Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Determine the objective response rate (plexiform neurofibromas [PN] volume decrease >= 20%
compared to baseline) to selumetinib in adult patients with NF1 and inoperable PN.

SECONDARY OBJECTIVES:

I. Correlate 3 dimensional (3D) magnetic resonance imaging (MRI) responses with percent
target inhibition phosphorylated (p)ERK in PN biopsies obtained pretreatment and on treatment
with selumetinib.

II. Analysis of histomorphology and molecular signature of tumor samples, as well as
pathological evaluation of tumor changes on treatment.

III. Analyze paired biopsies for mechanisms of response and resistance to selumetinib:
measurement of pAKT, pMEK, tumor kinome, and tumor transcriptome.

IV. Compare changes in pERK as a result of MEK inhibition in dermal neurofibromas and in PN.

V. Evaluate immune infiltrate of plexiform neurofibromas, as well as peripheral blood for
presence of circulating tumor cells.

VI. Evaluate steady state pharmacokinetics of selumetinib (in blood) and correlate steady
state levels with response and changes in pERK as a result of MEK inhibition in tumor
samples.

VII. Analyze bone marrow derived precursor cells and cytokines from blood samples obtained
pretreatment and on treatment with selumetinib.

VIII. Compare volumetric response and target inhibition and pathway activation in PN and
nodular lesions.

IX. Establish patient derived xenografts. X. Characterize the effect of selumetinib on pain,
quality of life, and physical functioning.

XI. Determine baseline functional impairments secondary to PN, and the effect of selumetinib
on functional outcomes depending on PN location.

XII. Determine the effect of selumetinib on the PN growth rate based on volumetric analysis
of MRI studies obtained prior to enrollment (if available and amenable to volumetric
analysis).

XIII. Determine time to progression (TTP) and progression free survival (PFS) in progressive
PN (>= 20% increase in PN volume within 12-15 months prior to enrollment).

XIV. Evaluate change in dermal neurofibroma burden using digital photography.

OUTLINE:

Patients receive selumetinib orally (PO) twice daily (BID) (approximately every 12 hours) on
days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have positive genetic testing for NF1 in a Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory or a diagnosis of NF1 based on
clinical National Institutes of Health (NIH) consensus criteria of at least one other
diagnostic criterion in addition to the presence of a PN; NF1 mutation analysis will
be performed on germline deoxyribonucleic acid (DNA) as described by Messiaen &
Wimmer; histologic confirmation of tumor is not necessary in the presence of
consistent clinical and imaging findings, but should be considered if malignant
transformation of a PN is clinically suspected; additional criteria are as follows:

- 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

- 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 as per criteria
above; measurability and suitability for volumetric MRI analysis of the target PN must
be confirmed with the National Cancer Institute (NCI) Pediatric Oncology Branch (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? or ?nodular PN? versus "solitary nodular PN" prior to
enrollment

- The PN must be inoperable, defined as a 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
either causes morbidity or it is growing and has the potential to cause 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,
and lesions of the extremity that cause limb hypertrophy or loss of function or pain;
PN growth will be defined as a >= 20% increase in PN volume within approximately 3
years prior to enrollment on this trial

- Patients must have a PN amenable to a percutaneous biopsy to participate in the biopsy
portion of this study, and must be willing to undergo pre-, and on treatment tumor
biopsies; there should be no contraindication for serial biopsies; NOTE: up to 10
patients who meet all criteria, but have PN which cannot be biopsied safely, will be
eligible for the treatment portion of the study

- Must be able to undergo serial MRI scans for response evaluation

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (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 continuous positive airway pressure [CPAP] will also be
considered ambulatory for the purpose of the study)

- 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 upper limit of normal (ULN), with the exception of patients
with Gilbert syndrome

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) &
aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
3.0 X ULN

- Creatinine =< upper limit of 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 partial thromboplastin time (PTT) =<
40 seconds (unless due to lupus anticoagulant); in patients not meeting these
parameters, clearance by hematology will be required prior to undergoing a biopsy

- Normal ejection fraction (echocardiogram [ECHO]) >= 53% (if a range is given then the
upper value of the range will be used) or cardiac MRI

- Fridericia's corrected QT interval (QTcF) =< 450 msec

- 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

- Patients with NF1 will only be eligible if complete tumor resection is not considered
to be feasible without substantial risk or morbidity, or if a patient with a surgical
option refuses surgery

- 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, or other 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 no prior radiation therapy should have been
directed at the target PN

- At least 4 weeks must have elapsed since receiving medical therapy directed at
the PN

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

- Patients who received prior medical therapy for their PN must have recovered from
the acute toxic effects of all prior therapy to =< grade 1 Common Terminology
Criteria for Adverse Events version 4 (CTCAE v4) before entering this study

- 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 NCI, 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 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 CD4 counts and who have no requirement for
antiviral therapy will be eligible

- Pregnant or breast-feeding females are excluded; 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

- Supplementation with vitamin E greater than 100% of the daily recommended dose

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

- 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

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

- Uncontrolled hypertension (despite medical therapy); blood pressure should be < 140/90
in accordance with American Heart Association definition of hypertension

- 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 either
induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and
CYP3A4

- Known cardiac disorder, including:

- Known inherited coronary disease

- Symptomatic heart failure (New York Heart Association [NYHA] class II-IV prior or
current cardiomyopathy, or severe valvular heart disease)

- Current cardiomyopathy

- Severe valvular heart disease

- Atrial fibrillation

- Ejection fraction (ECHO) < 53%

- QTcF > 450 msec

- Known ophthalmologic conditions, such as:

- Current or past history of central serous retinopathy

- 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 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

- Subjects with any other significant abnormality on ophthalmic examination 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 CTC AE grade >= 2, from previous anti-NF1
therapy, except for alopecia

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