Binimetinib for the Treatment of Pediatric Progressive or Recurrent Adamantinomatous Craniopharyngioma

Inclusion Criteria

• Patients must be ≥ 12 months and ≤ 25 years of age at the time of study enrollment.
• Patients with histologically-confirmed adamantinomatous craniopharyngioma (ACP) * Histologic confirmation of ACP may be made on solid tumor or, if no solid tumor can be safely obtained, cyst fluid with classic ACP characteristics of thick, cholesterol-rich, greenish-brown liquid in the context of imaging features consistent with craniopharyngioma, including lobulated, cystic/solid mass with calcifications that originates in the sellar/suprasellar region.
• Patients must have measurable disease. * Stratum 1: Patients with progressive or recurrent ACP who demonstrate cystic and/or solid recurrence or progression at least 6 months post completion of radiation therapy * Stratum 2: Patients with measurable ACP who have undergone surgery but have NOT previously undergone irradiation (but may have received prior systemic or intracystic therapy). Progressive disease is allowed but not required.
• Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age. Note: Neurologic deficits in patients with central nervous system (CNS) tumors must have been stable for at least 7 days prior to study enrollment. Patients 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.
• Patients must have recovered or stabilized from the acute toxic effects of prior treatments. * Biologic (anti-neoplastic agent): At least 7 days must have elapsed after the last (systemic or intracystic) dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. * Immunotherapy: At least 42 days after the completion of any type of systemic immunotherapy, e.g. tumor vaccines. * Monoclonal antibodies: At least 21 days after the last dose of a monoclonal antibody. * Radiation therapy: Patients must have had their last (conventional or hypofractionated) fraction of: ** Focal irradiation > 6 months prior to enrollment ** No prior craniospinal irradiation is permitted. * Corticosteroids: Patients receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment * Myelosuppressive systemic therapy: At least 21 days must have elapsed after the last systemic myelosuppressive therapy. * Surgery: At least 6 weeks must have elapsed since surgery. * MEK inhibitors: patients should not have received prior therapy with any other MEK inhibitors
• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm^3
• Platelet count ≥ 1000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Hemoglobin > 8 g/dL (may be transfused)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female) * 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female) * 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female) * 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female) * 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female)
• Total bilirubin ≤ 1.5 x institutional upper limit of normal
• Aspartate transferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) ≤ 2.5 x institutional upper limit of normal
• Alanine transaminase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal
• Left ventricular ejection fraction greater than the institutional lower limit of normal by echocardiogram
• Corrected QT interval (QTc) ≤ 480 msec (by Bazett formula)
• Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment.
• Patients with current seizure disorders may be enrolled if seizures are well-controlled on antiepileptic therapies.

Exclusion Criteria

• Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for at least 90 days after discontinuation of drug for females and at least 60 days for males. For females of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods (bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices; hormonal contraceptive methods must be supplemented by a barrier method) and agreement to refrain from donating eggs are required. For males of reproductive potential, agreement to remain abstinent (i.e., refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.
• Patients with a history of serious gastrointestinal disease, including poorly controlled or active inflammatory bowel disease or gastrointestinal perforation
• Patients who are unable to swallow, retain or absorb oral medications
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
• Patients who are currently receiving another investigational drug are not eligible.
• Patients who are currently receiving other anti-cancer agents are not eligible.
• Patients who have an uncontrolled infection are not eligible.
• Patients who have any significant concurrent medical or surgical condition that would jeopardize the patient’s safety or ability to complete the study, including, but not limited to, disease of the nervous, renal, hepatic, cardiac (such as symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), pulmonary, or endocrine system or a concurrent malignancy.
• Patients who have received a prior solid organ transplantation are not eligible.
• Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients who have a history of alcohol, drug, or chemical abuse within 6 months of screening.
• Patients who have had surgery within the last 6 weeks or who have concerns for poor postsurgical wound healing.
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to binimetinib and its excipients are not eligible.
• Patients who have a current or past history of significant retinal disease, such as central serous retinopathy, retinal vein occlusion or retinal detachment.