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.

Patients ≥ 1 year with progressive NF1 and PN(s) by serial imaging or causing significant morbidity and that can be analyzed by volumetric MRI are eligible for this study. Initially, the study will open to adult patients,18 years and older, (Stratum A). The pediatric patients (Statum B) will be receive the pediatric maximum tolerated dose (MTD) of binimetinib that is currently being established in an ongoing phase 1 study (NCT02285439). For adult subjects, binimetinib (established adult RP2D) is taken orally twice a day. Dosing will be continuous, with 28 days defined as a course and will continue for a total of 24 courses or until one of the Off Treatment or Off Study criteria are met. Subjects will undergo volumetric assays of their targeted PN using MRI after every 4 courses for the first year and then every 6 courses. MRI review of the volumetric assays will occur centrally under the guidance of Dr. Dombi at NCI. Subjects may receive additional courses beyond course 8 only if there is at least a 15% reduction in volume of the target tumor, as measured from baseline. Treatment beyond course 12 will be only be given to those subjects who achieve a response of ≥ 20% tumor shrinkage by volumetric analysis and can continue on therapy up to an additional year for a maximum of 24 total courses. For those who respond to binimetinib after 12 courses, an MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug in order to determine whether response is maintained post-therapy. Subjects will be carefully monitored for development of binimetinib associated toxicities. Subjects will be removed from the study for significant toxicity, treatment delay of ≥ 21 days, or objective progression of tumor growth by ≥ 20% by volumetric analysis at any time.

The investigational nature and objectives of this trial, the procedures and treatment involved, the risks, discomforts, and benefits, and potential alternatives therapies will be carefully explained to the subject and/or subject's parent(s) or guardian by the site Principal Investigator or designated associate investigator. A signed informed consent document will be obtained prior to determining eligibility and entry criteria to this trial. Subjects entered on this trial will be treated with therapeutic intent and response to therapy will be closely monitored. This protocol involves greater than minimal risk but presents the potential for direct benefit to individual subjects.

Schedule of study evaluations are summarized below:

Pre-Study (Eligibility Screening):

• Physical assessment, vital signs and neurological exam
• Complete medical history including past and current medical conditions, treatments, and surgeries.
• Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks
• Review of current medications
• Blood draw (about two tablespoons) for routine safety tests
• Serum or urine pregnancy test for females of childbearing age
• Eye exam
• Electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan of your heart
• MRI of neurofibroma tumors
• Functional evaluation: Depending on the location of your plexiform neurofibroma, specific functional assessments will be performed. The functional assessments may include a 6-Minute Walk-Test if you have a plexiform neurofibroma affecting your legs or airway, evaluation of muscle strength and range of motion if you have plexiform neurofibroma affecting your arms or legs, and/or grooved pegboard test if you have plexiform neurofibroma affecting your hands. The study team will review all evaluations that apply to you in detail
• Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist (upon study entry)
• Photography of visible PN (optional)

End of course 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24:

• Medical history update and hospitalization since last study visit
• Physical assessment, vital signs, and neurological exam
• Karnofsky/Lansky performance status to assess your ability to perform everyday tasks
• Review of your medication diary and any side effects you may be experiencing
• Review of current medications
• Blood draw (about two tablespoons) for routine safety tests
• Serum or urine pregnancy test for females of childbearing age

End of course 4, 8, 12, 18, and 24:

• Eye exam
• MRI of neurofibromas
• ECHO and ECG
• Functional evaluation: (see description above)
• Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist
• Photography of visible PN (optional): If you agree to take part, photographs of visible PN will be taken. Photos will be taken before treatment and then after cycles 4, 8, 12, 18, and 24.

End of course 1 and 4:

• Blood draw (about one tablespoon) for cytokine studies (optional)

End of Treatment Visit (this is an additional visit if the visit is not within the specified times mentioned above):

• Physical assessment, vital signs and neurological exam
• Medical history update and hospitalization since last study visit
• Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks
• Review of your medication diary and any side effects you may be experiencing
• Review of current medications
• Blood draw (about two tablespoons) for routine safety tests
• Serum or urine pregnancy test for females of childbearing age
• Eye exam
• Electrocardiogram (ECG) and ECHO or multigated acquisition (MUGA) scan of your heart
• MRI of neurofibroma tumors (for those who respond to binimetinib after 12 courses, an MRI at 4 and 12 months after stopping drug)
• Functional evaluation: (see description above)
• Completion of health-related questionnaires on quality of life, pain assessment, bowel and bladder dysfunction, and PN symptom checklist
• Photography of visible PN (optional)

The sample size is 20 subjects for each adult and children cohorts with a minimum target of 17 evaluable subjects per cohort. Evaluable is defined as: any subjects who received ≥ one dose of binimetinib and had a ≥ Grade 3 binimetinib associated toxicity, or in absence of a ≥ Grade 3 toxicity, any subjects who completed one full course of therapy; subjects who have completed at least two courses of therapy and had their first follow-up MRI evaluation except for discovery of a target tumor other than a PN; and any subjects who has at least two samples drawn for plasma cytokines/growth factors, one at baseline and at least one other after starting therapy.

Data Safety Monitoring Board (DSMB) and a Medical Monitor have been established for this study for the purpose of ensuring data compliance and regular monitoring. An early stopping rules have been defined within the protocol. The early stopping rule will invoked for both Strata separately to potentially prevent accrual subjects onto the study in the event that binimetinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT) requiring removal from study (10% or higher) during the first 2 courses. Toxicity will be continuously monitored. If at any time >2 of the first 10 subjects or 4 or more of the first 15 total subjects are removed for toxicity, then accrual will be stopped until the DSMB reviews the safety and efficacy data for the study. Based on the review, the DSMB can either recommend termination of the study or reopen recruitment. The Medical Monitor is a qualified physician who is not associated with this protocol and is a member of the DSMB. The Medical Monitor may perform oversight functions duties: may discuss the research protocol with the investigators, interview human subjects, and consult with others outside of the study about the research; shall have the authority to stop the research protocol in progress, remove individual subjects from protocol, and take whatever steps are necessary to protect the safety and well being of human subjects until the Institutional Review Board (IRB) can assess the monitor's report; and shall have the responsibility to promptly report the observation and findings to the IRB or other designated official/organization. The Medical Monitor is specifically required to review and provide written report of all unanticipated problems involving risk to subjects or others and serious adverse events.

In addition, as part of the Data Safety Monitoring Plan, the Study Chairs and the NF Consortium Clinical Research Nurse Manager will review subject eligibility, study progress, safety issues, protocol deviations and adverse events. Monthly reports will be generated by the NF Consortium Data Management Center to assess completeness of data. Monthly phone conferences will take place between NF Consortium Operations Center and the Protocol Team to address data issues.

The sample size for this trial is based on safety and feasibility factors. The data needed for safety is based on risk versus benefit, and for feasibility, we expect at least efficacy of 25% response rate. For safety reasons, subjects who do not achieve at least 15% reduction in volume of target tumor after 8 courses will be discontinued from the trial, as the likelihood of achieving a 20% reduction in tumor volume by 12 months is minimal. Safety analysis set will be described and summarized based on information regarding study treatment administrations, drug dosing and course compliance, and safety variables (e.g. adverse events/serious adverse events). All analyses for outcome results will be based on evaluable subjects. Given the difference in the clinical behavior of PN in the adults and pediatric subjects, the adult and children stratum will be analyzed independently.

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.