MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

• INCLUSION CRITERIA:

• Patients must have positive genetic testing for NF1 in a CLIA certified laboratoryor a diagnosis of NF1 based on clinical NIH consensus criteria of at least one otherdiagnostic criterion in addition to the presence of a PN. NF1 mutation analysis willbe performed on germline DNA. Histologic confirmation of tumor is not necessary inthe presence of consistent clinical and imaging findings, but should be consideredif malignant transformation of a PN is clinically suspected. Additional criteria areas follows:

• Six or more cafe-au-lait macules (>=0.5cm in prepubertal subjects or >=1.5 cmin 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 orthinning of long bone cortex)

• A first-degree relative with NF1

• Measurable disease: Patients must have at least one measurable PN, defined as alesion of at least 3 cm measured in one dimension. Patients who underwent surgeryfor resection of a PN are eligible provided the PN was incompletely resected and ismeasurable as per criteria above. Measurability and suitability for volumetric MRIanalysis of the target PN must be confirmed with the NCI POB prior to enrolling apatient. The target PN will be defined as the clinically most relevant PN, which hasto be amenable to volumetric MRI analysis. PN will be classified as typical PNversus nodular PN versus solitary nodular PN prior to enrollment

• The PN must be inoperable, defined as a PN that cannot be surgically completelyremoved without risk for substantial morbidity due to: encasement of or closeproximity to vital structures, invasiveness, or high vascularity of the PN. The PNeither causes morbidity or it is growing and has the potential to cause morbiditysuch as (but not limited to): Head and neck lesions that could compromise the airwayor great vessels, paraspinal lesions that can cause myelopathy, brachial or lumbarplexus lesions that could cause nerve compression and loss of function, lesions thatcould result in major deformity (e.g., orbital lesions) or are significantlydisfiguring, and lesions of the extremity that cause limb hypertrophy or loss offunction or pain. PN growth will be defined as a >=20% increase in PN volume withinapproximately 3 years prior to enrollment on this trial.

• Patients must have a PN amenable to a percutaneous biopsy to participate in thebiopsy portion of this study, and must be willing to undergo pre-, and on treatmenttumor 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, willbe 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 (Patients who are wheelchair bound because of paralysissecondary to a plexiform neurofibroma should be considered ambulatory when they areup in their wheelchair. Similarly, patients with limited mobility secondary to needfor mechanical support (such as an airway PN requiring tracheostomy or CPAP) willalso be considered ambulatory for the purpose of the study.)

--ECOG Performance Status:*

• Grade/ECOG

• 0 Fully active, able to carry on all pre-disease performance withoutrestriction

• 1 Restricted in physically strenuous activity but ambulatory and able to carryout 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 workactivities. Up and about more than 50% of waking hours

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

• 4 Completely disabled. Cannot carry on any self-care. Totally confined to bedor 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 AndResponse Criteria Of The Eastern Cooperative Oncology Group. Am J ClinOncol 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 ofpatients with Gilbert Syndrome

• ALT(SGPT) & AST(SGOT) <=3.0 X ULN

• Creatinine <=upper limit of normal institutional limits

• OR

• Creatinine clearance >=60 mL/min/1.73 m^2 for patients with creatinine levelsabove institutional normal

• Hematologic parameters for patients undergoing biopsy only: Patients should have INR <=1.4 and PTT <=40 seconds (unless due to lupus anticoagulant). In patients notmeeting these parameters, clearance by hematology will be required prior toundergoing a biopsy.

• Cardiac Function: Normal ejection fraction (ECHO) >=53% (if a range is given thenthe 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 thewillingness to sign a written informed consent document.

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

• 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.

• Prior therapy: Patients with NF1 will only be eligible if complete tumor resectionis not considered to be feasible without substantial risk or morbidity, or if apatient 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 medicaltherapy directed at their PN.

• Since selumetinib is not expected to cause substantial myelosuppression, therewill be no limit to number of prior myelosuppressive regimen for PN or othertumor 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 VEGFRinhibitors are eligible for enrollment.

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

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

• At least 4 weeks must have elapsed since receiving medical therapy directed atthe PN.

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

• Patients who received prior medical therapy for their PN must have recoveredfrom the acute toxic effects of all prior therapy to <= grade 1 before enteringthis study.

• Informed Consent: Diagnostic or laboratory studies performed exclusively todetermine eligibility for this trial must only be done after obtaining writteninformed consent from all patients, which can be accomplished using the screeningconsent for this protocol. Studies or procedures that were performed for clinicalindications (not exclusively to determine eligibility) may be used for screening orbaseline values even if the studies were done before informed consent was obtained,if the patient agrees.

EXCLUSION CRITERIA:

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

• May not have a NF1 related tumor such as optic pathway glioma or malignantperipheral nerve sheath tumor, which requires treatment with chemotherapy orsurgery.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, active bleeding diatheses or renal transplant, including any patientknown to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), orpsychiatric illness/social situations that would limit compliance with studyrequirements. Patients with HIV who have adequate CD4 counts and who have norequirement for antiviral therapy will be eligible.

• Pregnant or breast-feeding females are excluded due to potential risks of fetal andteratogenic adverse events of an investigational agent. Males or females ofreproductive potential may not participate unless they have agreed to use aneffective 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 theMRI protocol. Prosthesis or orthopedic or dental braces that would interfere withvolumetric analysis of target PN on MRI.

• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g.,inflammatory bowel disease), or significant bowel resection that would precludeadequate 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 criterion, unless clinically indicated, patients should avoidtaking other additional non-study medications that may interfere with the studymedications. In particular, patients should avoid medications that are known toeither induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2,CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.

• Known Cardiac Disorder, including:

• Known inherited coronary disease

• Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, orsevere 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) oruncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma andincreased IOP who do not have meaningful vision (light perception only or nolight perception) and are not experiencing pain related to the glaucoma, may beeligible after discussion with the study chair.

• Subjects with any other significant abnormality on ophthalmic examinationshould be discussed with the Study Chair for potential eligibility

• Ophthalmological findings secondary to long-standing optic pathway glioma (suchas visual loss, optic nerve pallor or strabismus) or long-standingorbito-temporal PN (such as visual loss, strabismus) will NOT be considered asignificant abnormality for the purposes of the study

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

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

• Have any unresolved chronic toxicity with CTC AE grade >= 2, from previous anti-NF1therapy, except for alopecia.

• Clinical judgment by the investigator that the patient should not participate in thestudy