A Phase II Study of Binimetinib in Children and Adults with NF1 associated Plexiform Neurofibromas

PNOC010 / NF108

Rationale for Study

Neurofibromatosis type 1 (NF1) is a common autosomal dominant, genetic disorder with an incidence of 1:3000. NF1 is caused by a mutation in the NF1 tumor suppressor gene. NF1 is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign peripheral nerve tumors. These tumors may cause significant morbidity including disfigurement and pain, and may be life-threatening when they compress vital structures such as the spinal cord, trachea and great vessels. Recent clinical data provide a strong rationale for targeting MEK in the treatment of NF1-associated neoplasms in patients. Binimetinib (also known as MEK162 or ARRY-438162) is a potent, selective, allosteric small-molecule inhibitor of MEK that is uncompetitive with adenosine triphosphate (ATP). Binimetinib is currently being evaluated clinically in healthy subjects and in cancer patients.

Trial Requirement/Treatment

Patients with NF1 and PN(s) that are progressive (growing) or causing significant morbidity will take binimetinib by mouth twice a day. One course is 28 days. Subsequent courses will immediately follow, with no break in the administration of drug. Clinical assessment will be required every 4 months for the first 12 months, then every 6 months for the next 12 months.

Primary Objectives

To determine the proportion of children and adults with NF1 associated plexiform neurofibromas who will have an objective response to binimetinib defined as a 20% or greater decrease in tumor volume reduction by 12 courses.

Secondary Objectives

To evaluate the feasibility and toxicity of protracted binimetinib administration in this patient population. 

Inclusion Criteria

Key Inclusion Criteria:

  • Clinical diagnosis of NF1 or constitutional NF1 mutation
  • Progressive plexiform neurofibromas or PNs that are causing significant morbidity
  • PNs must be measurable by MRI
  • Age ≥ 1 year
  • Karnofsky ≥50 for patients >16 years of age and Lansky ≥50 for patients ≤ 16 years of age
  • 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 imaging. 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. Please contact for further details of prior therapy restrictions.
  • Adequate Bone Marrow Function
  • Adequate Renal Function
  • Adequate Liver Function
  • Adequate Neurologic Function
  • Adequate Cardiac Function
  • Negative pregnancy test

 Exclusion Criteria

Key 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 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: central serous retinopathy; retinal vein occlusion; known intraocular pressure > 21 mmHg or uncontrolled glaucoma; subjects with any other significant abnormality on exam.
  • Uncontrolled arterial hypertension despite medical treatment.
  • Impaired cardiovascular function or clinically significant cardiovascular diseases
  • Other concurrent sever 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, active hepatitis B, and/or active hepatitis C infection.
  • Impairment of gastrointestinal function or gastrointestinal disease.
  • History of Gilbert’s syndrome or patients who are known to be homozygous for UGT1A1.
  • Patients who have neuromuscular disorders that are associated with elevated CK
  • 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.
  • Prior treatment with a MEK inhibitor of any kind.

Note: Other protocol Inclusion/Exclusion criteria apply