A Phase II Study of Binimetinib in Children and Adults with NF1 associated Plexiform Neurofibromas (PNOC010)

This is a phase II open label study that will evaluate children ≥ 1 year of age and adults
with neurofibromatosis type 1 (NF1) and plexiform neurofibromas treated with the MEK
inhibitor, binimetinib. The primary objective is to determine if there is an adequate level
of disease responsiveness to binimetinib in children and adults with NF1 and inoperable
plexiform neurofibromas. The objective response to binimetinib is defined as ≥ 20% decrease
in tumor volume reduction by 12 courses.

Inclusion Criteria

- Clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR a documented
constitutional NF1 mutation

- Plexiform neurofibroma(s) that are progressive or causing significant morbidity

- Presence of new plexiform neurofibroma on MRI or CT (documented by comparison with
prior MRI or CT)

- Measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. Tumors must
be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria)

- Patients must be ≥ 18 years of age at the time of enrollment.

- Performance Level: Karnofsky or Lansky ≥ 50%. If unable to walk due to paralysis, but
in a wheelchair, patients will be considered ambulatory for the purpose of assessing
the performance level

- Ability to swallow capsules/tablets

- Ability to comply with follow up procedures

- The effects of binimetinib 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, for
the duration of study participation, and 3 months after completion of binimetinib
administration. 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.

- Negative urine or serum β-HCG test (females of childbearing potential only).

Prior Therapy:

- Patients are eligible if complete resection of a plexiform neurofibroma with
acceptable morbidity is not feasible, or if a subject with surgical option refuses
surgery,

- Patients who underwent surgery for a progressive plexiform neurofibroma will be
eligible to enter the study after the surgery, provided the plexiform neurofibroma was
incompletely resected and is evaluable by volumetric analysis.

- Patients previously treated for a plexiform neurofibroma or other tumor/malignancy,
but must have fully recovered from the acute toxic effects of all prior chemotherapy
or radiotherapy prior to entering this study.

- Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this
study.

- At least 7 days since the completion of therapy with a hematopoietic growth factor
that supports platelet, red or white cell number or function.

- At least 4 weeks since the completion of therapy with a biologic anti-neoplastic
agent. For agents that have known adverse events occurring beyond 14 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur.

- Patients must not have received an investigational drug within 4 weeks.

- Patients with endocrine deficiencies are allowed to receive physiologic or stress
doses of steroids, if necessary.

- Radiation ≥ 6 months from involved field radiation to index plexiform neurofibroma(s),
≥ 6 weeks must have elapsed if patient has received radiation to areas outside index
plexiform neurofibroma(s). Patients who have received radiation to the orbit at any
time are excluded.

- At least 3 weeks since undergoing any major surgery and must be recovered from effects
of surgery.

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 for at least 7 days prior to enrollment)

- Hemoglobin ≥ 10.0 gm/dL without transfusions.

- Adequate renal function defined as:

- Maximum serum creatinine based on age/gender or a creatinine clearance or
radioisotope GFR ≥ 70 ml/min/1.73 m²

- Adequate liver function defined as:

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

- SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN) for age

- Serum albumin ≥ 2 g/dL

- Adequate cardiac function defined as:

- Left ventricular fractions (LVEF) ≥ 50% as determined by a multigated acquisition
(MUGA) scan or echocardiogram

- QTc interval ≤ 480 ms.

Exclusion Criteria

- Chronic treatment with systemic steroids or another immunosuppressive agent.

- Evidence of an active optic glioma or other low-grade glioma, requiring treatment with
chemotherapy or radiation therapy. Patients not requiring treatment are eligible for
this protocol.

- Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other
malignancy requiring treatment in the last 12 months.

- Patients who have received radiation to the orbit at any time previously.

- Ophthalmologic conditions:

- 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 review. Patients with orbital plexiform neurofibromas should have
IOP measured prior to enrollment.

- Patients with any other significant abnormality on ophthalmic examination will be
reviewed 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

- Uncontrolled arterial hypertension despite medical treatment defined as CTCAE grade 3
or higher.

- Impaired cardiovascular function or clinically significant cardiovascular diseases,
including:

- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
months prior to screening

- Symptomatic chronic heart failure, history or current evidence of clinically
significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to
screening except atrial fibrillation and paroxysmal supraventricular tachycardia

- Other concurrent severe and/or uncontrolled medical disease, which could compromise
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,
severe infection, severe malnutrition, chronic liver or renal disease, active upper GI
tract ulceration, congestive heart failure, etc.)

- Subjects who have an uncontrolled infection.

- Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
and/or active hepatitis C infection.

- Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
bowel resection).

- History of Gilbert's syndrome or patients who are known to be homozygous for UGT1A1
(7/7).

- Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
muscular atrophy)

- Patients who are planning to embark on a new strenuous exercise regimen after first
dose of study treatment. NB: muscular activities, such as strenuous exercise, that can
result in significant increases in plasma CK levels should be avoided while on
binimetinib treatment.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to binimetinib.

- Women who are pregnant or breastfeeding.

- Any other condition that would contraindicate, in the Investigator's judgement, the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g. infection/inflammation, intestinal obstruction,
unable to swallow medication, social/ psychological issues, etc.

- History of noncompliance to medical regimens.

- Patients unwilling to or unable to comply with the protocol, or who in the opinion of
the investigator may not be able to comply with the safety monitoring requirements of
the study.

- Prior treatment with a MEK inhibitor of any kind.