Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma

PRIMARY OBJECTIVES:

I. Determine if selumetinib can result in shrinkage cutaneous neurofibromas.

SECONDARY OBJECTIVES:

I. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised
prior treatment and on treatment with selumetinib for analysis of percent inhibition of
phosphorylated ERK (pERK), and changes in phosphorylated AKT (pAKT).

EXPLORATORY OBJECTIVES:

I. Assess the effect of selumetinib on the development on new cutaneous neurofibromas while
on treatment with selumetinib.

II. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s)
excised prior treatment and on treatment with selumetinib for analysis of the tumor kinome.

III. Assess the effect of selumetinib skin related morbidity using the Skindex patient
reported outcome measure.

IV. Quantify the development of new cutaneous neurofibromas on treatment with selumetinib.

V. Detailed pathologic analysis of cutaneous neurofibromas pretreatment and on treatment with
selumetinib for changes in cell composition (including macrophage and mast cell
infiltration).

VI. Investigate alterations that correlate with cutaneous neurofibroma (cNF) response to
selumetinib treatment with pilot genomic, deoxyribonucleic acid (DNA) methylation, and
transcriptomic studies.

OUTLINE:

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
every 28 days for up to 24 cycles in the absence of disease progression or unacceptable
toxicity. Patients who experience a volume decrease in the target cutaneous neurofibromas may
continue treatment for 12 additional cycles.

Inclusion Criteria:

- Patients must have a documented germline neurofibromatosis 1 (NF1) mutation in a
Clinical Laboratory Improvement Act (CLIA) certified laboratory or a diagnosis of NF1
based on clinical National Institutes of Health (NIH) consensus criteria; in addition
to substantial cutaneous neurofibroma burden, at least one of the criteria below have
to be present:

- Six or more cafe-au-lait macules (>= 0.5 cm 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

- Histologic confirmation of tumor is not necessary in the presence of consistent
clinical findings

- Patients must have substantial cutaneous neurofibroma burden causing distress to the
patient by disfigurement or itching; patients must have >= 9 measurable cutaneous
neurofibromas; for the purpose of this study measurability will be defined for each of
the lesions selected as target lesions as a neurofibroma with a longest diameter >= 4
mm in the longest diameter

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Hemoglobin >= 10 g/dL (not requiring red blood cell [RBC] transfusions)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL (not requiring platelet transfusions)

- Total bilirubin =< 1.5 X upper limit of normal (ULN), with the exception of patients
with Gilbert syndrome who are required to have =< 3 X ULN

- Alanine transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X ULN

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Hematologic parameters for patients undergoing biopsy only: patients should have
international normalized ratio (INR) =< 1.4 and prothrombin time (PT) =< 40 seconds
(unless due to lupus anticoagulant); in patients not meeting these parameters,
clearance by hematology will be required prior to undergoing a biopsy

- Ability of subject or legally authorized representative (LAR) to understand and the
willingness to sign a written informed consent document

- Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated

- 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

- Since there is no standard effective chemotherapy for patients with NF1 and cutaneous
neurofibromas, patients may be treated on this trial without having received prior
medical therapy directed at their plexiform neurofibromas (PN)

- Since selumetinib is not expected to cause substantial myelosuppression, there will be
no limit to number of prior myelosuppressive regimens previously received for NF1
related; or other tumor manifestations

- Patients who have received previous investigational agents or biologic therapy, such
as tipifarnib, pirfenidone, Peg-intron, sorafenib, or other vascular endothelial
growth factor (VEGFR) inhibitors are eligible for enrollment

- Growth factors that support platelet or white cell number or function must not have
been administered within the past 7 days and are not permitted while on the study

- At least 6 weeks must have elapsed prior to enrollment since the patient received any
prior radiation therapy, and the target cutaneous neurofibromas have to be in areas
outside of a prior radiation field

- At least 4 weeks must have elapsed since receiving medical therapy directed at NF1
related tumor manifestations

- At least 4 weeks must have elapsed since any surgeries, with evidence of completed
wound healing

- Patients who received prior medical therapy for a NF1 related tumor must have
recovered from the acute toxic effects of all prior therapy to =< grade 1 Common
Terminology Criteria for Adverse Events (CTCAE) version (v) 5 before entering this
study

- The effects of selumetinib on the developing human fetus at the recommended
therapeutic dose 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, for the duration of study participation, and for 4
weeks after dosing with selumetinib ceases; women of child-bearing potential must have
a negative pregnancy test prior to entry; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, the patient
should inform her treating physician immediately; please note that the selumetinib
manufacturer recommends that adequate contraception for male patients should be used
for 12 weeks post-last dose due to sperm life cycle

- Diagnostic or laboratory studies performed exclusively to determine eligibility for
this trial must only be done after obtaining written informed consent from all
patients, which can be accomplished using the study specific informed consent or
another consent, such as the National Cancer Institute (NCI), Pediatric Oncology
Branch (POB) screening protocol; studies or procedures that were performed for
clinical indications (not exclusively to determine eligibility) may be used for
screening or baseline 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 an
investigational agent within the past 30 days

- May not have a NF1 related tumor such as optic pathway glioma or malignant peripheral
nerve sheath tumor, which requires treatment with chemotherapy, radiation, or surgery

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, active bleeding diatheses or renal transplant, including any patient known
to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements;
patients with HIV who have adequate cluster of differentiation (CD)4 counts and who
have no requirement for antiviral therapy will be eligible

- Pregnant or breast-feeding females are excluded due to potential risks of fetal and
teratogenic adverse events of an investigational agent; 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

- Prior treatment with selumetinib or another specific MEK 1/2 inhibitor

- No supplementation with vitamin E is permitted

- Inability to swallow capsules, since capsules cannot be crushed or broken

- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate absorption

- Strong inhibitors or inducers of hepatic microsomal isoenzymes

- While not an exclusion criterion, unless 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 strong
inhibitor or inducers of hepatic microsomal isoenzymes CYP1A2, CYP2C8, CYP2C9,
CYP2C19, CYP3A4/5, UGT1A1, UGT1A3 and transporters BCRP and P-gp

- Known cardiac disorder, including:

- Uncontrolled hypertension (blood pressure [BP] of >= 150/95 despite medical
support/management)

- Acute coronary syndrome within 6 months prior to starting treatment

- Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical
support/management

- Heart failure New York Heart Association (NYHA) class II or above

- Prior or current cardiomyopathy including but not limited to the following:

- Known hypertrophic cardiomyopathy

- Known arrhythmogenic right ventricular cardiomyopathy

- Baseline left ventricular ejection fraction (LVEF) =< 55%

- Previous moderate or severe impairment of left ventricular systolic function
(LVEF < 45% on echocardiography or equivalent on multi-gated acquisition scan
[MUGA]) even if full recovery has occurred

- Severe valvular heart disease

- Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on
electrocardiography (ECG) at rest

- Fridericia's correction formula (QTcF) interval > 450 msec or other factors that
increase the risk of QT prolongation or arrhythmic events (e.g., heart failure,
hypokalemia, family history of long QT interval syndrome) are excluded; the use
of medication(s) that can prolong corrected QT (QTc) interval is prohibited while
treated on this study

- Known ophthalmologic conditions, such as:

- Current or past history of retinal pigment epithelial detachment (RPED)/central
serous retinopathy (CSR)

- Current or past history of retinal vein occlusion

- Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma
and increased IOP who do not have meaningful vision (light perception only or no
light perception) may be eligible after discussion with the study chair

- Subjects with any other significant abnormality on ophthalmic examination
(performed by an ophthalmologist) should be discussed with the study chair for
potential eligibility

- 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

- 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

- Have had recent major surgery within a minimum of 4 weeks prior to starting study
treatment, with the exception of surgical placement for vascular access

- Have any unresolved chronic toxicity with CTCAE grade >= 2, from previous anti-NF1
therapy, except for alopecia

- Clinical judgment by the investigator that the patient should not participate in the
study