AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

-INCLUSION CRITERIA: 1. Age Phase I: \>=3 years and \<=18 years of age at the time of study enrollment, if able to swallow whole capsules. The age limits including young children were chosen because early childhood and puberty are considered to be the greatest risk for disease progression, and selumetinib may provide the most benefit to this young group of patients. In addition, an important objective of this study is to characterize the pharmacokinetics of selumetinib in the pediatric population since it has been well studied in adults. Age Phase II: \>=2 and \<= 18 years. BSA \>= 0.55 m\^2, and able to swallow whole capsules. 2. Diagnosis: Patients with NF1 and inoperable PN, defined as 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 has to cause (stratum 1) or have the potential to cause (stratum 2) significant morbidity, such as (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 could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Patients will be enrolled into stratum 1 or 2 based on PN related morbidity. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected. A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below: (NIH Consensus conference): * Six or more cafe-au-lait macules (\>=0.5cm in prepubertal subjects or \>=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 3. 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. Phase II: 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 4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity. * 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, imatinib or other targeted therapies are eligible for enrollment. At least 4 weeks must have elapsed since receiving medical therapy directed at the PN. Patients who received prior medical therapy for their PN must have recovered from the acute toxic effects of all prior therapy to \<= grade 1 before entering this study. * Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment. * At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy. * At least 4 weeks must have elapsed since any surgeries, with evidence of good wound healing. 5. Performance status: Patients \>= 16 years of age must have a Karnofsky performance level of \>=70%, and children \<= 16 years old must have a Lansky performance of \>=70%. Patients who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are up in their wheelchair. Similarly, patients with limited mobility secondary to need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of the study. 6. Hematologic Function: Patients must have an absolute neutrophil count \>=1500/microliter, hemoglobin \>=9g/dl, and platelets \>=100,000/microliter. 7. Hepatic Function: Patients must have 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. 8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR \>=60ml/min/1.73 m\^2 or a normal serum creatinine based on age, described below. Age (years) / Maximum Serum Creatinine(mg/dL): Age \<=5 / Maximum Serum Creatinine 0.8 mg/dL Age \>5 to \<=10 / Maximum Serum Creatinine 1.0 mg/dL Age \>10 to \<=15 / Maximum Serum Creatinine 1.2 mg/dL Age \>15 / Maximum Serum Creatinine 1.5 mg/dL 9. Cardiac Function: Normal ejection fraction (ECHO or cardiac MRI) \>= 53% (or the institutional normal; if a range is given then the upper value of the range will be used); QTC or QTcF \<=450 msec. 10. Adequate Blood Pressure defined as: A blood pressure (BP) \<= the 95th percentile for age, height, and sex measured. Adequate blood pressure can be achieved using medication for treatment of hypertension. 11. 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 or their legal guardians (if the patient is \<18 years old). When appropriate, pediatric patients will be included in all discussions. This can be accomplished through one of the following mechanisms: a) the NCI POB screening protocol, b) an IRB-approved institutional screening protocol, or c) the study-specific protocol. Documentation of the informed consent for screening will be maintained in the patient s research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained. 12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated. 13. 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: 1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment for all females of childbearing potential as per institutional standards (at NIH subjects 9 years and older or those showing pubertal development). 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. 2. Phase I: Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject inevaluable. 3. Use of an investigational agent within the past 30 days. 4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy. 5. Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have adequate CD4 count, not requiring antiretroviral medication, may be enrolled. 6. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study. 7. Inability to swallow capsules, since capsules cannot be crushed or broken. 8. Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI. 9. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption. 10. Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the subject meets criteria for re-treatment). 11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy. 12. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to initiation of therapy. 13. Patients not achieving adequate blood pressure in spite of antihypertensive therapy for control of blood pressure. 14. Cardiac Function: 1. Known inherited coronary disease 2. Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease) 3. Prior or current cardiomyopathy 4. Severe valvular heart disease 5. History of atrial fibrillation 15. Ophthalmologic conditions: 1. Current or past history of central serous retinopathy 2. Current or past history of retinal vein occlusion 3. Known intraocular pressure (IOP) \>= 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP). Patients 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. 4. Subjects with any other significant abnormality on ophthalmic examination should be discussed with the Study Chair for potential eligibility 5. 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 16. 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. 17. Recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access. 18. Any unresolved chronic toxicity with CTC AE grade \>= 2 from previous anti-NF1 therapy, except for alopecia. 19. Clinical judgement by the investigator that the patient should not participate in the study. 20. While not an exclusion criterion, unless considered 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.