Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas

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 echocardiogra