Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

Inclusion Criteria:

• Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfillingNational Institute of Health (NIH) criteria or Manchester criteria, or by detectionof 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 thefollowing: neurofibroma, meningioma, glioma, schwannoma, juvenile posteriorsubcapsular 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 thefollowing: neurofibroma, meningioma, glioma, schwannoma, juvenile posteriorsubcapsular 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 twoof: schwannoma, glioma, neurofibroma, cataract.

• Patients do not need to have a histologic diagnosis in order to start therapybut 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 progressivetumor 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 perpendiculardiameters of lesions in the preceding 18 months; any new lesion; or clinicaldeterioration 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 andvestibular schwannomas, meningiomas, or ependymomas patients may be treated on thistrial without having received prior medical therapy directed at their VS,meningiomas, or ependymomas.

• Since selumetinib is not expected to cause substantial myelosuppression, there willbe no limit to number of prior myelosuppressive regimen for these NF2 patients.

• Patients must have fully recovered from the acute toxic effects of all priorchemotherapy, immunotherapy, biologic therapy or radiotherapy prior to entering thisstudy except for alopecia.

• Myelosuppressive chemotherapy: Patients must have received their last dose of knownmyelosuppressive anticancer chemotherapy at least three weeks prior to studyregistration or at least six weeks if nitrosourea.

• Biologic agent: Patient must have received their last dose of the biologic agent ≥ 7days prior to study registration. For biologic agents that have a prolongedhalf-life, at least three half-lives must have elapsed prior to registration

• Monoclonal antibody treatment: At least three half-lives must have elapsed prior toregistration

• Corticosteroids:

• Patients who are receiving dexamethasone or other corticosteroids must be on astable or decreasing dose for at least 1 week prior to registration. It isrecommended that patients be off all steroid therapy or receive the least dose thatwill control their neurologic symptoms

• Prior radiotherapy

• XRT: ≥ 6 months must have elapsed if prior XRT to vestibular schwannoma or othertumor.

• Stem Cell Transplant or Rescue without TBI:

• No evidence of active graft vs. host disease and ≥ 3 months must have elapsed sincetransplant.

• 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 receivingplatelet 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) forage

• 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-enzymeinducing 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 ≤ 95thpercentile 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 ofHg 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 atleast 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 ethnicgroups 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 offetal and teratogenic adverse events as seen in animal/human studies. The effects ofselumetinib on the developing human fetus are unknown. For this reason, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry and for theduration of study participation, and for four weeks after dosing with selumetinibceases. The selumetinib manufacturer recommends that adequate contraception for malepatients should be used for 16 weeks post-last dose due to sperm life cycle. Womenof child-bearing potential must have a negative pregnancy test prior to studyregistration. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately.

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 (seriousinfections 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 weeksprior to the first dose of study treatment, or within a period during which theinvestigational drug or systemic anticancer treatment has not been cleared from thebody (e.g. a period of 5 'half-lives'), whichever is the most appropriate and asjudged by the investigator are not eligible.

• Patients who have taken another BRAF inhibitor such as Vemurafenib or Dabrafenibprior to study registration are not eligible. Prior treatment with selumetinib oranother 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 andINR monitored prior to each 4 week course.

• Patients who in the opinion of the investigator may not be able to comply with thesafety 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. UncontrolledAngina - Canadian Cardiovascular Society grade II-IV despite medical therapy (Appendix H) d. Symptomatic heart failure NYHA Class II-IV, prior or currentcardiomyopathy, or severe valvular heart disease (Appendix I) e. Prior or currentcardiomyopathy including but not limited to the following: i. Known hypertrophiccardiomyopathy 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 recoveryhas 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 forMUGA 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)/centralserous retinopathy (CSR) or retinal vein occlusion

2. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective ofIOP)

• Major surgery within 4 weeks of starting selumetinib. Portacath insertion, G Tubeplacement, and insertion of ventriculoperitoneal shunt are not considered majorsurgeries.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to selumetinib or combination medications or any excipient ofthese medicinal products.

• History of a medical or psychiatric illness, that in the investigator's judgmentrenders the patient incapable of further therapy on this protocol

• Patients with progressive disease associated with significant or disabling clinicalsymptoms requiring immediate intervention with surgery or radiation therapy are noteligible.