Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors

Inclusion Criteria

• •Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.
• •The NIH criteria includes presence of:
• •Bilateral vestibular schwannomas, OR
• •First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.
• •The Manchester criteria includes presence of:
• •Bilateral vestibular schwannomas, OR
• •First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
• •Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
• •Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract.
• •\- Patients do not need to have a histologic diagnosis in order to start therapy but must have measurable disease (in 2 dimensions) on MRI scan to be eligible.
• •For Stratum 1: Patients must have a target VS with the following qualities:
• •Associated with a word recognition score of \< 85% and \> 0% AND
• •Documented progression defined as: Either progressive hearing loss or progressive tumor growth in last 18 months defined as ≥ 20% increase in volume.
• •For Stratum 2: Patients must not meet the eligibility criteria as stated for Stratum 1 and have a target lesion that has exhibited progression.
• •Progression is defined as: ≥ 25% increase in sum of the products of perpendicular diameters of lesions in the preceding 18 months; any new lesion; or clinical deterioration related to disease.
• •\- Patients must be able to swallow capsules
• •* Age:
• •Patients must be ≥ 3 years to ≤ 45 years of age at start of treatment
• •\- Prior Therapy
• •Since there is no standard effective chemotherapy for patients with NF2 and vestibular schwannomas, meningiomas, or ependymomas patients may be treated on this trial without having received prior medical therapy directed at their VS, meningiomas, or ependymomas.
• •Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for these NF2 patients.
• •Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to entering this study except for alopecia.
• •Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea.
• •Biologic agent: Patient must have received their last dose of the biologic agent ≥ 7 days prior to study registration. For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration
• •Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration
• •\- Corticosteroids:
• •Patients who are receiving dexamethasone or other corticosteroids must be on a stable or decreasing dose for at least 1 week prior to registration. It is recommended that patients be off all steroid therapy or receive the least dose that will control their neurologic symptoms
• •\- Prior radiotherapy
• •XRT: ≥ 6 months must have elapsed if prior XRT to vestibular schwannoma or other tumor.
• •\- Stem Cell Transplant or Rescue without TBI:
• •No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since transplant.
• •\- Performance Status:
• •Karnofsky ≥ 60% for patients \> 16 years of age
• •Lansky ≥ 60 for patients ≤ 16 years of age.
• •\- 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 within a 7 day period prior to registration)
• •Hemoglobin ≥ 9 g/dL (may receive RBC transfusions)
• •Adequate Renal Function Defined as:
• •Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or
• •A serum creatinine ≤1.5×ULN for age and sex
• •Adequate Liver Function Defined as:
• •Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
• •AST(SGOT)/ALT(SGPT) ≤2.5×ULN institutional upper limit of normal for age
• •Central Nervous System Function:
• •\- Patients with seizure disorder may be enrolled if they are receiving non-enzyme inducing anticonvulsants and the seizures are well controlled.
• •Cardiac Function
• •Adequate cardiac function defined as:
• •LVEF ≥55% by ECHO
• •QTc interval ≤450 msecs by EKG
• •Hypertension
• •Patients, 3 to \< 18 years of age must have a blood pressure that is ≤ 95th percentile for age, height and gender at the time of registration.
• •Patients who are ≥18 years of age must have a blood pressure that is \<140/90 mm of Hg at the time of registration.
• •Patients may be on blood pressure medication provided that it is not on the contraindicated list and that the medication has not been adjusted in the previous 3 months.
• •\- Growth factors: All colony forming growth factor(s) have been discontinued for at least one week prior to registration (filgrastim, sargramostim, and erythropoietin). For patients on long acting growth factors, the interval should be two weeks.
• •Inclusion of Women and Minorities Both males and females of all races and ethnic groups are eligible for this study.
• •Informed Consent:
• •All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.