Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

Inclusion Criteria: * Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene. The NIH criteria includes presence of: * Bilateral vestibular schwannomas, OR * First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity. The Manchester criteria includes presence of: * Bilateral vestibular schwannomas, OR * First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR * Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR * Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract. \- Patients do not need to have a histologic diagnosis in order to start therapy but must have measurable disease (in 2 dimensions) on MRI scan to be eligible. * For Stratum 1: Patients must have a target VS with the following qualities: * Associated with a word recognition score of \< 85% and \> 0% AND * Documented progression defined as: Either progressive hearing loss or progressive tumor growth in last 18 months defined as ≥ 20% increase in volume. * For Stratum 2: Patients must not meet the eligibility criteria as stated for Stratum 1 and have a target lesion that has exhibited progression. * Progression is defined as: ≥ 25% increase in sum of the products of perpendicular diameters of lesions in the preceding 18 months; any new lesion; or clinical deterioration related to disease. \- Patients must be able to swallow capsules * Age: * Patients must be ≥ 3 years to ≤ 45 years of age at start of treatment \- Prior Therapy * Since there is no standard effective chemotherapy for patients with NF2 and vestibular schwannomas, meningiomas, or ependymomas patients may be treated on this trial without having received prior medical therapy directed at their VS, meningiomas, or ependymomas. * Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for these NF2 patients. * Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to entering this study except for alopecia. * Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea. * Biologic agent: Patient must have received their last dose of the biologic agent ≥ 7 days prior to study registration. For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration * Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration \- Corticosteroids: * Patients who are receiving dexamethasone or other corticosteroids must be on a stable or decreasing dose for at least 1 week prior to registration. It is recommended that patients be off all steroid therapy or receive the least dose that will control their neurologic symptoms \- Prior radiotherapy * XRT: ≥ 6 months must have elapsed if prior XRT to vestibular schwannoma or other tumor. \- Stem Cell Transplant or Rescue without TBI: * No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant. \- Performance Status: * Karnofsky ≥ 60% for patients \> 16 years of age * Lansky ≥ 60 for patients ≤ 16 years of age. \- Organ Function Requirements * Adequate Bone Marrow Function Defined as: \- Peripheral absolute neutrophil count (ANC) ≥ 1500/μL * Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to registration) * Hemoglobin ≥ 9 g/dL (may receive RBC transfusions) * Adequate Renal Function Defined as: * Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or * A serum creatinine ≤1.5×ULN for age and sex * Adequate Liver Function Defined as: * Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age * AST(SGOT)/ALT(SGPT) ≤2.5×ULN institutional upper limit of normal for age * Central Nervous System Function: \- Patients with seizure disorder may be enrolled if they are receiving non-enzyme inducing anticonvulsants and the seizures are well controlled. * Cardiac Function Adequate cardiac function defined as: * LVEF ≥55% by ECHO * QTc interval ≤450 msecs by EKG * Hypertension * Patients, 3 to \< 18 years of age must have a blood pressure that is ≤ 95th percentile for age, height and gender at the time of registration. * Patients who are ≥18 years of age must have a blood pressure that is \<140/90 mm of Hg at the time of registration. Patients may be on blood pressure medication provided that it is not on the contraindicated list and that the medication has not been adjusted in the previous 3 months. \- Growth factors: All colony forming growth factor(s) have been discontinued for at least one week prior to registration (filgrastim, sargramostim, and erythropoietin). For patients on long acting growth factors, the interval should be two weeks. * Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study. * Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Exclusion Criteria: * Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. The effects of selumetinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with selumetinib ceases. The selumetinib manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle. Women of child-bearing potential must have a negative pregnancy test prior to study registration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Note: Female subjects are considered "of child-bearing potential" if they are anatomically and physiologically capable of becoming pregnant. For girls of normal reproductive potential, the possibility of becoming pregnant requires ovulatory menstrual cycles and heterosexual intercourse. Although the timing of ovulation relative to menarche is variable, there is consistent evidence that some girls may have ovulatory cycles prior to menarche, and that, in healthy populations, regular ovulation may begin within a few months of menarche. Therefore, menarche is the most feasible clinical indicator of the biological potential for pregnancy. Male patients with sexual partners who are pregnant or who could become pregnant (i.e. women of child-bearing potential) must use acceptable, effective and reliable methods of contraception during the study and for at least 12 weeks after the last dose of selumetinib or for longer if required, depending on the prescribing information of the combination or concomitantly administered medications. * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely to interfere with the study procedures or results * Patients who are currently receiving another investigational drug within 4 weeks prior to the first dose of study treatment, or within a period during which the investigational drug or systemic anticancer 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 are not eligible. * Patients who have taken another BRAF inhibitor such as Vemurafenib or Dabrafenib prior to study registration are not eligible. Prior treatment with selumetinib or another MEK inhibitor is not allowed. * Patients with QTc interval of \> 450 msec * Patients who require enzyme inducing anti-convulsants to control seizures. * Anticoagulation: Patients receiving coumadin are eligible but must have their PT and INR monitored prior to each 4 week course. * Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. * The following cardiac conditions: a. Uncontrolled hypertension in adults (BP ≥ 140/90 mmHg despite medical therapy) b. Acute coronary syndrome within 6 months prior to starting treatment c. Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy (Appendix H) d. Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (Appendix I) e. Prior or current cardiomyopathy including but not limited to the following: i. Known hypertrophic cardiomyopathy ii. Known arrhythmogenic right ventricular cardiomyopathy f. Previous moderate or severe impairment of left ventricular systolic function (LVEF \<45% on echocardiography or equivalent on MuGA) if known even if full recovery has occurred. g. Severe valvular heart disease h. Baseline Left ventricular ejection fraction (LVEF) below the LLN or \<50% measured by echocardiography or institution's LLN for MUGA i. Atrial fibrillation with a ventricular rate \>100 bpm on ECG at rest * Ophthalmological conditions as follows: 1. Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion 2. Intraocular pressure (IOP) \> 21 mmHg or uncontrolled glaucoma (irrespective of IOP) * Major surgery within 4 weeks of starting selumetinib. Portacath insertion, G Tube placement, and insertion of ventriculoperitoneal shunt are not considered major surgeries. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib or combination medications or any excipient of these medicinal products. * History of a medical or psychiatric illness, that in the investigator's judgment renders the patient incapable of further therapy on this protocol * Patients with progressive disease associated with significant or disabling clinical symptoms requiring immediate intervention with surgery or radiation therapy are not eligible.