Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

This is a Phase 2 trial to assess the hearing response rate and radiographic response of VS
in children and young adults with NF2 who are treated with selumetinib. Dosing will be based
on age: For patients with NF2 who are 3 to < 18 years of age, dosing will be based on BSA.
Dosing is based on BSA calculated at the beginning of each course. For patients with NF2 who
are ≥ 18 to 45 years of age, dosing will be the standard adult dose of 75 mg BID.

Selumetinib is taken orally twice a day continuously. One course is equivalent to 28 days.
Therapy may continue for up to two years (26 courses) in the absence of disease progression
or unacceptable toxicity.

There will be two treatment strata. Stratum 1 is for those patients who have a target
vestibular schwannoma which is causing hearing loss. Stratum 2 will be reserved for patients
who exhibit growth of a tumor(s) besides vestibular schwannoma and are therefore not eligible
for stratum 1.

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) ≥ 1000/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 based on age/gender

- Adequate Liver Function Defined as:

- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for
age

- AST(SGOT)/ALT(SGPT) <3 X 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 ≥50% 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.

- 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)

- No 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

- 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.