Binimetinib for the Treatment of Neurofibromatosis Type 1 Associated Plexiform Neurofibromas, PNOC010 Study

Inclusion Criteria

• INITIAL ENROLLMENT: All subjects must have EITHER the clinical diagnosis of NF1 using the National Institute of Health (NIH) Consensus Conference criteria, OR have a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified lab
• INITIAL ENROLLMENT: Subjects must have plexiform neurofibroma(s) that are progressive OR are causing significant morbidity, such as (but not limited to) head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. Subjects with paraspinal plexiform neurofibromas will be eligible for this trial. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected
• INITIAL ENROLLMENT: For subjects enrolled for tumor progression, progression is defined as: * Presence of new plexiform neurofibroma on MRI or computed tomography (CT) (documented by comparison with prior MRI or CT), OR * A measurable increase in plexiform neurofibroma size (>= 20% increase in the volume, or a >= 13% increase in the product of the two longest perpendicular diameters, or a >= 6% increase in the longest diameter) documented by comparison of two scans (MRI or CT) in the time period of approximately 18 months or less prior to evaluation for this study
• INITIAL ENROLLMENT: For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, eligible tumors will be limited to tumors of the head & neck or those on other areas of the body that are unable to be concealed by standard garments. In order to enroll a plexiform neurofibroma for these indications, the study chair and/or co-chair must be contacted to review subject eligibility prior to enrollment
• INITIAL ENROLLMENT: Measurable disease: Subjects must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, the target lesion must be seen on at least 3 consecutive MRI slices and the field of view must contain the entire tumor of interest. Tumors must be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria). If the tumor is < 3 cm in longest diameter, the subject may still be eligible. Central review of the MRI of the target plexiform is required prior to enrollment to ensure that the tumor is measurable and amenable to volumetric analysis. Central review will take 3-7 days (please plan accordingly)
• INITIAL ENROLLMENT: Stratum A: Subjects must be >= 18 years of age at the time of enrollment Stratum B: Subjects must be >=1 year and < 18 years of age at the time of study enrollment
• INITIAL ENROLLMENT: Karnofsky or Lansky >= 50% * Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• INITIAL ENROLLMENT: Subjects are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a subject with surgical option refuses surgery. Subjects 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. Subjects may have been 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 * Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this study * Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function * Biologic (anti-neoplastic agent): At least 4 weeks since the completion of therapy with a biologic 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. These subjects must be discussed with the study chair on a case-by-case basis * Investigational drugs: Subjects must not have received an investigational drug within 4 weeks * Steroids: Subjects 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 subject has received radiation to areas outside index plexiform neurofibroma(s). Subjects who have received radiation to the orbit at any time are excluded * Surgery: At least 3 weeks since undergoing any major surgery and must be recovered from effects of surgery
• INITIAL ENROLLMENT: Peripheral absolute neutrophil count (ANC) >= 1500/uL (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Hemoglobin >= 10.0 gm/dL without transfusions (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Maximum serum creatinine based on age/gender as per institutional standards OR a creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x upper limit of normal (ULN) for age (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Serum albumin >= 2 g/dL (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: 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
• INITIAL ENROLLMENT: Left ventricular fractions (LVEF) >= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram, and corrected QT (QTc) interval =< 480 ms (performed within 2 weeks prior to enrollment)
• INITIAL ENROLLMENT: Ability to comply with follow up procedures
• INITIAL ENROLLMENT: Negative urine or serum beta-human chorionic gonadotropin (HCG) test (females of childbearing potential only)
• INITIAL ENROLLMENT: Patients must have a weight of > 10 kg at enrollment
• RE-TREATMENT ARM: Participants who had a partial response to binimetinib, completed 24 courses of initial treatment and discontinued treatment at that time as per study protocol
• RE-TREATMENT ARM: Progression of the originally identified target PN (defined as > 20% increase in tumor volume compared with post course 24 volume) within one year of stopping initial treatment as per central review
• RE-TREATMENT ARM: Must have recovered to grade 1 or less from any prior binimetinib-related toxicities
• RE-TREATMENT ARM: Karnofsky or Lansky > 50%. Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• RE-TREATMENT ARM: Must meet all organ function requirements

Exclusion Criteria

• Chronic treatment with systemic steroids or another immunosuppressive agent. Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary
• Evidence of an active optic glioma or other low-grade glioma, requiring treatment with chemotherapy or radiation therapy. Subjects 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
• Subjects 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 discussion with the study chair. Patients with orbital plexiform neurofibromas should have IOP measured prior to enrollment * 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
• Uncontrolled arterial hypertension despite medical treatment defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher. Use age and gender appropriate normal values > 95th percentile ULN for pediatric patients
• 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 gastrointestinal [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)
• Subjects 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 breast feeding
• Any other condition that would, in the investigator’s judgment, contraindicate 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, social/psychological issues, etc
• History of noncompliance to medical regimens
• Subjects 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
• RE-TREATMENT ARM: Participants who stopped binimetinib treatment for any other reason other than discontinuation after completion of 24 courses of initial treatment as per protocol
• RE-TREATMENT ARM: Treatment with tumor-directed therapy for the target PN or any other tumor since discontinuing binimetinib
• RE-TREATMENT ARM: Surgery on the target PN since discontinuing binimetinib
• RE-TREATMENT ARM: > 13 months have elapsed since discontinuing binimetinib
• RE-TREATMENT ARM: All exclusion criteria must be met except for prior treatment with a MEK inhibitor of any kind