation of a PN is
clinically suspected. Additional criteria are as follows:

Six or more caf(SqrRoot)(Copyright)-au-lait macules ( (Bullet)0.5cm in prepubertal
subjects or (Bullet)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

-Measurable disease: Patients must have at least one measurable PN, defined as a lesion of
at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a
PN are eligible provided the PN was incompletely resected and is measurable as per
criteria above. Measurability and suitability for volumetric MRI analysis of the target PN
must be confirmed

with the NCI POB prior to enrolling a patient. The target PN will be defined as the
clinically most relevant PN, which has to be amenable to volumetric MRI analysis. PN will
be classified as typical PN versus nodular PN versus solitary nodular PN prior to
enrollment (See

section 3.1 and Appendix I).

-The PN must be inoperable, defined as a PN 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 either causes morbidity or
it is

growing and has the potential to cause 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, and lesions
of the extremity that cause limb hypertrophy or loss of function or pain. PN growth will
be defined as a (Bullet)20% increase in PN volume within approximately 3 years prior to
enrollment on this trial.

- Patients must have a PN amenable to a percutaneous biopsy to participate in the
biopsy portion of this study, and must be willing to undergo pre-, and on treatment
tumor biopsies. There should be no contraindication for serial biopsies. NOTE: Up to
10 patients who meet all criteria, but have PN which cannot be biopsied safely, will
be eligible for the treatment portion of the study.

- Must be able to undergo serial MRI scans for response evaluation

- Age > 18 years

- ECOG performance status < 2

--ECOG PERFORMANCE STATUS*

- Grade ECOG

- 0 Fully active, able to carry on all pre-disease performance without restriction

- 1 Restricted in physically strenuous activity but ambulatory and able to carry
out work of a light or sedentary nature, e.g., light house work, office work

- 2 Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours

- 3 Capable of only limited self-care, confined to bed or chair more than 50% of
waking hours

- 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or
chair

- 5 Dead

- As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey,
D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin
Oncol 5:649-655, 1982.

- Patients must have normal organ and marrow function as defined below:

- hemoglobin > 10 g/dL (not requiring RBC transfusions)

- absolute neutrophil count > 1,500/mcL

- platelets > 100,000/mcL (not requiring platelet transfusions)

- total bilirubin < 1.5 upper limit of normal (ULN), with the exception of
patients with Gilbert Syndrome

- ALT(SGPT) & AST(SGOT) < 3.0 X ULN

- creatinine within normal institutional limits

OR

--creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal.

- Hematologic parameters for patients undergoing biopsy only: Patients should have INR
< 1.4 and PT 40 seconds (unless due to lupus anticoagulant). In patients not meeting
these parameters, clearance by hematology will be required prior to undergoing a
biopsy.

- Cardiac Function: Normal ejection fraction (ECHO) (Bullet) 53% (if a range is given
then the upper value of the range will be used) or cardiac MRI; QTcF 450 msec.

- Ability of subject or Legally Authorized Representative (LAR)) to understand and the
willingness to sign a written informed consent document.

- 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.

- Prior therapy: Patients with NF1 will only be eligible if complete tumor 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, patients
may be treated on this trial without having received prior medical therapy directed at
their PN.

Since selumetinib is not expected to cause substantial myelosuppression, there will be no
limit to number of prior myelosuppressive regimen for PN or other tumor manifestations
associated with NF1 such as optic glioma.

Patients who have received previous investigational agents or biologic therapy, such as
tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR inhibitors are eligible for
enrollment.

Growth factors that support platelet or white cell number or function must not have been
administered within the past 7 days and are not permitted while on the study.

At least 6 weeks must have elapsed prior to enrollment since the patient received any
prior radiation therapy, and no prior radiation therapy should have been directed at the
target PN.

At least 4 weeks must have elapsed since receiving medical therapy directed at the PN.

At least 4 weeks must have elapsed since any surgeries, with evidence of completed wound
healing.

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.

-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, which can be accomplished using the NCI, POB screening protocol. Studies or

procedures that were performed for clinical indications (not exclusively to determine
eligibility) may be used for screening or baseline values even if the studies were done
before informed consent was obtained, if the patient agrees.

2.1.2 Exclusion Criteria

- Patients who are receiving any other investigational agents, or have received an
investigational agent within the past 30 days.

- May not have a NF1 related tumor such as optic pathway glioma or malignant peripheral
nerve sheath tumor, which requires treatment with chemotherapy or surgery.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, active bleeding diatheses or renal transplant, including any patient
known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or
psychiatric illness/social situations that would limit compliance with study
requirements. Patients with HIV who have adequate CD4 counts and who have no
requirement for antiviral therapy will be eligible.

- Pregnant or breast-feeding females are excluded due to potential risks of fetal and
teratogenic adverse events of an investigational agent. Males or females of
reproductive potential may not participate unless they have agreed to use an
effective contraceptive method. Abstinence is an acceptable method of birth control.

- Prior treatment with selumetinib or another specific MEK 1/2 inhibitor.

- Supplementation with vitamin E greater than 100% of the daily recommended dose.

- Inability to swallow capsules, since capsules cannot be crushed or broken.

- Inability to undergo MRI and/or contraindication for MRI examinations following the
MRI protocol (Appendix I). Prosthesis or orthopedic or dental braces that would
interfere with volumetric analysis of target PN on MRI.

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.

- Uncontrolled hypertension (despite medical therapy); blood pressure should be <
140/90 in accordance with American Heart Association definition of hypertension.

- While not an exclusion criteria, unless clinically indicated, patients should avoid
taking other additional non-study medications that may interfere with the study
medications. In particular, patients should avoid medications that are known to
either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2,
CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib
(Appendix II).

- Known Cardiac Disorder, including:

- Known inherited coronary disease

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

- Current cardiomyopathy

- Severe valvular heart disease

- Atrial fibrillation

- Ejection fraction (ECHO) < 53%

- QTcF > 450 msec

- Known Ophthalmologic conditions, such as:

- Current or past history of central serous retinopathy

- Current or past history of retinal vein occlusion

- Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma
and increased IOP who do not have meaningful vision (light perception only or no
light perception) may be eligible

after discussion with the study chair.

- Subjects with any other significant abnormality on ophthalmic examination (performed
by an ophthalmologist) 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) or long-standing orbito-temporal PN
(such as visual loss, 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

- Have had recent major surgery within a minimum of 4 weeks prior to starting study
treatment, with the exception of surgical placement for vascular access.

- Have any unresolved chronic toxicity with CTC AE grade (Bullet) 2, from previous
anti-NF1 therapy, except for alopecia.

- Clinical judgment by the investigator that the patient should not participate in the
stu

Minimum Eligible Age: 18 Years

Maximum Eligible Age: 99 Years

Eligible Gender: Both