Clinical trial NCT04497142
Conditions: Glioma, Malignant Surgery Seizures
Keywords: Glioma Surgery Seizures
Sponsor: Dana-Farber Cancer Institute
Start date: 2020-11-05; Completion date: 2023-05-16
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to learn more about seizures in people with primary brain tumors. It will evaluate whether an antiseizure medication decreases hyperexcitability activity around tumors and prevents seizures.

The procedure and study drug involved in this study are:

* Electrocorticography
* Perampanel (Fycompa)

Detailed description:
This research study is a Pilot Study, which is the first time investigators are examining brain activity after taking perampanel.

The U.S. Food and Drug Administration (FDA) has approved perampanel as a treatment option for seizures. It has not been approved for the treatment of brain tumors. Recording of brain activity (electrocorticography) during surgery is an established clinical procedure, which will be performed for investigational purposes. This research study is studying brain recordings and perampanel treatment in participants with brain tumors for the following reasons:

* People with brain tumors commonly have seizures.
* Perampanel was developed as an anti-seizure medication, which works by blocking a signaling pathway between brain cells, mediated by AMPA receptors.
* Previous research has shown abnormal brain activity around tumors resulting from increased AMPA receptor activation.
* Perampanel is expected to decrease abnormal brain activity and prevent seizures by blocking AMPA receptor signaling.

This study involves two groups of participants, one group who receives the antiseizure medication perampanel, and the other group who receives the usual antiseizure medication (typically levetiracetam) at the time of surgery. Participants have the option to choose which group to participate if they have a preference.

The research study procedures include screening for eligibility, recording brain activity during surgery, and study treatment including evaluations and follow up visits. Participants will receive the study drug for as long as they do not have serious side effects and their disease does not get worse, up to a maximum of 12 months.

It is expected that about 20 people will take part in this research study.

The National Institute of Health (NIH) is supporting this study by providing funding for the research. Eisai Inc, a pharmaceutical company, is supporting this research study by providing the study medication.

Arms: arm 1: * Participants will take a predetermined first dose of perampanel on the day before their tumor surgery
* During surgery, an approximately 4x6cm recording grid will be placed on the surface of the brain over the tumor, and brain activity around the tumor will be recorded for 10 minutes during surgery (Electrocorticography).
* After surgery participants will take perampanel at a predetermined dose once a day for as long as they do not have serious side effects and their disease does not get worse, up to a maximum of 12 months. Participants will be provided a drug and seizure diary to document drug and seizure information and have monthly study visits either in clinic or by phone. arm 2: * Participants will receive standard of care medication before surgery.
* During surgery, an approximately 4x6cm recording grid will be placed on the surface of the brain over the tumor, and brain activity around the tumor will be recorded for 10 minutes during surgery (Electrocorticography).
* After surgery participants will take standard of care medications as predetermined by their doctor. Participants will be provided a drug and seizure diary to document drug and seizure information and have monthly study visits either in clinic or by phone.
* Participants will be followed up to 12 months after completing surgery.
Interventions: intervention 1: Perampanel intervention 2: Standard of Care
Intervention descriptions: intervention 1: Tablet taken orally 1x daily. intervention 2: Predetermined standard of care drug and dosing

Protocol documents:
Prot_SAP_001.pdf: 
 
 
                                                                     Office for Human Research Studies
  
Notification of IRB Outcome - Approval
 
Date:  July 27, 2020
To:     Jong Woo Lee
From: The Office for Human Research Studies (OHRS)
 
 On 07/27/2020 the IRB reviewed the following protocol:
IRB Protocol Number:20-059
Type of Review:Submission Response for Initial Review Submission Packet
Title:Pilot study of perampanel on peritumoral hyperexcitability and seizure control in newly diagnosed 
high grade glioma
Principal Investigator: Lee, Jong Woo
iRIS Reference Number:349473
Review Process:Expedite 
Sponsor(s): DF/HCC Investigator, Dana-Farber/Harvard Cancer Center, NIH Brain SPORE
Submit Date:07/03/2020 11:13:06 AM EDT
Participating Sites:Brigham and Women's Hospital (BWH)      
Documents Revised:
Submission Components Approved
Document Type
Version
Date Approved
Submission-Initial Review Submission Packet
Version 1.1
 
Attachment Form-Study Team List
Version 1.0
 
Consent Form-Clean Consent Cohort 2
Version 4.0
07/27/2020
Consent Form-Clean Consent Cohort 1
Version 4.0
07/27/2020
Document-Subject Reimbursement Form
Version 1.0
07/27/2020
Document-Biomedical Protocol
Version 7.0
07/27/2020
Document-Drug Diary
Version 2.0
07/27/2020
Document-Seizure diary
Version 1.0
07/27/2020
 
 
 
Current state of additional determinations (made previously or on this submission):   
Risk Level:
Greater than Minimal Risk under 45 CFR 46 / 
21 CFR 56 
 
Investigational 
Drug Use:
IND Exempt as per 21 CFR 312 
 
Documentation 
of Consent:
Written consent in accordance with 45 CFR 
46.117/ 21 CFR 50.27 
 
HIPAA:
HIPAA Authorization for research approved 
under 45 CFR 164.508 (a) (1) 
Partial waiver of HIPAA Authorization for 
Research approved under 45 CFR164.512 (i) 
(2) (ii) 
 


1 
NCI Protocol #: N/A 
 
DF/HCC Protocol #: 20-059  
 
TITLE:  Pilot study of perampanel on peritumoral hyperexcitability and seizure control in newly 
diagnosed high grade glioma 
 
Coordinating Center: 
 
 
Brigham and Women’s Hospital 
 
*Principal Investigator (PI): 
Jong Woo Lee, MD, PhD 
 
Brigham and Women’s Hospital 
 
jlee38@bwh.harvard.edu 
 
Other Investigators: 
Steven Tobochnik, MD 
 
Brigham and Women’s Hospital 
 
stobochnik@bwh.harvard.edu 
 
 
Daniel Weisholtz, MD 
 
Brigham and Women’s Hospital 
 
dweisholtz@partners.org 
 
 
Patrick Wen, MD 
 
Dana-Farber Cancer Institute 
 
patrick_wen@dfci.harvard.edu 
 
 
Antonio Chiocca, MD, PhD 
 
Brigham and Women’s Hospital 
 
eachiocca@bwh.harvard.edu 
 
 
Alexandra Golby, MD 
 
Brigham and Women’s Hospital 
 
agolby@bwh.harvard.edu 
 
 
Pier Paolo Peruzzi, MD, PhD 
 
Brigham and Women’s Hospital 
 
pperuzzi@bwh.harvard.edu 
 
 
Timothy Smith, MD, PhD, MPH 
 
Brigham and Women’s Hospital 
 
trsmith@bwh.harvard.edu 
 
 
W. Linda Bi, MD, PhD 
 
Brigham and Women’s Hospital 
 
wbi@bwh.harvard.edu 
 
 


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Nathalie Agar, PhD 
 
Brigham and Women’s Hospital 
 
nathalie_agar@dfci.harvard.edu 
 
 
Statistician: N/A 
 
Study Coordinator: N/A 
 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
 
NCI-Supplied Agent(s): N/A 
Other Agent(s): 
Perampanel 
NSC # N/A 
Eisai Inc. 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
SCHEMA 
 
Cohort 1 will be recruited and treated concurrently with Cohort 2 
 
 
 
HGG =  high grade glioma 
ECoG = electrocorticography 
SF = seizure frequency 
PD = progressive disease 


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TABLE OF CONTENTS 
 
SCHEMA…………… .....................................................................................................................2 
1. 
OBJECTIVES.. ....................................................................................................................5 
1 
Study Design ............................................................................................................5 
1.1 
Primary Objectives ...................................................................................................5 
1.2 
Secondary Objectives ...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Study Disease(s) .......................................................................................................5 
2.2 
IND Agent(s) ...........................................................................................................6 
2.3 
Other Agent(s) ..........................................................................................................6 
2.4 
Rationale ..................................................................................................................7 
2.5 
Correlative Studies Background ..............................................................................7 
3. 
PARTICIPANT SELECTION .............................................................................................8 
3.1 
Eligibility Criteria ....................................................................................................8 
3.2 
Exclusion Criteria ....................................................................................................9 
3.3 
Inclusion of Women and Minorities ......................................................................10 
4 
REGISTRATION PROCEDURES ...................................................................................10 
4.1 
General Guidelines for DF/HCC Institutions ........................................................10 
4.1 
Registration Process for DF/HCC Institutions .......................................................11 
4.2 
General Guidelines for Other Investigative Sites ..................................................11 
4.3 
Registration Process for Other Investigative Sites .................................................11 
5. 
TREATMENT PLAN ........................................................................................................11 
5.1. 
Treatment Regimen ................................................................................................11 
5.2. 
Pre-Treatment Criteria ...........................................................................................12 
5.3. 
Agent Administration .............................................................................................12 
5.4. 
General Concomitant Medication and Supportive Care Guidelines ......................12 
5.5. 
Criteria for Taking a Participant Off Protocol Therapy .........................................12 
5.6. 
Duration of Follow Up ...........................................................................................13 
5.7. 
Criteria for Taking a Participant Off Study ...........................................................13 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................14 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................14 
7.1. 
Adverse Event List .................................................................................................14 
7.2. 
Adverse Event Characteristics ...............................................................................15 
7.3. 
Adverse Event Reporting .......................................................................................15 
7.4. 
Reporting to Hospital Risk Management ...............................................................16 
7.5. 
Routine Adverse Event Reporting .........................................................................16 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................16 


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8.1. 
Perampanel .............................................................................................................16 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................18 
9.1. 
Electrocorticography ..................................................................................19 
9.2. 
Laboratory Correlative Studies ..................................................................19 
10. 
STUDY CALENDAR .......................................................................................................20 
11. 
MEASUREMENT OF EFFECT .......................................................................................22 
11.1. Antitumor Effect ....................................................................................................22 
11.2. Seizure Response ...................................................................................................25 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................25 
12.1. Data Reporting .......................................................................................................25 
12.2. Data Safety Monitoring ..........................................................................................25 
12.3. Collaborative Agreements Language .....................................................................26 
13. 
STATISTICAL CONSIDERATIONS...............................................................................26 
13.1. Study Design/Endpoints ........................................................................................26 
13.2. Sample Size, Accrual Rate and Study Duration ....................................................27 
13.3. Stratification Factors ..............................................................................................27 
13.4. Interim Monitoring Plan ........................................................................................27 
13.5. Analysis of Primary Endpoints ..............................................................................27 
13.6. Analysis of Secondary Endpoints ..........................................................................27 
13.7. Reporting and Exclusions ......................................................................................28 
14. 
PUBLICATION PLAN .....................................................................................................28 
REFERENCES……… ..................................................................................................................29 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................32 
APPENDIX B 
MULTI-CENTER GUIDELINES .............................................................33 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS ..............................................................................................................34 
APPENDIX D 
BIOASSAY TEMPLATES .......................................................................36 
 


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1. OBJECTIVES 
 
Study Hypothesis #1: Perampanel treatment reduces peritumoral hyperexcitability in newly 
diagnosed high grade glioma (HGG). 
 
Study Hypothesis #2: Perampanel treatment in newly diagnosed HGG is associated with 
improvement in seizure control. 
 
1 
Study Design 
 
This pilot study (Cohort 1) in participants with newly discovered radiologic lesions consistent 
with HGG evaluates the effect of perampanel on peritumoral hyperexcitability, measured by the 
rate of high frequency oscillations on intra-operative electrocorticography (ECoG), compared to 
a contemporary observational control group (Cohort 2) of participants undergoing ECoG and 
standard peri-operative seizure management. To estimate the effect size of early perampanel 
treatment on ongoing seizure control, participants in Cohort 1 will be maintained post-
operatively on perampanel, adjusted on a clinical basis until evidence of disease progression (or 
maximum of 12 months), and compared to participants in Cohort 2 receiving standard of care 
post-operative seizure management.  
 
1.1 
Primary Objectives 
 
Primary Objective: Measure the effect of perampanel on peritumoral hyperexcitability using 
intraoperative ECoG at the time of initial glioma resection. We will analyze high frequency 
oscillations (80-500 Hz) as a biomarker of peritumoral hyperexcitability and epileptogenicity. 
The rate of high frequency oscillations over 10 minutes of recording in the tumor margins will be 
compared between perampanel treated participants (Cohort 1) and control participants (Cohort 
2). 
 
1.2 
Secondary Objectives 
 
Secondary Objective: Estimate the clinical effect of perampanel maintenance therapy on seizure 
control. We will measure seizure-free rates between the time of initial glioma resection and 
radiographic tumor progression (up to a maximum of 12 months), in participants continued on 
perampanel post-operatively (Cohort 1) compared to control participants (Cohort 2).  
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
This study evaluates peritumoral hyperexcitability and tumor-associated seizures in HGG, 
including WHO Grade III anaplastic astrocytoma and WHO Grade IV glioblastoma. Seizures are 
seen in up to 60% of patients with HGG,1 and contribute to decreased quality of life.2 While 
seizures generally occur earlier in the disease course, up to half of patients with HGG and 


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glioma-associated epilepsy continue to have uncontrolled seizures despite anti-seizure 
medications.3,4 To date, there are no evidence-based guidelines or widely accepted standards of 
care regarding the use and duration of anti-seizure medications to prevent seizures in this 
population, or evidence to guide the choice of one anti-seizure medication over another.5 
 
Different glioma subtypes have unique propensities for the development of seizures, suggesting 
that gliomagenesis and epileptogenesis are inter-related, and that variable mechanisms may be 
involved.6,7 Among the mechanistic pathways with the most experimental evidence is 
dysregulation of glutamatergic signaling, whereby excitatory glutamatergic signaling pathways 
are upregulated in the glioma microenvironment, and contribute to excitotoxicity.7,8 Preclinical 
studies demonstrate an increase peritumoral glutamatergic hyperexcitability mediated through 
multiple mechanisms, including activation of the system xc- cystine-glutamate transporter, and 
AMPA-receptor mediated neuron-glioma synaptic activity.9,10 Recent evidence indicates that 
glioma growth is dependent on glutamatergic neuronal activity, mediated by the release of 
neuroligin-3 and the downstream activation of PI3K-mTOR signaling.8,11,12 Glutamate release 
from glioma cells leads to the development of neuronal-glial synaptic connections, 
hyperexcitability, and further tumor growth in a positive feedback loop. Thus, excessive 
excitatory signaling appears to be a shared mechanism underlying tumor growth and 
epileptogenesis, and a promising therapeutic target. 
 
The clinical relevance of peritumoral hyperexcitability in management of glioma-associated 
epilepsy remains uncertain, however early evidence linking glioma growth with excessive 
neuronal synaptic activity offers the possibility of targeted therapies with enhanced efficacy.8,10 
Through its anti-glutamatergic actions, the AMPA-receptor antagonist perampanel has been 
shown to inhibit glioblastoma growth in vitro,13 and has been associated with radiologic glioma 
responses in a small clinical case series.14 In a small series patients with glioma-associated 
epilepsy refractory to at least two anti-seizure medications, perampanel resulted in seizure 
freedom in half of cases.15 Therefore, perampanel treatment may have the potential to inhibit 
neuronal activity-dependent glioma progression and improve seizure control through reduction 
of peritumoral hyperexcitability. 
 
2.2 
IND Agent(s) 
 
N/A 
 
2.3 
Other Agent(s) 
 
Perampanel is a non-competitive AMPA-receptor antagonist, which obtained initial FDA 
approval in 2012 for the adjunctive treatment of focal and generalized epilepsy, and gained FDA 
approval in 2017 for use as monotherapy for the treatment of focal epilepsy. In three placebo-
controlled trials of perampanel in drug-resistant focal epilepsy, a combined response rate (≥50% 
seizure reduction) was observed in 19%, 29%, 35%, and 35% of patients treated with placebo, 
4mg, 8mg, and 12mg, respectively.16  
 
With high bioavailability (~100%) and blood-brain barrier penetration,17 and long half-life 
(average 105 hours), effective levels in the brain can be achieved after a single loading dose. 


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Doses up to 32mg have been used safely in humans, and a median dose of 6mg has been found to 
terminate status epilepticus after a median of 24 hours.18 The minimum therapeutic dose is 4mg 
daily. In placebo-controlled trials, the rate of perampanel discontinuation due to adverse effects 
in subjects receiving doses of 4mg was 3%, compared to 5% receiving placebo.16 Given these 
data, perampanel will be given as a single loading dose of 6mg on the day prior to resection, then 
continued at 4mg daily. Additional dose adjustments will be made on a clinical basis, as per 
institutional standards. Dose and schedule modifications will not affect the objectives of this 
study. 
 
Perampanel is extensively metabolized via primary oxidation (primarily mediated by CYP3A4/5 
and to a lesser extent by CYP1A2 and CYP2B6) and sequential glucuronidation. Perampanel is 
eliminated mostly in the feces (48%) and to a lesser extent in the urine (22%). Moderate and 
strong CYP3A4 inducers decrease plasma levels of perampanel by approximately 50-67%.16 
 
2.4 
Rationale 
 
Preclinical studies of glioma-associated epilepsy demonstrate an increase in peritumoral 
glutamatergic hyperexcitability mediated through multiple mechanisms, including activation of 
the system xc- cystine-glutamate transporter,9,19 and AMPA-receptor mediated neuron-glioma 
synaptic activity.10,12 Through its anti-glutamatergic actions, perampanel has demonstrated both 
anti-tumor and anti-seizure effects in vitro and in vivo.13,14 In one series of patients with glioma-
associated epilepsy, perampanel was associated with a reduction in tumor volume in half of 
cases, correlated with plasma drug levels.14 Additionally, objective seizure responses of 75-100% 
have been reported in small series of patients with drug-resistant glioma-associated epilepsy 
treated with perampanel after the failure of at least two other anti-seizure medications.14,15 Thus, 
perampanel treatment may have the potential to inhibit neuronal activity-dependent glioma 
progression and improve seizure control through reduction of peritumoral hyperexcitability. 
Since glioma progression is independently associated with increased seizure frequency,1,20 this 
study aims to correlate perampanel use with reduction in peritumoral hyperexcitability at initial 
diagnosis, and estimate the effect of maintenance therapy on seizure control up to the time of 
progressive disease. 
 
 
2.5 
Correlative Studies Background 
 
Interictal high frequency oscillations (HFOs) measured using intracranial EEG have been 
previously associated with the seizure onset zone,21–23 and resection of regions generating HFOs 
associated with improved seizure outcomes in retrospective analyses of surgical epilepsy series.24 
High frequency activity has also been demonstrated in peritumoral regions in intra-operative 
ECoG recordings,10,25 representing a promising biomarker of peritumoral epileptogenicity. As 
described in Section 1, the primary objective is a correlative study testing the hypothesis that 
perampanel will reduce peritumoral HFOs through a mechanism of targeting excessive 
peritumoral glutamatergic activity. 
 
Glioma-related excitotoxicity is primarily attributed to excessive glutamate release and impaired 
re-uptake in the peritumoral environment.26 In-vivo microdialysis in the tumor margins of high 


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grade gliomas have demonstrated a metabolic profile involving decreases in glucose, and 
increases in lactate/pyruvate ratios, glutamate, and glycerol concentrations.27 However, whether 
specific electrophysiologic signatures reflect these local metabolic tissue changes remains 
uncertain. This protocol involves a correlative tissue analysis of peritumoral metabolites and 
principal excitatory/inhibitory neurotransmitters to define excitotoxic changes in relation to 
electrophysiologic excitability. Molecular analysis will be performed using a mass spectrometry 
method that bypasses the needs for systemic injections of molecular probes required for 
traditional molecular imaging methods. 
 
Mass spectrometry is a well-established analytical technique used to identify and characterize 
molecules based upon their accurate mass. More specifically here, we will use Matrix Assisted 
Laser Desorption Ionization (MALDI) mass spectrometry imaging (MSI) to directly map the 
distribution of metabolites and neurotransmitters in tissue sections with correlation to 
histopathology evaluation of the tissue.  
 
3. 
PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have radiologic evidence of anaplastic astrocytoma or glioblastoma 
multiforme within 14 days of enrollment. 
 
3.1.2 Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension as ≥10 mm (≥1 cm) with CT or MRI.  See 
Section 11 (Measurement of Effect) for the evaluation of measurable disease. 
 
3.1.3 Age ≥18 years.   
 
3.1.4 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 Participants must have adequate organ and marrow function as defined below: 
 
- 
leukocytes  
 
≥3,000/mcL 
- 
absolute neutrophil count 
 
≥1,500/mcL 
- 
platelets  
 
≥100,000/mcL 
- 
total bilirubin 
 
≤ institutional upper limit of normal (ULN) 
- 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN 
- 
glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 (see Appendix B) 
 
3.1.6 Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.7 For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV 
viral load must be undetectable on suppressive therapy, if indicated. 
 
3.1.8 Participants with a history of hepatitis C virus (HCV) infection must have been treated 


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9 
and cured.  For participants with HCV infection who are currently on treatment, they are 
eligible if they have an undetectable HCV viral load. 
 
3.1.9 Participants with a prior or concurrent malignancy whose natural history or treatment 
does not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.10 Participants with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, participants should be class 2B or better. 
 
3.1.11 The effects of perampanel on the developing human fetus are unknown. For this reason 
and because some anti-seizure medications are known to be teratogenic, 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 and for the duration of study 
participation.  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. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants with brain metastases due to confounding effects on the study objectives. 
 
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to perampanel. 
 
3.2.3 Participants receiving any medications or substances that are moderate or strong inducers 
of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is 
important to regularly consult a frequently-updated medical reference.  As part of the 
enrollment/informed consent procedures, the participant will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the participant is considering a new over-the-counter medicine or herbal product. 
 
3.2.4 Participants with uncontrolled intercurrent illness. 
 
3.2.5 Participants with psychiatric illness/social situations that would limit compliance with 
study requirements. 
 


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3.2.6 Pregnant women are excluded from this study because perampanel is an anti-seizure 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with perampanel, breastfeeding should be discontinued if the mother is treated 
with perampanel. 
 
3.2.7 Participants with a history of suicide attempt or current active suicidal ideation with 
intent as defined by Columbia Suicide Severity Rating Scale (C-SSRS) type 4-5, due to 
the potential for suicidal ideation with the use of all anti-seizure medications. 
 
3.2.8 Participants who are unable to swallow pills. 
 
3.2.9 Participants with tumor associated seizures greater than one month before planned 
surgery. 
 
3.2.10 Participants currently receiving treatment with more than one anti-seizure medication. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4 
REGISTRATION PROCEDURES 
 
In order to maximize enrollment into the pilot study over a short time, and given the difficulty in 
recruiting participants within a narrow pre-operative time window, we will perform concurrent 
recruitment into the single arm pilot group (Cohort 1) and a contemporary observational control 
group (Cohort 2). Eligible participants will be informed and provided the consent forms for both 
study groups, and those who have no preference will be enrolled in the cohort with the smaller 
current enrollment, while those who express a preference will be enrolled into the cohort of their 
preference (up to a maximum enrollment of 10 per cohort). This will enable eligible participants 
to be enrolled who decline to be randomized. We do not anticipate a systemic bias in endpoints 
using this method of enrollment, as potentially confounding factors (described in Section 13) are 
not expected to influence enrollment preferences, although we cannot completely exclude it. 
 
4.1 General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 


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Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off study in the CTMS (OnCore) with an appropriate date and reason 
entered.   
 
4.1 
Registration Process for DF/HCC Institutions 
 
Applicable DF/HCC policy (REGIST-101) must be followed.   
 
4.2 General Guidelines for Other Investigative Sites 
 
N/A 
 
4.3 Registration Process for Other Investigative Sites 
 
N/A 
 
 
5. TREATMENT PLAN 
 
5.1. Treatment Regimen 
 
Perampanel will be given every day until meeting the study endpoint(s). Reported adverse events 
and potential risks are described in Section 7. Appropriate dose modifications are described in 
Section 6. Other anti-seizure medication(s) may be administered during perampanel maintenance 
therapy as clinically indicated. 
 
Cohort 1 
Participants who are already receiving an anti-seizure medication pre-operatively for treatment 
of tumor-associated seizures will receive their last dose at least 36 hours before scheduled 
surgery start-time, and then will be switched to perampanel. The loading dose of perampanel will 
be 6mg by mouth, given on the day prior to surgery (12-36 hours before scheduled start time), 
followed by a maintenance dose of 4mg by mouth once a day. Participants will be requested to 
maintain a drug diary of each dose of medication.  The drug diary will be returned to clinic staff 
at the end of each month. 
 
Study day 
Perampanel dose 
Day 1 (load) 
6mg 
Day 2+ (maintenance) 
4mg 
 
Cohort 2 
Perioperative and post-operative seizure management will be performed by the primary treating 
physician(s) according to institutional standards. 
 


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5.2. Pre-Treatment Criteria 
 
N/A 
 
5.3. Agent Administration 
 
5.3.1. CTEP and/or CIP IND Agent(s), or other IND agent 
 
N/A 
 
5.3.2. Other Agent(s) 
 
Perampanel: 
Each perampanel dose will be a single tablet taken by mouth once a day. A loading dose of 6mg 
will be administered 12-36 hours prior to planned surgery start time. Maintenance dosing of 4mg 
will start 24 hours after the loading dose, and continued daily. Perampanel may be administered 
with or without food. It should not be crushed, chewed, or dissolved. Doses should be retaken if 
missed or vomited. There is no specific observation period required. There are no specific 
caregiver precautions. 
 
5.3.3. Other Modality(ies) or Procedures 
 
Electrocorticography (ECoG): 
Intraoperative electrocorticography (ECoG) will be performed for 10 minutes using an Xltek 
machine (Natus Medical Inc, Pleasanton, CA), sampled at 1000 Hz per channel, with a subdural 
4x5 electrode grid overlying the tumor margins, according to institutional clinical protocols. At 
least 10 minutes prior to ECoG, inhaled anesthetics and propofol infusion will be stopped, as per 
standard institutional practices. Subsequent tumor resection will be performed at the discretion of 
the neurosurgeon, and high frequency activity will be analyzed independently post-operatively 
(see Section 9.1). 
 
5.3.4. Investigational Imaging Agent Administration 
 
N/A 
 
5.4. General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of perampanel with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Overall PI should 
be alerted if the participant is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes. Appendix C presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
5.5. Criteria for Taking a Participant Off Protocol Therapy 
 


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Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
12 months or until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the study protocol when any of these criteria apply.  The 
reason for removal from protocol, and the date the participant was removed, must be documented 
in the case report form (CRF). Alternative care options will be discussed with the participant. 
Perampanel may be continued on a clinical basis by the primary treating physician. If the 
participant is taken off protocol for active suicidal ideation with intent (defined by the Columbia 
Suicide Severity Rating Scale Type 4-5), the Principal Investigator will arrange for immediate 
psychiatric evaluation. 
 
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. 
 
5.6. 
Duration of Follow Up 
 
Participants will be followed as clinically indicated after removal from protocol or until death, 
whichever occurs first. Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. After completion 
of the study, if the treating neurologist cannot be contacted or the participant no longer wishes to 
see their treating neurologist, the principal investigator will help the participant to transition care 
to a different treating neurologist and will follow them clinically until then. 
 
5.7. Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Disease progression 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 


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The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure the 
participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Perampanel dose modifications are permitted as clinically indicated to optimize seizure control 
and minimize adverse effects. Dose adjustment may be performed by the primary treating 
neurologist and/or study investigators. For any adjustment, the Principal Investigator, Dr. Lee, 
will be notified. A maximum daily maintenance dose for this study will be 8mg.  
 
At the completion of the study, if perampanel is not clinically indicated and/or planned to be 
withdrawn, the daily dose will be tapered down by 2mg per week to the minimum therapeutic 
dose of 4mg, then stopped. If perampanel is being discontinued for lack of seizure efficacy, an 
alternative anti-seizure medication chosen at the discretion of the primary treating neurologist 
will be started and titrated to a therapeutic dose, after which perampanel will be tapered off as 
above. If the participant experiences a serious adverse event attributed to perampanel, the drug 
may be stopped immediately if, at discretion of the Principal Investigator, the benefits outweigh 
the risks. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1. 
Adverse Event List 
 
7.1.1. Adverse Event List for Perampanel 
 
Based on pooled adverse events seen in ≥2% of patients and more frequently than 
placebo in controlled trials of perampanel at a dose of 4mg for drug-resistant focal 
epilepsy (N=172),16 the most likely adverse events to be seen in this study include:  
- dizziness 
- somnolence 
- irritability 
- fatigue 
- vertigo 
- anxiety 
- weight gain 
- oropharyngeal pain 
 
Participants will be referred to the package insert(s) for the comprehensive list of 


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adverse events. 
 
7.2. Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version  5.0.  A copy of the CTCAE version  5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. Adverse Event Reporting  
 
7.3.1. In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
7.3.2. Investigators must report to the Overall PI any adverse event (AE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of 
treatment on the local institutional SAE form.  
 
7.3.3. DF/HCC Adverse Event Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.3.4. Protocol-Specific Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 


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Events not considered to be serious adverse events for this protocol are: 
 
-Hospitalization for seizure 
 -Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 
7.4. Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy.  
 
7.5. Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the agent administered in this 
study can be found in Section 7.1. 
 
8.1. Perampanel 
 
8.1.1. Description 
 
The chemical name of the active ingredient is 2-(1′,6′-dihydro-6′-oxo-1′-phenyl[2,3′-
bipyridin]-5′-yl)-benzonitrile, hydrate (4:3). The molecular formula is C23H15N3O • 
3⁄4H2O and the molecular weight is 362.90 (349.39 for anhydrous perampanel). 
 
Perampanel is rapidly and completely absorbed after oral administration with negligible 
first-pass metabolism. Median time to reach peak concentration (tmax) ranged from 0.5 to 
2.5 hours under fasted condition. Co-administration of perampanel tablet with a high fat 
meal had no impact on the total exposure (AUC0-inf) of perampanel and reduced the peak 
plasma concentration (Cmax) of perampanel by 11%-40%. The tmax was delayed by 
approximately 1-3 hours in fed state compared to that under fasted conditions. 
 
Data from in vitro studies indicate that, in the concentration range of 20 to 2000 ng/mL, 
perampanel is approximately 95- 96% bound to plasma proteins, mainly bound to 
albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55-0.59. 
 
Perampanel is extensively metabolized via primary oxidation and sequential 
glucuronidation. Oxidative metabolism is primarily mediated by CYP3A4/5 and to a 
lesser extent by CYP1A2 and CYP2B6, based on results of in vitro studies using 
recombinant human CYPs and human liver microsomes. Other CYP enzymes may also 


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be involved. 
 
Following administration of radiolabeled perampanel, unchanged perampanel accounted 
for 74-80% of total radioactivity in systemic circulation, whereas only trace amounts of 
individual perampanel metabolites were detected in plasma. 
 
Following administration of a radiolabeled perampanel tablet dose to 8 healthy elderly 
subjects, 22% of administered radioactivity was recovered in the urine and 48% in the 
feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of 
oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled 
data from 19 Phase 1 studies reported that t1/2 of perampanel was 105 hours on average. 
Apparent clearance of perampanel in healthy subjects and patients was approximately 12 
mL/min. 
 
The concomitant use of known moderate and strong CYP3A4 inducers including 
carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma 
levels of perampanel by approximately 50-67%. 
 
Perampanel Cmax and AUC0-72h were not altered when a single 6-mg dose of perampanel 
tablet was administered to healthy female subjects following a 21-day course of oral 
contraceptives containing ethinylestradiol 30 μg and levonorgestrel 150 μg. Co-
administration of perampanel 4 mg tablet once daily with an oral contraceptive 
containing ethinylestradiol 30 μg and levonorgestrel 150 μg for 21 days did not alter Cmax 
or AUC0-24h of either ethinylestradiol or levonorgestrel in healthy female subjects. In 
another study, a single dose of the oral contraceptive was administered following 21-day 
once daily dosing of perampanel 12 mg or 8 mg tablets in healthy females. Perampanel at 
12 mg did not alter AUC0-24h of ethinylestradiol but decreased its Cmax by 18%, and also 
decreased Cmax and AUC0-24h of levonorgestrel by 42% and 40%, respectively. 
Perampanel at 8 mg did not have significant effect on Cmax or AUC0-24h of either 
ethinylestradiol or levonorgestrel, with a decrease in AUC0-24h of levonorgestrel (9% on 
average). 
 
8.1.2. Form 
 
Perampanel drug product will be as follows: 
-4mg tablet, red, round, debossed with “4” on one side and “Є 277” on the other 
-6mg tablet, pink, round, debossed with “6” on one side and “Є 294” on the other 
-8mg tablet, purple, round, debossed with “8” on one side and “Є 295” on the other 
 
Tablets contain the following inactive ingredients: lactose monohydrate, low substituted 
hydroxypropyl cellulose, povidone, microcrystalline cellulose, magnesium stearate, 
hypromellose, polyethylene glycol, talc, titanium dioxide, red ferric oxide (4mg, 6mg, 
8mg), black ferric oxide (8mg). 
 
8.1.3. Storage and Stability 
 


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Tablets: store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). 
 
8.1.4. Compatibility 
 
There are no known compatibility issues. 
 
8.1.5. Handling 
 
Routine handling is recommended. 
 
8.1.6. Availability 
 
Perampanel is commercially available and manufactured by Eisai Inc; it will be provided 
free of charge for this study by Eisai. 
 
8.1.7. Preparation 
 
No preparation is required. 
 
8.1.8. Administration 
 
Perampanel will be administered by mouth once a day. 
 
8.1.9. Ordering 
 
Investigators will order and acquire perampanel directly from Eisai Inc. 
 
 
8.1.10. Accountability 
 
The investigator, or a responsible party designated by the investigator, will maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11. Destruction and Return 
 
Perampanel will be destroyed on site or returned to the research pharmacy according to 
institutional policies, and documented in the Drug Accountability Record Form. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 


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9.1. 
Electrocorticography 
 
As the primary outcome for this study, HFOs will be measured in intra-operative ECoG 
recordings from all participants in Cohort 1 and Cohort 2. ECoG data will be analyzed post-
operatively. HFOs will be visually identified after filtering (FIR, order 500, bandpass 80-500 Hz) 
using Persyst Insight (Persyst Development Corp, Solana Beach, CA). The rate of HFOs per 
channel per subject will measured for analysis. 
 
ECoG is a standard clinical procedure utilized for epilepsy and brain tumor surgery. There will 
be no deviations from standard institutional protocols for this study. The investigators are 
experienced in the performance of this procedure and analysis of ECoG data. The use of ECoG is 
expected to increase the length of surgery by 15-20 minutes. 
 
There is a low chance (3-4%) that ECoG may reveal subclinical electrographic seizures or highly 
epileptiform activity that would not be otherwise identified,31 and would allow for immediate 
treatment to decrease the risk of intra-operative brain injury. 
 
 
9.2. 
Laboratory Correlative Studies 
 
9.2.1. Intraoperative Stereotactic Molecular Imaging 
 
This protocol involves an optional ancillary/exploratory tissue study involving mass 
spectrometry analysis and histopathology evaluation. The aim of this correlative analysis is to 
measure the metabolic profile, neurotransmitter profile, and study drug tissue distribution in 
resected tissue specimens. Although glutamatergic excitotoxicity is thought to contribute to 
tissue necrosis,26 the relationship between excitotoxic tissue injury and electrophysiologic 
biomarkers in human glioma is poorly understood. We hypothesize that peritumoral 
hyperexcitability and excitotoxic metabolic profiles will be correlated with the tissue distribution 
and concentration of anti-seizure medications in the peritumoral microenvironment. We propose 
to study the correlation between ECoG high frequency activity, histopathology, drug tissue 
distribution, neurotransmitter concentrations, and metabolic profile from surgical specimens.  
 
This analysis of surgical tissue will be performed in collaboration with Dr. Nathalie Agar, using 
methods according to Partners IRB protocol 2011P002387. Identification of drug and 
metabolites in surgical tissue specimens will be performed with MALDI MSI and a 
neuronavigation system to allow the subsequent infusion of molecular information into the MRI. 
This technique has been validated by Dr. Agar and collaborators for detection of tumor 
metabolites,32 tumor subtype classification,33 and therapeutic drug distribution.34 Given that 
multiple samples will be analyzed per participant, this study enrolling up to 20 participants 
across cohorts will be sufficient to demonstrate interpretable and meaningful results.  
 
9.2.1.1. 
Collection of Specimens 
No changes will be made to the routine clinical care of patients in this study. All aspects of the 
surgical management including preoperative and postoperative care will be carried out per the 
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will not affect the manner or quantity of tissue removed. In addition to the bulk tumor specimen 
as routinely sent, numerous small specimens will be collected during the resection using tumor 
forceps at sampling positions registered to pre-operative MRI images using a navigation system 
(General Electric Instatrak or BrainLab Vector Vision). All specimens will be sent to the BWH 
Tissue Biorepository. When the Tissue Biorepository has confirmed that enough tissue has been 
collected to make a diagnosis, specimens will be made available MALDI MSI.  
 
9.2.1.2. 
Handling of Specimens 
Specimens for correlative analysis will be banked by the SPORE Pathology Core (Directors: 
David Louis MD, Keith Ligon MD, PhD). A dedicated pathology banking assistant will track 
and collect tissue for fresh, frozen, and culture analysis. The tissue will be quality control 
screened by a banking Neuropathologist Staff and scored for percentage tumor composition, 
necrosis, inflammation, and normal brain tissue content. Specimens will be analyzed by MALDI 
MSI (Bruker Daltonics), and associated with histopathology for tumor cell prevalence and select 
histological features. Microscopy images of standard histopathology staining will be co-
registered with mass spectrometry images of a given tissue section to resolve the molecular 
signature of distinct histology features such as cell density, necrosis, and vascularization. The 
histopathological validation will be correlated to radiology and clinical information via Mirax 
Digital Slide Desktop (MDSD) database (Zeiss). As part of this study, we will study the 
differences in the molecules that occur within different regions of the tumor (e.g. at the 
boundaries between tumor and normal tissues). Metabolic profiling will involve analysis of 
tissue pH, lactate, pyruvate, and lipid composition. Neurotransmitter profiling will involve 
analysis of glutamate, glutamine, and GABA composition. Drug distribution will be performed 
for perampanel and levetiracetam.   
 
9.2.1.3. 
Shipping of Specimens 
Specimens will not be shipped off site. 
 
9.2.1.4. 
Sites Performing Correlative Study 
Tissue analysis will be performed at BWH by Nathalie Agar. All correlative analyses will be 
performed at BWH. 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans  
must be done <2 weeks prior to the start of therapy. If the participant’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours of assessment. Study visits will be 
performed at monthly intervals by clinic or phone interviews. Clinical response will be evaluated 
at each study visit. Adverse events will be assessed with each study visit at minimum, and more 
frequently as clinically indicated.


21 
 
Baseline 
 
Pre-surgery 
 
During surgery 
Post-surgery 
maintenance 
Off Studyd 
Perampanel administration 
(Cohort 1) 
 
A 
 
Every day 
 
Electrocorticography 
 
 
X 
 
 
Tumor biopsy 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Concurrent Medications 
X-----------------------------------------------------------------------------------------------------X 
Physical exam 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
 
 
 
 
Performance status 
X 
 
 
Every month 
 
B-HCG 
Xb 
 
 
 
 
Serum chemistrya 
X 
 
 
 
 
Seizure Frequency 
X 
 
 
Every month 
 
Tumor Measurements 
X 
 
 
Xc 
 
Radiologic Evaluation 
X 
 
 
Xc 
 
Adverse Event Evaluation 
 
X------------------------------------------------------------------------------Xe 
A: 
Perampanel: Dose as assigned 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (women of childbearing potential). 
c: 
At discretion of primary treating neuro-oncologist. 
d: 
Perampanel may be continued on a clinical basis off protocol. 
e: 
Adverse events will be evaluated up to 30 days after study completion. 
 


22 
 
11. MEASUREMENT OF EFFECT 
 
11.1. Antitumor Effect 
 
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed according to institutional standards at the discretion of the primary treating 
neuro-oncologist.  For the purposes of this study, participants will be re-evaluated after every 
MRI for the study endpoint of progressive disease or death, defined by the criteria proposed by 
the Response Assessment in Neuro-Oncology (RANO) working group.35 
 
11.1.1. Definitions 
 
Evaluable for objective response. Only those participants who have measurable disease 
present at baseline and have received at least one dose of therapy will be considered 
evaluable for response. These participants will have their response classified according to 
the definitions stated below. Participants who exhibit objective disease progression or die 
prior to the end of the first month will also be considered evaluable. 
 
11.1.2. Disease Parameters 
 
Measurable disease. Bidimensionally, contrast-enhancing, measurable lesions with 
clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible 
on 2 axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor 
around a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If 
there are too many measurable lesions to measure at each evaluation, the investigator 
must choose the largest two to be followed before a participant is entered on study. The 
remaining lesions will be considered non-measurable for the purpose of objective 
response determination. Unless progression is observed, objective response can only be 
determined when all measurable and non-measurable lesions are assessed. 
 
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1cm. 
 
11.1.3. Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 2 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
 
 
 


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11.1.4. Response Criteria 
 
Complete response (CR). All of the following criteria must be met:  
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease.  
b) No new lesions.  
c) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
d) Participants must be on no steroids or on physiologic replacement doses only.  
e) Stable or improved non-enhancing (T2/FLAIR) lesions.  
f) Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related. Participants with non-measurable disease cannot 
have a complete response. The best response possible is stable disease.  
 
Partial response (PR). All of the following criteria must be met:  
a) Greater than or equal to 50% decrease compared to baseline in the sum of products 
of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered 
only stable disease.  
b) No progression of non-measurable disease.  
c) No new lesions.  
d) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
e) The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan.  
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan.  
g) Stable or improved, for clinical signs and symptoms present at baseline and 
recorded to be disease related clinically. 
 
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease.  
 
Progressive disease (PD). The following criterion must be met:  
a) 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (over best response or baseline if no decrease) on stable or increasing 
doses of corticosteroids  
and/or one or more of the of the following:  
b) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids steroids compared to baseline scan or best response following 
initiation of therapy, not due to co-morbid events (radiation therapy, demyelination, 
ischemic injury, infection, seizures, post-operative changes, or other treatment 
effects).  
c) Any new lesion.  


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d) Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g. seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.). The definition of clinical deterioration is left to the discretion 
of the investigator, but it is recommended that a decline in the Karnofsky 
Performance Score (KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 
from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 
days, be considered neurologic deterioration, unless attributable to co-morbid events 
or changes in corticosteroid dose.  
e) Failure to return for evaluation due to death or deteriorating condition. 
 
Stable disease (SD). All of the following criteria must be met:  
a) Does not qualify for CR, PR, or progression.  
b) All measurable and non-measurable sites must be assessed using the same 
techniques as baseline.  
c) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been 
increased, the last scan considered to show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to the baseline dose.  
d) Stable clinically. Unknown response status. Progressive disease has not been 
documented and one or more measurable or non-measurable lesions have not been 
assessed. 
 
11.1.5. Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6. Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 


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Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
 
11.1.7. Response Review 
 
Review of MRI or CT scans will be performed by Dr. Wen or his designee. 
 
11.2. Seizure Response 
 
Seizure response will be evaluated every 4 weeks for the secondary endpoint of time to seizure 
recurrence, measured from the date of surgery. Seizure frequency will be monitored using a 
seizure diary form completed by participants and reviewed every 4 weeks. Baseline seizure 
frequency will be defined by the number of clinical seizures reported by participants in the 
month preceding surgery. Seizure freedom is defined by the absence of seizures. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1. Data Reporting 
 
12.1.1. Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2. Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2. Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 


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PI and study team. 
 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of 
all deaths while being treated and during active follow-up; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request.  
 
12.3. Collaborative Agreements Language 
 
N/A 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a pilot study with a primary electrophysiologic outcome and a secondary exploratory 
clinical outcome of seizure response. The protocol is statistically powered to detect a meaningful 
reduction in peritumoral hyperexcitability as measured by high frequency activity on ECoG. For 
the secondary outcome, this protocol is intended to estimate the seizure response effect size of 
early perampanel treatment on tumor-associated seizures in HGG. 
 
13.1. Study Design/Endpoints 
 
Pilot Study: Preliminary Study 
• Primary objective: Compare rates of peritumoral HFOs (mean number of HFOs per 
minute) between participants treated with perampanel versus standard of care. 
• Secondary objective: Compare time to seizure recurrence between participants treated 
with perampanel versus standard of care up to the time of HGG progression. 
• Maximum total accrual: 10 participants in Cohort 1, 10 participants in Cohort 2. 
• Sample size justification: Using the mean HFO rate across participants receiving standard 
of care (Cohort 2) as the normalized ineffective rate (P1=1.0), we define a target effective 
rate for the treatment arm (Cohort 1) of P2=0.60. Using a two sample power calculation, 
the intended sample size of 10 participants in each cohort will provide 82.5% power to 
detect a true 40% or greater reduction in the normalized mean HFO rate with perampanel 
compared to standard of care (a=0.05, two-sided). 
• Statistical methods for primary objective: The primary endpoint is the mean number of 
HFOs per minute. This will be averaged across participants in each cohort, and compared 
using the Mann-Whitney U test (two-sided, α=0.05). In sensitivity analyses, we will 
compare HFO rates between cohorts stratified by potential confounding variables, 
including temporal lobe tumor location, IDH1/2 mutation, and pre-operative seizures. 
• Statistical methods for secondary objective: The secondary endpoint is the time to first 
post-operative seizure. Time to first post-operative seizure will be estimated in time-to-
event analysis from the date of surgery using the Kaplan-Meier method. Comparison 


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between Cohort 1 and Cohort 2 will be performed using the log-rank test (a=0.05). In 
sensitivity analyses, we will compare time to first post-operative seizure between cohorts 
stratified by potential confounding variables, including temporal lobe tumor location, 
extent of resection (gross total vs subtotal resection), presence of IDH1/2 mutation, and 
presence of pre-operative seizures. 
• Data processing and statistical analysis will be performed using R 3.5.3 (The R 
Foundation for Statistical Computing). 
• These results will be used to support or refute the hypothesis that perampanel has targeted 
anti-epileptogenic activity in glioma-associated epilepsy, and may inform the design and 
feasibility of future clinical studies of targeting the glutamatergic pathway in this patient 
population. 
 
Correlative Analysis: Intraoperative Stereotactic Molecular Imaging 
• Aim 1: Correlate lactate/pyruvate ratio by mass spectrometry with HFO rate in adjacent 
ECoG electrodes. 
• Aim 2: Correlate glutamate and GABA signal intensities by mass spectrometry imaging 
with HFO rate in adjacent ECoG electrodes. 
• Aim 3: Correlate anti-seizure drug signal intensity by mass spectrometry imaging with 
HFO rate in adjacent ECoG electrodes. 
• Statistical analysis: correlations will be measured using Spearman’s rank correlation 
coefficient. 
 
13.2. Sample Size, Accrual Rate and Study Duration 
 
A total of 20 evaluable participants will be accrued within one year (up to 10 participants per 
cohort). Up to an additional 12 months of follow-up will be required on the last participant 
accrued to observe the participant’s response to protocol therapy, for a total study duration of 2 
years. There are no defined ethnic or racial accrual targets. 
 
13.3. Stratification Factors 
 
N/A 
 
13.4. Interim Monitoring Plan 
 
All participants will undergo continuous safety monitoring. 
 
13.5. Analysis of Primary Endpoints 
 
See Section 13.1 
 
13.6. Analysis of Secondary Endpoints 
 
See Section 13.1 
 


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13.7. Reporting and Exclusions 
 
13.7.1. Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.7.2. Evaluation of the Primary Efficacy Endpoint 
 
All participants in Cohort 1 who receive at least one dose of study treatment and all 
participants in Cohort 2 will be evaluable for response. 
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
MULTI-CENTER GUIDELINES 
 
N/A 


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APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
Perampanel interacts with many drugs that are processed by your liver.  Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study.  It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Perampanel interacts with a certain specific enzyme(s) in your liver.  
• The enzyme in question is/are CYP3A4, and perampanel is broken down by this enzyme in 
order to be cleared from your system. 
• Perampanel must be used very carefully with other medicines that need these liver enzymes 
to be effective or to be cleared from your system.   
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 


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o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking perampanel. 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.   
 
Your study doctor’s name is Jong Woo Lee, MD, PhD, and he or she can be contacted at 617-
732-7432. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
BIOASSAY TEMPLATES 
 
N/A