Phase 1 Study of ABI-009 (Nab-rapamycin) for Surgically-Refractory Epilepsy (RaSuRE)
Phase: PHASE1
Conditions: Epilepsy Intractable
Sponsor: Seattle Children's Hospital

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Seattle Children's Hospital
Clinical Research Protocol
Phase 1 study of ABI-009 (nab-rapamycin) for Surgically-Refractory Epilepsy (RaSuRE)
Protocol Number:
RS-001
Version Date:
October 31, 2018
Investigational Product:
ABI-009 (nab-rapamycin, AADi Bioscience, Inc)
IND Number:
139135
Development Phase:
Phase 1
Sponsor-Investigator:
Jason S. Hauptman, MD PhD
Seattle Children’s Hospital
4800 Sand Point Way NE
Seattle, WA 98105
Approval:
PI or Sponsor Signature (Name and Title)
Date
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time.  The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure.  Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information.  

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and providing 
the Sponsor-Investigator with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol.
Protocol Number:  RS-001
Protocol Title:  Phase 1 study of ABI-009 (nab-rapamycin) for Surgically-Refractory Epilepsy 
(RaSuRE)
Protocol Date:  10/31/2018
Investigator Signature
Date
Print Name and Title
Site Name:
Seattle Children's Hospital
Address:
4800 Sand Point Way NE
Seattle, WA 98105

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TABLE OF CONTENTS
1
BACKGROUND ...............................................................................................................................17
1.1
INTRACTABLE EPILEPSY IN CHILDREN .......................................................................................................17
1.2
CLINICAL CHARACTERISTICS OF PEDIATRIC EPILEPSY SURGERY PATIENTS................................................18
1.3
PERIOPERATIVE CONSIDERATIONS AND SURGICAL APPROACHES...............................................................19
1.4
OUTCOMES AFTER EPILEPSY NEUROSURGERY IN CHILDREN ......................................................................20
1.5
MTOR ........................................................................................................................................................20
1.6
MTOR AND EPILEPSY......................................................................................................................................23
1.7
OVERVIEW OF CLINICAL EFFECTS OF MTOR INHIBITORS ON SEIZURES....................................................24
1.8
ABI-009....................................................................................................................................................25
1.9
PRECLINICAL PHARMACOLOGY, PHARMACOKINETICS, AND TOXICITY OF ABI-009 .................................25
1.10
CLINICAL PHARMACOKINETICS OF ABI-009.............................................................................................26
1.11
CLINICAL STUDIES WITH ABI-009.....................................................................................................................26
1.12
CLINICAL EXPERIENCE WITH ABI-009 IN PEDIATRIC PARTICIPANTS ........................................................27
1.13
COMPARISON OF EXPOSURE OF ABI-009 AND ORAL MTOR INHIBITORS..................................................28
1.14
DISTRIBUTION OF ABI-009 IN THE BRAIN.................................................................................................30
2
STUDY RATIONALE......................................................................................................................31
2.1
RISK / BENEFIT ASSESSMENT....................................................................................................................32
3
STUDY OBJECTIVES.....................................................................................................................34
3.1
PRIMARY OBJECTIVE.................................................................................................................................34
3.2
SECONDARY OBJECTIVES.................................................................................................................................34
3.3
EXPLORATORY OBJECTIVES......................................................................................................................35
4
STUDY DESIGN...............................................................................................................................35
4.1
STUDY OVERVIEW ....................................................................................................................................35
5
CRITERIA FOR EVALUATION ...................................................................................................36
5.1
PRIMARY ENDPOINTS................................................................................................................................36
5.2
SECONDARY ENDPOINTS...........................................................................................................................36
6
PARTICIPANT SELECTION.........................................................................................................37
6.1
STUDY POPULATION..................................................................................................................................37
6.2
INCLUSION CRITERIA ................................................................................................................................37
6.3
EXCLUSION CRITERIA ...............................................................................................................................38
7
CONCURRENT MEDICATIONS..................................................................................................39
7.1
ALLOWED MEDICATIONS AND TREATMENTS ............................................................................................40
7.2
PROHIBITED MEDICATIONS AND TREATMENTS .........................................................................................40
8
STUDY DRUG DOSING..................................................................................................................40
8.1
METHOD OF ASSIGNING PARTICIPANTS TO DOSING GROUPS ....................................................................40
8.2
BLINDING..................................................................................................................................................40
8.3
FORMULATION OF TEST AND CONTROL PRODUCTS...................................................................................40
8.4
SUPPLY OF STUDY DRUG TO THE SITE.......................................................................................................41
8.5
DOSE-LIMITING TOXICITIES......................................................................................................................41
8.6
DOSE MODIFICATION OR DISCONTINUATION OF STUDY DRUG .................................................................41
8.7
MANAGEMENT OF KNOWN ADVERSE EVENTS ASSOCIATED WITH MTOR INHIBITORS ................................43
8.8
STUDY DRUG ACCOUNTABILITY...............................................................................................................46
9
STUDY PROCEDURES AND GUIDELINES...............................................................................46

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9.1
CLINICAL ASSESSMENTS...........................................................................................................................46
9.2
CLINICAL LABORATORY MEASUREMENTS............................................................................................................48
9.3
PHARMACOKINETIC MEASUREMENTS .......................................................................................................49
9.4
RESEARCH LABORATORY MEASUREMENTS ..............................................................................................49
9.5
SPECIMENS FOR LONG-TERM BIOREPOSITORY STORAGE..........................................................................49
10
EVALUATIONS BY VISIT.............................................................................................................49
10.1
SCREENING ASSESSMENTS (DAY -14 TO 0) ...............................................................................................49
10.2
VISIT 1 – MAY ALSO BE SCREENING VISIT (DAY 0)....................................................................................50
10.3
VISIT 2 – END OF BASELINE (DAY 30 +5/-2 DAYS)....................................................................................50
10.4
VISITS 3, 4, & 5: ABI-009 DOSES 1-3 (+/-2 DAYS) ..........................................................................................51
10.5
VISIT 6: POST-DOSING ONE-WEEK ASSESSMENT (+/-2 DAYS) ..................................................................51
10.6
FOLLOW-UP VISITS 7, 8, & 9: 30, 60, AND 90 DAYS POST-DOSING (+/-7 DAYS)........................................52
10.7
EARLY PERMANENT DISCONTINUATION OF STUDY DOSING .....................................................................52
11
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION......................................53
11.1
ADVERSE EVENTS .....................................................................................................................................53
11.2
SERIOUS ADVERSE EXPERIENCES (SAE)...................................................................................................54
11.3
MEDICAL MONITORING.............................................................................................................................54
11.4
MONITORING SUSPECTED TOXICITIES FOR DISCONTINUED PARTICIPANTS .................................................54
12
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS.......................................55
12.1
EARLY PERMANENT DISCONTINUATION OF ABI-009 DOSING ..................................................................55
12.2
SCREEN FAIL CRITERIA.............................................................................................................................55
12.3
EARLY WITHDRAWAL OF PARTICIPANTS FROM THE STUDY......................................................................55
12.4
REPLACEMENT OF PARTICIPANTS..............................................................................................................56
13
PROTOCOL VIOLATIONS ...........................................................................................................56
14
DATA SAFETY MONITORING ....................................................................................................56
15
STATISTICAL METHODS AND CONSIDERATIONS .............................................................56
15.1
GENERAL CONSIDERATIONS......................................................................................................................56
15.2
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................................57
15.3
ANALYSIS OF PRIMARY ENDPOINT - SAFETY ENDPOINTS..........................................................................57
15.4
ANALYSIS OF PRIMARY ENDPOINT – TOLERABILITY (STUDY DRUG DISCONTINUATION AND COMPLIANCE)
58
15.5
ANALYSIS OF SECONDARY ENDPOINTS .....................................................................................................58
15.6
SAMPLE SIZE.............................................................................................................................................58
16
DATA COLLECTION, RETENTION AND CLINICAL MONITORING ................................58
16.1
DATA COLLECTION INSTRUMENTS............................................................................................................58
16.2
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS .............................................................59
16.3
MONITORING.............................................................................................................................................60
16.4
PARTICIPANT CONFIDENTIALITY...............................................................................................................60
17
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................................60
17.1
PROTOCOL AMENDMENTS.........................................................................................................................60
17.2
INSTITUTIONAL REVIEW BOARD ...............................................................................................................60
17.3
INFORMED CONSENT FORM.......................................................................................................................61
17.4
PUBLICATIONS ..........................................................................................................................................61
17.5
INVESTIGATOR RESPONSIBILITIES.............................................................................................................62
18
REFERENCES..................................................................................................................................62

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APPENDIX 1. SCHEDULE OF EVENTS ..............................................................................................71
LIST OF TABLES
Table 1: Predicted Rapamycin Blood Levels after ABI-009 IV Administration..........................30
Table 2: Rapamycin Levels in Brain and Blood after ABI-009 IV Administration.....................33
Table 3: ABI-009 Cohort Dosing Schedule...................................................................................37
Table 4: Hematological and non-hematological toxicities and ABI-009 dosing adjustments ......43
Table 5.  Pneumonitis Management and ABI-009 Dosing............................................................46
Table 6.   Weight Specific Guidelines for Therapeutic Use of Loperamide .................................47
Table 7.  AE Severity Grading ......................................................................................................55
LIST OF FIGURES
Figure 1:
Tumor Volume and Animal Survival following Treatment with IV ABI-009 and 
Oral mTOR Inhibitors....................................................................................................................30
Figure 2:
Distribution of Radioactivity in Tissues in Male Rats...............................................31

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LIST OF ABBREVIATIONS AND ACRONYMS
AED
anti-epileptic drug
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
ANC 
absolute neutrophil count
AST 
aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical (Classification System)
AUC 
area under the curve
BUN 
blood urea nitrogen
CBC 
complete blood cell (count)
CR 
complete response
CRA 
Clinical Research Associate
CRF 
case report form
CSF 
cerebral spinal fluid
CTCEA 
Common Terminology Criteria for Adverse Events
CTMS 
Clinical Trial Management System
DLT 
dose limiting toxicity
DSMC 
Data and Safety Monitoring Committee
DSMP 
Data and Safety Monitoring Plan
FCBP 
female of childbearing potential
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
HBeAg 
Hepatitis B “e” antigen
HBV 
hepatitis B virus
HCV 
hepatitis C virus
HGB 
hemoglobin
HIV 
human immunodeficiency virus
ICH 
International Conference on Harmonization
IND 
investigational new drug application
IRB 
Institutional Review Board
IV 
intravenous
LDH 
lactate dehydrogenase
LFT 
liver function test
MedDRA 
Medical Dictionary for Regulatory Activities
MRI 
magnetic resonance imaging
MTD 
maximum tolerated dose
NCI 
National Cancer Institute
ORR 
overall response rate
PEComa
perivascular epithelioid tumor
PO 
Per os (by mouth, orally)
RBC 
red blood cell (count)
SD 
standard deviation
SGA
subependymal giant cell astrocytoma
SGOT 
serum glutamic oxaloacetic transaminase
SGPT 
serum glutamic pyruvic transaminase
TSC
Tuberous Sclerosis Complex

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ULN 
upper limit of normal
WBC 
white blood cell (count)

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STUDY COMMITTEE
Principle Investigator/Study Chair
Jason Hauptman, MD, PhD
Neurosurgery
Seattle Children’s Hospital
4800 Sand Point Way NE
Seattle, WA 98105
206.987.2544
Jason.hauptman@seattlechildrens.org
Study Co-Chair
Sarah Leary, MD
Hematology/Oncology
Seattle Children’s Hospital
4800 Sand Point Way NE
Seattle, WA 98105
206.987.2106
Sarah.leary@seattlechildrens.org
Study Co-Chair
Russell Saneto, DO, PhD
Neurology
Seattle Children’s Hospital
4800 Sand Point Way NE
Seattle, WA 98105
206.987.2078
Russ.saneto@seattlechildrens.org
Study Statistician
Frankline Onchiri, PhD
Seattle Children's Research Institute
1900 9th Ave.
Seattle, WA 98101
206.884.1593
Frankline.onchiri@seattlechildrens.org 

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PROTOCOL SYNOPSIS
TITLE
Phase 1 study of ABI-009 (nab-rapamycin) for Surgically-Refractory 
Epilepsy (RaSuRE)
SPONSOR-
INVESTIGATOR
Jason S. Hauptman, MD, PhD
Seattle Children’s Hospital
4800 Sand Point Way NE
Seattle, WA 98105
FUNDING 
ORGANIZATION
AADi Bioscience, Inc.
Seattle Children’s Hospital
NUMBER OF 
SITES
1
RATIONALE
Seizures that are refractory to both medical and surgical therapy 
increase the risk of morbidity and mortality in children with epilepsy. 
At this point in time, options for these children are sparse and 
suboptimal. This hypothesis-driven phase 1 study aims to evaluate the 
use of a mammalian target of rapamycin [mTOR] inhibitor, ABI-009, in 
this subset of challenging participants. The underlying hypotheses being 
tested in trial are: (1) ABI-009 is a safe and well-tolerated medication in 
children who have medically-refractory epilepsy and have failed 
epilepsy surgery, and (2) The addition of ABI-009 therapy to the 
current clinical standard of continued antiepileptic medications results 
in improved epilepsy control. This is unique among trials of anti-
epileptic medications in that it also studies mTOR inhibition in a non-
Tuberous Sclerosis Complex (TSC) specific population for whom few 
additional effective therapies exist.
STUDY DESIGN
This is a prospective, single-center, phase 1 safety study to investigate 
the safety, tolerability, seizure control, and quality of life in participants 
with medically-refractory epilepsy who failed epilepsy surgery. These 
participants will have continued seizures despite being at least 3 months 
post-epilepsy surgery (resective surgery with an intent to cure). Upon 
enrollment, participants will be continued and observed on their pre-
existing, clinically prescribed antiepileptic drug (AED) regimen for 1 
month. At the 1-month mark, participants will receive weekly ABI-009 
intravenously at different dose levels in cohorts of 3 participants each 
using the standard 3+3 dose-finding design. ABI-009 will be continued 
for a total of 3 weeks. ABI-009 will then be discontinued and the 
participants will be observed for an additional 3 months. We intend an 
expansion of the maximum tolerated dose (MTD) cohort to an 
estimated additional 6 participants for a maximum possible enrollment 
of 18 participants.
DURATION OF 
SUBJECT 
PARTICIPATION 
Participants will be on study for about five months.
Initial control period: 1 month
Dosing period: 3 weeks 

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AND DURATION 
OF STUDY 
Follow-up: 3 months 
PRIMARY 
OBJECTIVE
Safety and Tolerability: 

Determine dose-limiting toxicities (DLTs) and MTD of ABI-
009 in participants with surgically-refractory epilepsy

Record the adverse events (AEs) and document their severity 
with ABI-009 dosing for medically intractable epilepsy that has 
failed surgical resection, administered in conjunction with their 
pre-existing AED regimen. Record the compliance of families 
with medication and record the number of participants that 
withdraw from study either voluntarily or by necessity 
secondary to AEs.

Columbia-Suicide Severity Rating Scale (C-SSRS) serious 
suicidal ideation score stays below a 4 rating.
SECONDARY 
OBJECTIVES
Efficacy and Quality of Life:
Efficacy is defined as the change from in seizure frequency between 
baseline and follow-up, expressed as percentage reduction in seizure 
rate (reduction in seizure frequency from baseline, calculated as 
(Baseline frequency [seizures/week] – frequency at follow-up 
[seizures/week])/Baseline frequency [seizures/week]) and median 
percentage reduction in seizure frequency. Treatment response rate 
will be defined as the proportion of participants achieving at least a 
25% reduction in seizure frequency from baseline. Seizure frequency 
will be defined as the ratio between the number of seizures and the 
number of days on which seizure information was known within the 
same period of time (for either baseline or maintenance phase). 
Additional secondary endpoints will include frequency of seizure-free 
days during the maintenance period, seizure-free rate (participants 
remaining seizure free during the entire maintenance period), and 
rapamycin blood level–response relationship analysis. 
Evaluate quality of life indices for participants before, during, and after 
dosing with ABI-009 in conjunction with pre-existing AED regimens. 
NUMBER OF 
PARTICIPANTS
Up to 18
PARTICIPANT 
SELECTION 
CRITERIA: 
Inclusion Criteria
Inclusion Criteria:
1. Written informed consent (and assent when applicable) obtained 
from participant or participant’s legal representative 
2. Willingness and able to adhere to the study visit schedule and other 
protocol requirements
3. Male or female ≥3 and ≤26 years of age at Visit 1
a.
Because no dosing or adverse event data are currently 
available on the use of ABI-009 in participants <3 years of 

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age, these young children are excluded from this study.
4. Documentation of a diagnosis of medically intractable epilepsy as 
defined by the failure of at least 2 appropriately dosed and tolerated 
AEDs to eliminate all clinical seizures over a 6-month period prior 
to epilepsy surgery
5. Documentation of resective epilepsy surgery following appropriate 
presurgical evaluation
6. Documentation of continued clinical seizures that persist at least 3 
months following resective epilepsy surgery. In order to proceed 
with enrollment and study drug initiation, participants must have 
had >8 seizures in the last 30 days without 2 consecutive weeks of 
seizure freedom.
7. Documentation that the participant is not a candidate for or refuses 
any additional resective epilepsy surgery
8. Participants must have adequate bone marrow function (ANC 
≥1,000/mm3, platelet count of ≥100,000/mm3, and hemoglobin ≥ 9 
gm/dL) before study drug dosing.
9. Participants must have adequate liver function (SGPT/ALT ≤ 5 
times ULN and bilirubin ≤5 times ULN) before study drug dosing.
10. Participants must have adequate renal function before study drug 
dosing, defined as: Creatinine clearance or radioisotope GFR 
≥70mL/min/1.73 m2 or a serum creatinine based on age/gender as 
follows:
11. Participants must have a fasting cholesterol level <350 mg/dL and 
triglycerides <400 mg/dL before starting study drug. In case one or 
both of these are exceeded, the participant can only be included after 
initiation of appropriate lipid lowering medication and 
documentation of cholesterol <350mg/dL and triglycerides 
<400mg/dl before study drug dosing.
12. Participants must have normal oxygen saturation before study drug 
dosing.
13. The effects of ABI-009 on the developing human fetus at the 
recommended therapeutic dose are unknown. For this reason and 

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because ABI-009 are known to be teratogenic, participants of child-
bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 6 months 
after the last dose of ABI-009. Should a female participant become 
pregnant or suspect she is pregnant while participating in this study, 
she should inform her treating physician immediately. 
a.
Participants of child-bearing potential must not be 
breastfeeding or pregnant as evidenced by a negative 
pregnancy test before enrollment and before initiating study 
drug dosing.
PARTICIPANT 
SELECTION 
CRITERIA: 
Exclusion Criteria
Exclusion Criteria:
1. For females of child bearing potential: 
a.
Positive pregnancy test at any visit or
b. Lactating or
c.
Unwilling to practice a medically acceptable form of 
contraception (acceptable forms of contraception: 
abstinence, hormonal birth control, intrauterine device, or 
barrier method plus a spermicidal agent), unless surgically 
sterilized or postmenopausal during the study 
2. Participant has any other condition that, in the opinion of the Site 
Investigator/designee, would preclude informed consent or assent, 
make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study 
objectives. 
3. Participant has received immunization with attenuated live vaccines 
within 1 week of study entry and/or is planning to receive 
immunization with attenuated live vaccines during study period. 
Examples of live vaccines include intranasal influenza, measles, 
mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a 
typhoid vaccines. Close contact with those who have received 
attenuated live vaccines should be avoided during dosing with ABI-
009.
4. Participant tests positive for Hepatitis C antibodies or the Hepatitis 
B antigen. HBsAg and HCVAb blood test must be done at screening 
(HBsAg only needs to be screened in patients who have not 
received the full complement of Hepatitis B immunizations). 
Alternatively, if the patient has received the complement of 
Hepatitis B immunizations and documentation is provided, this 
would suffice.
5. A known history of HIV seropositivity. HIV-positive patients on 
combination antiretroviral therapy are ineligible because of the 

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potential for pharmacokinetic interactions with ABI-009. In 
addition, these patients are at increased risk of lethal infections 
when treated with marrow-suppressive therapy.
6. Participant is receiving chronic, systemic treatment with 
corticosteroids or another immunosuppressive agent. Note: Patients 
that are currently using inhaled, intranasal, ocular, topical or other 
non-oral or non-IV steroids are not necessarily excluded from the 
study but must be discussed with the study chair.
7. Participant has been previously treated with a systemic mTOR 
inhibitor for epilepsy. Skin cream use with rapamycin or 
everolimus, however, is permitted.
8. Participant has a known hypersensitivity to human albumin, ABI-
009, or other rapamycins (e.g. sirolimus, everolimus, temsirolimus).
9. Participant is receiving any other concurrent anticancer or 
investigational therapy. Participants will be permitted to enroll in 
the study after a 30-day washout of previously used investigational 
drugs.
10. Participant has any clinically significant unrelated systemic illness 
that would compromise their ability to tolerate protocol procedures.
11. Participant is unable to return for treatment and follow-up visits to 
assess toxicity to the study drug.
12. Participant has an uncontrolled intercurrent illness including, but not 
limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, active 
lung disease, or psychiatric illness/social situations that would limit 
compliance with study requirements.
TEST PRODUCT, 
DOSE, AND 
ROUTE OF 
ADMINISTRATION
For dose finding, ABI-009 will start at 5 mg/m2/dose IV, once a week 
for three weeks, in cohorts of 3 participants each using the standard 3+3 
dose-finding design.
Dose-levels
ABI-009 in mg/m2
-2
1
-1
2.5
1
5
2
10
3
20
Escalation to the next dose level with a new cohort of 3 participants will 
occur after no DLT is observed. There will be no intra-participant dose 
escalation allowed. If a DLT occurs in a cohort, an additional 3 
participants will be recruited to the cohort. If no further DLTs occur, 

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then a new cohort of 3 participants at the next higher dose level can be 
enrolled. If 2/6 participants at dose level 1 experience a DLT, then that 
cohort will be closed to further enrollment and 3 participants will be 
enrolled at the next lower dose level, and so on. The MTD is the highest 
dose level in which ≤1 participant has a DLT. 
Once the MTD has been determined, the MTD cohort will be opened 
for an additional 6 participants. These participants will adhere to the 
identical protocol of the rest of their cohort.
Product will be administered IV every seven days for three weeks.
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
There is no control product for this study. Participants will serve as their 
own controls by continuing their pre-existing AED regimen for 1 month 
after enrollment prior to starting dosing with ABI-009. In order to 
proceed with drug administration participants will have to have had >8 
seizures in 30 days without 2 consecutive weeks of seizure freedom.
CONCOMMITANT 
MEDICATIONS
Allowed: Standard therapy for epilepsy is allowed except for treatments 
noted in the prohibited medications section below. Pre-existing AEDs 
must not be titrated while participants are enrolled in the study, unless 
the dose change is solely to address subtherapeutic levels as determined 
by the treating neurologist. Rescue medication is allowed for prolonged 
seizure event or cluster of seizures. 
Prohibited: The following medication changes are prohibited during 
participation in the trial, and as such will be considered a protocol 
violation:

Any changes in dosage of AED regimen, unless solely to 
address subtherapeutic levels of AEDs as determined by the 
treating neurologist.

Any additions or removal of AEDs to the participant’s AED 
regimen during participation unless medically necessary and 
discussed with investigator
PRIMARY 
ENDPOINT
Safety:
DLT and MTD
Incidence of adverse events and clinically significant abnormal lab 
values
Tolerability:
Number of participants withdrawn from study
Adherence to prescribed ABI-009 regimen
Columbia-Suicide Severity Rating Scale (C-SSRS) serious suicidal 
ideation score stays below a 4 rating.
SECONDARY 
Efficacy:

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ENDPOINTS
Seizure frequency 
Percentage reduction in seizure frequency 
Median percentage reduction in seizure frequency 
Response rate
Frequency of seizure-free days 
Seizure-free rate
Rapamycin blood level–response relationship
Other:
Quality of life and behavioral index
Determine weekly whole blood rapamycin trough levels for three 
consecutive weeks 
STATISTICS
Primary Analysis 
Plan
Analysis of Primary Endpoints
The number of SAEs and AEs will be summarized for each dosing 
group as follows: (i) The proportion of participants with at least one 
(S)AE, (ii) The average number of (S)AEs per participant, and (iii) The 
rate of (S)AEs per participant week of follow-up. Histograms showing 
the frequency of the number of (S)AEs in each dosing group will be 
included. Rates of (S)AEs by System Organ Class (SOC) will be 
presented by treatment group. Poisson regression modeling for count 
data will be used to derive rate ratios and 95% CIs for each SOC. 
Safety lab data at each study visit and changes from baseline will be 
summarized by dosing group. In addition, the following clinical 
laboratory summaries will be presented by dosing group: (i) the 
incidence of clinically significant abnormalities at each study visit; and 
(ii) tables summarizing the frequencies of participants below, within, 
and above the normal reference ranges at baseline and end of study; and 
(iii) tables displaying baseline to end of study shifts in each laboratory 
value (shifts between below, within or above normal range).
The number of hospitalization events and proportion of participants 
hospitalized from baseline to final day of study will be summarized and 
compared by treatment group. Poisson regression modeling will be used 
to derive rate ratios and 95% CIs.
Study compliance will be assessed via compliance with scheduled 
weekly infusions.  
Analysis of Secondary Endpoints
Efficacy is defined as the change in seizure frequency between baseline 
and follow-up, expressed as percentage reduction in seizure rate 
(reduction in seizure frequency from baseline, calculated as (Baseline 
frequency [seizures/week] – frequency at follow-up 

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[seizures/week])/Baseline frequency [seizures/week]) and median 
percentage reduction in seizure frequency. Treatment response rate 
will be defined as the proportion of participants achieving at least a 
25% reduction in seizure frequency from baseline. Seizure frequency 
will be defined as the ratio between the number of seizures and the 
number of days on which seizure information was known within the 
same period of time (for either baseline or maintenance phase). 
Additional secondary endpoints will include frequency of seizure-free 
days during the maintenance period, seizure-free rate (participants 
remaining seizure free during the maintenance period), and rapamycin 
blood level–response relationship analysis. These endpoints will be 
analyzed using appropriate statistical tests, such as the test of 
proportions and time to event analyses.
Quality of Life for Children with Epilepsy Parent Form (QOLCE) [1] 
and Nisonger Child Behavioral Rating Form (NCBRF) [2, 3] scores will 
be compared using appropriate statistical tests for ordinal data, 
including Wilcoxon signed rank tests, logistic regression, or 
contingency tables.
Rationale for 
Number of 
Participants
In this phase 1 study, it is estimated that a maximum of up to 18 
participants will be required to achieve the MTD; however, MTD could 
be reached with as few as 9 participants, but also possible that the MTD 
is not reached in this study. With the MTD expansion cohort, it is 
estimated that additional 6 participants would bring the maximum 
number of participants enrolled to 18. A total of up to 18 participants 
should be enough for a safety and tolerability study in an orphan 
condition.

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1
BACKGROUND
1.1
Intractable epilepsy in children
Unlike adults, the primary objective of epilepsy surgery in the pediatric population is to avoid the 
adverse consequences of uncontrolled epilepsy, particularly with regards to cognitive and 
developmental outcomes [4].  Additionally, aggressive seizure control in young children is 
mandatory to avoid the development of the epileptic encephalopathy [5]. It is this desire to avoid 
the untoward sequelae of intractable epilepsy in developing children that underscores the 
necessity for early diagnosis and referral to a pediatric epilepsy surgery center. 
A critical point is that the diagnosis of therapy-resistant (i.e., intractable) epilepsy can be made 
early without an exhaustive trial of antiepileptic medications. This concept has been borne out of 
epidemiological studies done early last decade. Among children in the general population, the 
incidence of epilepsy has been estimated at five cases per 10000 per year [6, 7].  Of these, from 
23% to 33% will become pharmacoresistant [8-10].  Pharmacoresistant epilepsy is usually 
defined as one or more seizures per month that persist after trying more than two antiepilepsy 
drugs (AED) [11]. Pharmacoresistance is best predicted by the response to AEDs.  Once a 
patient has failed two to four AEDs, the chances that additional medications will stop the 
seizures are less than 5% [12]. If there is an associated lesion on MRI, the chance that additional 
medications will stop the seizures is near zero [13, 14]. 
Epilepsy syndrome classification predicts response to medical therapy. Nearly all children with 
genetic/idiopathic epilepsy experience near-optimal seizure control with medication. Of these, 
approximately 59% experience remission at one year and 40% of children have less than one 
seizure a month. Thus, 99% of children with genetic epilepsy have near-complete seizure 
control.  Approximately 92% of children with cryptogenic/unknown epilepsy achieve near-
optimal seizure control at two years. Remission rates for metabolic/structural epilepsy, on the 
other hand, are not as high with medical therapy with about 50% uncontrolled on AEDs. Many 
children considered for epilepsy surgery have metabolic/structural seizures.  Furthermore, the 
development of new AEDs has not significantly impacted seizure control in children of this latter 
group [15]. 
Risk factors, such as mental retardation, perinatal anoxia, a history of neonatal convulsions, a 
history of status epilepticus, and symptomatic etiology increase the risk of refractory epilepsy in 
children [16]. Younger age at seizure onset and frequent seizures (more than once per month) are 
also independent risk factors for the development of treatment resistance. Furthermore, high 
initial seizure frequency and focal EEG findings correlate with intractability. 
Suboptimal seizure control in infants, children, and adolescents poses serious 
neurodevelopmental consequences, spanning cognitive, behavioral, and psychosocial domains. 
Intellectual dysfunction (IQ <79) can be detected in 57% of children with uncontrolled unilateral 
temporal lobe epilepsy [17]. Independent of etiology, intractable seizures during the first 24 
months of life is a significant risk factor for mental retardation [18]. Intellectual deterioration is 
particularly rampant when seizures occur daily. When uncontrolled unilateral temporal lobe 
epilepsy begins in the first 12 months of life, the incidence of intellectual impairment is 
approximately 83%. Inadequately controlled infantile spasms may result in severe impairments 
of cognition, language, social skills, and communication abilities that appear to be clinically 
similar to autism [19]. 

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Beyond cognition, suboptimal seizure control may result in poor psychosocial outcomes 
compared with patients whose epilepsy is controlled [20]. Psychosocial deficiencies manifest as 
lower rates of high school completion, employment, marriage, and overall socioeconomic 
productivity. Early surgical intervention for intractable seizures results in improved IQ scores 
and developmental indices [5, 21-25].
Early intervention to control seizure frequency is also critical to reducing seizure-related 
morbidity and mortality. Compared to children without disease, children with refractory epilepsy 
are at risk of higher rates of morbidity and death [26-28]. The mortality risk of uncontrolled 
epilepsy is approximately 0.5% per year and accumulates over the child’s lifetime.  Examples of 
the seizure-related mortality include sudden unexplained death due to epilepsy (SUDEP), 
aspiration pneumonia, trauma, accidents, drowning, and status epilepticus. Importantly, SUDEP 
risk does not change with medically controlled seizures, but is only reduced in the population 
made seizure-free.
In order to reduce the risk of developmental decline and decrease seizure-related morbidity and 
mortality, surgical therapy should be considered as a therapeutic option in the management of 
some therapy-resistant children. Furthermore, psychosocial function and quality of life indices 
may benefit greatly from seizure control. 
1.2
Clinical characteristics of pediatric epilepsy surgery patients
The general clinical features of pediatric epilepsy surgery patients are those associated with a 
high risk of inducing an epileptic encephalopathy.  This is best illustrated from the results of an 
international survey of pediatric epilepsy surgery centers for the calendar year 2004 [29].  For 
example, age at seizure onset is two years or less in 83% and seizures frequency is daily or 
greater in 65% of cases.  Of note, fewer than 32% of children receive their epilepsy surgery 
within two years of onset.  Thus, many children are exposed to an epilepsy duration that is 
associated with the poorest developmental outcomes.  
Etiologies are often quite variable in patients undergoing pediatric epilepsy neurosurgery.  
Cortical dysplasia (CD), a congenital structural aberration consisting of cortical dyslamination 
and columnar disorganization, is the most commonly encountered substrate in pediatric epilepsy 
surgery. Cortical dysplasia can be graded as severe or mild [30, 31]. While milder forms of CD 
solely involve defects in lamination, severe cortical dysplasia consists of cortical dyslamination 
with the addition of abnormal cytomegalic neurons and balloon cells in the cortex and 
subcortical white matter [32, 33]. Severe CD is more likely to present at younger ages, have 
higher seizure frequencies, and be extratemporal [34]. Though CD is most often detected using 
conventional structural MRI, abnormalities may be subtle or undetectable.  In addition, scalp 
EEG may be non-localized from 23% to 50% of cases. For this reason, adjunctive neuroimaging 
such as FDG-PET, MEG, and ictal-SPECT may be utilized.  FDG-PET, in particular, is positive 
in 75 to 90% of CD cases [35].  Focal CD is most often found in the frontal and temporal lobes, 
though larger lesions may involve multiple lobes or a cerebral hemisphere. In our experience, 
children with early-onset epilepsy tend to have larger dysplastic lesions with more severe CD 
histopathology. 
The second most common substrate found in pediatric epilepsy surgery patients is low-grade 
neoplastic tumors, such as gangliogliomas and dysembryoplastic neuroepithelial tumors 
(DNETs).  Seizures are the first clinical presentation in about 80% of patients with low-grade 

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tumors [36, 37].  DNETs may also be found in association with regions of cortical dysplasia. 
Fortunately, high seizure remission rates result from complete resection of these tumors [38]. 
Other structural abnormalities leading to pediatric epilepsy surgery may result from perinatal 
infarcts or infections such as bacterial or viral encephalitides [39]. While hippocampal sclerosis 
is the most common etiology in adult epilepsy surgery patients, it is less frequent in children.  
Other etiologies are much less frequent in pediatric epilepsy surgery patients.  In Sturge-Weber, 
for example, suboptimal seizure control may lead to developmental delay and progressive 
hemiparesis. For this reason, children may require focal or hemispheric resections to prevent 
developmental decline [40]. Tuberous sclerosis complex (TSC), a phakomatosis that results in 
hamartomatous lesions throughout the body, is another fairly rare condition referred for epilepsy 
surgery consideration. In TSC patients, seizures may be focal or multifocal, are often treatment-
resistant, and may impair neurocognitive development [41-43]. Even though in many of these 
cases there are several tubers as well as multifocal EEG abnormalities, optimal seizure control 
may result from resection of the epileptogenic cortical tuber(s) [44-46]. 
Rasmussen’s syndrome, hypothalamic hamartoma, and hemimegaloencephaly are other less-
frequently encountered substrates in pediatric epilepsy surgery. Rasmussen’s syndrome is a 
disease of unknown cause where progressive involvement of one hemisphere leads to 
hemiparesis and intractable seizures [47]. While steroids, immunoglobulins, and plasmapheresis 
provide temporary relief, hemispherectomy is the only known effective treatment. Laundau-
Kleffner syndrome, an epileptic aphasia that associated with severe developmental regression 
and intractable seizures, may respond to surgical intervention [48]. Hemimegalencephaly is a 
phenomenon where one hemisphere is hypertrophied and contains abnormal and dysplastic 
glioneuronal proliferation [49]. Children with hemimegalencephaly have unilateral or bilateral 
EEG abnormalities often with hypsarrhythmia or suppression bursts. These children also present 
with macrocrania, mental retardation, and contralateral paresis. Hemispherectomy provides the 
best chances for seizure control and normalization of psychomotor development velocity [50]. 
1.3
Perioperative considerations and surgical approaches
The particular surgical treatment and timing of surgery are customized to the individual child. 
Children may present with acute status epilepticus and urgent surgery may be needed to control 
life-threatening seizures [51]. Operations that may be offered include invasive recording using 
grid and depth electrodes, resection of the epileptic lesion, disconnection of the abnormal cortex, 
or palliation of seizure frequency. About 80% of operations performed are aimed at diagnosis 
and/or resection, while 20% are palliative. The most common types of surgery range from 
cerebral hemispherectomy to focal resections.  Of the multiple techniques of hemispherectomy-
hemispherotomy described, many have similar seizure control rates. These surgeries have similar 
efficacy compared to temporal lobectomy for complex partial limbic seizures. 
The majority of palliative procedures in the United States are placement of vagus nerve 
stimulators, with corpus callosotomy performed in rare instances. Palliative surgery is offered to 
children with unresectable epilepsy, such as seen in Lennox-Gastaut syndrome [52, 53]. 
Radiosurgery is currently being investigated as a less invasive alternative, particularly for 
hypothalamic hamartoma and medial temporal lobe epilepsy [54-58]. To date, the use of 
radiosurgery to treat infants and children has not been adequately studied.  Another surgical 
technology being investigated involves stereoendoscopy, particularly for treating hypothalamic 

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hamartomas [59, 60]. Resective and palliative surgeries continue to be the mainstay of treatment 
in a majority of these children.
1.4
Outcomes after epilepsy neurosurgery in children
Approximately 60% to 80% of children will become seizure free after epilepsy neurosurgery [15, 
27, 61-71]. The two most consistent factors associated with the highest chance of seizure control 
are: (1) a lesion identified on MRI scan, and (2) complete excision of the lesion [72-75]. Seizure 
remission rates are higher in children who have temporal resections compared to extratemporal 
resections. The best predictor of long-term optimal seizure control is early seizure control after 
epilepsy surgery. If the patient has no seizures during the first 6 months after surgery, they have 
up to a 95% chance of remaining completely seizure-free over time [76]. Up to 30% to 50% of 
children will have AEDS withdrawn following successful epilepsy surgery [28, 77-79]. 
Focal resections may result in seizure remission rate that approaches 88% for hippocampal 
sclerosis, 81% for tumor, and 62% for cortical dysplasia [65]. Compared to focal or lobar 
resections, patients with more widespread and/or diffuse pathology (e.g. hemimegalencephaly) 
requiring hemispheric surgery or disconnection have lower seizure remission rates [80]. It is 
possible that these diffuse EEG patterns indicate an interface between the early lesion and the 
developing brain [81]. 
Surgical mortality is from 0.25% to 2% for procedures such as temporal lobectomy and 
hemispherectomy, while permanent surgical morbidity is reported to be less than 5% [82]. 
Temporal resections are most often complicated by visual field deficits, while extratemporal 
resections are most often complicated by transient hemiparesis. Infrequently, infarcts, permanent 
hemiparesis (temporal lobe resections), and language deficits may occur. In general, the risks of 
surgery are less than the risks associated with the natural history of treatment-resistant epilepsy 
[75].  Re-operations for a failed first epilepsy surgery occur in approximately 14% of pediatric 
patients [29].  Most re-operations involve extending the resection to include areas thought not to 
be involved with the epileptogenic process with the first operation.  
Conclusion: In children with intractable epilepsy who are candidates for surgical resection, 
seizure freedom is by no means guaranteed. Depending on underlying pathology, seizures 
persist in 40% or more children. The options for these children, beyond palliative surgical 
procedures and continued medication trials, are non-existent.
1.5
mTOR
mTOR is a ubiquitous 289kDa serine/threonine kinase whose structure places it in the family of 
phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) [83]. mTOR is dysregulated in a 
number of human diseases, including tuberous sclerosis and epilepsy. Inhibition of mTOR 
reduces cell proliferation, angiogenesis, and glucose uptake by cells in both in vivo and in vitro 
studies [84-87].
Activation of mTOR begins with the binding of a variety of extracellular ligands to receptor 
tyrosine kinases. These ligands include mitogens, trophic factors, and hormones [88]. In neurons, 
mTOR activation is also modulated by N-methyl-D-aspartate receptors (NMDAR), alpha-amino-
3- hydroxy-5- methyl-4-isoxazolepropionic acid receptors (AMPARs), brain-derived 
neurotrophic factor (BDNF) and dopaminergic and metabotropic glutamate receptors (mGluRs) 
[89]. Calcium influx through NMDARs or voltage-gated calcium channels, which stimulates 

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both the ERK/MAPK and PI3K pathways through calcium/calmodulin, ras, and cAMP, is 
another important upstream activator of mTOR [90]. Receptor tyrosine kinase activation then 
leads to activation of PI3K, which in turn causes Akt to be recruited to the cell membrane and 
become phosphorylated [88]. This phosphorylation of Akt is catalyzed by two different enzymes: 
phosphoinositol-dependent protein kinase 1 (PDK1, which is dependent on PI3K activation) and 
mTORC2, a relatively rapamycin-resistant complex of mTOR. Akt is also negatively regulated 
by phosphatase and tensin homologue (Pten), the major antagonist of PI3K/Akt-dependent 
signaling [91]. Upon activation, Akt, also a serine/threonine kinase, proceeds to phosphorylate 
(and thereby inactivate) tuberous sclerosis protein 2 (Tsc2) [88]. Tsc2, along with its counterpart 
tuberous sclerosis protein 1 (Tsc1), form the Tsc1/Tsc2 complex. When activated, the Tsc1/Tsc2 
complex acts as a GAP (GTPase-activating protein) for Rheb (Ras homolog enriched in brain 
protein), thus inhibiting it. When the Tsc1/Tsc2 complex is neutralized through Akt activation, 
however, resultant Rheb disinhibition leads to activation of mTOR and formation of mTORC1. 
Activated Rheb is not, however, capable of increasing mTORC2 activity. In fact, little is known 
about upstream activators of mTORC2.
mTOR complex 1 (mTORC1) consists of the proteins mTOR, raptor (regulatory associated 
protein of mTOR), Pras40, and mLST8 [83]. Raptor is critical for mTORC1 function (it is an 
adaptor protein and binds to and presents substrates to the catalytic region of mTOR). In 
particular, raptor binds S6K and 4EBP, allowing them to undergo phosphorylation by mTORC1. 
Raptor is also an area that itself undergoes phosphorylation to modulate mTOR activity by 
proteins such as AMPK, p90 ribosomal S6 kinase (RSK), and mTORC1 itself. Raptor also acts 
as a regulatory subunit of mTOR and can be phosphorylated at a variety of serine residues by 
enzymes such as AMPK and ribosomal S6 kinase, and Rheb to either promote or inhibit 
mTORC1 activity. The remaining mTORC1 proteins serve either a scaffolding or regulatory 
capacity. Deptor is a protein that is able to independently bind and negatively regulate mTORC1. 
mTORC1 is sensitive to rapamycin, which competes with raptor to bind the FRB domain of 
mTOR [89]. mTORC1 has a variety of important functions, many of which have been 
characterized by using rapamycin. Perhaps the two most notable and well-described substrates of 
mTORC1 are 4E-BP1 and p70S6K, both of which are phosphorylated by mTORC1 [83]. When 
unphosphorylated, 4E-BP1, a translation repressor, inhibits translation of 5' capped mRNAs by 
binding translation initiation factor 4E (eIF-4E). Upon phosphorylation by mTORC1, 4E-BP1 
dissociates from eIF-4E and allows translation to occur. Phosphorylation of p70S6K, on the 
other hand, results in subsequent phosphorylation and activation of ribosomal protein S6 (a 
protein necessary for the translation of 5' terminal oligopyrimidine (TOP) mRNAs). Importantly, 
4E-BP1 and p70S6K have been found to be the key effectors regulating cell growth and cell 
cycle progression [92, 93]. Additional targets of p70S6K include insulin receptor substrate-1 
(IRS-1), glycogen synthase kinase 3 (GSK3), translation elongation factor 2 (eEF2) kinase, and 
Bad [83]. IRS-1 is important for activation of the IGF-1 receptor, which, in turn, leads to 
activation of the PI3K pathway. When IRS-1 is phosphorylated, its actions on IGF-1 are 
inhibited and thus the PI3K pathway is negatively regulated. GSK3 is an important effector 
protein that has roles in cytoskeletal structure, cell growth, metabolism, and cell cycle regulation 
[94, 95]. In the CNS, GSK3 has been shown to have a critical influence on synaptic plasticity 
[96]. Bad, a proapoptotic molecule, is phosphorylated and inactivated by p70S6K [97].
While 4E-BP1 and p70S6K have been described as the canonical targets of mTORC1, additional 
effectors have been identified [98]. Mitochondrial metabolism directly correlates with mTORC1 

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activity. Another transcription factor that is activated by mTORC1 is STAT3. STAT3 is a focus 
of scientific interest with regards to oncogenesis, stem cell differentiation, immunity, and a 
variety of human diseases [99, 100]. Two additional effectors found downstream of mTORC1 
include serum- and glucocorticoid-inducible kinase-1 (SGK1) and hypoxia-inducible factor 
(HIF). SGK-1 is thought to mediate a raptor-dependent effect on the cyclin-dependent kinase 
inhibitor, p27 (KIP1), thus exerting control over cell cycle progression. HIF is an important 
molecule that is involved in the expression of a variety of genes that modulate angiogenesis, 
erythropoiesis, and metabolism. As the name implies, HIF is activated under hypoxic conditions.
mTOR complex 2 (mTORC2) is only similar in structure to mTORC1 in that it contains mTOR 
and the protein mLST8. In addition to these two components, mTORC2 also contains rictor 
(rapamycin insensitive companion of mTOR), Sin1, and protor. Rictor is necessary for the 
assembly, stability, and activity of mTORC2 [101]. In particular, rictor is required for mTORC2 
interaction with PKCa. Like mTORC1, deptor is able to bind mTORC2 and negatively regulate 
its kinase activity [102]. mTORC2 is unaffected by acute exposure to rapamycin [83]. Chronic 
exposure does inhibit mTORC2 activity through disruption of new mTORC2 complex assembly 
[103]. In fact, only rictor that is newly synthesized can be affected by rapamycin; thus, existing 
mTORC2 complexes appear to be all that is resistant to rapamycin therapy [89]. That said, 
chronic rapamycin treatment results in suppression of Akt and PKC signaling through a 
reduction in mTORC2. 
As of yet, the upstream signaling pathway of mTORC2 is relatively unknown. There is some 
evidence that mTORC2 may be activated through either PI3K signaling or through crosstalk with 
mTORC1 via p70S6K [102]. Also, some data suggest that mTORC2 may be positively regulated 
by the Tsc1/Tsc2 complex in a fashion that is independent of its inhibitory activity on mTORC1 
[102, 104]. When Tsc1 or Tsc2 are conditionally deleted, mTORC1 levels are elevated and 
mTORC2 levels are suppressed. This is particularly interesting because it may help to explain 
why lesions that are seen when Tsc1 or Tsc2 is lost (as in tuberous sclerosis) are benign and not 
cancerous. Because mTORC2 may be jointly regulated by Tsc1/Tsc2 (positively) and 
mTORC1/p70S6K (negatively), when mTORC1 is constitutively active (such as in tuberous 
sclerosis) these feedback loops aid in dampening Akt activation [102].
One target of mTORC2 is protein kinase C-alpha (PKC), which, through phosphorylation, has its 
activity, stability, and localization regulated [89]. Among the many known functions of PKC, 
perhaps the most notable with regards to neuronal activity is its regulation of synaptic plasticity. 
PKC also is involved in cell growth and actin cytoskeletal organization [105], regulation of ion 
channels [106], modulation of GABAA receptor function and trafficking [107, 108], and 
calcium-dependent vesicular signaling in astrocytes [109]. Regulation of cell size by mTORC2 
has also been shown to occur through another downstream effector, serum- and glucocorticoid-
induced protein kinase 1 (SGK1) [83]. Also, the family of SGKs are important in sodium 
transport regulation and in oncogenesis [102, 110]. Besides PKC and SGK1, perhaps mTORC2's 
most prominent downstream target is Akt. Through Akt, mTORC2 exerts control over cell size, 
cell survival, cytoskeletal arrangement, metabolic function, apoptosis, protein expression, cell 
motility, and oncogenic transformation [111].

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1.6
mTOR and epilepsy
In models of pilocarpine-induced seizures, it has been shown that about 30 min after pilocarpine 
injection levels of phosphorylated S6K increase and peak at 1 h within the hippocampus and 
cortex [112]. This rise in phosphorylated S6K can be blocked by pre-treatment with systemic 
rapamycin (5 mg/kg/day) for three days prior to pilocarpine injection, though the pre-treatment 
does not affect the severity of the acute seizures. Pilocarpine-treated animals with recurrent 
spontaneous seizures who are treated with chronic systemic rapamycin (5 mg/kg/day for three 
days, then every other day for three weeks), on the other hand, demonstrate a reduction in seizure 
frequency and duration during treatment that gradually increases following withdrawal of 
rapamycin. In a model of pilocarpine-induced status epilepticus, continuous infusion of 
rapamycin into the dorsal hippocampus prevented mossy fiber sprouting in the molecular and 
granular layers that then emerged upon withdrawal of treatment [113]. Interestingly, when 
rapamycin was started after mossy fiber sprouting began (2 months after seizure onset), no 
effects were seen. This effect on mossy fiber sprouting has been confirmed by others [112]. 
In another model of temporal lobe epilepsy induced by kainate injection, elevation in 
phosphorylated S6K was noted at 1 h after kainate injection with a peak at 3-6 h and a return to 
baseline at 24 h in hippocampus and cortex [114]. An additional phase of rising phosphorylated 
S6K levels was noted in the hippocampus only, starting at 3 days after injection, peaking by 5 
days, and returning to baseline by 5 weeks. Similar to the studies by Huang et al. [112] 
rapamycin was administered systemically (6 mg/kg/day) for three days before injection. The 
biphasic rise in phosphorylated S6K was blocked by this treatment; again, however, the severity 
of the acute seizures was not affected. Furthermore, rapamycin pre-treatment reduced kainate 
seizure-induced hippocampal cell death, kainate-seizure induced dentate granule cell 
neurogenesis, supragranular mossy fiber sprouting, and chronic recurrent kainate-induced 
spontaneous epilepsy. When rapamycin treatment was changed from a pre-treatment to a post-
treatment paradigm (6 mg/kg/day for 6 days starting 24 h after onset of kainate status epilepticus 
and then every other day from that point forward), late phase mTOR activation, mossy fiber 
sprouting, and chronic kainate-induced spontaneous seizures were all reduced. There was no 
effect on cell death or neurogenesis.
Several studies have suggested that rapamycin may play an important role in the suppression of 
congenital and acquired epilepsy. In one model of tuberous sclerosis where Tsc1 is conditionally 
deleted from most cortical neurons, both rapamycin and RAD-001 increase survival, improve the 
histological phenotype (cortical organization, soma size and polarity, and myelination), and 
reduce seizures [115]. Additional work has shown that rapamycin completely reverses the 
elevated endoplasmic reticulum and oxidative stress that can lead to cell death in Tsc2-deficient 
hippocampal neurons and Tsc1 deficient brain lysates [116]. In another model of cortical 
dysgenesis in which PTEN is conditionally deleted from cortical neurons, rapamycin 
administration also improved the histological abnormalities (enlarged, disorganized neurons), 
reduced abnormal EEG activity, and suppressed the frequency and duration of spontaneous 
seizures [117]. In animal model of tuberous sclerosis in which Tsc1 is conditionally deleted in 
[primarily] glia, rapamycin had significant beneficial effects as well [118]. When rapamycin was 
given systemically starting at P14 (before the onset of seizures), astrogliosis was prevented, 
epilepsy did not develop, and animals did not die prematurely. When rapamycin was begun after 
the onset of epilepsy (at 6 weeks), seizure frequency was decreased, interictal EEG was 
improved, and survival was prolonged.

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1.7
Overview of Clinical Effects of mTOR Inhibitors on Seizures
The effects of mTOR inhibitors on the reduction of seizures have been demonstrated in several 
clinical studies with rapamycin and everolimus.  
In an open-label prospective study, 52 pediatric participants with the diagnosis of TSC 
complicated with epilepsy received rapamycin treatment for at least 24 weeks [119]. This study 
was conducted in China. The drug dosage was 1 mg/m2/d, average 0.7 mg/d (0.35-1.20 mg/d). 
The median age at onset of epilepsy was 4.8 months (4 days-49 months), the median age for 
treatment with rapamycin was 27 months (4.5-172.5 months). Ten children had a family history 
of TSC. In 24 children with TSC gene detection, TSC1 mutation was detected in 4 cases and 
TSC2 mutation in 20. Before rapamycin therapy, 59.62% (31/52) participants took more than 3 
antiepileptic drugs, of whom 10 cases even took more than 5 kinds of antiepileptic drugs. In 
participants received rapamycin treatment for 24, 48, 72, and 96 weeks, seizure free rate was 
25% (13/52), 19% (6/31), 29% (5/17), and 25% (3/12) respectively. The authors report a “total 
effective rate” of 73% (38/52), 74% (23/31), 76% (13/17), and 75% (9/12) respectively, though it 
is unclear how exactly that terminology is being used. The use of antiepileptic drug types was 
reduced with reduction in seizure frequency. Before rapamycin therapy, the average frequency of 
seizures was 70.27 times/d and the average number of antiepileptic drugs was 1.30. After 24, 48, 
72, and 96 weeks' treatment, the average seizure frequency was reduced to 1.94-2.80 times/d and 
the mean number of concomitant antiepileptic drugs were reduced to 0.83-0.97. On every visit 
during the follow-up, blood and urine routine tests, liver and kidney function test showed no 
abnormality. Blood concentrations of rapamycin remained below 10 µg/L (average 6.5 µg/L). In 
this study it is unclear how often these levels were measured (presumably whole blood trough 
but not certain). The main side effect was oral ulcer which happened in 23.08% of patients 
(12/52) and would generally disappear 2-3 days later. Of all patients, 17.31% (9/52 cases) had 
upper respiratory infection.
Everolimus (Novartis Pharmaceuticals) is a chemically modified rapamycin derivative that is 
currently approved for the treatment of pediatric and adult patients with TSC who have 
subependymal giant cell astrocytomas (SGA) that need to be treated but cannot be surgically 
resected. The first, largest study to be published evaluating everolimus in TSC was in 2010 
[120]. This open label study enrolled 28 children with SGA treated with everolimus 3mg/m2 to a 
blood trough concentration of 5-15ng/ml. In addition to a significant reduction in the volume of 
SGA, improvements in quality of life and reductions in seizure frequency were also observed. 
Overall, the medication had few grade 3 AEs and was well tolerated. The two-year open-label 
extension of the EXIST-1 trial, which looked at SGA and angiomyolipoma outcomes, supported 
longer-term use of everolimus, with a sustained efficacy in reducing the size of the SGAs [121, 
122]. The safety and tolerability in this group was also reasonable, with a 5% dropout rate and 
16% SAE rate. In the open-label EXIST-2, treatment was continued up to 4 years, with an 8.9% 
dropout rate [123].
The most relevant iteration of the everolimus trials for TSC was the EXIST-3, a double-blind 
placebo-controlled study evaluating everolimus as an adjunctive therapy for treatment-resistant 
focal-onset seizures in TSC [124]. These participants, all of which were already receiving 1-3 
AEDs at the time of enrollment, had ≥16 seizures over an 8-week period to qualify for the study. 
Participants were assigned to placebo, low-dose everolimus (3-7ng/mL), or high-dose everolimus 
(9-15ng/mL). The primary endpoint in this study was change in seizure frequency from baseline, 

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with the response rate defined as the proportion of participants achieving ≥50% reduction in 
seizure frequency. In the study, the median percentage reduction in seizure frequency was 29% 
in the low dose group and 40% in the high-dose group, also with reasonable safety and 
tolerability results.
In a recent single-center, open prospective study of 15 pediatric participants with TSC and 
epilepsy, 80% of participants treated with everolimus responded with seizure reduction [125]. In 
the study, the safety and tolerability of treatment appeared favorable, with no participants 
withdrawn from treatment over the course of the trial.  In another study out of Cincinnati 
Children’s Hospital, 78% of children treated with everolimus reported ≥50% reduction in seizure 
frequency at 2 years [126]. Over 94% of AEs were mild or moderate.  There are also smaller 
scattered reports in the literature also associating a reduction in seizure frequency in children 
with SGA treated with everolimus [127-129].
1.8
ABI-009 
ABI-009 (nab-rapamycin) is a nanoparticle form of human albumin-bound rapamycin with a 
mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-
bound (nab®) technology. ABI-009 is freely dispersible in saline and is suitable for intravenous 
administration, and has produced both a favorable safety profile and evidence of efficacy in 
patients with metastatic solid tumors [130]. The nab technology may enhance tumor penetration 
and accumulation via the albumin receptor-mediated (gp60) endothelial transcytosis. Albumin is 
highly soluble, has long plasma half-life, broad binding affinity, making it an ideal candidate for 
drug delivery [131, 132]. Importantly, albumin has been shown to be able to penetrate the blood-
brain barrier (BBB). In biodistribution studies in rats, ABI-009 showed significant brain uptake 
at 5 days (AADi internal data, see Section 0).
1.9
Preclinical Pharmacology, Pharmacokinetics, and Toxicity of ABI-009
Preclinical primary pharmacology studies in vivo demonstrated significant antitumor activity of 
ABI-009 as a single agent administered intravenously at 40 mg/kg, 3 times weekly for 4 weeks, 
across different tumor xenograft models in nude mice [133-137]. This dose level correlates to 
approximately 120 mg/m2 in human. These findings are consistent with published information on 
rapamycin as an mTOR inhibitor and the role of mTOR in tumor growth [138].
Preclinical pharmacokinetic (PK) studies in rats showed that IV ABI-009 exhibited linear PK 
with respect to dose and large volume of distribution (Vz), due to efficient tissue extraction of 
rapamycin from the central blood compartment [135]. Shortly after dosing, tissue rapamycin 
level was 3-5 folds higher than that of blood, indicating efficient extraction. The terminal half-
life of ABI-009 was long in rats, ranging from 13.4 - 25.8 hours and resulted in significant blood 
level at 48 hours (~10 ng/mL) and 120 hours (>1 ng/ml). Consistent with rapamycin literature 
[139], excretion of ABI-009 was primarily through the fecal route (68.57 - 69.99%) with 
minimum contribution from the renal route (7.73 - 8.84%).
The safety and toxicity of ABI-009 were evaluated in a series of preclinical studies. In a Good 
Laboratory Practice (GLP) repeat-dose toxicity study in male and female rats, ABI-009 
administered IV was well tolerated at doses up to 90 mg/kg (equivalent to 540 mg/m2 human 
dose) when delivered every 4 days for 3 cycles. Nonclinical toxicology studies of ABI-009 
showed no new or unexpected toxicity compared to what is already known for rapamycin and 

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other rapalogs [140-142]. Refer to the Investigators’ Brochure of ABI-009 for more detailed 
preclinical safety information.
1.10
Clinical Pharmacokinetics of ABI-009
Clinically, ABI-009 has unique characteristics amongst the available mTOR inhibitors. ABI-009 
produced a fairly dose proportional increase of Cmax and AUC across the dose range tested, and it 
significantly inhibited mTOR targets S6K and 4EBP1. The PK profile of rapamycin 
administered as ABI-009 is categorically different from those of the other oral or IV 
administered mTOR inhibitors. Intravenous infusion of ABI-009 from 45 to 150 mg/m2 results in 
high Cmax of rapamycin upon administration followed by a long half-life of approximately 60 hrs 
that allows once weekly dosing. Peak levels of rapamycin after ABI-009 are well above 1000 
ng/mL range that may have significant tumor penetration effect. Oral mTOR inhibitors such as 
rapamycin or everolimus have poor absorption with a high inter- and intra-patient variability and 
a poor safety profile that requires low basal levels (low ng/mL level) to be maintained over the 
course of treatment. Temsirolimus on the other hand is a prodrug of sirolimus (rapamycin) and as 
a result, high levels of rapamycin are not achieved (< 100 ng/mL) [143]. Clinically, 
administration of ABI-009 at the maximum tolerated dose of 100 mg/m2 IV weekly led to a 
much higher exposure to rapamycin (sirolimus) as compared with daily oral rapamycin at 5 
mg/day (Cmax 130-200 fold, AUC 16-27 fold, AUC/dose ~3-5 fold higher with ABI-009), 
temsirolimus weekly IV at 25 mg (Cmax ~50 fold, AUC ~12 fold, AUC/dose ~2 fold for ABI-
009), and daily oral everolimus at 4-10 mg/day (Cmax 50-70 fold, AUC 12-29 fold, AUC/dose 
~4-5 fold higher with ABI-009) [130, 143, 144]. Unlike with other mTOR inhibitors, micromolar 
concentrations are reached and maintained for several hours with ABI-009 which could 
potentially circumvent acquired resistance to mTOR inhibitors via retroactivation of AKT by 
TORC2 [145, 146].  
1.11
Clinical Studies with ABI-009
ABI-009 has been tested in study CA401, a completed phase 1 study in participants with 
advanced nonhematological malignancies using weekly administration of ABI-009 [130]. 
Currently, there are several ongoing trials investigating the safety and efficacy of single-agent 
ABI-009 in various disease areas, including a trial in participants with malignant perivascular 
epithelioid tumors (PEComas), a rare type of soft-tissue tumors (NCT02494570), and a trial in 
by the Children’s Oncology Group in pediatric oncology participants (ADVL1514, 
NCT02975882). In addition to studies in various cancer, ABI-009 is also being investigated in 
participants with severe pulmonary arterial hypertension (PAH, NCT NCT02587325).
Study CA401 (Advanced Nonhematological Malignancies)
In a phase 1 dose escalation, tolerability and pharmacokinetics study conducted at MD Anderson 
Cancer Center (Protocol CA-401), ABI-009 was well tolerated with evidence of responses and 
SD in various solid tumors including renal cell carcinoma and bladder cancer, both of which 
typically overexpress mTOR [130]. Twenty-six participants were treated with 45, 56.25, 100, 
125, 150 mg/m2 ABI-009 per week for 3 weeks, followed by a week of rest (28-day cycle). ABI-
009 was administered intravenously. The MTD was established at 100 mg/m2.
Nineteen participants were evaluable for efficacy. One participant in the 45 mg/m2 (95 mg actual 
rapamycin dose) cohort diagnosed with adenocarcinoma of the kidney and with bone and 

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intrathoracic metastases had a confirmed PR. The target lesion of this participant was reduced by 
35.1% and the duration of response lasted 183 days. Two (11%) participants (at doses 45 and 
125 mg/m2, with actual rapamycin doses of 88 mg and 193 mg, respectively) had an overall 
tumor evaluation of SD (confirmed): 1 participant with mesothelioma had SD for 365 days and 1 
participant with a neuroendocrine tumor in the left axillary node had SD for 238 days. 
For all cohorts and all grades, 25 of 26 (96%) participants experienced at least 1 treatment-
related adverse event (TRAE). The most common nonhematologic TRAEs reported were 
mucosal inflammation (10 participants, 38%), fatigue (7 participants, 27%), rash (6 participants, 
23%), diarrhea (6 participants, 23%), and nausea (5 participants, 19%). Most of these AEs were 
grade 1/2 events, with only three grade 3 nonhematologic AEs (2 elevated AST and 1 dyspnea). 
Specifically, at the MTD (100 mg/m2), all 7 participants experienced at least 1 TRAE of any 
grades, and the most common AEs were thrombocytopenia, mucositis, and fatigue (5 
participants, 71% each). A total of 7 participants (27%) had infections, including candidiasis, 
oral candidiasis, cellulitis, folliculitis, and urinary tract infection. All these events were grade 1 
or 2.
Four (15%) participants experienced at least 1 treatment-related serious AE, including cardiac 
arrhythmia (grade 2) and mood alteration (grade 3) both in the 125 mg/m2 cohort, vomiting 
(grade 3) in the 45 mg/m2 cohort, and dyspnea (grade 3) in the 100 mg/m2 cohort. 
The most common hematologic TRAE, for all cohorts and grades, were thrombocytopenia 
(58%), followed by hypokalemia (23%), anemia and hypophosphatemia (19% each), and 
neutropenia (15%). Most of these events were grade 1/2, and only one grade 4 hematologic event 
occurred (thrombocytopenia in the 150 mg/m2 arm). At the MTD, the only hematologic AE was 
a grade 3 anemia.
Study PEC-001 (Malignant PEComa)
Study PEC-001 is a phase 2, multi-center, single arm, open-label, multi-institutional study to 
determine the efficacy and safety profile of ABI-009 administered by IV infusion in participants 
with malignant PEComa. The primary objective of this study is to investigate the efficacy of the 
mTOR inhibitor ABI-009 in advanced malignant PEComa. The secondary objectives are to 
further investigate the efficacy and safety of intravenous (IV) ABI-009 100 mg/m2 given weekly 
for 2 of 3 weeks in participants with advanced malignant PEComa. At least 30 evaluable 
participants will be enrolled in study PEC-001.
Study PAH-001 (Severe Pulmonary Arterial Hypertension)
This study is a prospective phase 1, single arm, open-label, multi-institutional study to determine 
the MTD, safety, and preliminary efficacy of IV ABI-009 in participants with severe PAH. ABI-
009 is administered weekly for 16 weeks with a dose range of 1-10 mg/m2.
More information is provided in the ABI-009 Investigator’s Brochure. 
1.12
Clinical Experience with ABI-009 in Pediatric Participants
ABI-009 is currently being investigated in a multicenter phase 1 study (ADVL1514) by the 
Children's Oncology Group (COG) in pediatric participants with recurrent or refractory solid 
tumors. The aims of the trial will be to establish the maximum tolerated pediatric dose of ABI-
009 administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle, 
in combination with temozolomide and irinotecan (administered on Days 1-5), and to investigate 

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the toxicities, pharmacokinetics, and pharmacodynamics of ABI-009 in pediatric participants 
with recurrent or refractory solid tumors, including CNS tumors. The study uses the Rolling Six 
escalation/de-escalation design, and the starting dose of ABI-009 is 35 mg/m2.
As of Jan 30, 2018, 6 participants have been enrolled and received treatment. Overall, the 
adverse events observed with ABI-009 in pediatric participants are consistent with those 
observed in previous clinical studies in adults. The main dose limiting toxicity of ABI-009, 
administered as a single agent and in combination with cytotoxic agents temozolomide and 
irinotecan, is grade 3 thrombocytopenia (2 out of 5 participants receiving ABI-009 at 35 mg/m2). 
As per the protocol de-escalation guidelines, the new cohort of participants will receive an ABI-
009 dose of 20 mg/m2 in combination with temozolomide and irinotecan.
1.13
Comparison of Exposure of ABI-009 and Oral mTOR Inhibitors
Preclinical and clinical PK studies showed that ABI-009 administered IV exhibits an overall 
linear PK (Cmax and AUC) with respect to dose. In contrast, oral rapamycin has poor 
bioavailability (14% with oral solution, 18% with tablet) and its uptake is affected by food [147]. 
The oral bioavailability is higher with everolimus at ~30% but is still heavily affected by food, 
which can reduce Cmax by ~60% and AUC by ~16% [143]. Clinically, administration of ABI-009 
at the maximum tolerated dose of 100 mg/m2 IV weekly led to a much higher drug exposure as 
compared with daily oral rapamycin at 5 mg/day (Cmax 130-200 fold, AUC 16-27 fold higher 
with ABI-009) and oral everolimus at 4-10 mg/day (Cmax 50-70 fold, AUC 12-29 fold higher 
with ABI-009) [130, 143, 144]. The exposure normalized to dose (AUC/dose) is also 
significantly higher with ABI-009 compared with oral rapamycin (~3-5 fold) and oral everolimus 
(~4-5 fold) [130, 143, 144].
PK modeling and limited clinical data have also suggested that weekly IV administration of ABI-
009 at doses similar to or lower than oral rapamycin and everolimus can achieve a weekly trough 
rapamycin blood level within the targeted therapeutic range of 5-15 ng/ml with oral mTOR 
inhibitors. In the current study, the starting dose of ABI-009 is 5 mg/m2/week, with potential 
dose escalation to 10 and 20 mg/m2/week or de-escalation to 2.5 and 1 mg/m2/week. Linear 
modeling of rapamycin blood concentration one week after ABI-009 IV administration using 
phase 1 clinical PK data indicates that a weekly dose of ABI-009 at 5-20 mg/m2 can still 
maintain a relevant therapeutic weekly whole blood rapamycin trough level (see table below) 
with doses below 5 mg/m2 reaching somewhat lower levels.
Table 1:
Predicted Rapamycin Blood Levels after ABI-009 IV Administration
Time Post-infusion (hr)
Dose 
(mg/m2) 
0
1
4
8
24
48
72
96
168
1
28.44
9.45
7.40
5.20
3.64
2.43
1.42
1.39
0.71
2
56.88
18.89
14.80
10.39
7.27
4.86
2.84
2.79
1.42
3
85.32
28.34
22.20
15.59
10.91
7.29
4.26
4.18
2.13
5
142.20
47.23
37.00
25.99
18.18
12.15
7.10
6.97
3.56
10
284.40
94.46
73.99
51.97
36.35
24.30
14.20
13.94
7.11
20
568.80
188.92
147.98
103.94
72.70
48.60
28.40
27.88
14.22

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In an ongoing phase 1 clinical study of ABI-009 in participants with severe pulmonary arterial 
hypertension (PAH-001), rapamycin blood levels one week after IV ABI-009 administration are 
available from 3 participants. The whole blood trough rapamycin levels are within the range of 
4.3-9.1 ng/ml for the 5 mg/m2/week ABI-009 dose and 7.3-17.5 ng/ml for the 10 mg/m2/week 
dose, in general agreement with the PK modeling. Although there is no pediatric PK data with 
ABI-009 currently available, overall the current dose escalation scheme is justified based on 
existing and predicted adult clinical PK data. 
The planned ABI-009 weekly starting dose levels in this study are lower than the previous dose 
of everolimus in similar clinical settings. In EXIST-3, a double-blind placebo-controlled study 
evaluating everolimus as an adjunctive therapy for treatment-resistant focal-onset seizures in 
TSC with mostly pediatric participants [124], the median dose received by participants in the 
everolimus low-exposure group was 5.2 mg/m2/day (range 13–14.5) and the median whole blood 
rapamycin trough level (Cmin) observed at the end of the core phase was 5.1 ng/mL (1.4–25.3), 
whereas in the high-exposure group the median dose was 7.5 mg/m2/day (1.4–24.4) and the 
median Cmin was 8.3 ng/mL (0.8–22.0).
Figure 1:
Tumor Volume and Animal Survival following Treatment with IV ABI-009 
and Oral mTOR Inhibitors
Due to its different PK profile, ABI-009 can achieve greater drug exposure than oral mTOR 
inhibitors at the same dose level. Consistent with this PK observation, preclinical study results 
also demonstrate significantly greater antitumor activity and prolonged survival with ABI-009 
administered IV compared with equal weekly dosing of oral rapamycin and oral everolimus 
(AADi internal data). In athymic mice bearing UMUC3 human bladder cancer xenografts, ABI-
009 was administered IV at 7.5 mg/kg, twice weekly (total weekly dose: 15 mg/kg), whereas 
rapamycin and everolimus were administered PO at 3 mg/kg/day, 5 days per week to achieve the 
same weekly total dose. The tumor growth inhibition (TGI) was 69.6% with ABI-009, 
significantly greater than oral rapamycin (TGI 24.3%; p < 0.00001 vs ABI-009, ANOVA) and 

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oral everolimus (TGI 36.2%; p = 0.0023 vs ABI-009, ANOVA). The median overall survival 
was also significantly longer with ABI-009 (not reached) compared with oral rapamycin (21 
days; p < 0.05, log rank test) and oral everolimus (19 days; p < 0.05, log rank test). Results from 
this preclinical study clearly demonstrate superior therapeutic efficacy of ABI-009 to oral mTOR 
inhibitors.
1.14
Distribution of ABI-009 in the Brain
Albumin has been shown to be able to penetrate the blood-brain barrier (BBB) and distribute in 
the brain. Preclinical and clinical studies demonstrate the usefulness of albumin and albumin-
bound drugs in the treatment of glioblastoma. In a clinical study, intravenous administration of 5-
aminofluorescein-labeled albumin 0.5-4 days prior to surgery at 0.5-1 mg/kg in 13 participants 
resulted in the fluorescent visualization of malignant gliomas in 11 participants (84%), which 
facilitated the complete resection of glioblastoma in 9 participants (69%) [148]. In an orthotopic 
mouse GBM xenograft model, albumin-linked aldoxorubicin but not doxorubicin significantly 
delayed tumor growth and prolonged survival. In a Phase 2 study of participants with recurrent 
GBM, aldoxorubicin treatment resulted in 3 PR, 7 SD, and 11 PD in 21 participants [149]. 
As an albumin-bound nanoparticle, ABI-009 is potentially a suitable treatment option for disease 
indications in the brain, including epilepsy. In a biodistribution study in rats, radiolabeled ABI-
009 showed significant brain uptake at 5 days (AADi internal data). As shown in Figure 2, the 
radioactivity accumulation in the brain was comparable to all other major organs 5 days after a 
single IV dose of radiolabeled ABI-009.
Figure 2:
Distribution of Radioactivity in Tissues in Male Rats

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Further, in a recent PK/biodistribution study, female SD rats received a single intravenous dose 
of ABI-009 at 1.7, 9.5, and 17 mg/kg. The lowest dose of 1.7 mg/kg corresponded with 10 
mg/m2 human dose (Dose level 2) proposed in the current clinical protocol. The rapamycin 
concentrations in blood and brain at different time points between 2 to 120 hours were analyzed 
by LC-MS/MS. The data are in Table 2 below.
 Table 2:
Rapamycin Levels in Brain and Blood after ABI-009 IV Administration
Brain (ng/g)
Blood (ng/ml)
ABI-009 
(mg/kg)
Time (hr)
Mean
SD
Mean
SD
Brain/Blood 
Ratio
2
42.4
4.0
58.5
1.2
0.7
8
38.2
3.6
24.9
5.1
1.5
24
40.8
13.3
9.6
2.9
4.3
72
31.8
8.6
2.7
0.5
11.9
1.7 (N = 
3/group)
120
94.9
4.5
1.2
0.4
77.9
2
215.3
33.5
560.3
106.7
0.4
8
263.7
27.6
160.3
21.5
1.6
24
328.0
39.7
15.1
5.6
21.7
72
246.3
10.6
4.3
2.3
58.0
9.5 (N = 
3/group)
120
225.3
54.2
1.1
0.3
201.5
2
568.3
84.6
1510.0
115.3
0.4
8
640.7
56.0
372.7
31.5
1.7
24
884.0
86.8
34.5
15.1
25.6
72
606.0
70.7
3.0
0.7
203.4
17 (N = 
3/group)
120
522.3
53.5
2.1
0.5
243.7
At all times and all doses, tissue levels of rapamycin in the brain were well above the threshold 
of 5 ng/ml (or ng/g, assuming density of tissue is 1 g/ml) which is recognized as the threshold for 
therapeutic activity. The levels in the brain were stable over the 5-day study period suggesting 
accumulation over time despite clearance from the blood over the same time period.  In 
summary, results from this study clearly demonstrated drug distribution to the brain with ABI-
009 IV administration.
Everolimus is the 40-O-(2-hydroxyethyl) derivative of rapamycin and works similarly to 
rapamycin as an allosteric mTORC1 inhibitor by binding to FKBP12. The IC50 of rapamycin is 
~0.1 nM in HEK293 cells [150], and the IC50 of everolimus is 1.6-2.4 nM in a cell-free assay 
[151]. As everolimus has been shown in multiple clinical studies to reduce seizure frequency 
[120, 124-126], ABI-009, which contains rapamycin and may have the advantage of CNS 
penetration due to albumin, is also likely to be effective as a treatment for epilepsy.
2
STUDY RATIONALE
The proposed participants in question pose a challenging clinical population. Given the 20-40% 
chance of failure with resective surgery, and the fact that once a child is intractable the chances 
of additional AEDs eliminating seizures ≤5%, options are limited. Aside from palliative surgical 
procedures such as corpus callosotomy, vagal nerve stimulation (VNS), or responsive 
neurostimulation (RNS), there are no other novel approaches. There is a strong suggestion in the 

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preclinical literature of an association between mTOR activity and epilepsy/epileptogenesis, 
particularly in malformations of cortical development. The clinical experience with mTOR 
inhibitors as related to epilepsy, however, has really been limited to the TSC population. Of 
course, this is intuitive given the defined genetic contribution and the characterization of the 
relevant pathways. However, there is a growing body of evidence supporting the dysregulation 
of PI3K/Akt/mTOR in a variety of pathologies encountered in pediatric epilepsy surgery, 
including focal cortical dysplasia (FCD) [152-154]. In fact, whole exome sequencing of children 
with FCD and hemimegaloencephaly from peripheral samples demonstrates an association 
between mTOR mutations and an entire spectrum of pediatric brain malformation/epilepsy 
phenotypes [154]. Given the lack of options for these children, animal model data with 
rapamycin and the emerging evidence that the mTOR inhibitor may play a role in treating 
epilepsy, it seems practical that the next step would be to treat these children with ABI-009 as a 
therapeutic endeavor.
2.1
Risk / Benefit Assessment
The mTOR inhibitors (rapamycin/sirolimus, temsirolimus and everolimus) as a class have 
similar side effects and safety profiles and one can refer to the package inserts of the marketed 
mTOR inhibitors for safety information.  No new side effects were noted with ABI-009 (see 
investigator brochure). 
The safety data available in the literature to date for all completed controlled and uncontrolled 
clinical studies suggest that: (a) mTOR inhibitors are generally well tolerated at both daily and 
weekly dose schedules, and (b) mTOR inhibitors give a favorable safety profile, with adverse 
events (AEs) being manageable, reversible, and non-cumulative. Most common adverse 
reactions (incidence ≥10%) associated with mTOR inhibitors are stomatitis, rash, fatigue, 
asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, pneumonitis, cough, 
peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most common grade 
3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and pneumonitis. 
Non-infectious pneumonitis is a class effect of rapamycin derivatives, and some of these cases 
have been severe and on rare occasions, fatal outcomes have been observed. 
mTOR inhibitors have immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including reactivation 
of hepatitis B virus, have been described in patients taking mTOR inhibitors. Some of these 
infections have been severe (e.g. leading to respiratory or hepatic failure) and occasionally have 
had a fatal outcome.
The most common laboratory abnormalities (incidence ≥50%) associated with mTOR inhibitors 
are anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and 
increased creatinine. The most common grade 3-4 laboratory abnormalities (incidence ≥3%) 
were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. 
Comprehensive clinical safety data and nonclinical toxicology information are available for long 
term dosing with rapamycin and other mTOR inhibitors, which have been included in previous 
regulatory submissions with ABI-009 (IND 125669 and Investigator’s Brochure, version 5.0).

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Long term clinical studies with rapamycin and everolimus in both adult and pediatric patient 
populations demonstrate acceptable safety and tolerability. Rapamycin is approved for the 
prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants based 
on results from 2 clinical studies, with study duration of 24 months and 36 months respectively 
at 2 or 5 mg/day or 14-35 mg/week (Rapamune® Package Insert). The safety and effectiveness 
of everolimus have been established in pediatric patients age 1 year and older with Tuberous 
Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and in 
pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Everolimus 
did not appear to adversely impact growth and pubertal development in the 115 pediatric SEGA 
patients treated with everolimus for a median duration of 4.1 years (Afinitor® Package Insert). 
Notably, the toxicological findings in the nonclinical toxicity studies (summarized below) with 
rapamycin were not considered to be real issues in terms of human safety, as most were not 
encountered in the long-term clinical studies in patients. 
Importantly, the proposed doses in our current study with ABI-009 is significantly lower 
compared with the doses of rapamycin and everolimus used in previous long term clinical 
studies. The initial ABI-009 dose of 5 mg/m2/week results in an estimated 5 mg/week dose 
depending on the age and body surface of the patient, compared with substantially higher 
rapamycin doses of 14 and 35 mg/week for 24 or 36 months in renal transplant patients, or 
estimated everolimus doses of 36.4 and 52.5 mg/week (median dose for low-exposure group: 5.2 
mg/m2/day, high-exposure group: 7.5 mg/m2/day) over extensive period in pediatric patients with 
TSC-associated partial-onset seizures (French, 2016). Therefore, the proposed ABI-009 dose in 
this study should result in an acceptable safety profile that is similar to those observed in 
previous rapamycin and everolimus clinical studies, and there is sufficient clinical and 
nonclinical safety data with rapamycin and other mTOR inhibitors to support ABI-009 dosing 
for similar periods as rapamycin.
Extensive long term nonclinical studies have previously been conducted for rapamycin to 
support long term clinical administration, with repeated-dose daily PO studies in mice for up to 3 
months, in rats for up to 1 year (dose range for 1-month study: 0.05-5 mg/kg/d; 3-month: 0.05-5 
mg/kg/d; 0.5-2 mg/kg/d; 0.5-5 mg/kg/d; 6-month: 0.05-5 mg/kg/d; 1-year: 0.2-6 mg/kg/d), and in 
monkeys for up to 6 months (dose range for 1-month study: 0.05-15 mg/kg/d; 3 and 6-month: 
0.05-10 mg/kg/d) (NDA 21-083, Pharmacologist’s Review). In rats, the major changes and target 
organ toxicities included depression of body weight gain, lymphoid atrophy (spleen, lymph 
nodes, thymus), increased incidence of focal myocardial degeneration, pancreatic islet cell 
degeneration with associated hyperglycemia, elevated triglycerides and cholesterol, pulmonary 
phospholipidosis, testicular tubular atrophy, ovarian atrophy, increased hemosioderosis, 
increased fibrinogen. and a high-turnover form of osteopenia. In monkeys, the major changes 
and target organ toxicities included chronic diarrhea, colitis and typhlitis, increases in fibrinogen, 
lymphoid atrophy and testicular tubular atrophy. Toxic effects of rapamycin have been observed 
on the male reproductive system, including testicular toxicities. Rapamycin was also associated 
with embryo and fetal toxicity in rats (Rapamune® Package Insert). Notably, the toxicological 
findings in the nonclinical toxicity studies with rapamycin were not considered to be real issues 
in terms of human safety, as most were not encountered in the long-term clinical studies in 
patients.
There is indisputable neurological morbidity to uncontrolled seizures, including resultant deficits 
in cognitive, behavioral, and psychosocial function [17-20]. Intractable seizures also present a 

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high mortality risk [26-28]. The mortality risk of uncontrolled epilepsy is approximately 0.5% 
per year and accumulates over the child’s lifetime. In this subset of challenging cases, the 
relatively low risk of significant morbidity associated with mTOR inhibitor treatment warrants 
an attempt to see if ABI-009 has potential as a safe and effective therapy.
3
STUDY OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to assess the safety and tolerability of ABI-009 over a 
range of doses and to determine the DLT and MTD in participants with surgically-refractory 
epilepsy. 
Safety: Defined as the incidence of AEs and SAEs during the study period. We will assess 
adverse events according to the National Cancer Institute Common Toxicity Criteria for 
Adverse Events version 4.03. MTD will be determined based on safety assessment, 
including the Columbia-Suicide Severity Rating Scale (C-SSRS) which will be 
administered at baseline, after study drug, and during follow-up.
Tolerability: Defined as the rate of withdrawal from the study, either voluntary or as 
medically directed as well as rate of compliance with medication regimen.
Columbia-Suicide Severity Rating Scale (C-SSRS) serious suicidal ideation score stays 
below a 4
3.2
Secondary Objectives
The secondary objectives of this study are to:

Determine efficacy. Efficacy is defined as the change in seizure frequency between 
baseline and follow-up, expressed as percentage reduction in seizure rate (reduction in 
seizure frequency from baseline, calculated as (Baseline frequency [seizures/month] –
frequency at follow-up [seizures/month])/Baseline frequency [seizures/month]) and 
median percentage reduction in seizure frequency. Treatment response rate will be 
defined as the proportion of participants achieving at least a 25% reduction in seizure 
frequency from baseline. Seizure frequency will be defined as the ratio between the 
number of seizures and the number of days on which seizure information was known 
within the same period of time (for either baseline or maintenance phase). Additional 
secondary endpoints will include frequency of seizure-free days during the maintenance 
period, seizure-free rate (participants remaining seizure free during the maintenance 
period), and rapamycin blood level–response relationship analysis. 

Determine quality of life and behavioral changes. Quality of Life for Children with 
Epilepsy Parent Form (QOLCE) [1] and Nisonger Child Behavioral Rating Form 
(NCBRF) [2, 3] will be completed at baseline, at the completion of maintenance, and at 
the completion of the 3 month follow-up period. 

Determine weekly whole blood rapamycin trough levels for three consecutive weeks. 

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3.3
Exploratory Objectives
For children enrolled in the study who underwent epilepsy surgery at our institution, informed 
consent will be sought for us to use their previously acquired/banked surgical tissue (including 
fibroblast cultures) for the following exploratory aims:

To explore associations between histopathologic diagnosis and seizure outcomes

To explore associations between pS6 positivity and seizure outcomes

To analyze key molecular features including activation of the PI3K, mTOR and MAPK 
pathways as they relate to seizure outcomes

To possibly perform additional genomic studies or obtain previously performed genomic 
analyses including genomic profiling from peripheral samples and correlate to seizure 
outcomes

Explore any relationships between safety, efficacy and whole blood rapamycin trough 
levels

Explore any relationships between AED levels (acquired outside the study through 
clinical standard of care) and rapamycin levels during the study
None of the exploratory aims would require additional experimental procedures to the 
participants throughout the study beyond those explicitly discussed in the protocol. Tissue 
would only be tested on participants who have already consented to and have banked tissue 
within our institution from prior epilepsy-related procedures.
4
STUDY DESIGN
4.1
Study Overview
This is a prospective, single-center, non-randomized open-label phase 1 study to investigate 
multiple dose levels of ABI-009 for surgically-refractory epilepsy. Up to 18 participants are 
planned to be enrolled into the study.
The duration of participation for each participant is up to 18 weeks, including a 4-week baseline 
period to obtain baseline outcome rates, a 3-week active study period and a 12-week follow-up 
period (see Figure 1). After the baseline period, participants will be started on the assigned dose 
of ABI-009, given once weekly for a total of 3 weeks. Dose levels to be tested are below: 
For dose finding, ABI-009 will be tested in cohorts of 3 participants each using the standard 3+3 
dose-finding design. Initial starting dose will be at 5 mg/m2/week.
Table 3: ABI-009 Cohort Dosing Schedule
Dose  levels
ABI-009 in mg/m2
-2
1
-1
2.5
1
5
2
10

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3
20
Escalation to the next dose level with a new cohort of 3 participants will occur after no DLT was 
observed. There will be no intra-participant dose escalation allowed. If a DLT occurs in a cohort, 
an additional 3 participants will be recruited to the cohort. If no further DLTs occur, then a new 
cohort of 3 participants at the next higher dose level can be enrolled. If 2/6 participants at a dose 
level experience a DLT, then the cohort will be closed to further enrollment and 3 participants 
will be enrolled at the next lower dose level, and so on. The MTD is the highest dose level in 
which ≤1 participant has a DLT. There will be no intra-participant dose escalation allowed.
Once the MTD has been determined, the MTD cohort will be opened for an estimated additional 
6 participants. These participants will adhere to the identical protocol of the rest of their cohort.
Product will be administered IV every 7 days for 3 weeks.  
For a detailed review of visits, please see Appendix 1.
Total duration of the study is expected to be about one year. 
5
CRITERIA FOR EVALUATION
5.1
Primary Endpoints
I. Safety

DLT and MTD

Incidence of adverse events and clinically significant abnormal lab values during dosing
II. Tolerability

Voluntary or medically-determined withdrawal from study

Adherence to medication regimen

C-SSRS serious suicidal ideation score stays below a 4 rating
5.2
Secondary Endpoints
I.
Efficacy 

Seizure frequency 

Percentage reduction in seizure frequency 

Median percentage reduction in seizure frequency 

Response rate

Frequency of seizure-free days 

Seizure-free rate

Rapamycin blood level–response relationship
II.
Quality of life and behavioral changes

Quality of Life for Children with Epilepsy Parent Form (QOLCE) [1] and 

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
Nisonger Child Behavioral Rating Form (NCBRF)  [2,3] 

Both will be completed at baseline, at the completion of maintenance, and at the 
completion of the 3-month follow-up period.
III.
Weekly whole blood rapamycin trough levels for three consecutive weeks. 
6
PARTICIPANT SELECTION
6.1
Study Population
Participants with a diagnosis of medically intractable epilepsy who meet all of the inclusion and 
none of the exclusion criteria will be eligible for participation in this study. Participants must be 
enrolled before study procedures begin.
6.2
Inclusion Criteria
1. Written informed consent (and assent when applicable) obtained from participant or 
participant’s legal representative 
2. Be willing and able to adhere to the study visit schedule and other protocol requirements
3. Male or female ≥3 and ≤26 years of age at Visit 1
b. Because no dosing or adverse event data are currently available on the use of ABI-
009 or other mTOR inhibitors in participants <3 years of age, these young children 
are excluded from this study.
4. Documentation of a diagnosis of medically intractable epilepsy as defined by the failure of at 
least 2 appropriately dosed and tolerated AEDs to eliminate all clinical seizures over a 6-
month period, prior to epilepsy surgery
5. Documentation of resective epilepsy surgery following appropriate pre-surgical evaluation
6. Documentation of continued clinical seizures that persist at least 3 months following 
resective epilepsy surgery. In order to proceed with enrollment and study drug initiation, 
participants will have to have had >8 seizures in the last 30 days without 2 consecutive weeks 
of seizure freedom, as noted by a daily seizure diary.
7. Documentation that the participant is not a candidate for or refuses any additional resective 
epilepsy surgery
8. Participants must have adequate bone marrow function (ANC ≥1,000/mm3, platelet count of 
≥100,000/mm3, and hemoglobin ≥9 gm/dL) before study drug dosing.
9. Participants must have adequate liver function (SGPT/ALT ≤5 times ULN and bilirubin ≤5 
times ULN) before study drug dosing.
10. Participants must have adequate renal function, defined as: Creatinine clearance or 
radioisotope GFR ≥70mL/min/1.73 m2 or a serum creatinine before study drug dosing based 
on age/gender as follows:

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11. Participants must have a fasting cholesterol level <350 mg/dL and triglycerides <400 mg/dL 
before starting study drug. In case one or both of these are exceeded, the participant can only 
be included after initiation of appropriate lipid lowering medication and documentation of 
cholesterol <350mg/dL and triglycerides <400mg/dl before study drug dosing.
12. Participants must have normal oxygen saturation before study drug dosing.
13. The effects of ABI-009 on the developing human fetus at the recommended therapeutic dose 
are unknown. For this reason and because rapamycin is known to be teratogenic, female 
participants 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 female participant become pregnant or suspect she 
is pregnant while participating in this study, she should inform her treating physician 
immediately. 
a.
Participants of child bearing potential must not be breastfeeding or pregnant as 
evidenced by a negative pregnancy test at enrollment and before study drug initiation.
6.3
Exclusion Criteria
1. For females of child bearing potential: 
a.
Positive pregnancy test at Visit 1, or
b. Lactating, or
c.
Unwilling to practice a medically acceptable form of contraception (acceptable forms 
of contraception: abstinence, hormonal birth control, intrauterine device, or barrier 
method plus a spermicidal agent), unless surgically sterilized or postmenopausal 
during the study. 
2. Participant has any other condition that, in the opinion of the Site Investigator/designee, 
would preclude informed consent or assent, make study participation unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving the study 
objectives. 
3. Participants has received immunization with attenuated live vaccines within one week of 
study entry and/or is planning to receive immunization with attenuated live vaccines during 
study period. Examples of live vaccines include intranasal influenza, measles, mumps, 
rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. Close contact 

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with those who have received attenuated live vaccines should be avoided during the ABI-009 
dosing period.
4. Participant tests positive for Hepatitis C antibodies or the Hepatitis B antigen. HBsAg and 
HCVAb blood test must be done at screening (HBsAg only needs to be screened in patients 
who have not received the full complement of Hepatitis B immunizations). Alternatively, if 
the patient has received the complement of Hepatitis B immunizations and documentation is 
provided, this would suffice.
5. A known history of HIV seropositivity. HIV-positive patients on combination antiretroviral 
therapy are ineligible because of the potential for pharmacokinetic interactions with ABI-
009. In addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.
6. Participant is receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Note: Patients that are currently using inhaled, intranasal, ocular, 
topical or other non-oral or non-IV steroids are not necessarily excluded from the study but 
must be discussed with the study chair.
7. Participant has been previously treated with a systemic mTOR inhibitor for epilepsy. Skin 
cream use with rapamycin or everolimus, however, is permitted.
8. Participant has a known hypersensitivity to human albumin, ABI-009 or other rapamycins 
(e.g. sirolimus, everolimus, temsirolimus).
9. Participant is receiving any other concurrent anticancer or investigational therapy. 
Participants will be permitted to enroll in the study after a 30-day washout of previously used 
investigational drugs.
10. Participant has any clinically significant unrelated systemic illness that would compromise a 
participant’s ability to tolerate protocol procedures.
11. Participant is unable to return for dosing and follow-up visits to assess toxicity to the study 
drug.
12. Participant has uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, active lung disease, or psychiatric illness/social situations that would limit 
compliance with study requirements. Study Specific Tolerance for Inclusion/Exclusion 
Criteria
Patients who fail to meet one or more of the inclusion criteria or who meet any of the exclusion 
criteria will not be enrolled in this study. Waivers of any of the above study entry criteria will not 
be granted.
7
CONCURRENT MEDICATIONS
All participants should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.

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7.1
Allowed Medications and Treatments
Standard therapy for epilepsy and related conditions is allowed except for treatments noted in the 
exclusion criteria described above and as noted in the prohibited medications section below. A 
stable therapeutic regimen between screening and Visit 1 is the goal, as well as through the 
baseline period. Once enrolled and started into the baseline observation period, changes in AED 
medication regimen are not permitted unless it is solely for dose adjustments secondary to sub- 
or super-therapeutic serum levels. Participants that have been on a chronic AED regimen will be 
mandated to continue them throughout the entire study period. Treatment for prolonged seizures 
(>5 minutes) or clusters of seizures can be used per participant’s previous rescue prescription.  
7.2
Prohibited Medications and Treatments
Administration of immunosuppressant or chemotherapeutic drugs, IV/PO corticosteroids 
prescribed outside the context of the investigational protocol, and attenuated live vaccines, as 
well as any investigational drugs or biologics, is prohibited while the participant is enrolled in 
the study. 
8
STUDY DRUG DOSING
8.1
Method of Assigning Participants to Dosing Groups
Up to 18 eligible participants will be enrolled to receive the study drug (ABI-009). There will be 
no randomization, and this will be an open-label trial. Participants will be assigned according to 
a standard 3+3 dose escalation design, in the order that they are enrolled.
Participants must meet all inclusion criteria and no exclusion criteria should apply. The 
participant must have signed and dated an approved, current version of all applicable consent 
forms. To allow non-English speaking participants to participate in this study, bilingual health 
services will be provided in the appropriate language when feasible.
8.2
Blinding
This is an open label study; no blinding to dosing assignment will be performed. 
8.3
Formulation of Test and Control Products
8.3.1
Formulation and Administration of Test Product
Refer to the Pharmacy Manual for complete information.
ABI-009 is provided as a lyophilized powder containing 100 mg rapamycin/vial. Each vial of 
study drug will be labeled per standard requirements.
8.3.2
Formulation of Control Product
No control product will be used in this study.

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8.4
Supply of Study Drug to the Site
AADi will ship the study drug to the investigational site. The initial study drug shipment will be 
shipped after site approval to enroll (i.e., all required regulatory documentation has been received 
by AADi and a contract has been executed). Subsequent study drug shipments will be made as 
needed.
8.4.1
Dosage/Dosage Regimen
All participants receive study drug every 5-9 days for 3 weeks.   
8.4.2
Study Drug Preparation and Dispensing
Study drug will be prepared by the site’s investigational pharmacist (or designee) per the 
Pharmacy Manual provided by AADi. 
8.4.3
Administration Instructions 
Refer to Pharmacy Manual. The rate of IV administration should not exceed 3.3 mg/m2/min. The 
rate is based on clinical experience with adult participants, as ABI-009 at 100 mg/m2 can be 
safely administered with 30-min IV infusion.
8.4.4
Storage
Storage for the study drug is at 2-8oC in a secure area under restricted access. If the temperature 
of study drug storage exceeds or falls below this range, this should be reported to AADi and 
Sponsor and captured as a deviation. 
8.5
Dose-Limiting Toxicities
Definition of Dose Limiting Toxicity (DLT):
Any grade 3 or higher toxicity and designated by the principle investigator as definitely or 
probably related (level of attribution) to the study drug, and occurring within 30 days of study 
drug dosing, or as specified per toxicity in the protocol.
8.6
Dose Modification or Discontinuation of Study Drug
For participants who are unable to tolerate the protocol-specified dosing schedule secondary to 
DLT, dose adjustments are permitted in order to keep the participant on study drug. If 
administration of ABI-009 must be interrupted due to DLT, drug dosing will be interrupted or 
modified according to rules described in the table below. Toxicity will be assessed using the 
NIH/NCI Common Terminology Criteria for Adverse Events, version 5.0. If a participant 
requires a dose delay of ≥3 weeks from the intended day of the next scheduled dose, then the 
participant must be discontinued from the study or may resume only with the approval of the 
Principle Investigator.
Table 4: Hematological and non-hematological toxicities and ABI-009 dosing adjustments
TOXICITY
ACTIONS
Non-hematological toxicity
Grade 2
If the toxicity is tolerable to the participant, maintain the same dose. If 

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(pneumonitis management 
detailed separately in 8.7.4)
the toxicity is intolerable to participant, interrupt ABI-009 until recovery 
to grade 1 or better. Then reintroduce ABI-009 at same dose.
If event returns to intolerable grade 2, then interrupt ABI-009 until 
recovery to grade 1 or better. Then reintroduce ABI-009 at the lower 
dose level (refer to Table 3). Reintroduction of ABI-009 may occur 
once.
Grade 3
(except hyperlipidemia*)
(pneumonitis management 
detailed separately in 8.7.4)
Interrupt ABI-009 until recovery to grade 1 or better. Then reintroduce 
ABI-009 at the lower dose level. For pneumonitis consider the use of a 
short course of corticosteroids. Reintroduction of ABI-009 may occur 
once.
Grade 4
Discontinue ABI-009.
Hematological toxicity
Grade 2 Thrombocytopenia 
(platelets <75, ≥50x109/L)
Interrupt ABI-009 until recovery to grade 1 or better (>75x109/L). Then 
reintroduce ABI-009 at initial dose. If thrombocytopenia again returns to 
grade 2, interrupt ABI-009 until recovery to grade 1 or better. Then 
reintroduce ABI-009 at the lower dose level (refer to Table 3). 
Reintroduction of ABI-009 may occur once.
Grade 3 Thrombocytopenia 
(platelets <50, ≥25 x109/L)
Interrupt ABI-009 until recovery to grade 1 or better (platelets 
≥75x109/L). Then resume ABI-009 at one dose level lower. If grade 3 
thrombocytopenia recurs, discontinue ABI-009.
Grade 4 Thrombocytopenia 
(platelets <25x109/L)
Discontinue ABI-009.
Grade 3 Neutropenia 
(neutrophils <1, 
≥0.5x109/L)
Interrupt ABI-009 until recovery to grade 1 or better (neutrophils 
≥1.5x109/L). Then resume ABI-009 at the initial dose. If ANC again 
returns to Grade 3, hold ABI-009 until the ANC ≥1.5x109/L. Then 
resume ABI-009 dosing at the lower dose level (refer to Table 3). 
Discontinue participant from study drug for a third episode of grade 3 
neutropenia.
Grade 4 Neutropenia 
(neutrophils <0.5x109/L)
Interrupt ABI-009 until recovery to grade 1 or better (neutrophils 
≥1.5x109/L). Then resume ABI-009 at the lower dose level (refer to 
Table 3). If grade 3 or grade 4 neutropenia occurs despite this dose 
reduction, discontinue ABI-009.
Grade 3 febrile neutropenia 
(not life-threatening)
Interrupt ABI-009 until resolution of fever and neutropenia to grade 1 or 
better. Hold further ABI-009 until the ANC ≥1,500/mm3 and fever has 
resolved. Then resume ABI-009 at the lower dose level (refer to Table 
3). If febrile neutropenia recurs, discontinue ABI-009.
Grade 4 febrile neutropenia 
(life-threatening)
Discontinue ABI-009.
Any hematological or non-
hematological toxicity 
requiring interruption for 
≥3 weeks
Discontinue ABI-009.
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies.
All interruptions or changes to study drug administration must be recorded.

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8.6.1
Dose Modification for Participants on inducers of CYP3A4 and/or PgP
Co-administration with strong inducers of CYP3A4 or P-glycoprotein (PgP) should be avoided 
when possible. Co-administration with moderate CYP3A4 or PgP inducers should be used with 
caution. That said, there may be participants on CNS agents known to be inducers of CYP3A4 
(barbiturates, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, valproic acid, 
benzodiazepines) that need to be continued on their medication regimen. No dosage adjustment 
of ABI-009 will be made for these participants; they will be dosed at the current stage of dose 
finding based on Table 3. 
8.6.2
Dose Modification for Participants on inhibitors of CYP3A4 and/or PgP
Co-administration with strong inhibitors of CYP3A4 or P-glycoprotein (PgP) should also be 
avoided when possible. Co-administration with moderate CYP3A4 inhibitors (e.g., 
erythromycin, fluconazole) or PgP inhibitors should be used with caution. If the participant 
requires co-administration of moderate CYP3A4 inhibitors or PgP inhibitors, ABI-009 dose will 
be reduced to the next lower dose according to Table 3. (Additional dose reductions to every 
other day may be required to manage toxicities. If the inhibitor is discontinued the ABI-009 dose 
should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor 
after a washout period of 2 to 3 days. Seville orange, star fruit, grapefruit and their juices affect 
P450 and PgP activity. Concomitant use should be avoided.
8.6.3
Missed Study Drug Doses
Missed doses of study drug should be recorded. Our intention is to tightly adhere to the weekly 
schedule of medication administration.
8.7
Management of known adverse events associated with mTOR inhibitors
8.7.1
Management of Hepatitis reactivation/flare
Monitoring and prophylactic treatment for hepatitis B reactivation should occur based on the 
institutional standard for pediatric participants and in consultation with a pediatric 
gastrointestinal specialist and/or pediatric infectious disease.
8.7.2
Management of stomatitis/oral mucositis/mouth ulcers
Stomatitis/oral mucositis/mouth ulcers due to mTOR inhibitors should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with mTOR inhibitors as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, please 
classify the adverse event as such. Please follow the paradigm below for treatment of 
stomatitis/oral mucositis/mouth ulcers:
1. For mild toxicity (Grade 1), conservative measures such as non-alcoholic mouth wash or salt 
water (0.9%) mouthwash several times a day until resolution is recommended
2. For more severe toxicity (Grade 2 in which case participants have pain but are able to maintain 
adequate oral alimentation, or Grade 3 in which case participants cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or 

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phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog 
in Orabase®).
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents.
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be 
avoided in all participants due to their strong inhibition of mTOR inhibitor metabolism, thereby 
leading to higher mTOR inhibitor exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided unless a 
viral infection is diagnosed.
Note: Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the NCI-CTCAE for adverse events, v5.
8.7.3
Management of hyperlipidemia and hyperglycemia
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. 
Blood tests to monitor hyperlipidemia must be taken in the fasting state. Hyperlipidemia and 
hypertriglyceridemia should be treated according to local best clinical practice. Participants 
should be monitored clinically and through serum chemistry for the development of 
rhabdomyolysis and other adverse events as required in the product label/data sheets for 
HMGCoA reductase inhibitors. Hyperglycemia has been reported in clinical trials. Monitoring of 
fasting serum glucose is recommended prior to the start of mTOR inhibitor dosing and 
periodically thereafter. Optimal glycemic control should be achieved before starting study drug 
dosing.
8.7.4
Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in participants taking 
mTOR inhibitors. Some of these have been severe and on rare occasions, a fatal outcome was 
observed. 
A diagnosis of non-infectious pneumonitis should be considered in participants presenting with 
nonspecific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, 
and in whom infectious, neoplastic and other non-medicinal causes have been excluded by 
means of appropriate investigations. Participants should be advised to report promptly any new 
or worsening respiratory symptoms. Participants who develop radiological changes suggestive of 
non-infectious pneumonitis and have few or no symptoms may continue mTOR inhibitor dosing 
without dose alteration. If symptoms are moderate (Grade 2), consideration should be given to 
interruption of dosing until symptoms improve. The use of corticosteroids may be indicated.  
mTOR inhibitor may be reintroduced once at a reduced dose until recovery to Grade 1 or better. 
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), mTOR inhibitor 
dosing should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve. Dosing with mTOR inhibitors may be re-initiated at a reduced dose 
depending on individual clinical circumstances.
Table 5.  Pneumonitis Management and ABI-009 Dosing

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Pneumonitis
Grade
Required Investigations
Management of 
Pneumonitis
ABI-009 Dose Adjustment
Grade 1
CT scans with lung windows 
and pulmonary function 
testing including spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat chest 
x-ray/CT scan every 2 cycles 
until return to baseline.
No specific 
therapy 
required.
Administer 100% of ABI-009 dose
Grade 2
CT scans with lung windows 
and pulmonary function 
testing including spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat chest 
x-ray/CT scan every cycle 
until return to baseline. 
Consider bronchoscopy.
Symptomatic 
therapy. If 
cough is 
troublesome 
prescribe 
corticosteroids.
Reduce ABI-009 dose until 
recovery to ≤Grade 1. ABI-009 may 
also be interrupted is symptoms are 
troublesome. Participants will be 
withdrawn from the study if they 
fail to recover to ≤Grade 1 within 3 
weeks.
Grade 3
CT scans with lung windows 
and pulmonary function 
testing including spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat chest 
x-ray/CT scan every cycle 
until return to baseline. 
Bronchoscopy recommended.
Prescribe 
corticosteroids if 
infection is ruled 
out. Taper as 
medically 
indicated.
Hold ABI-009 until recovery to 
≤Grade 1. ABI-009 may also be 
May restart protocol treatment 
within 3 weeks at a reduced dose 
(by one level) if evidence of clinical 
benefit. Participants will be 
withdrawn from the study if they 
fail to recover to ≤Grade 1 within 3 
weeks.
Grade 4
CT scans with lung windows 
and pulmonary function 
testing including spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat chest 
x-ray/CT scan every cycle 
until return to baseline. 
Bronchoscopy recommended.
Prescribe 
corticosteroids if 
infection is ruled 
out. Taper as 
medically 
indicated.
Discontinue ABI-009
8.7.5
Management of Febrile neutropenia
Febrile neutropenia should be managed according to the local institutional guidelines.
Measures include laboratory testing, blood and urine cultures, and institution of broad spectrum 
antibiotics.
8.7.6
Management of Diarrhea
Following the loperamide dosing guidelines in Table 8 for participants experiencing diarrhea is 
recommended. Prophylactic administration is NOT recommended. Participants are advised to 
call with first signs of poorly formed stools or an increased frequency of bowel movements.
Table 6.   Weight Specific Guidelines for Therapeutic Use of Loperamide

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8.8
Study Drug Accountability
An accurate and current accounting of the dispensing of study drug for each participant will be 
maintained on an ongoing basis by a member of the study site staff. The amount of study drug 
dispensed will be recorded on the Investigational Drug Accountability Record. The study 
monitor will verify these documents throughout the course of the study.
9
STUDY PROCEDURES AND GUIDELINES
The procedures described below will be performed at the visits noted in the Schedule of Events 
(Appendix 1) and in Section 9.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the participant or participant’s legal representative. If appropriate, assent must also be 
obtained prior to conducting any study-related activities.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented as noted in the 
Schedule of Events. Dose, route, unit, frequency of administration, indication for administration 
and dates of medication will be captured.
9.1.2
Demographics
Demographic information (date of birth, sex, race) will be recorded. 
9.1.3
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded.
9.1.4
Epilepsy history
Epilepsy history will be recorded, including seizure types, proposed etiology, age of diagnosis, 
history of AED treatments and reasons for discontinuation/failure, history of pre-surgical 
investigations, history of epilepsy surgery including surgery type, date, postsurgical course, and 
relevant pathology.

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9.1.5
Physical Examination
A complete or abbreviated physical examination will be performed by a licensed professional 
(MD, NP, RN, PA) as noted in the Schedule of Events. The abbreviated exam includes 
neurological, respiratory, cardiovascular, and abdominal assessments.  
After screening, new abnormal physical exam findings must be documented as adverse events 
(AEs). 
9.1.6
Weight and Height  
Weight will be measured on the same scale and recorded as noted in the Schedule of Events. 
Adults and children may remain in clothes (without shoes). A standing height will be measured 
and recorded as noted in the Schedule of Events.
9.1.7
Vital Signs
Resting (preferably a minimum of 5 minutes) measurements of body temperature, blood 
pressure, pulse and respirations will be performed and recorded as noted in the Schedule of 
Events.
9.1.8
Oximetry
A resting (preferably a minimum of 5 minutes) measurement of oximetry will be measured on 
room air and recorded at as noted in the Schedule of Events.
9.1.9
Participant Questionnaire: Quality of Life for Children with Epilepsy Parent 
Form (QOLCE)
The QOLCE is a parental questionnaire used to probe the quality of life of children with 
epilepsy. It is a 4-page survey where parents are asked to rate their child and takes less than 10 
minutes to complete. The questionnaire will be given at the end of the 1-month baseline period, 
at the end of the 3-week dosing period, and again at the end of the 3-month follow-up period.  
9.1.10 Participant Questionnaire: Nisonger Child Behavioral Rating Form 
(NCBRF)
The NCBRF is a 66-item parental questionnaire regarding their child’s behavior. It should take 
about 5-10 minutes to complete. The questionnaire will be given at the end of the 1-month 
baseline phase, at the end of the 3-week treatment phase, and again at the end of the 3-month 
follow-up period.
9.1.11 Epilepsy Diary
Participants and their parents/guardians will be requested to complete a daily diary to record any 
new symptoms in between visits, and most importantly to record seizures. This diary will be 
mandatory during enrollment in the study. The diary will include the numbers and types of 
seizure events that occur daily and will be requested to be completed daily to avoid memory bias. 
The diary will be reviewed as noted in the Schedule of Events and adverse events will be 
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9.1.12 Investigator Opinion
As specified in evaluations by visit, at the start of the visit the investigator will opine on the 
status of the seizures recorded – whether they seem to be the same, worse, somewhat better, or 
better when compared to the prior visit. This will be labeled and treated as an opinion, and will 
be based on the recorded seizure frequencies, the descriptions of the seizures as provided by 
participants and their families, and expert experience.
9.1.13 Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a suicidal ideation and behavior rating scale to identify risk in participants. The 
questionnaire will be given at the end of the 1-month baseline phase, at the end of the 3-week 
treatment phase, and again at the end of the 3-month follow-up period. Participant serious 
suicidal ideation scores must remain below a 4 in order to stay on study.
9.1.14 Adverse Events
Information regarding occurrence of adverse events will be captured throughout each 
participant’s study participation, starting at enrollment and ending once the participant has 
terminated from the study. Duration (start and end dates), grade, seriousness, outcome, treatment 
and relation to study drug will be recorded on the CRF.
9.2
Clinical Laboratory Measurements 
9.2.1
Hematology
Blood will be obtained as noted in the Schedule of Events and sent to each site’s clinical 
hematology lab for a complete blood count (hemoglobin, hematocrit, red blood cell count, white 
blood cell count, white blood cell differential, and platelet count). If values are found to be 
abnormal, a sample will be collected and these parameters re-evaluated at the next study visit. If 
blood sample is unusable for testing, a second sample will be requested from the patient provided 
blood volume total is within safety range.
9.2.2
Blood Chemistry Profile
Blood will be obtained as noted in the Schedule of Events and sent to each site’s clinical 
chemistry lab for determination of sodium, potassium, chloride, bicarbonate, calcium, fasting 
glucose, albumin, total protein, BUN, serum creatinine, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid, phosphorus, fasting serum lipid profile (total cholesterol, triglycerides, 
HDL and LDL). If values are abnormal, a sample will be collected and these parameters re-
evaluated at the next study visit. If blood sample is unusable for testing, a second sample will be 
requested from the patient provided blood volume total is within safety range.
9.2.3
Pregnancy Test
Urine or blood (approximately 2 cc) will be collected from females who are of childbearing age 
and capable of becoming pregnant for a pregnancy test as noted in the Schedule of Events and 
tested in clinic according to site standard procedures. If urine test is positive, confirmation with 
appropriate blood testing is to be performed.

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9.3
Pharmacokinetic Measurements
No pharmacokinetic measurements will be attained for this study.
9.4
Research Laboratory Measurements
Whole blood rapamycin trough levels will be drawn for three consecutive weeks. If blood 
sample is unusable for testing, a second sample will be requested from the patient provided blood 
volume total is within safety range.
9.5
Specimens for Long-Term Biorepository Storage
No additional specimens designated for this study will be kept for long-term bio-repository 
storage.
10 EVALUATIONS BY VISIT
10.1
Screening Assessments (Day -14 to 0)
1. Review the study with the participant (participant’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate.
2. Review eligibility (including epilepsy history)
3. Perform extended physical examination
4. Record demographics data
5. Record medical history, including a history of epilepsy, diagnosis date, and prior epilepsy 
treatments.
6. Vital signs (Height, pulse, blood pressure, respiration rate, temperature and weight)
7. Current medications and baseline conditions
8. Neurologic exam
9. Pulse oximetry (must be >93)
10. Laboratory assessments as required per the schedule of evaluations (need to be from within 
the last 30 days)
a.
Complete Blood Count (CBC) with differential and platelet count
b. Blood chemistry assessment, including:
i. Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin
ii. Total protein, BUN, serum creatinine
iii. Total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus
iv. Fasting serum lipid profile (total cholesterol, triglycerides, HDL and LDL)
c.
Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)

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d. Hepatitis B and C screening. Hepatitis B screening can be deferred in participants 
who have a history of having received the entire Hepatitis B immunization series and 
documentation is provided.
e.
Serum or urine pregnancy test: If participant is of child-bearing potential, pregnancy 
test should be done at screening and monthly thereafter. If urine test is positive, 
confirmatory blood testing will be performed.
f.
HIV seropositivity screening, if necessary.
11. If available and consent to archive has been given: Archival brain tissue tumor samples from 
a prior surgery will be used to test for molecular analyses. An email from the 
pathology/genetics department(s) may be used to confirm tissue availability at the time of 
enrollment. 
10.2
Visit 1 – may also be Screening visit (Day 0)
1.  Review the study with the participant/participant’s legal representative and obtain written 
informed consent and HIPAA authorization and assent, if appropriate.
2. Assign the participant a unique screening number.
3. Record concomitant medications.
4. Perform abbreviated physical exam
5. Measure and record height and weight.
6. Obtain and record vital signs.
7. Initiate epilepsy diary
10.3
Visit 2 – End of Baseline (Day 30 +5/-2 days)
1. Review participant diary for compliance and seizure frequency.
2. Ensure participant has had >8 seizures in the last 30 days without 2 weeks of seizure freedom 
to continue onto next phase.
3. Collect baseline AEs
4. Administer C-SSRS, QOLCE and NCBRF 
5. Record changes to concomitant medications.
6. Perform abbreviated physical exam
7. Obtain and record vital signs. Pulse oximetry must be >93 to continue.
8. Collect blood for clinical laboratory tests (chemistry, hematology). 
9. Collect urine for pregnancy test (if child-bearing potential).
a.
If positive confirm with blood test
10. Laboratory assessments as required per the schedule of evaluations
a.
Complete Blood Count (CBC) with differential and platelet count.
b. Blood chemistry assessment, including:

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i. Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin,
ii. Total protein, BUN, serum creatinine.
iii. Total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,
iv. Fasting serum lipid profile (total cholesterol, triglycerides, HDL and LDL)
11. Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR).
10.4
Visits 3, 4, & 5: ABI-009 Doses 1-3 (+/-2 days)
1. Review adverse events.
2. Review epilepsy diary.
3. Investigator opinion regarding seizures recorded: same, worse, somewhat better, better.
4. Record changes to concomitant medications.
5. Perform abbreviated physical exam
6. Measure and record height and weight.
a.
BSA calculation (Calculated ONLY on Dose 1 visit; to be recalculated only if the 
weight changes by > 10% in subsequent cycles) 
7. Obtain and record vital signs. Pulse oximetry must be >93 to continue.
8. Collect blood for clinical laboratory tests (chemistry, hematology). 
9. Laboratory assessments as required per the schedule of evaluations
a.
Complete Blood Count (CBC) with differential and platelet count
b. Blood chemistry assessment (required for Visit 4), including:
i. Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin,
ii. Total protein, BUN, serum creatinine.
iii. Total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,
iv. Fasting serum lipid profile (total cholesterol, triglycerides, HDL and LDL)
10. Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)
11. Whole blood rapamycin trough levels
12. Dose modification as appropriate (only in the case of toxicities mandating a dose change as 
per section 8.6)
13. Administer study drug
10.5
Visit 6: Post-Dosing One-Week Assessment (+/-2 days)
1. Review adverse events.
2. Review epilepsy diary.

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3. Investigator opinion regarding seizures recorded: same, worse, somewhat better, better.
4. Record changes to concomitant medications.
5. Perform abbreviated physical examination.
6. Obtain and record vital signs.
7. Collect urine for pregnancy test (if child-bearing potential).
a.
If positive confirm with blood test
8. Collect blood for clinical laboratory tests (chemistry, hematology). 
9. Laboratory assessments as required per the schedule of evaluations
c.
Complete Blood Count (CBC) with differential and platelet count
d. Blood chemistry assessment, including:
i. Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, albumin,
ii. Total protein, BUN, serum creatinine.
iii. Total bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,
iv. Fasting serum lipid profile (total cholesterol, triglycerides, HDL and LDL)
10. Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)
11. Whole blood rapamycin trough level
12. Administer C-SSRS, QOLCE, and NCBRF
10.6
Follow-up Visits 7, 8, & 9: 30, 60, and 90 Days Post-Dosing (+/-7 days)
1. Review participant diary for compliance and seizure frequency.
2. Safety follow-up labs at Visit 7 per PI discretion following Visit 6 labs.
3. Investigator opinion regarding seizures recorded: same, worse, somewhat better, better
4. Record changes to concomitant medications.
5. Perform abbreviated physical exam (30 days post-doing only).
6. Measure and record height and weight (at final study visit).
7. Obtain and record vital signs (30 days post-dosing only).
8. On final visit (90 days post-dosing) administer C-SSRS, QOLCE and NCBRF
10.7
Early Permanent Discontinuation of Study Dosing  
1. Administer C-SSRS, QOLCE, and NCBRF. 
2. Record any adverse events.
3. Record changes to concomitant medications.
4. Perform abbreviated physical exam.

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5. Measure and record height and weight.
6. Obtain and record vital signs.
7. Collect blood for clinical laboratory tests (chemistry, hematology).
8. Collect urine for pregnancy test (if child-bearing potential).
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1
Adverse Events
An AE is any untoward medical occurrence in a clinical investigation of a participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment. An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product. An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the current 
Investigator’s Brochure or of greater severity or frequency than expected based on the 
information in the Investigator’s Brochure.
The Investigator will probe, via discussion with the participant, for the occurrence of AEs during 
each participant visit and record the information in the site’s source documents. All AEs are to 
be collected, from enrollment through end of the subject's study participation, and recorded in 
the participant CRF.  Attribution will be unrelated, unlikely, possible, probably, or definite.
Taking into account the targeted population and the secondary endpoints of the study, Grade 1 
and 2 seizures as defined by the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (CTCAE) v5 will not be tracked as adverse events and will not be included in 
the baseline patient assessment. 
AE Severity
The CTCAE v5 should be used to assess and grade AE severity, including laboratory 
abnormalities. If the experience is not covered in the modified criteria, the guidelines shown in 
Table 3 below should be used to grade severity. It should be pointed out that the term “severe” is 
a measure of intensity and that a severe AE is not necessarily serious.
Table 7.  AE Severity Grading
Severity (Toxicity 
Grade)
Description
Mild (1)
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate (2)
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate Instrumental activities of daily living (e.g., preparing meals, using the 
telephone, managing money) 
Severe (3)
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (e.g., bathing, dressing, feeding self, using toilet, 
taking medications)

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Life-threatening (4)
Life-threatening consequences; urgent intervention indicated
Death (5)
Death related to AE
11.2
Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the participant or require intervention to prevent one of the 
outcomes listed above. 
11.2.1 Serious Adverse Experience Reporting
The study site will document all SAEs that occur (whether or not related to study drug) on an 
SAE Report Form. The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed.
Reporting of an SAE via  SAE Report Form must be (1) sent to the site investigator, (2) 
reviewed by the site investigator and (3) sent to the study chair and scientific director of AADi 
within one business day of the site learning of the event. The study site will send the SAE 
report by email (electronic or scanned copy). When available or requested, follow-up 
information shall be reported via the SAE Report Form and sent to the site investigator and to the 
study chair and scientific director of AADi.
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB) and federal regulations, the site investigator will report SAEs to the IRB. 
11.3
Medical Monitoring
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan. Medical monitoring will include a regular assessment of the number and type of 
serious adverse events.
11.4
Monitoring suspected toxicities for discontinued participants
Participants whose treatment is permanently discontinued due to an adverse event or abnormal 
laboratory value suspected to be related to ABI-009 must be followed at least weekly until the 
adverse event or abnormal laboratory resolves or returns to grade 1. If a participant requires a 
dose delay of ≥3 weeks from the intended day of the next scheduled dose, then the participant 
must be discontinued from the study.

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12  DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS
12.1
Early Permanent Discontinuation of ABI-009 Dosing
A participant may be permanently discontinued from ABI-009 dosing at any time if the 
participant, the investigator, or the Sponsor feels that it is not in the participant’s best interest to 
continue. The following is a list of possible reasons for early permanent discontinuation of study 
treatment: 

Participant or participant’s legal representative decision 

Protocol violation 

C-SSRS serious suicidal ideation score is increased to a 4 rating

Death 

Pregnancy

Refusal to complete patient diary, QOLCE, NCBRF, or C-SSRS questionnaires
If a participant is permanently discontinued from dosing early due to an adverse event, the 
participant will be followed and treated by the Investigator until the abnormal parameter or 
symptom has resolved or stabilized.  
All participants who permanently discontinue study dosing early should come in for an early 
permanent discontinuation of study treatment visit as soon as possible and complete all 
remaining scheduled visits and procedures.
12.2
Screen Fail Criteria
Any consented participant who is excluded from the study before enrollment is considered a 
screen failure. All screen failures must be documented with the reason for the screen failure 
adequately stated.  If a participant screen fails prior to enrollment, they can be rescreened up to 3 
times if the site staff feels they meet eligibility criteria.  Rescreened participants will have to 
complete all screening procedures (i.e., data from previous screenings cannot be used). Lab test 
screening may be done twice per screening.  
12.3
Early Withdrawal of Participants from the Study
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. This may include participants who withdraw from study 
treatment early and who decline to continue to come in for remaining follow-up visits or it may 
include participants who completed treatment and decline to come in for remaining follow up 
visits.  
Reasonable attempts will be made by the investigator to provide a reason for early participant 
withdrawals.  The reason for the participant’s early withdrawal from the study will be specified 
in the participant’s source documents.  Participants who withdraw early from the study should be 
encouraged to come in for a final early study withdrawal visit (and the procedures to be followed 
would include those for their next scheduled visit).  

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12.4
Replacement of Participants
Participants who withdraw from the study after having been both enrolled and having received at 
least 1 dose of ABI-009 will not be replaced. Participants may be replaced if they have been 
enrolled but withdraw prior to receiving any study drug or fail minimum seizure frequency 
required to receive study drug (≥8 seizures over the past 30 days with ≤2 weeks without 
seizures).  
13 PROTOCOL VIOLATIONS
A protocol violation occurs when the participant, investigator, study staff or the Sponsor fails to 
adhere to the protocol requirements.  Protocol violations for this study include, but are not 
limited to, the following:

Failure to meet inclusion/exclusion criteria

Inappropriate administration of study drug

Failure of adherence to study schedule
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The principle investigator will determine if a protocol violation should result in early 
permanent discontinuation of ABI-009 dosing for a participant.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder. The site will report 
the violation to their IRB in accordance with their IRB reporting requirements.
14 DATA SAFETY MONITORING
An independent Data Safety Monitoring Board consisting of at least three members will convene 
as frequently as necessary to review all participants enrolled on study. The DSMB will convene 
at minimum before the opening of each dose escalation cohort, and before opening MTD cohort 
expansion. All AEs experienced by participants on study will be summarized for review by the 
DSMB regardless of suspected relationship to the study drug. SAEs which are determined to be 
possibly, probably or definitely related to study drug will be reported to the DSMB within 5 days 
of occurrence, and any death of a participant that occurs while they are actively on study, 
regardless of relatedness to study drug, will be reviewed by the DSMB prior to enrollment of 
subsequent participants on study.
15 STATISTICAL METHODS AND CONSIDERATIONS
15.1
General Considerations
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written, describing all analyses that will be performed. The SAP will contain any modifications 
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For the purposes of analyses, baseline period will be defined as Days 0-30. Except where 
otherwise noted, comparisons of continuous variables between pre and post treatment periods 
will utilize t-tests or linear regression, test of proportions and analysis of count data using 
Poisson regression. Except where otherwise noted, all tests will be two-sided and statistical 
significance will be determined at the 0.05 level. Missing data methods for the primary and key 
secondary endpoints will be described in the SAP. No adjustment for multiple comparisons will 
be made.  
15.1.1 Data Sets Analyzed
All analyses will be performed using a pre-/post-treatment comparison within participants. The 
primary safety/tolerability analysis and key secondary endpoints will be repeated in the per-
protocol population, which is defined as participants having completed >80% of study drug 
doses and have incurred no major protocol violations. The per-protocol analyses will analyze 
participants according to the treatment they received.
15.2
Demographic and Baseline Characteristics
Baseline demographic and clinical characteristics of the study participants such as age, gender, 
race, ethnicity, height, weight, body mass index, tissue diagnosis at the time of their epilepsy 
surgery (when available), use of concomitant medications (AEDs) will be summarized using 
means and standard deviations for continuous variables, and counts and proportions for 
categorical variables.
15.3
Analysis of Primary Endpoint - Safety Endpoints
All reported treatment emergent SAEs and AEs will be coded using MedDRA and grouped by 
body system. Treatment emergent AEs are defined as AEs presenting post study treatment 
initiation. SAEs and AEs will be tabulated using standard coding terms sorted by body system. 
The incidence of AEs in each treatment arm will be tabulated by seriousness, severity, and 
relationship to study drug. If an AE is reported more than once during the study period for a 
given participant, the greatest severity and the worst-case relationship will be presented in tables.
The number of SAEs and AEs will be summarized as follows: (i) The proportion of participants 
with at least one (S)AE, (ii) The average number of (S)AEs per participant, and (iii) The rate of 
(S)AEs per participant week of follow-up. Histograms showing the frequency of the number of 
(S)AEs in each treatment group will be included. Rates of (S)AEs by System Organ Class (SOC) 
will be presented by treatment group. Poisson regression modeling will be used to derive rate 
ratios and 95% CIs for each SOC. 
Safety lab data at each study visit and changes from baseline will be summarized by treatment 
group. In addition, the following clinical laboratory summaries will be presented by treatment 
group: (i) the incidence of clinically significant abnormalities at each study visit; and (ii) tables 
summarizing the frequencies of participants below, within, and above the normal reference 
ranges at baseline and end of study; and (iii) tables displaying baseline to end of study shifts in 
each laboratory value (shifts between below, within or above normal range).
The number of hospitalization events and proportion of participants hospitalized will be 
summarized and compared by treatment group. Poisson regression modeling will be used to 
derive rate ratios and 95% CIs to compare hospitalization rates between treatment groups.

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15.4
Analysis of Primary Endpoint – Tolerability (Study Drug Discontinuation and 
Compliance)
The proportion of participants permanently discontinuing study drug will be tabulated by 
treatment group. Drug discontinuation events will be categorized as: (1) Permanently 
discontinued study drug and (2) Permanently discontinued study drug and withdrew from study. 
The reason for permanent drug discontinuation will be summarized.
Treatment compliance will be assessed via compliance with scheduled weekly infusions.  
15.5
Analysis of Secondary Endpoints
Efficacy is defined as the change in seizure frequency between  baseline and follow-up expressed 
as percentage reduction in seizure rate (reduction in seizure frequency from baseline, 
calculated as (Baseline frequency [seizures/week] – frequency at follow-up 
[seizures/week])/Baseline frequency [seizures/week]) and median percentage reduction in 
seizure frequency. Treatment response rate will be defined as the proportion of participants 
achieving at least a 25% reduction in seizure frequency from baseline. Seizure frequency will 
be defined as the ratio between the number of seizures and the number of days on which seizure 
information was known within the same period of time (for either baseline or maintenance 
phase). Additional secondary endpoints will include frequency of seizure-free days during the 
maintenance period, seizure-free rate (participants remaining seizure free during the 
maintenance period), and rapamycin blood level–response relationship analysis. These 
endpoints will be analyzed using appropriate statistical tests, such as the t-test and ANOVA.
Quality of Life for Children with Epilepsy Parent Form (QOLCE) [1] and Nisonger Child 
Behavioral Rating Form (NCBRF) [2,3] scores will be compared using appropriate statistical 
tests for ordinal data, including Wilcoxon signed rank tests, logistic regression, or contingency 
tables.
15.6
Sample Size 
This is intended to be small phase 1 study of an orphan disease focusing on safety and 
tolerability as primary endpoints. We anticipate recruiting up to 18 patients for studying an 
orphan disease, taking into account recruitment feasibility and the 3+3 dose escalation paradigm 
with an MTD cohort expansion.
16 DATA COLLECTION, RETENTION AND CLINICAL MONITORING
16.1
Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each participant who signs informed consent. 
Study personnel at Seattle Children's will enter data from source documents corresponding to a 
participant’s visit into the protocol-specific electronic CRF when the information corresponding 
to that visit is available. This will be done according to the study timeline detailed in the 
protocol. The epilepsy diary, in particular, will be submitted directly by the parents on a daily 
basis electronically through REDCap to reduce memory bias. Participants will not be identified 
by name in the study database or on any study documents to be collected by the Sponsor (or 
designee), but will be identified by a site number, participant number and initials.

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If a correction is required for a CRF, the time and date stamp tracks the person entering or 
updating CRF data and create an electronic audit trail.
The Investigator is responsible for all information collected on participants enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator. At the completion of the study, a copy of the CRF data will be 
archived and retained by the site Investigator. 
Data Management Procedures
SCH utilizes REDCap for their EDC studies. The REDCap EDC system is designed to be US 
Code of Federal Regulations (CFR) 21 Part 11 compliant, with a robust audit trail system and 
electronic signature capabilities. Study personnel will enter data from a participant’s visit onto 
electronic CRF screens via a web browser. Study participants will not be identified by name in 
the study database or on any data capture screens but will be identified by initials and a unique 
participant identification number. The Biostatistics and Clinical Data Management group will be 
responsible for data processing, in accordance with procedural documentation. Database lock 
will occur once quality assurance procedures have been completed. All procedures for the 
handling and analysis of data will be conducted using good computing practices for the handling 
and analysis of data for clinical trials.  
Data Quality Control and Reporting
After data have been entered into the study database, data validation checks will be applied on a 
regular basis. Queries are entered, tracked, and resolved through the EDC system directly. The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented in an audit trail. 
Security and Archival of Data
The EDC system is hosted by REDCap. Data are regularly backed up.
REDCap maintains 21 CFR Part 11-compliant electronic systems, with procedures in place to 
safeguard against unauthorized acquisition of data. Any authorized communication with the 
REDCap is conducted via SSL (128-bit) encryption. Robust password procedures, consistent 
with 21 Part 11, are in place. Robust physical security procedures are in place at the Data Center 
to prevent unauthorized personnel physical access to the server rooms. EDC account access is 
maintained and monitored by the Biostatistics and Clinical Data Management.
Other databases will be stored on Seattle Children’s servers and are safeguarded against 
unauthorized access by established security procedures. Network accounts are password 
protected and maintained and monitored by Seattle Children’s. Data is backed up regularly 
according to the Information Services group’s procedures. 
16.2
Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, or Regulatory Agency (e.g., FDA) inspectors 
upon request. A file for each participant must be maintained that includes the signed Informed 
Consent, HIPAA Authorization, Assent Form (if applicable) and copies of all source 
documentation related to that participant.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived.

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All study documents (e.g., participant files, signed informed consent forms, copies of CRFs, 
Essential Document and Study Reference Binders) must be kept secured for a period of two 
years following marketing of the investigational product or for two years after centers have been 
notified that the IND has been discontinued or for a non-IND study for five years after database 
lock.  There may be other circumstances for which the Sponsor is required to maintain study 
records and, therefore, the Sponsor should be contacted prior to removing study records for any 
reason.
16.3
Monitoring
By signing this protocol, the Investigator grants permission to the appropriate regulatory 
authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation.  
Monitoring visits will be conducted according to the U.S. CFR 21 Part 312 and ICH Guidelines 
for GCP (E6) and to ensure investigator compliance to 21 CFR Parts 50, 56 and 312 and to GCP.  
16.4
Participant Confidentiality
In order to maintain participant confidentiality, only a site number, participant number and 
participant initials will identify all study participants on CRFs and other documentation. 
Additional participant confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement.
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only. Clinical information will not be released 
without written permission of the participant, except as necessary for monitoring by the FDA. 
The Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC).
17.1
Protocol Amendments
Protocol amendments cannot be implemented without prior written IRB approval except as 
necessary to eliminate immediate safety hazards to participants.  A protocol amendment intended 
to eliminate an apparent immediate hazard to participants may be implemented immediately, 
provided the IRBs are notified within five working days.
17.2
Institutional Review Board
The protocol and consent form will be reviewed and approved by the IRB prior to study 
initiation. Serious adverse experiences regardless of causality will be reported to the IRB in 
accordance with the standard operating procedures and policies of the IRB, and the Investigator 
will keep the IRB informed as to the progress of the study. The Investigator will obtain assurance 
of IRB compliance with regulations.
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning participant 

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recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB. The IRB’s written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is initiated. 
The IRB’s unconditional approval statement will be transmitted by the Investigator to AADi 
prior to the shipment of study supplies to the site. This approval must refer to the study by exact 
protocol title and number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the participants 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained.  
The IRB must be informed of revisions to other documents originally submitted for review, 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB, new information that may affect 
adversely the safety of the participants of the conduct of the study, an annual update and/or 
request for re-approval, and when the study has been completed.
17.3
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the IRB.  
The consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB.  The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonisation and will also comply 
with local regulations. The Investigator will send an IRB-approved copy of the Informed 
Consent Form to the Sponsor (or designee) for the study file.
A properly executed, written, informed consent will be obtained from each participant prior to 
entering the participant into the trial. Information should be given in both oral and written form 
and participants (or their legal representatives) must be given ample opportunity to inquire about 
details of the study.  If appropriate and required by the local IRB, assent from the participant will 
also be obtained. If a participant is unable to sign the informed consent form (ICF) and the 
HIPAA authorization, a legal representative may sign for the participant. A copy of the signed 
consent form (and assent) will be given to the participant or legal representative of the 
participant and the original will be maintained with the participant’s records.
During the course of the study, if modifications are made to the consent form that impact the 
participant, the participant will be re-consented as described above. 
17.4
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions. The publication or presentation of any study results shall comply 

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with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996.
17.5
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1. Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects.
2. Personally conduct or supervise the study (or investigation).
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee).
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports).
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the participants/subjects.
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312.
18 REFERENCES
1.
Sabaz, M., et al., Validation of the quality of life in childhood epilepsy questionnaire in 
American epilepsy patients. Epilepsy Behav, 2003. 4(6): p. 680-91.
2.
Aman, M.G., et al., The Nisonger CBRF: a child behavior rating form for children with 
developmental disabilities. Res Dev Disabil, 1996. 17(1): p. 41-57.
3.
Tasse, M.J., et al., The Nisonger Child Behavior Rating Form: age and gender effects 
and norms. Res Dev Disabil, 1996. 17(1): p. 59-75.
4.
Shields, W.D., et al., Treatment of infantile spasms: medical or surgical? Epilepsia, 
1992. 33 Suppl 4: p. S26-31.
5.
Jonas, R., et al., Surgery for symptomatic infant-onset epileptic encephalopathy with and 
without infantile spasms. Neurology, 2005. 64(4): p. 746-50.
6.
Olafsson, E., et al., Incidence of unprovoked seizures and epilepsy in Iceland and 
assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol, 
2005. 4(10): p. 627-34.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 63 of 72
7.
Camfield, C.S., et al., Incidence of epilepsy in childhood and adolescence: a population-
based study in Nova Scotia from 1977 to 1985. Epilepsia, 1996. 37(1): p. 19-23.
8.
Berg, A.T., et al., Defining early seizure outcomes in pediatric epilepsy: the good, the 
bad and the in-between. Epilepsy Res, 2001. 43(1): p. 75-84.
9.
Berg, A.T., et al., Two-year remission and subsequent relapse in children with newly 
diagnosed epilepsy. Epilepsia, 2001. 42(12): p. 1553-62.
10.
Berg, A.T., et al., How long does it take for epilepsy to become intractable? A 
prospective investigation. Ann Neurol, 2006. 60(1): p. 73-9.
11.
Berg, A.T., et al., Early development of intractable epilepsy in children: a prospective 
study. Neurology, 2001. 56(11): p. 1445-52.
12.
Kwan, P. and M.J. Brodie, Early identification of refractory epilepsy. N Engl J Med, 
2000. 342(5): p. 314-9.
13.
Berg, A.T., et al., Remission of epilepsy after two drug failures in children: a prospective 
study. Ann Neurol, 2009. 65(5): p. 510-9.
14.
Spooner, C.G., et al., New-onset temporal lobe epilepsy in children: lesion on MRI 
predicts poor seizure outcome. Neurology, 2006. 21: p. 2147-2153.
15.
Chapell, R., et al., Management of treatment-resistant epilepsy. Evid Rep Technol Assess 
(Summ), 2003. 77: p. 1-8.
16.
Altunbasak, S., O. Herguner, and H.R. Burgut, Risk factors predicting refractoriness in 
epileptic children with partial seizures. J Child Neurol, 2007. 22(2): p. 195-9.
17.
Cormack, F., et al., The development of intellectual abilities in pediatric temporal lobe 
epilepsy. Epilepsia, 2007. 48(1): p. 201-4.
18.
Vasconcellos, E., et al., Mental retardation in pediatric candidates for epilepsy surgery: 
the role of early seizure onset. Epilepsia, 2001. 42(2): p. 268-74.
19.
Caplan, R., et al., Developmental outcome with and without successful intervention. Int 
Rev Neurobiol, 2002. 49: p. 269-84.
20.
Sillanpaa, M., et al., Long-term prognosis of seizures with onset in childhood. N Engl J 
Med, 1998. 338(24): p. 1715-22.
21.
Asarnow, R.F., et al., Developmental outcomes in children receiving resection surgery 
for medically intractable infantile spasms. Dev Med Child Neurol, 1997. 39(7): p. 430-
40.
22.
Freitag, H. and I. Tuxhorn, Cognitive function in preschool children after epilepsy 
surgery: rationale for early intervention. Epilepsia, 2005. 46(4): p. 561-7.
23.
Loddenkemper, T., et al., Developmental outcome after epilepsy surgery in infancy. 
Pediatrics, 2007. 119(5): p. 930-5.
24.
Jonas, R., et al., Cerebral hemispherectomy: hospital course, seizure, developmental, 
language, and motor outcomes. Neurology, 2004. 62(10): p. 1712-21.
25.
Steinbok, P., et al., Epilepsy surgery in the first 3 years of life: a Canadian survey. 
Epilepsia, 2009. 50(6): p. 1442-9.
26.
Tellez-Zenteno, J.F., L.H. Ronquillo, and S. Wiebe, Sudden unexpected death in 
epilepsy: evidence-based analysis of incidence and risk factors. Epilepsy Res, 2005. 
65(1-2): p. 101-15.
27.
Tellez-Zenteno, J.F., R. Dhar, and S. Wiebe, Long-term seizure outcomes following 
epilepsy surgery: a systematic review and meta-analysis. Brain, 2005. 128(Pt 5): p. 1188-
98.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 64 of 72
28.
Tellez-Zenteno, J.F., et al., Long-term outcomes in epilepsy surgery: antiepileptic drugs, 
mortality, cognitive and psychosocial aspects. Brain, 2007. 130(Pt 2): p. 334-45.
29.
Harvey, A.S., et al., Defining the spectrum of international practice in pediatric epilepsy 
surgery patients. Epilepsia, 2008. 49(1): p. 146-55.
30.
Palmini, A., et al., Terminology and classification of the cortical dysplasias. Neurology, 
2004. 62(6 Suppl 3): p. S2-8.
31.
Vinters, H.V., Histopathology of brain tissue from patients with infantile spasms. Int Rev 
Neurobiol, 2002. 49: p. 63-76.
32.
Cepeda, C., et al., Pediatric cortical dysplasia: correlations between neuroimaging, 
electrophysiology and location of cytomegalic neurons and balloon cells and 
glutamate/GABA synaptic circuits. Dev Neurosci, 2005. 27(1): p. 59-76.
33.
Cepeda, C., et al., Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral 
developmental hypothesis. Epilepsy Behav, 2006. 9(2): p. 219-35.
34.
Lerner, J.T., et al., Assessment and surgical outcomes for mild type I and severe type II 
cortical dysplasia: a critical review and the UCLA experience. Epilepsia, 2009. 50(6): p. 
1310-35.
35.
Salamon, N., et al., FDG-PET/MRI coregistration improves detection of cortical 
dysplasia in patients with epilepsy. Neurology, 2008. 71(20): p. 1594-601.
36.
Chang, E.F., et al., Seizure characteristics and control following resection in 332 patients 
with low-grade gliomas. J Neurosurg, 2008. 108(2): p. 227-35.
37.
Lee, J., et al., Dysembryoplastic neuroepithelial tumors in pediatric patients. Brain Dev, 
2009. 31(9): p. 671-81.
38.
Minkin, K., et al., Surgical strategies and seizure control in pediatric patients with 
dysembryoplastic neuroepithelial tumors: a single-institution experience. J Neurosurg 
Pediatrics, 2008. 1(3): p. 206-10.
39.
Lee, J.W., et al., Management of intracranial cavernous malformation in pediatric 
patients. Childs Nerv Syst, 2008. 24(3): p. 321-7.
40.
Di Rocco, C. and G. Tamburrini, Sturge-Weber syndrome. Childs Nerv Syst, 2006. 22(8): 
p. 909-21.
41.
Curatolo, P., et al., Management of epilepsy in tuberous sclerosis complex. Expert Rev 
Neurother, 2008. 8(3): p. 457-67.
42.
Chandra, P.S., et al., Infantile spasm-associated microencephaly in tuberous sclerosis 
complex and cortical dysplasia. Neurology, 2007. 68(6): p. 438-45.
43.
Chandra, P.S., et al., FDG-PET/MRI coregistration and diffusion-tensor imaging 
distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a 
preliminary report. Epilepsia, 2006. 47(9): p. 1543-9.
44.
Wu, J.Y., et al., Non-invasive testing and early surgery linked with seizure freedom in 
tuberous sclerosis complex. Neurology, 2009. in press.
45.
Wu, J.Y., et al., Magnetic source imaging localizes epileptogenic zone in children with 
tuberous sclerosis complex. Neurology, 2006. 66(8): p. 1270-2.
46.
Weiner, H.L., et al., Epilepsy surgery in young children with tuberous sclerosis: results 
of a novel approach. Pediatrics, 2006. 117(5): p. 1494-502.
47.
Bien, C.G., et al., Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a 
European consensus statement. Brain, 2005. 128(Pt 3): p. 454-71.
48.
Irwin, K., et al., Multiple subpial transection in Landau-Kleffner syndrome. Dev Med 
Child Neurol, 2001. 43(4): p. 248-52.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 65 of 72
49.
Salamon, N., et al., Contralateral hemimicrencephaly and clinical-pathological 
correlations in children with hemimegalencephaly. Brain, 2006. 129(Pt 2): p. 352-65.
50.
Cook, S.W., et al., Cerebral hemispherectomy in pediatric patients with epilepsy: 
comparison of three techniques by pathological substrate in 115 patients. J Neurosurg, 
2004. 100(2 Suppl Pediatrics): p. 125-41.
51.
Koh, S., et al., Status epilepticus and frequent seizures: incidence and clinical 
characteristics in pediatric epilepsy surgery patients. Epilepsia, 2005. 46(12): p. 1950-4.
52.
Wong, T.T., et al., Corpus callosotomy in children. Childs Nerv Syst, 2006. 22(8): p. 
999-1011.
53.
Patwardhan, R.V. and G.W. Mathern, Surgical treatment of therapy-resistant epilepsy. 
American Academy of Neurology Continuum: Livelong Learning in Neurology, 2004. 
10(4): p. 100-118.
54.
Quigg, M. and N.M. Barbaro, Stereotactic radiosurgery for treatment of epilepsy. Arch 
Neurol, 2008. 65(2): p. 177-83.
55.
Regis, J., et al., Gamma knife surgery for epilepsy related to hypothalamic hamartomas. 
Semin Pediatr Neurol, 2007. 14(2): p. 73-9.
56.
Bartolomei, F., et al., Long-term efficacy of gamma knife radiosurgery in mesial temporal 
lobe epilepsy. Neurology, 2008. 70(19): p. 1658-63.
57.
Hoggard, N., et al., The clinical course after stereotactic radiosurgical 
amygdalohippocampectomy with neuroradiological correlates. Neurosurgery, 2008. 
62(2): p. 336-44; discussion 344-6.
58.
Romanelli, P., A. Muacevic, and S. Striano, Radiosurgery for hypothalamic hamartomas. 
Neurosurg Focus, 2008. 24(5): p. E9.
59.
Ng, Y.T., et al., Endoscopic resection of hypothalamic hamartomas for refractory 
symptomatic epilepsy. Neurology, 2008. 70(17): p. 1543-8.
60.
Procaccini, E., et al., Surgical Management of Hypothalamic Hamartomas with Epilepsy: 
The Stereoendoscopic Approach. Neurosurgery, 2006. 59(4 Suppl 2): p. ONS336-
ONS346.
61.
Kim, S.K., et al., Epilepsy surgery in children: outcomes and complications. J Neurosurg 
Pediatrics, 2008. 1(4): p. 277-83.
62.
Davidson, S. and M.A. Falconer, Outcome of surgery in 40 children with temporal-lobe 
epilepsy. Lancet, 1975. 1(7919): p. 1260-3.
63.
Gilliam, F., et al., Epilepsy surgery outcome: comprehensive assessment in children. 
Neurology, 1997. 48(5): p. 1368-74.
64.
Gleissner, U., et al., Postsurgical outcome in pediatric patients with epilepsy: a 
comparison of patients with intellectual disabilities, subaverage intelligence, and 
average-range intelligence. Epilepsia, 2006. 47(2): p. 406-14.
65.
Kan, P., C. Van Orman, and J.R. Kestle, Outcomes after surgery for focal epilepsy in 
children. Childs Nerv Syst, 2008. 24(5): p. 587-591.
66.
Khan, R.B., et al., Seizures in children with low-grade tumors: outcome after tumor 
resection and risk factors for uncontrolled seizures. J Neurosurg, 2006. 104(6 Suppl): p. 
377-82.
67.
Sinclair, D.B., et al., Pediatric epilepsy surgery at the University of Alberta: 1988-2000. 
Pediatr Neurol, 2003. 29(4): p. 302-11.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 66 of 72
68.
Terra-Bustamante, V.C., et al., Surgically amenable epilepsies in children and 
adolescents: clinical, imaging, electrophysiological, and post-surgical outcome data. 
Childs Nerv Syst, 2005. 21(7): p. 546-51.
69.
Van Oijen, M., et al., Resective epilepsy surgery in childhood: the Dutch experience 
1992-2002. Eur J Paediatr Neurol, 2006. 10(3): p. 114-23.
70.
Wiebe, S., et al., A randomized, controlled trial of surgery for temporal-lobe epilepsy. N 
Engl J Med, 2001. 345(5): p. 311-8.
71.
Wyllie, E., et al., Seizure outcome after epilepsy surgery in children and adolescents. 
Ann Neurol, 1998. 44(5): p. 740-8.
72.
Krsek, P., et al., Incomplete resection of focal cortical dysplasia is the main predictor of 
poor postsurgical outcome. Neurology, 2009. 72(3): p. 217-23.
73.
Mathern, G.W., Challenges in the surgical treatment of epilepsy patients with cortical 
dysplasia. Epilepsia, 2009. 50 Suppl 9: p. 45-50.
74.
Mathern, G.W., Epilepsy surgery patients with cortical dysplasia: present and future 
therapeutic challenges. Neurology, 2009. 72(3): p. 206-7.
75.
Mathern, G.W. and O. Delalande, Surgical treatment of therapy-resistant epilepsy in 
children, in Pediatric Epilepsy: Diagnosis and Treatment 3rd Edition, J.M. Pellock, 
B.F.D. Bourgeosis, and W.E. Dodson, Editors. 2008, Demos: New York. p. 791-800.
76.
Lachhwani, D.K., et al., Discontinuation of medications after successful epilepsy surgery 
in children. Pediatr Neurol, 2008. 38(5): p. 340-4.
77.
Sinclair, D.B., et al., Discontinuation of antiepileptic drugs after pediatric epilepsy 
surgery. Pediatr Neurol, 2007. 37(3): p. 200-2.
78.
Hoppe, C., et al., Discontinuation of anticonvulsant medication after epilepsy surgery in 
children. Epilepsia, 2006. 47(3): p. 580-3.
79.
Dwivedi, R., et al., Surgery for Drug-Resistant Epilepsy in Children. N Engl J Med, 
2017. 377(17): p. 1639-1647.
80.
Mathern, G.W., et al., Postoperative seizure control and antiepileptic drug use in 
pediatric epilepsy surgery patients: the UCLA experience, 1986-1997. Epilepsia, 1999. 
40(12): p. 1740-9.
81.
Wyllie, E., et al., Successful surgery for epilepsy due to early brain lesions despite 
generalized EEG findings. Neurology, 2007. 69(4): p. 389-97.
82.
Tonini, C., et al., Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res, 
2004. 62(1): p. 75-87.
83.
Bai, X. and Y. Jiang, Key factors in mTOR regulation. Cell Mol Life Sci, 2010. 67(2): p. 
239-53.
84.
Guba, M., et al., Rapamycin inhibits primary and metastatic tumor growth by 
antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med, 2002. 
8(2): p. 128-35.
85.
Mabuchi, S., et al., RAD001 (Everolimus) delays tumor onset and progression in a 
transgenic mouse model of ovarian cancer. Cancer Res, 2007. 67(6): p. 2408-13.
86.
Vinals, F., J.C. Chambard, and J. Pouyssegur, p70 S6 kinase-mediated protein synthesis 
is a critical step for vascular endothelial cell proliferation. J Biol Chem, 1999. 274(38): 
p. 26776-82.
87.
Wullschleger, S., R. Loewith, and M.N. Hall, TOR signaling in growth and metabolism. 
Cell, 2006. 124(3): p. 471-84.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 67 of 72
88.
Swiech, L., et al., Role of mTOR in physiology and pathology of the nervous system. 
Biochim Biophys Acta, 2008. 1784(1): p. 116-32.
89.
Hoeffer, C.A. and E. Klann, mTOR signaling: at the crossroads of plasticity, memory and 
disease. Trends Neurosci, 2010. 33(2): p. 67-75.
90.
Garelick, M.G. and B.K. Kennedy, TOR on the brain. Exp Gerontol, 2011. 46(2-3): p. 
155-63.
91.
Chang, N., et al., Phosphatase PTEN in neuronal injury and brain disorders. Trends 
Neurosci, 2007. 30(11): p. 581-6.
92.
Fingar, D.C., et al., Mammalian cell size is controlled by mTOR and its downstream 
targets S6K1 and 4EBP1/eIF4E. Genes Dev, 2002. 16(12): p. 1472-87.
93.
Fingar, D.C., et al., mTOR controls cell cycle progression through its cell growth 
effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol, 
2004. 24(1): p. 200-16.
94.
Zhang, H.H., et al., S6K1 regulates GSK3 under conditions of mTOR-dependent feedback 
inhibition of Akt. Mol Cell, 2006. 24(2): p. 185-97.
95.
Inoki, K., et al., TSC2 integrates Wnt and energy signals via a coordinated 
phosphorylation by AMPK and GSK3 to regulate cell growth. Cell, 2006. 126(5): p. 955-
68.
96.
Ma, T., et al., Dysregulation of the mTOR pathway mediates impairment of synaptic 
plasticity in a mouse model of Alzheimer's disease. PLoS One, 2010. 5(9).
97.
Harada, H., et al., p70S6 kinase signals cell survival as well as growth, inactivating the 
pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A, 2001. 98(17): p. 9666-70.
98.
Dunlop, E.A. and A.R. Tee, Mammalian target of rapamycin complex 1: signalling 
inputs, substrates and feedback mechanisms. Cell Signal, 2009. 21(6): p. 827-35.
99.
Inghirami, G., et al., New and old functions of STAT3: a pivotal target for individualized 
treatment of cancer. Cell Cycle, 2005. 4(9): p. 1131-3.
100.
Kisseleva, T., et al., Signaling through the JAK/STAT pathway, recent advances and 
future challenges. Gene, 2002. 285(1-2): p. 1-24.
101.
Masri, J., et al., mTORC2 activity is elevated in gliomas and promotes growth and cell 
motility via overexpression of rictor. Cancer Res, 2007. 67(24): p. 11712-20.
102.
Sparks, C.A. and D.A. Guertin, Targeting mTOR: prospects for mTOR complex 2 
inhibitors in cancer therapy. Oncogene, 2010. 29(26): p. 3733-44.
103.
Sarbassov, D.D., et al., Prolonged rapamycin treatment inhibits mTORC2 assembly and 
Akt/PKB. Mol Cell, 2006. 22(2): p. 159-68.
104.
Huang, J. and B.D. Manning, The TSC1-TSC2 complex: a molecular switchboard 
controlling cell growth. Biochem J, 2008. 412(2): p. 179-90.
105.
Otani, H., et al., Involvement of protein kinase C and RhoA in protease-activated receptor 
1-mediated F-actin reorganization and cell growth in rat cardiomyocytes. J Pharmacol 
Sci, 2011. 115(2): p. 135-43.
106.
Hu, Z.L., et al., Disruption of PICK1 attenuates the function of ASICs and PKC 
regulation of ASICs. Am J Physiol Cell Physiol, 2010. 299(6): p. C1355-62.
107.
Herring, D., et al., PKC modulation of GABAA receptor endocytosis and function is 
inhibited by mutation of a dileucine motif within the receptor beta 2 subunit. 
Neuropharmacology, 2005. 48(2): p. 181-94.
108.
Poisbeau, P., et al., Modulation of synaptic GABAA receptor function by PKA and PKC 
in adult hippocampal neurons. J Neurosci, 1999. 19(2): p. 674-83.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 68 of 72
109.
Yasuda, K., et al., PKC-dependent inhibition of CA2+-dependent exocytosis from 
astrocytes. Glia, 2011. 59(1): p. 143-51.
110.
Bruhn, M.A., et al., Second AKT: the rise of SGK in cancer signalling. Growth Factors, 
2010. 28(6): p. 394-408.
111.
Wu, P. and Y.Z. Hu, PI3K/Akt/mTOR pathway inhibitors in cancer: a perspective on 
clinical progress. Curr Med Chem, 2010. 17(35): p. 4326-41.
112.
Huang, X., et al., Pharmacological inhibition of the mammalian target of rapamycin 
pathway suppresses acquired epilepsy. Neurobiol Dis, 2010. 40(1): p. 193-9.
113.
Buckmaster, P.S., E.A. Ingram, and X. Wen, Inhibition of the mammalian target of 
rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent 
model of temporal lobe epilepsy. J Neurosci, 2009. 29(25): p. 8259-69.
114.
Zeng, L.H., N.R. Rensing, and M. Wong, The mammalian target of rapamycin signaling 
pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci, 2009. 
29(21): p. 6964-72.
115.
Meikle, L., et al., Response of a neuronal model of tuberous sclerosis to mammalian 
target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to 
improved survival and function. J Neurosci, 2008. 28(21): p. 5422-32.
116.
Di Nardo, A., et al., Tuberous sclerosis complex activity is required to control neuronal 
stress responses in an mTOR-dependent manner. J Neurosci, 2009. 29(18): p. 5926-37.
117.
Ljungberg, M.C., et al., Rapamycin suppresses seizures and neuronal hypertrophy in a 
mouse model of cortical dysplasia. Dis Model Mech, 2009. 2(7-8): p. 389-98.
118.
Zeng, L.H., et al., Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis 
complex. Ann Neurol, 2008. 63(4): p. 444-53.
119.
Zou, L., et al., [Efficacy and safety of rapamycin in treatment of children with epilepsy 
complicated with tuberous sclerosis]. Zhonghua Er Ke Za Zhi, 2014. 52(11): p. 812-6.
120.
Krueger, D.A., et al., Everolimus for subependymal giant-cell astrocytomas in tuberous 
sclerosis. N Engl J Med, 2010. 363(19): p. 1801-11.
121.
Franz, D.N., et al., Everolimus for subependymal giant cell astrocytoma in patients with 
tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 
study. Lancet Oncol, 2014. 15(13): p. 1513-20.
122.
Franz, D.N., et al., Long-Term Use of Everolimus in Patients with Tuberous Sclerosis 
Complex: Final Results from the EXIST-1 Study. PLoS One, 2016. 11(6): p. e0158476.
123.
Bissler, J.J., et al., Everolimus long-term use in patients with tuberous sclerosis complex: 
Four-year update of the EXIST-2 study. PLoS One, 2017. 12(8): p. e0180939.
124.
French, J.A., et al., Adjunctive everolimus therapy for treatment-resistant focal-onset 
seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-
blind, placebo-controlled study. Lancet, 2016. 388(10056): p. 2153-2163.
125.
Samueli, S., et al., Efficacy and safety of Everolimus in children with TSC - associated 
epilepsy - Pilot data from an open single-center prospective study. Orphanet J Rare Dis, 
2016. 11(1): p. 145.
126.
Krueger, D.A., et al., Long-term treatment of epilepsy with everolimus in tuberous 
sclerosis. Neurology, 2016. 87(23): p. 2408-2415.
127.
Aguilera, D., et al., Response of subependymal giant cell astrocytoma with spinal cord 
metastasis to everolimus. J Pediatr Hematol Oncol, 2014. 36(7): p. e448-51.
128.
Mingarelli, A., et al., Dramatic relapse of seizures after everolimus withdrawal. Eur J 
Paediatr Neurol, 2017.

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 69 of 72
129.
Cappellano, A.M., et al., Successful everolimus therapy for SEGA in pediatric patients 
with tuberous sclerosis complex. Childs Nerv Syst, 2013. 29(12): p. 2301-5.
130.
Gonzalez-Angulo, A.M., et al., Weekly nab-Rapamycin in Patients with Advanced 
Nonhematologic Malignancies: Final Results of a Phase I Trial. Clin Cancer Res, 2013. 
19(19): p. 5474-5484.
131.
Kremer, P., et al., Efficacy and tolerability of an aminopterin-albumin conjugate in 
tumor-bearing rats. Anticancer Drugs, 2002. 13(6): p. 615-23.
132.
Kratz, F., Albumin as a drug carrier: design of prodrugs, drug conjugates and 
nanoparticles. J Control Release, 2008. 132(3): p. 171-183.
133.
Kennecke, H., et al. Effect of nab-rapamycin versus rapamycin in colorectal cancer cell 
lines and associations with KRAS and PI3K mutations. in Proceedings of the 47th 
American Society of Clinical Oncology (ASCO) Annual Meeting. 2011. Chicago, IL,: J 
Clin Oncol 
134.
Trieu, V., et al. CNS safety, antitumor activity, and antiangiogenic activity of nab-
rapamycin (ABI-009). in Proceedings of the 100th American Association for Cancer 
Research Annual Meeting (AACR). 2009. Denver CO: AACR.
135.
De, T., et al. Nanoparticle albumin-bound (nab) rapamycin as an anticancer agent. in 
Proceedings of the 98th American Association for Cancer Research Annual Meeting 
(AACR). 2007. Los Angeles CA: AACR.
136.
Cirstea, D., et al., Dual inhibition of akt/mammalian target of rapamycin pathway by 
nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in 
multiple myeloma. Mol Cancer Ther, 2010. 9(4): p. 963-75.
137.
Desai, N., O. D'Cruz, and V. Trieu. Potent antitumor effects of nab-rapamycin (ABI-009) 
in combination with kinase inhibitors erlotinib and perifosine. in Proceedings of the 
100th American Association for Cancer Research Annual Meeting (AACR). 2009. Denver 
CO: AACR.
138.
Fasolo, A. and C. Sessa, Targeting mTOR pathways in human malignancies. Curr Pharm 
Des, 2012. 18(19): p. 2766-77.
139.
Sehgal, S.N., Sirolimus: its discovery, biological properties, and mechanism of action. 
Transplant Proc, 2003. 35(3 Suppl): p. 7S-14S.
140.
Pfizer, Prescribing Information: TORISEL Kit (temsirolimus) injection, for intravenous 
infusion only. 2011.
141.
Pfizer, Rapamune Prescribing Information. 2011.
142.
Novartis, Everolimus (Afinitor) Prescribing Information. 2017.
143.
Danesi, R., J.P. Boni, and A. Ravaud, Oral and intravenously administered mTOR 
inhibitors for metastatic renal cell carcinoma: pharmacokinetic considerations and 
clinical implications. Cancer Treat Rev, 2013. 39(7): p. 784-92.
144.
Garrido-Laguna, I., et al., Integrated preclinical and clinical development of mTOR 
inhibitors in pancreatic cancer. Br J Cancer, 2010. 103(5): p. 649-55.
145.
Banaszynski, L.A., C.W. Liu, and T.J. Wandless, Characterization of the 
FKBP.rapamycin.FRB ternary complex. J Am Chem Soc, 2005. 127(13): p. 4715-21.
146.
Shor, B., et al., A new pharmacologic action of CCI-779 involves FKBP12-independent 
inhibition of mTOR kinase activity and profound repression of global protein synthesis. 
Cancer Res, 2008. 68(8): p. 2934-43.
147.
Buck, M., Immunosuppression with Sirolimus after Solid Organ Transplantation in 
Children Pediatric Pharmacotherapy, 2006. 12(2).

Protocol RS-001
Confidential
Version 2
Version Date:  October 31, 2018
Page 70 of 72
148.
Kremer, P., et al., Intraoperative fluorescence staining of malignant brain tumors using 
5-aminofluorescein-labeled albumin. Neurosurgery, 2009. 64(3 Suppl): p. 53-60; 
discussion 60-1.
149.
Groves, M. and M.D. Jana Portnow, Brian C. Boulmay, M.D.3, SantP. Chawla, M.D.4, 
Hillary Dinh, Ph.D.5, Shanta Chawla, M.D.5, Scott Wieland, Ph.D.5, and Daniel Levitt, 
M.D., Ph.D.5, Phase 2 study of aldoxorubicin in relapsed glioblastoma. J Clin Oncol, 
2016. 34: p. suppl; abstr 2027.
150.
Edwards, S.R. and T.J. Wandless, The rapamycin-binding domain of the protein kinase 
mammalian target of rapamycin is a destabilizing domain. J Biol Chem, 2007. 282(18): 
p. 13395-401.
151.
Sedrani, R., et al., Chemical modification of rapamycin: the discovery of SDZ RAD. 
Transplant Proc, 1998. 30(5): p. 2192-4.
152.
Lim, J.S., et al., Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. 
Am J Hum Genet, 2017. 100(3): p. 454-472.
153.
Moller, R.S., et al., Germline and somatic mutations in the MTOR gene in focal cortical 
dysplasia and epilepsy. Neurol Genet, 2016. 2(6): p. e118.
154.
Mirzaa, G.M., et al., Association of MTOR Mutations With Developmental Brain 
Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary 
Mosaicism. JAMA Neurol, 2016. 73(7): p. 836-845.
155.
Cohen EE, Wu K, Hartford C, et al. Phase 1 Studies of Sirolimus Alone or in 
Combination with Pharmacokinetic Modulators in Advanced Cancer Patients. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2012;18(17):4785-4793.
156.
Sivendran S, Agarwal N, Gartrell B, et al. Metabolic complications with the use of mTOR 
inhibitors for cancer therapy. Cancer treatment reviews. 2014;40(1):190-196. 
157.
Aapro M, Andre F, Blackwell K, Calvo E, Jahanzeb M, Papazisis K, Porta C, Pritchard 
K, Ravaud A (2014). Adverse event management in patients with advanced cancer 
receiving oral everolimus: focus on breast cancer. Ann Oncol 25(4): 763-773.

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APPENDIX 1. SCHEDULE OF EVENTS
SCREENING 
DAY -14 TO 
DAY 0*
VISIT 
1: 
DAY 0
VISIT 
2: DAY 
30**
VISIT 
3: 
DOSE 1
VISITS 4&5: 
DOSES 2 AND 
3
VISIT 6: ONE 
WEEK POST-
DOSING
VISITS 7&8: 30 
AND 60 DAYS 
POST-DOSING
VISIT 9: 90 
DAYS POST- 
DOSING
EARLY 
PERMANENT 
DISCONTINUATION
Informed Consent Process
X
Enrollment Eligibility Checklist
X
Demographics
X
Extended Physical Exam 
X
Neurological Exam
X
Hepatitis C, and Hepatitis B, HIV if 
necessary A
X
Epilepsy and Medical History
X
Height, Weight, and BSA
X
X
X
X
Vitals
X
X
X
X
X
Pulse OximetryF
X
X
X
X
CBC with Differential C
X
X
X
X
X
XB (visit 7 only)
X
Serum Chemistries with Coagulation 
Assessment E
X
X
X
XB (visit 4 
required)
XB
XB (visit 7 only)
X
Urine Pregnancy G
X
X
Study Continuation Checklist
X
X
X
X
X
Abbreviated Physical Exam
X
X
X
X
X
XD
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Dispense Seizure Diary and Glossary
X
Administer QOLCE, NCBRF, & C-SSRS
X
X
X
X
Review Seizure Diary 
X
X
X
X
X
X
Investigator Opinion
X
X
X
X
X
Dosing Checklist
X
X
Study Drug Administration 
X
X
Adverse Events 
X
X
X
X
X
X
X
Whole Blood Rapamycin Level H
X
X
X
*Screening may be combined with Visit 1
**Visit 2 may also be Visit 3 Dose 1

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A Hepatitis C (and if necessary, Hepatitis B) test: 2 mL SST gold top tube. HIV seropositivity test, if necessary: 2 mL gold top tube. If testing for all together, can 
use one 4 mL SST gold top tube.
B Only if previous chemistries or coagulation profiles are abnormal or are otherwise clinically indicated.
C CBC with differential: 1 mL EDTA lavender top tubes if testing with blood trough rapamycin levels. If testing alone can collect only 0.5 mL in EDTA tube.
D Only at 30 days post-treatment
E 2 x 4 mL SST gold top tubes. Serum chemistry: Na, K, Cl, CO2, Ca, fasting glucose, BUN, creatinine, total protein, albumin, total bilirubin, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, uric acid, Ph, fasting serum lipid profile. Coagulation 
assessment:1.8 mL Sodium Citrate light blue top tubes. Coagulation assessment including prothrombin time, partial thromboplastin time, international 
normalized ratio (PT/PTT/INR).
F Must be greater than 93% on room air to continue with study procedures
G Only participants of child-bearing potential, and only monthly at most. If serum test is needed to confirm positive urine test, 1 mL SST gold top tube
H 0.5 mL EDTA lavender top tube if testing alone. Refrigerate if drawing on a Friday or when there may be a delay in lab processing.