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

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)