Perampanel in Seizure Patients With Primary Glial Brain Tumors

This is a Phase 2 single-arm study to assess the efficacy of perampanel as an adjunctive
anti-epileptic drug (AED) in patients with primary glioma that are presenting refractory
partial onset seizure activity (defined as 3 or more seizures in a 28-day period). In this
study, patients will be started on a dose of 2 mg of perampanel daily taken orally at bedtime
for 2 weeks. At the start of week 3 perampanel will be titrated up in dose in 2mg increments
per week up to 8mg daily, as long as it is well tolerated by the patient. The highest dose of
perampanel will be 8 mg orally at bedtime. Once this is achieved, patients will remain on a
maintenance dose of 8 mg for 12 more weeks. The planned treatment dose is 8mg, but the dose
can be modified by the physician based on patient reported tolerability. Titration and taper
periods will be determined by the physician in the case where patients do not reach the
planned treatment dose of 8 mg daily. Patients will be assessed in the Brain Tumor Center
Clinic every 8 weeks. Study assessments will be made at enrollment, 8 weeks, 16 weeks, and 24
weeks. Assessments will include history and physical examination (H&P) including Karnofsky
Performance Status (KPS), neurological examination, evaluation of seizure history,
patient-reported outcomes of QoL, and computer based neurocognitive testing. After a total of
16 weeks of therapy, perampanel will be tapered for 3 weeks and then will be discontinued,
such that Week 20 patients will no longer be taking perampanel. Patients will then be
monitored through Week 24. Patients will continue to take their original AED regimen after
they stop perampanel. Patients will remain on their original AED regimen during this
treatment time and the dose of their original AED regimen at the start of the study will not
be changed while they are on study. If seizure control is achieved during the maintenance
period or if seizures occur during the tapering period, patients can be continued on
perampanel per the discretion of the treating physician. In this instance, perampanel will be
prescribed by the treating physician and not provided within the confines of the study.
Efficacy will be assessed using a log of patient-reported seizure activity. As is standard
procedure at the PRTBTC, patients will be given a log to record the number of seizures that
occur. Research team members will regularly contact patients for reminders and reports from
the log. Safety will be assessed with the following laboratory evaluations: complete blood
count (CBC) with differential, complete metabolic panel (CMP), and toxicity assessment.

This study has been designed with 90% power to detect an increase in the 50% responder rate
during the maintenance period from a benchmark of 20% to 35%. Assuming a type I error rate of
0.1, 61 patients will be required. Based on prior studies the early discontinuation rate was
16%, therefore 71 patients will be enrolled to compensate for patients discontinuing prior to
the completion of the maintenance period.

Inclusion Criteria:

1. Patients must be diagnosed with a primary glioma and have refractory partial onset
seizure activity (defined as 3 or more seizures in a 28-day period) on levetiracetam
monotherapy

2. Adult patients (≥ 18 years old)

3. Karnofsky ≥ 70%

4. Hematocrit ≥ 29%, ANC ≥ 1,500 cells/L, platelets ≥ 100,000 cells/L

5. Serum creatinine ≤ 1.5 mg/dL, serum AST and bilirubin ≤ 1.5 times the upper limit of
normal

6. If sexually active, patients will take contraceptive measures for the duration of
protocol treatment and continue until two months after treatment. The effectiveness of
hormonal contraceptives containing levonorgestrel has been shown to be reduced by
perampanel at a 12 mg dose.1 Therefore, alternative or back-up methods of
contraception are recommended.

7. Signed informed consent approved by the Duke Institutional Review Board

Exclusion Criteria:

1. Pregnant or breastfeeding (Both perampanel and other Anti-epileptic drugs are
classified as Pregnancy Category C drugs.)

2. Chronic excessive use of psycho-pharmaceuticals, alcohol, illicit drugs, or narcotics

3. Inability to complete or perform measures of patient-reported outcomes or
neurocognitive testing on the computer

4. Known allergy to perampanel

5. Concomitant use of known cytochrome P450 inducers such as carbamazepine, phenytoin, or
oxcarbazepine (see Appendix A)

6. Previous history of suicidal ideation, homicidal ideation, depression leading to
hospitalization or mood disturbance leading to hospitalization.