Conditions: Glioblastoma Gliosarcoma
Keywords: Newly Diagnosed Glioblastoma Epithelial Growth Factor Receptor (EGFR) Temozolomide ABT-414 Radiology Therapy Oncology Group Antibody Drug Conjugate Brain Tumor Brain Tumor Group EGFRvIII EGFR Amplified First Line Therapy Brain Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 691
Healthy volunteers: no

Brief summary:
This study seeks to determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide (TMZ) followed by combination of ABT-414 with adjuvant TMZ prolongs overall survival (OS) among participants with newly diagnosed glioblastoma (GBM) with epidermal growth factor receptor (EGFR) amplification.

In addition, there is a Phase 1, open-label, multicenter sub-study to assess the pharmacokinetics, safety and tolerability of ABT-414 in participants with newly diagnosed EGFR-amplified GBM who have mild or moderate hepatic impairment.

Detailed description:

Arms:
arm 1: Depatuxizumab mafodotin is given on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Depatuxizumab mafodotin is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase. arm 2: Placebo is given on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Placebo is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase. arm 3: Depatuxizumab mafodotin is given to participants with hepatic impairment on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Depatuxizumab mafodotin is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase.

Interventions: intervention 1: Temozolomide intervention 2: Depatuxizumab mafodotin intervention 3: Radiation intervention 4: Placebo for ABT-414
Intervention descriptions: intervention 1: Oral Capsule intervention 2: Intravenous (IV) Infusion intervention 3: None intervention 4: IV Infusion (IV)

Protocol document:
Prot_000.pdf: 
Protocol Number RTOG 3508/AbbVie M13-813
Version Date:  26May2019
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Radiation Therapy Oncology Group (RTOG) FOUNDATION COLLABORATION 
WITH ABBVIE INC.
RTOG 3508/AbbVie M13-813
(EudraCT 2015-001166-26)
AMENDMENT 9
 
 
NCT02573324


Protocol Number RTOG 3508/AbbVie M13-813
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A Randomized, Placebo Controlled Phase 3 Study of ABT-414 with Concurrent 
Chemoradiation and Adjuvant Temozolomide in Subjects with Newly Diagnosed 
Glioblastoma (GBM) with Epidermal Growth Factor Receptor (EGFR) Amplification 
(Intellance1)
Investigator:


Protocol Number RTOG 3508/AbbVie M13-813
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Protocol Number RTOG 3508/AbbVie M13-813
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Protocol Number RTOG 3508/AbbVie M13-813
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Sponsor:
AbbVie Inc. (AbbVie)
AbbVie IND AbbVie Investigational Product:
ABT-414
Date:
26 May 2019
Development Phase:
3
Study Design: 
This is a randomized Phase 3 of ABT-414 in 
combination with radiation therapy and 
Temozolomide (TMZ) in subjects with newly 
diagnosed Glioblastoma with EGFR amplification.
Medical Monitors/Emergency Contact:
Should in case of subject safety concerns or medical emergencies the Medical Monitors are both 
unavailable, please call the following central back-up number:
Phone:


Protocol Number RTOG 3508/AbbVie M13-813
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* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable 
regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie/RTOG Foundation is permitted without prior written 
authorization from AbbVie.
Protocol Agent
Agent
Supply
IND #
EudraCT #
IND Sponsor
ABT-414
AbbVie
115,080
2015-001166-26
AbbVie
Temozolomide
Commercial
N/A
N/A
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
30 April 2015
Amendment 1
01 July 2015
Amendment 2 (VHP Amendment)
10 September 2015
Amendment 3
08 March 2016
Amendment 4
07 December 2016
Amendment 5
13 January 2017
Amendment 6
06 December 2017
Amendment 7
29 May 2018
Amendment 8
29 November 2018
The purpose of this Amendment is to:

Add brief summary of results for the protocol-specified interim efficacy analysis in the 
Introduction

Provide modified study procedures and instructions for study drug dosing in Appendix X 
for those subjects currently receiving ABT-414 who choose to continue ABT-414.  No 
additional efficacy data will be collected, and procedures have been minimized to include 
those necessary for study drug dosing, safety monitoring and collection of safety data 
related to adverse events and serious adverse events. 
Rationale:  The interim efficacy analysis results overall indicated no survival benefit for 
adding ABT-414 to standard RT/TMZ therapy in newly diagnosed GBM patients. 
However, given that no new clinically significant safety risks were identified, the RTOG 
Steering Committee and AbbVie believe it is appropriate to allow subjects who are 
currently receiving ABT-414 to continue ABT-414 treatment if the investigator and 
subject believe it is in the subject’s best interest.


Protocol Number RTOG 3508/AbbVie M13-813
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TABLE OF CONTENTS
1.0
INTRODUCTION AND BACKGROUND .......................................................12
1.1
Differences Statement............................................................................................19
1.2
Benefits and Risks..................................................................................................19
2.0
OBJECTIVES.....................................................................................................20
2.1
Primary Objective..................................................................................................20
2.2
Secondary Objectives.............................................................................................20
2.3
Exploratory Objectives ..........................................................................................20
2.4
Biomarkers.............................................................................................................21
2.5
Hepatic Impairment Sub-Study Objectives ...........................................................21
3.0
Subject SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA .....22
3.1
Inclusion Criteria ...................................................................................................23
3.2
Exclusion Criteria ..................................................................................................25
4.0
Study Overview and Study Procedures...............................................................28
4.1
Study Overview .....................................................................................................28
4.2
Study Procedures ...................................................................................................38
4.3
Definition of Disease Assessments........................................................................53
5.0
TREATMENT PLAN.........................................................................................55
5.1
Treatment Plan Overview ......................................................................................55
5.2
Radiation Therapy..................................................................................................56
5.2.1
Treatment Technology...............................................................................56
5.2.2
Immobilization and Simulation..................................................................57
5.2.3
Imaging for Structure Definition, Image Registration/Fusion and 
Follow-Up..................................................................................................57
5.2.4
Definition of Target Volumes and Margins...............................................58
5.2.5
Definition of Critical Structures and Margins ...........................................61
5.2.6
Dose Prescription.......................................................................................63
5.2.7
Compliance Criteria...................................................................................64
5.2.8
Treatment Planning Priorities ....................................................................66
5.2.9
Dose Calculations ......................................................................................67
5.2.10 Subject-Specific QA ..................................................................................67
5.2.11 Daily Treatment Locations/IGRT..............................................................67
5.2.12 Case Review...............................................................................................68
5.2.13 Radiation Therapy Adverse Events ...........................................................69
5.3
Temozolomide (TMZ) ...........................................................................................69
5.3.1
TMZ Administration..................................................................................69
5.3.2
Chemotherapy Review...............................................................................71
5.4
ABT-414 / Placebo Treatment...............................................................................72
5.5
Eye Drops for Prophylactic Treatment of ABT-414 Eye Toxicity........................73
5.6
Duration of Therapy...............................................................................................75
5.7
Integral Assay/Biomarker......................................................................................77
5.7.1
Availability of Results ...............................................................................78


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5.8
General Concomitant Medication and Supportive Care Guidelines......................79
5.8.1
Permitted Supportive/Ancillary Care and Concomitant 
Medications................................................................................................79
5.8.2
Prohibited Therapies..................................................................................80
5.8.3
Unblinding Procedure................................................................................80
5.9
Method of Assigning Subjects to Treatment Groups.............................................81
5.10
Treatment Compliance...........................................................................................81
5.11
Drug Accountability...............................................................................................82
5.12
Discussion and Justification of Study Design........................................................82
5.12.1 Discussion of Study Design and Choice of Control Groups......................82
5.12.2 Appropriateness of Measurements.............................................................83
5.12.3 Suitability of Subject Population ...............................................................83
5.12.4 Selection of Doses in the Study.................................................................83
6.0
Removal of Subjects From Therapy or Assessment...........................................86
6.1
Discontinuation of Individual Subjects..................................................................86
6.1.1
Discontinuation of Temozolomide ............................................................89
6.1.2
Discontinuation of ABT-414 or Placebo ...................................................89
6.1.3
Discontinuation of Radiation.....................................................................89
6.2
Discontinuation of Entire Study.............................................................................89
7.0
Adverse Events ...................................................................................................90
7.1
Complaints.............................................................................................................90
7.2
Medical Complaints...............................................................................................90
7.2.1
Definitions..................................................................................................91
7.3
Adverse Event Severity..........................................................................................93
7.4
Adverse Event Collection Period...........................................................................94
7.5
Adverse Event Reporting.......................................................................................95
7.6
Pregnancy...............................................................................................................97
8.0
Toxicity Management and Dose Modifications..................................................99
8.1
ABT-414/Placebo Toxicity Management..............................................................99
8.1.1
Dose Modifications for ABT-414/Placebo ................................................99
8.1.2
Ophthalmologic Toxicities.......................................................................100
8.1.3
Severe Allergic Reactions (Grade 3 or Grade 4) .....................................103
8.1.4
Moderate Allergic Reactions (Grade 1 or Grade 2).................................104
8.1.5
Dermatologic Toxicities...........................................................................104
8.1.6
Hepatic Laboratory Abnormalities (ABT-414/Placebo)..........................104
8.1.7
Other Toxicities .......................................................................................105
8.2
Ocular Steroid Toxicity Management..................................................................106
8.3
Temozolomide Toxicity Management.................................................................106
8.3.1
Temozolomide During Concomitant Radiation Therapy ........................106
8.3.2
Post-Radiation (Adjuvant) Temozolomide..............................................108
8.4
Hepatic Laboratory Abnormalities ......................................................................111
9.0
Drug Information ..............................................................................................115
9.1
TMZ.....................................................................................................................115
9.1.1
TMZ Supply.............................................................................................115


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9.2
ABT-414 ..............................................................................................................115
9.2.1
Identification of Investigational Product(s) .............................................115
9.2.2
Packaging and Labeling of Blinded ABT-414/Placebo...........................115
9.2.3
Storage and Disposition of ABT-414/Placebo.........................................116
9.2.4
Preparation/Reconstitution of Dosage Form............................................116
9.2.5
Product Complaint ...................................................................................116
10.0
Pathology/BIOSPECIMENS ............................................................................118
11.0
DATA AND RECORDS ..................................................................................119
11.1
Source Documents ...............................................................................................119
11.2
Case Report Forms...............................................................................................119
12.0
Quality Assurance Reviews for Drug and Radiation Therapy..........................121
13.0
Protocol Deviation ............................................................................................122
14.0
Statistical Considerations..................................................................................123
14.1
Study Design........................................................................................................123
14.2
Statistical Methods...............................................................................................123
14.3
Primary Endpoints Study Design.........................................................................124
14.4
Study Monitoring of Primary Objectives.............................................................125
14.5
Accrual/Study Duration Considerations ..............................................................126
14.6
Secondary or Exploratory Endpoints (Including Correlative Science Aims)......127
14.7
Exploratory Hypothesis and Endpoints ...............................................................129
15.0
Ethics.................................................................................................................131
15.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB).......131
15.2
Ethical Conduct of the Study...............................................................................131
15.3
Subject Information and Consent.........................................................................131
16.0
DATA QUALITY ASSURANCE....................................................................133
17.0
USE OF INFORMATION................................................................................134
18.0
COMPLETION OF STUDY ............................................................................135
19.0
Investigator's Agreement ..................................................................................136
20.0
REFERENCES .................................................................................................137
APPENDIX I
Summary of RANO Response Criteria.............................................................140
APPENDIX II
RTOG 3508/AbbVie STUDY M13-813 protocol synopsis..............................144
Appendix III
Adverse Events Expected Due to GBM or Progression of GBM.....................154
Appendix IV
New York Heart Association Functional Classification...................................157
Appendix V
Responsibilities of the Clinical Investigator.....................................................158


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Appendix VI
RPA Classification Criteria...............................................................................160
Appendix VII
Child-Pugh score...............................................................................................161
Appendix VIII
List of Abbreviations and Definition of Terms.................................................162
APPENDIX IX. SUBJECTS WITH MILD TO MODERATE HEPATIC IMPAIRMENT.......165
Appendix X
SUBJECTS CONTINUING PARTICIPATION AFTER MAIN STUDY ......178
Appendix XI
Protocol Amendment:  list of changes..............................................................181


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RTOG 3508/AbbVie:  M13-813
SCHEMA
SCREENING REQUIREMENTS
Central Pathology Review for confirmation of histology and adequacy of tissue for MGMT and EGFR analysis. 
Testing for EGFR amplification, MGMT promoter methylation, and EGFRvIII must be complete before 
Randomization.  Only subjects with EGFR amplified tumors and available results for MGMT and EGFRvIII testing 
will be eligible. See protocol for details.
↓
RANDOMIZATION REQUIREMENTS
STRATIFY
MGMT methylation status:  methylated vs. Unmethylated*
RPA class:  III vs. IV vs. V
Region of the world:  US/Canada vs. Other
EGFRvIII mutation status: mutated vs. Other
RANDOMIZE
↓
↓
Arm A
RT:  ~60 Gy in ~30 fractions over 42 days (d) (up to 
49 d)**
+
Temozolomide:  Daily for 42 d (up to 49 d)**
+
Blinded ABT-414:  D1 of Weeks 1, 3 and 5
Approximately 28 d after completion of 
chemoradiation
Temozolomide:  D1-5 of 28-d cycle x 6 cycles**
+
Blinded ABT-414:  D1 and D15 of q 28-d cycle x 
12 cycles
Arm B
RT:  ~ 60 Gy in ~30 fractions over 42 d (up to 49 d)**
+
Temozolomide:  Daily for 42 d (up to 49 d)**
+
Blinded Placebo:  D1 of Weeks 1, 3 and 5
Approximately 28 d after completion of 
chemoradiation
Temozolomide:  D1-5 of 28-d cycle x 6 cycles**
+
Blinded Placebo:  D1 and D15 of q 28-d cycle x 
12 cycles
*
A test result of "insufficient tissue" indeterminate or invalid for MGMT is exclusionary (unless a valid MGMT
result is available from another approved local or central testing lab, as described in the protocol), and the 
subject will not be able to be continue to randomization.
**
Per local prescribing information or local institutional guidelines.  See Section 5.2 for alternative radiation 
therapy options.


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1.0
INTRODUCTION AND BACKGROUND
Study RTOG 3508/M13-813 is a clinical study of ABT-414 for subjects with newly diagnosed 
glioblastoma (GBM).  ABT-414 is an antibody drug conjugate (ADC) designed for the treatment 
of tumors harboring amplified genomic EGFR.  This is a Phase 3 randomized double-blind, 
placebo-controlled trial comparing the efficacy and safety of ABT-414 versus placebo, each as 
concurrent treatment with standard-of-care therapy of radiation/temozolomide (TMZ) plus 
adjuvant TMZ and followed by ABT-414/placebo monotherapy.
In addition there is an ABT-414 sub-study in subjects with hepatic impairment outlined in 
Appendix IX.  The revised schedule of procedures is provided in Appendix IX, Table 3H.  The 
objective of the sub-study is to assess the pharmacokinetics, safety and tolerability of ABT-414 
in subjects with mild and moderate hepatic impairment.
Glioblastoma (GBM)
GBM is the most common and most aggressive type of primary brain tumor in adults, affecting 
8,000 to 10,000 people per year in North America alone.1  The median survival time from 
diagnosis is 3 months without any treatment.  With treatment, patients can expect an average 
survival of 1 to 2 years.  The survival depends greatly on many patient and tumor specific 
factors, including tumor stage, age, resectability, and genetic characteristics as well as 
performance status.  Treatments may include surgical resection of the tumor, chemotherapy, 
radiation therapy, and immunotherapy.  Despite advances in treatments, the prognosis of patients 
with GBM remains poor.
The current standard-of-care therapy for newly diagnosed glioblastoma following surgical 
debulking is radiation therapy (RT) in combination with temozolomide (TMZ), followed by 
6 months of further TMZ monotherapy.2  The standard of care  is based on the results from a 
definitive Phase 3 trial conducted by the European Organization for Research and Treatment of 
Cancer (EORTC) and National Cancer Institute of Canada (NCIC) that demonstrated a survival 
benefit for patients treated with TMZ in addition to surgery and radiation.3  In this study, patients 
in the radiation therapy plus concomitant and adjuvant TMZ arm had a longer median survival 
time (14.6 versus 12.1 months) and a greater 2-year survival rate (27% versus 10%) than patients 
in the radiation therapy alone arm.
Despite these improvements afforded by the addition of TMZ, the vast majority of patients will 
have their tumor recur after aggressive primary therapy.  At the time of recurrence, the prognosis 
is quite dismal, with median survival times measured in months and response rates commonly 


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reported to be in the single digits.  Treatment to prevent tumor re-growth is direly needed in 
order to make the most significant impact on the prognosis of those with this devastating disease.
One of the unique molecular characteristics of GBM tumors is the aberrant signaling, expression, 
mutation, and gene amplification of the epidermal growth factor receptor, or EGFR.  The EGFR
has been hypothesized to play a critical role in the development of GBM and thus has an 
extremely high rate of overexpression (nearing 60% or more), amplification (approximating 
40 – 50%), and mutations (approximately 25% overall have been reported to harbor the 
constitutively active EGFR variant III (EGFRvIII) mutation).  This makes the EGFR an attractive 
target for drug therapy.  Unfortunately, EGFR signaling inhibitors have not been successful to 
date, likely due to the multiple signaling bypass pathways as well as the underlying and reactive 
mutational resistance mechanisms, and limited brain penetration of tyrosine kinase inhibitors at 
routine dosing used in other solid tumors.  Other methods to exploit the EGFR, such as using the 
receptor as a target for selective chemotherapy or immunotherapy delivery, remain attractive.  
ABT-414 binds specifically to activated wild-type EGFR and EGFRvIII mutant GBM and, as an 
antibody drug conjugate, is constructed to deliver a potent toxin that circumvents most signaling 
resistance mechanisms and does not depend on inhibition of EGFR signaling.
ABT-414:  An Antibody Drug Conjugate that Targets Amplified EGFR
ABT-414 is an antibody drug conjugate (ADC) designed for the treatment of tumors harboring 
amplified genomic EGFR.  Antibody drug conjugates are a rapidly growing class of cancer drugs 
that combine the targeting properties of monoclonal antibodies (mAbs) with the anti-tumor 
effects of potent cytotoxic drugs.  Significant advancements in linker stability and toxin potency 
are primarily responsible for the resurgence in ADC development.  A recent example of a 
clinically relevant, advanced ADC is brentuximab vedotin (Adcetris®), an anti-CD30 ADC 
which received US Food and Drug Administration approval in 2011 for Hodgkin's lymphoma 
and anaplastic large cell lymphoma due to a high percentage of tumor responses in these largely 
chemotherapy refractory populations.  The distinct clinical advantage to ADCs is their ability to 
deliver toxic payloads directly to a tumor, bypassing many downstream resistance mechanisms 
related to intracellular signaling.
ABT-414 is a newer generation antibody-drug conjugate, consisting of:  1) a veneered 
"humanized" recombinant IgG1κ antibody that has binding properties specific to a unique 
epitope of human EGFR with 2) non-cleavable maleimido-caproyl linkers each attached to 3) a 
potent antimicrotubule agent, monomethylauristatin F (MMAF).  The antibody binds to the 
EGFR epitope (even in the absence of EGFRvIII mutation), is internalized, and then intracellular 
enzymes release the toxin leading to inhibition of microtubule function, the disruption of critical 


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cellular processes and cell death.  Importantly, ABT-414 binds to an epitope that is available 
predominantly on tumor cells with the EGFRde2-7 (EGFRvIII) deletion mutant or on tumor cells 
with activated wild-type EGF receptors.  The epitope is largely inaccessible when EGFR is 
expressed at normal physiological levels; thus, ABT-414 has limited binding to non-activated, 
wild-type EGFR expressed on normal tissues.  These properties, therefore, favor limited effects 
of the toxin on normal tissues while maintaining a high degree of activity on EGFR-amplified 
tumor cells.  Nonclinical studies to date have confirmed that ABT-414 has potency greater than 
what is observed with clinically available agents in a variety of human xenograft animal models,
with at least an equivalent toxicity profile.
Clinical Data of ABT-414 in GBM
Study M12-356 is a Phase 1, open-label study designed to assess the safety and 
pharmacokinetics of ABT-414 as monotherapy, in combination with TMZ, or in combination 
with RT and TMZ in subjects with newly diagnosed or recurrent GBM.  In this study, ABT-414 
is given every 2 weeks by intravenous (IV) infusion, with treatment arms as follows:

Arm A (ABT-414/RT/TMZ):  Subjects with newly diagnosed GBM who start ABT-414 
along with concomitant radiotherapy and TMZ and later continue ABT-414 along with 
adjuvant TMZ.

Arm B (ABT-414/TMZ):  Subjects who start ABT-414 with TMZ alone (without 
radiotherapy).  Arm B subjects can be either newly diagnosed subjects, who are starting 
concomitant ABT-414/TMZ treatment after completion of initial concomitant radiotherapy 
and TMZ, or GBM subjects with recurrent disease, arising during or after adjuvant TMZ 
treatment.

Arm C (ABT-414 monotherapy):  Subjects with recurrent GBM only, who receive 
ABT-414 monotherapy.
As of January, 2016, 47 newly diagnosed GBM subjects in Arm A have received ABT-414 at 
dose levels ranging from 0.5 to 3.2 mg/kg in combination with radiation and TMZ.  An objective 
response rate attributable to ABT-414 treatment alone cannot be accurately assessed in the newly 
diagnosed setting because of concomitant RT/TMZ, pseudoprogression, and/or minimal residual 
disease post-operatively.  Although recurrence-free survival data are immature given the 
relatively brief follow-up to date on these subjects, the maximum tolerated dose (MTD) 
(2.4 mg/kg), as well as the recommended Phase 2 dose (2.0 mg/kg) in Arm A have been 
identified.  As of the same cutoff date, 28 subjects with recurrent, measurable disease were 
enrolled either in Arm B (concomitant ABT-414 and TMZ) or Arm C (ABT-414 monotherapy).  
Of these, 18 subjects had EGFR-amplified tumors, and 6 (33%) subjects thus far have 


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demonstrated confirmed, objective responses as measured using Response Assessment in 
Neuro-oncology (RANO) criteria.  Objective responses in the subjects with EGFR-amplified 
disease were seen at doses ranging from 1.0 – 1.5 mg/kg, with onset as early as 2 months after 
treatment initiation but with maximum response thus far seen as late 6 months into treatment.  
Importantly, these responses were observed in both Arms B and C, including one of the 
2 complete responses (CR)s observed after ABT-414 monotherapy treatment.  None of the 
subjects with tumors negative for EGFR amplification has experienced a confirmed objective
response.  The MTD and recommended phase 2 dose in Arms B and C was 1.25 mg/kg.
The dose-limiting toxicities (DLTs) observed after ABT-414 exposure have been limited to 
manifestations from the formation of corneal deposits related to cys-mcMMAF, a syndrome 
hereafter referred to as microcystic keratopathy.  This is thought to be a result of damage directly 
to the transient amplifying cells of the limbus, cells that differentiate and give rise to the corneal 
epithelium.  However, with the exception of these ocular adverse events, as described in detail 
below, adverse events reported were usually Grade 1 or 2, infrequent, and more likely related to 
the underlying cancer, concomitant chemotherapy or chemoradiotherapy.  DLTs for all groups in 
both studies were comprised of a variety of different preferred terms for eye-related signs 
(including keratitis, corneal cysts, corneal deposits, ocular hyperemia) and symptoms (most 
commonly vision blurred, photophobia, dry eye, eye pain, foreign body sensation in eyes, and 
lacrimation increased).  Similar findings have been reported for other ADCs utilizing the 
cys-mcMMAF toxin.4  Given that the cornea regenerates every 3 – 4 weeks, to date, all cases of 
microcystic keratopathy have resolved without long-term sequelae after drug discontinuation.  
Both the incidence and severity of eye toxicity appear to be dose-related.  While ABT-414 dose 
reduction for subjects with high-grade toxicities generally reduces symptom severity and allows 
for continued dosing, the overall incidence rate remains very high at the recommended Phase 2 
doses proposed for further clinical studies.
The microcystic keratopathy noted in Study M12-356 is similarly described with other 
chemotherapy agents, including high-dose cytarabine.  Prophylactic steroid eye drops are 
routinely used to control these symptoms.  Thus, prophylactic steroid ophthalmologic solution 
was administered to subjects in Study M12-356 once ocular toxicities were observed.  
One subject in Study M12-356 who had stopped ABT-414 treatment due to a Grade 3 eye 
toxicity at the 1.0 mg/kg level without steroid ocular prophylaxis was able to tolerate the same 
1.0 mg/kg dose level when ABT-414 was restarted along with steroid prophylaxis.  Based on this 
and other experiences, ocular steroid prophylaxis is indicated for all subjects receiving ABT-414 
treatment at dose levels of 1.0 mg/kg and above.


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The dose of ABT-414 in combination with adjuvant TMZ is 1.25 mg/kg, based on the 
tolerability of ABT-414 in Arm B of Study M12-356.  At this dose (and with steroid 
prophylaxis) during maintenance TMZ cycles, 2/10 subjects had ocular DLTs, but only 1 was 
attributable to ABT-414.  To date, approximately 6 subjects have been treated at the 
recommended Phase 2 dose as part of an expanded safety cohort.  Of these, although eye toxicity 
of any grade is very common, only approximately 20% have reported severe ocular adverse 
events (Grade 3 or greater).
The results from Arm A of Study M12-356, in which all subjects received ABT-414 combined 
with concomitant RT/TMZ, demonstrate that higher doses of ABT-414 with this combination 
can be tolerated.  The recommended Phase 2 dose was declared at 2.0 mg/kg every other week, 
with no observed Grade 3 or higher toxicities observed.  Higher doses were associated with at 
least 1 dose-limiting toxicity event and were not well tolerated.
As previously mentioned, the ocular manifestations of microcystic keratopathy to date have been 
reversible after withholding ABT-414, for 4 to 6 weeks.  Subjects who restart ABT-414 at lower 
doses (~1.0 mg/kg) have less severe toxicities and can generally tolerate further therapy.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be found 
in the Investigator’s Brochure (IB).33
INTELLANCE-2 Preliminary Results in Recurrent GBM
INTELLANCE-2 (Study M14-483) was a Phase 2, open-label, randomized study evaluating the 
efficacy and safety of Depatux-M (Depatuxizumab Mafodotin) alone or in combination with 
TMZ compared to lomustine (CCNU) or TMZ in subjects at first recurrence of GBM whose 
tumors were EGFR-amplified.  Each subject was randomized in a 1:1:1 ratio to one of 
three study arms:

Arm 1 (n = 88):  Depatux-M 1.0 mg/kg IV q2 weeks in combination with TMZ 
150 – 200 mg/m2 on Days 1 – 5 of each 28-day cycle.

Arm 2 (n = 86):  Depatux-M monotherapy 1.0 mg/kg IV infusion q2 weeks.

Arm 3 (n = 86):  Control arm subjects were treated according to the timing of relapse in 
relation to their last cycle of TMZ (the same factor was used to stratify randomization):
o
Arm 3A:  Subjects relapsing < 16 weeks after the first day of the last TMZ cycle were 
treated with lomustine 110 mg/m2 on Day 1 of every 42-day treatment period.
o
Arm 3B:  Subjects relapsing ≥ 16 weeks after the first day of the last TMZ cycle were 
treated with TMZ 150 – 200 mg/m2 on Days 1 – 5 of each 28-day cycle.


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The ABT-414/TMZ combination group (Arm 1) showed a 29% decrease in OS hazard rate 
compared to the control group treated with TMZ or lomustine (Arm 3), a result which nearly 
achieved statistical significance (HR = 0.71 [0.50 – 1.02], 2-sided p-value = 0.062) despite the 
limited sample size of the Phase 2 study. The estimated percentage of patients surviving at 
1 year increased from 28% (Arm 3) to 40% (Arm 1).  Of note, in the subgroup of subjects who 
relapsed ≥ 16 weeks after the last TMZ cycle, the estimated HROS for the TMZ/ABT-414 
combination vs. TMZ monotherapy was 0.52 (0.27 – 1.0; p = 0.05), suggesting that adding 
ABT-414 to TMZ treatment provides additional benefit on OS.
A post hoc analysis controlling for additional prognostic factors (including MGMT methylation 
status and baseline tumor size) showed an estimated HROS = 0.55 (p = 0.001), suggesting that the 
primary analysis may have underestimated the benefit of ABT-414/TMZ combination therapy.
ABT-414 monotherapy (Arm 2) showed activity similar to the active chemotherapy controls 
(Arm 3) (HR = 1.04, 2-sided p-value = 0.835).
Importantly, safety analyses showed that toxicity associated with ABT-414 was consistent with 
what was seen in Phase 1 studies, and no new safety signals were identified for ABT-414.  
Ocular side effects were reported by 77% of subjects taking ABT-414 overall, with 28% 
reporting Grade 3/4 ocular events.  2.9% of subjects discontinued ABT-414 treatment due to 
ocular side effects.  The incidence of adverse events known to be associated with TMZ 
(neutropenia and thrombocytopenia/decreased platelet count) in the ABT-414/TMZ combination 
group was similar to that of TMZ monotherapy.
Of note, the estimated HROS of 0.71 observed in recurrent GBM subjects in the INTELLANCE-2 
study, if replicated in a larger study, would be considered clinically meaningful and is consistent 
with the underlying assumption in the current INTELLANCE-1 trial of a HROS = 0.75.
INTELLANCE-2 preliminary results were presented at SNO 2017 and a detailed discussion of 
the preclinical toxicology, metabolism, and pharmacology will be updated in the Investigator's 
Brochure (IB).33
Additional Safety Information
Preliminary safety data were available for 468 subjects who received at least 1 dose of ABT-414 
in 4 open-label studies at the most recent IB update (version 6.0).  The Phase 2 Study M14-483 
(INTELLANCE-2) in recurrent GBM is the only trial for which safety data from a control arm 
(TMZ or lomustine monotherapy) is available.  Adverse events reported for more than 20% of 
subjects receiving ABT-414 were fatigue (35.5%), vision blurred (26.7%), headache and keratitis 


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(25.0% for each), dry eye (24.2%) and corneal epithelial microcysts (22.1%).  In addition to 
ocular side effects related to corneal epitheliopathy, treatment-emergent adverse events reported 
by ≥ 10% of subjects in the ABT-414 treatment groups and ≥ 5% more frequently than the 
lomustine/TMZ control group included headache, fatigue, constipation, and liver transaminase 
elevations (alanine aminotransferase and aspartate aminotransferase).  The rate of constipation 
was mainly accounted for by the ABT-414/TMZ combination arm, for which the rate was similar 
to that of subjects receiving TMZ monotherapy.
In the ongoing blinded Study M13-813 (RTOG 3508) in newly diagnosed GBM, one subject 
receiving ABT-414 (unblinded) with radiation and TMZ in the chemoradiation phase and with 
TMZ in the adjuvant phase experienced Grade 5 (fatal) events of acute liver injury and cerebral 
edema after approximately 5 months of treatment.  The subject had grade 4 GGT (> 33 × ULN) 
and grade 1 fatty liver at Screening.  The investigator considered the event of fatal acute liver 
injury to be reasonably possibly related to ABT-414.  The sponsor also assessed that there was a 
reasonable possibility that ABT-414 caused or contributed to the liver injury and subsequent 
death.  The above-described case is the only event of fatal liver injury that has been reported in 
ABT-414 open-label or blinded studies, in which approximately 800 people have received 
ABT-414 to date.
Summary of Results from Pre-planned Interim Efficacy Analysis
An interim efficacy analysis based on a data cut of 30 April 2019 was performed by the RTOG 
Independent Data Monitoring Committee (IDMC), at which time 346 OS events had been 
observed out of 639 subjects included in the main part of the study.  The primary analysis of OS 
based on the Intent-to-Treat (ITT) population showed no difference in OS between groups, with
a median OS of 18.9 vs. 18.7 months for ABT-414 and placebo, respectively.  The weighted 
(ρ = 0, γ = 0.2) stratified log-rank test p-value (1-sided) was 0.628, and the observed hazard ratio 
(HR) (95% CI) for OS was 1.01 (0.82, 1.25).  The median PFS was 8.0 vs. 6.3 months for 
ABT-414 and placebo, respectively, with a stratified log-rank test p-value (1-sided) of 0.029.  
The observed hazard ratio (HR) (95% CI) for PFS was 0.84 (0.70, 1.02).  Preliminary analysis of 
demographic and clinical characteristics did not reveal any factors predictive of OS benefit for 
the addition of ABT-414 to standard RT/TMZ therapy.
Overall, 99.4% and 97.8% of subjects experienced at least 1 adverse event, and 87.3% and 
62.3% experienced a Grade 3 or higher AE in the ABT-414 and placebo arms, respectively.  
Overall, 94.7% and 36.1% of subjects experienced at least 1 ocular adverse event related to 
corneal epitheliopathy, 61.0% and 0.6% experienced a Grade 3 or higher AE related to corneal 
epitheliopathy, and 11.8% and 0% discontinued study drug (ABT-414 or placebo) in the 


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ABT-414 and placebo arms due to corneal epitheliopathy, respectively.  The most common (> 
10%) events related to corneal epitheliopathy included keratopathy, vision blurred, photophobia, 
dry eye, eye pain, keratitis, and punctate keratitis.  Excluding events related to corneal 
epitheliopathy, events for which the incidence in the ABT-414 group was ≥ 5% greater than in 
the placebo group included thrombocytopenia, gamma-glutamyltransferase increased, aspartate 
aminotransferase increased, alanine aminotransferase increased, constipation, blood alkaline 
phosphatase increased, fatigue, and platelet count decreased.  Excluding events related to corneal 
epitheliopathy, Grade 3 or higher events for which the incidence in the ABT-414 group was at 
least 5% and was ≥ 2% greater than in the placebo group included thrombocytopenia, gamma-
glutamyltransferase increased, and alanine aminotransferase increased.
The interim efficacy analysis results overall indicate no survival benefit for adding ABT-414 to 
standard RT/TMZ therapy in newly diagnosed GBM patients.  However, given that no new 
important safety risks were identified, the RTOG Steering Committee and AbbVie believe it is 
appropriate to allow subjects who are currently receiving ABT-414 to continue ABT-414 
treatment if the investigator and subject believe it is in the subject's best interest.  For those 
subjects who choose to continue ABT-414, study procedures have been modified as described in 
Appendix X.  The appendix provides guidance for study drug administration and collection of 
safety data related to AEs and SAEs.  No additional efficacy data will be collected.
1.1
Differences Statement
This is the first placebo-controlled study evaluating the efficacy of ABT-414 in the treatment of 
newly diagnosed GBM.  In Study M12-356, the safety and tolerability of ABT-414 in newly 
diagnosed GBM subjects was evaluated in an open-label dose escalation study.
1.2
Benefits and Risks
ABT-414 is an ADC that has demonstrated initial evidence of clinical efficacy in 
EGFR-amplified GBM.  ABT-414 also demonstrates a favorable EGFR binding ratio of tumor to 
normal tissue.  These data together reflect an acceptable rationale and risk for treating 
EGFR-amplified GBM subjects with ABT-414 in the context of a clinical trial.


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2.0
OBJECTIVES
2.1
Primary Objective
To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus 
adjuvant TMZ prolongs Overall Survival (OS) among subjects with newly diagnosed GBM 
harboring EGFR amplification.
2.2
Secondary Objectives
To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus 
adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR
amplification for the following endpoints:

PFS (assessed by IRC)

OS for the MGMT unmethylated group

OS for the MGMT methylated subgroup

Time to deterioration in symptom severity score M.D. Anderson Symptom Inventory 
Brain Tumor Module (MDASI-BT)

Time to deterioration in symptom interference score (MDASI-BT)

Time to deterioration in neurocognitive functioning on the Hopkins Verbal Learning 
Test Revised (HVLT-R)

OS for the EGFRvIII-mutated tumor subgroup

PFS for EGFRvIII-mutated tumor subgroup
Safety:

Assessment of comparative safety
2.3
Exploratory Objectives
To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus 
adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR
amplification for the following endpoints:

OS at 1 year

OS at 2 years

PFS at 1 year

PFS at 2 years

PFS for the MGMT unmethylated and methylated sub-groups


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
OS for non-EGFRvIII subjects (comparison between arms)

PFS for non-EGFRvIII subjects (comparison between arms)

OS and PFS for Total EGFR expressions levels

EGFRvIII status (as a prognostic factor independent of treatment assignment) overall 
and among molecular subgroups

Change from baseline in HRQoL (EORTC QLQ-C30/BN20 scale scores)

Change from baseline in symptom severity factor groupings (MDASI-BT neurologic, 
cognitive, treatment and symptom interference (activity-related, mood-related)

Change from baseline in performance status (KPS)

Median time KPS score was maintained at 70 or higher

Time to deterioration in neurocognitive functioning on Controlled Oral Word 
Association (COWA-FAS)

Change from baseline in neurocognitive functioning (HVLT-R and COWA-FAS)

Change from baseline in Vision item on the MDASI-BT and EORTC BN20

Change from baseline in health status (EQ-5D-5L and EQ-5D-VAS)

Changes in EGFR molecular profile during therapy among subjects who undergo 
additional surgery as part of routine care

Pharmacokinetics of ABT-414, total ABT-806, and unconjugated cys-mcMMAF

Change from baseline in average daily (dexamethasone equivalent) corticosteroid 
dosing during treatment.
2.4
Biomarkers
Biospecimens (plasma, serum, tumor tissue) will be collected at designated time points 
throughout the study to conduct research with the intent of identifying biomarkers associated 
with subject outcome or to better characterize the disease.  A portion of the tumor tissue will be 
used to confirm GBM diagnosis (central review of tumor histopathology), determination of 
EGFR amplification (required for study entry), EGFRvIII variant, and 
O6-methylguaninemethlytransferese (MGMT) methylation status (required for subject 
randomization).
2.5
Hepatic Impairment Sub-Study Objectives
This open-label, single arm sub-study, described in Appendix IX, will assess the 
pharmacokinetics, safety and tolerability of ABT-414 in subjects with newly diagnosed 
EGFR-amplified GBM who have mild or moderate hepatic impairment.


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3.0
SUBJECT SELECTION, ELIGIBILITY, AND INELIGIBILITY 
CRITERIA
Note:  Exceptions to inclusion and exclusion criteria are not permitted.  For questions 
concerning eligibility, please contact your local monitor/Clinical Research Associate.
See Appendix IX for subject selection and eligibility criteria for subjects with mild to moderate 
hepatic impairment.
Submission of tumor tissue is required for all subjects (see Section 4.2:  Collection of Tumor 
Tissues).  Investigators should check with their site Pathology department regarding release of 
biospecimens before approaching subjects about participation in the trial.  (See details of tissue 
submissions in Study-Specific Laboratory Manual.)  It is expected that approximately 40 – 50% 
of subjects tested will have EGFR amplification.
Screening Requirements

Tumor tissue from surgery submitted for histological confirmation of GBM diagnosis by 
a central pathologist and for central biomarker testing for EGFR amplification, EGFRvIII
mutation, and MGMT promoter methylation status.  Results for each of these tests are 
required for study eligibility.

If the subject has a valid result on an approved MGMT assay from screening for a 
different study, those results will be accepted for eligibility and stratification in this study 
(see Section 5.7 for details).  Local MGMT testing also may be used for stratification 
purposes if approved by AbbVie or RTOG.  If a valid central test result also is or 
becomes available prior to randomization, the central result will be entered for 
stratification.
Randomization Requirements 

A brain MRI scan with and without contrast, performed at any time after diagnostic 
surgery or biopsy but prior to randomization, is required to serve as a baseline scan for 
RANO tumor response assessments.  The baseline MRI must include the image 
sequences (T1 with and without contrast, T2 FLAIR, etc.) required for making RANO 
assessments.  The most recent scan done prior to randomization will be used as the 
baseline scan.
o
If a subject starts chemoradiation more than 28 days after surgery, the baseline MRI 
will be performed no more than 21 (and preferably fewer) days before the start of 
chemoradiation.
o
Although not required for eligibility, an MRI scan collected within ~72 hours after 
resection is strongly encouraged as the best way to accurately assess the extent of 
surgical resection; if other post-operative scans are obtained, submit and record 
results of scan(s).


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o
An intraoperative brain MRI scan may be used as the post-operative baseline scan if it 
includes the required imaging sequences.

Randomization (requiring stratification based on EGFRvIII, MGMT, RPA results, and 
region of world) must be performed in Interactive Response Technology (IRT) before 
ABT-414/placebo is administered.

Prophylactic steroid drops (open label) begin 48 hours prior to first dose of 
ABT-414/placebo.

Chemoradiation (RT/TMZ + ABT-414/placebo) begins within 49 days (7 weeks) after 
biopsy/resection.
o
If a subject undergoes additional tumor resection(s) before randomization, the subject 
can be randomized if Chemoradiation starts within 49 days (7 weeks) of the latest 
resection and the subject meets all eligibility criteria.  The latest resection must have 
been performed within 30 days after the initial biopsy/resection.
3.1
Inclusion Criteria
A subject cannot be considered eligible for this study unless ALL of the following 
conditions are met.  Eligibility criteria for sub-study subjects with hepatic impairment are 
described in Appendix IX.
Subjects may only be randomized if additional criteria below are met:
1.
Histologically confirmed de novo Grade IV glioma (GBM, gliosarcoma or other 
subvariants) confirmed by central pathology tissue screening.
2.
EGFR amplification in tumor tissue confirmed by central assessment.
3.
Inclusion criterion removed in Amendment 5.
4.
The subject must have recovered from the effects of surgery, post-operative infection, and 
other complications before enrollment including, suture/staple removal from brain surgery 
and sufficient wound healing before randomization.
5.
≥ 18 years of age.
6.
Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization.
7.
Results for required stratification factors (EGFRvIII status, MGMT methylation status, 
Recursive Partitioning Analysis (RPA) class, and region of world) available prior to 
randomization.
8.
Subject has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to 
randomization as follows:


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a)
Absolute neutrophil count (ANC) ≥1,500/mm3;
b)
Platelets ≥ 100,000/mm3;
c)
Hemoglobin (Hgb) ≥ 9.0 g/dL (Note:  The use of transfusion or other intervention to 
achieve Hgb ≥ 9.0 g/dL is acceptable.);
d)
Renal function:  calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault 
formula;
e)
Hepatic function:  Total bilirubin ≤ 1.5 times upper limit of normal (ULN), Aspartate 
Aminotransferase (AST), and Alanine Aminotransferase (ALT) ≤ 3 times ULN.  
Subjects with Gilbert's syndrome documented in medical history may be enrolled if 
total bilirubin is < 3 times ULN.
9.
Electrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior to 
randomization.
10. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at 
least 1 year or surgically sterile by bilateral salpingectomy, bilateral oophorectomy or 
hysterectomy) should practice at least one accepted method of birth control listed below 
during study entry, for the entire duration of the study and for at least 6 months after 
treatment with ABT-414 and TMZ treatment has ended.  Male subjects should practice at 
least one of the accepted methods of birth control during study and for at least 6 months 
after ABT-414 and TMZ.  If using a condom, practice at least one other method of birth 
control listed below during the study and for at least 6 months after ABT-414 and TMZ:

Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 
1 month prior to Study Day 1;

Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation, initiated at least 1 month prior to Study Day 1;

Bilateral tubal occlusion/ligation;

True abstinence:  Refraining from heterosexual intercourse when this is in line with 
the preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable];

A vasectomized male subject or a vasectomized partner of a female subject;

Intrauterine device, IUD (females);

Intrauterine hormone-releasing system, IUS (females);

Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring 
with spermicidal jellies or cream) unless not deemed acceptable as highly effective 
contraception by local regulations.


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11. Women of child-bearing potential must have a negative pregnancy test (urine or serum) 
within 7 days prior to randomization.
12. Must voluntarily sign and date informed consent form, for tumor tissue biomarker testing
and for study participation, approved by an Independent Ethics Committee (IEC)/ 
Institutional Review Board (IRB), prior to the initiation of any screening or study-specific 
procedures.
3.2
Exclusion Criteria
Subjects with one or more of the following conditions are NOT eligible for this study.
Eligibility criteria for sub-study subjects with hepatic impairment are described in 
Appendix IX.
1.
Subject has multifocal GBM, defined as discrete sites of disease without contiguous 
T2/FLAIR abnormality that require distinct radiotherapy ports.  Satellite lesions that are 
associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that 
are encompassed within the same radiotherapy port as the main lesion(s) are permitted.
2.
Exclusion criterion removed in Amendment 5.
3.
Subject has recurrent GBM.
4.
Exclusion criterion removed in Amendment 5.
5.
Subject has metastatic GBM.
6.
Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that 
prior chemotherapy for a different cancer is allowable, except prior temozolomide.
7.
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap 
of radiation fields.
8.
Any prior therapy for glioblastoma, except surgery (intra-operative techniques to guide 
resection are allowed as are experimental imaging techniques).
9.
Prior invasive malignancy (except for non-melanomatous skin cancer; carcinoma in situ of 
the breast, oral cavity, or cervix) unless disease free for ≥ 2 years.
10. Prior, concomitant, or planned concomitant treatment with anti-neoplastic intent including 
but not limited to NovoTumor Treatment Fields (Novo TTF), EGFR-targeted therapy 
(including EGFRvIII-directed therapy), bevacizumab, Gliadel wafers or other intratumoral 
or intracavitary anti-neoplastic therapy, or other experimental therapeutics intended to 


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treat the tumor.  Diagnostic or imaging studies; quality of life; biomarker or 
epidemiological studies; and operative guides to improve extent of resection are allowed.
11. Subject has had major immunologic reaction to an IgG-containing agent.
12. Subject has had LASIK (laser-assisted in situ keratomileusis) procedure within the last 
1 year or cataract surgery within the last 3 months.
13. Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or 
excipients, and dacarbazine (contraindication for TMZ).
14. Subject is unsuitable for receiving ocular steroids:

Subject has any active viral disease of the cornea or conjunctiva, including epithelial 
herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella; mycobacterial 
infection of the eye; fungal diseases of ocular structures; or any other contraindication 
for ocular steroid use.

Subject has a known or suspected hypersensitivity to any ocular steroid.

Subject has primary open angle glaucoma or a history of steroid-induced intraocular 
pressure elevation.
15. Subject is a lactating or pregnant female.
16. Severe, active co-morbidity, defined as follows:
Severe hepatic impairment (Child-Pugh category C or higher [score of 10 or higher 
(Appendix VII)]); Subjects with mild or moderate hepatic impairment (Child-Pugh 
score of 5 – 9) may be eligible for treatment, as described in Appendix IX.

Unstable angina and/or congestive heart failure within the last 6 months;

Transmural myocardial infarction within the last 6 months;

Evidence of recent myocardial infarction or ischemia by the findings of 
S-T elevations of ≥ 2 mm using the analysis of an EKG performed within 21 days 
prior to enrollment;

New York Heart Association grade II or greater congestive heart failure requiring 
hospitalization within 12 months prior to enrollment (Appendix IV);

History of stroke, cerebral vascular accident (CVA) or transient ischemic attack 
within 6 months;

Serious and inadequately controlled cardiac arrhythmia;

Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
enrollment;

Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of enrollment;


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
Subjects with clinically defined Acquired Immune-Deficiency Syndrome 
(AIDS)-defining illness.  This is necessary to ensure subjects are likely to be able to 
receive the full TMZ regimen;

Active connective tissue disorders, such as lupus or scleroderma, that in the opinion 
of the Investigator may put the subject at high risk for radiation toxicity;

Any other major medical illnesses or psychiatric impairments that in the Investigator's 
opinion will prevent administration or completion of protocol therapy;
17. Subjects treated on any other therapeutic clinical protocols within 30 days prior to study 
entry or during participation in the study except intra-operative therapy to guide resection 
or experimental imaging without therapeutic intent.
18. Inability to undergo contrast-enhanced MRI scans.


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4.0
STUDY OVERVIEW AND STUDY PROCEDURES
4.1
Study Overview
This is a Phase 3 randomized double-blind, placebo controlled trial comparing the efficacy and 
safety of ABT-414 versus placebo, each as concurrent treatment with standard-of-care therapy of 
radiation therapy/TMZ plus adjuvant TMZ and followed by ABT-414/placebo monotherapy, in 
subjects with newly diagnosed GBM.
The study comprises a Screening Period of up to 7 weeks from surgery/biopsy; a 6-week 
concomitant Chemoradiation Phase; an Adjuvant Phase beginning approximately 4 weeks after 
completion of chemoradiation, and a Follow-Up Phase.  The Adjuvant Phase is comprised of 28-
day cycles, with subjects receiving concomitant TMZ and study drug (ABT-414/placebo) for the 
first 6 cycles, and study drug (ABT-414/placebo) monotherapy for the following 6 cycles.  
Subsequent cycles will start approximately 28 days from the start of the previous cycle, and the 
cycle schedule will not be affected by delays or interruptions in TMZ or ABT-414/placebo 
dosing.  Adjuvant treatment will be discontinued once disease progression has been determined.  
A Final Study Drug Visit will be performed upon discontinuation of study drug 
(ABT-414/placebo) for any reason, followed by 35-Day and 49 Day Follow-Up Visit (± 3 days).  
If subjects are unable to attend the 49 Day Follow-Up Visit, a phone call should be performed to 
obtain adverse event and concomitant medication information.  In the Follow-Up Phase, subjects 
who complete adjuvant treatment or discontinue study drug prior to disease progression will 
continue to undergo MR imaging and assessment of neurocognitive functioning and PRO 
approximately every 8 weeks up to and including at the time of disease progression, starting 
8 weeks after the last scheduled PRO assessments in the Adjuvant Phase.  After disease 
progression, overall survival will continue to be assessed quarterly.
A sample of pre-treatment tumor tissues will be collected and sent to central laboratories to 
confirm the diagnosis of GBM (required to enroll in the trial) and test for EGFR amplification 
(required to enroll in the trial), MGMT promoter methylation (a stratification factor), EGFRvIII 
mutation (a stratification factor) and other biomarkers prior to starting chemoradiation.  If a 
subject has a repeat surgery before initiating treatment then the tissue from either 
biopsy/resection may be used for histologic and EGFR amplification, EGFRvIII mutation and 
MGMT promoter methylation testing.  If molecular results are discordant between multiple 
specimens from the same patient, then the results that permit eligibility will be used, unless 
EGFR amplification results differ at 2 distinct sites of sampling.  Any question should be 
directed to the Medical Monitor(s).  Remaining sample tissue will be retained for other 


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exploratory molecular analysis where allowed by local regulations.  If local regulations do not 
allow tissue shipment or storage, the tissue will be immediately returned or destroyed after 
eligibility testing.
Screening procedures must be completed prior to Day 1 of the Chemoradiation Phase, which 
must start within 7 weeks after surgery.  Screening procedures will include signing of a main 
study consent form, medical history, Karnofsky Performance Scale (KPS) assessment and 
recursive partitioning analysis (RPA) classification (referenced in Appendix VI), baseline ECG, 
physical, ophthalmologic and neurological examinations, laboratory test (chemistry, hematology, 
urinalysis and coagulation) (≤ 21 days from treatment start), and serum or urine pregnancy test if 
applicable (≤ 7 days from treatment start).  Subjects will also complete neurocognitive testing 
and PRO measures.  Subjects must have a baseline brain MRI prior to the start of 
chemoradiation.  If a subject starts chemoradiation more than 28 days after surgery, the baseline 
brain MRI will be obtained no more than 21 (but preferably fewer) days prior to Day 1 Week 1 
of the Chemoradiation Phase.  The timing of the MRI should allow sufficient time to revise the 
radiation therapy plan if needed due to a significant change in tumor since surgery.  Safety-
related evaluations will be conducted 14 or fewer days prior to Day 1 of the Chemoradiation 
Phase.  Subjects who screen positive for EGFR amplification in the tumor tissue may enter the 
study if all inclusion/exclusion criteria are met.
Upon study entry, subjects will be stratified according to the following 4 factors:

Region of the world (United States/Canada or other country);

RPA classes (III, IV or V);

MGMT methylation (methylated or unmethylated);

EGFRvIII status (mutated or other).
If a subject has a repeat surgery prior to randomization, the extent of surgical resection after the 
repeat surgery (biopsy-only vs. partial/total resection) will be used for determining RPA class 
(see Appendix VI).
A test result of "insufficient tissue", invalid or indeterminate for MGMT is exclusionary (unless a 
valid MGMT result is available from  another approved local or central testing lab using 
approved methodology, as described in the protocol), and the subject will not be able to  continue 
to randomization.  EGFRvIII status of other is defined as wild type, indeterminate due to test 
failure, or insufficient tissue.
Subjects will be randomized within each stratum on a 1:1 ratio to receive:


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
Arm A:  ABT-414 during the Chemoradiation and Adjuvant Phases.

Arm B:  Placebo during the Chemoradiation and Adjuvant Phases.
During the Chemoradiation Phase, all subjects will undergo fractionated focal RT, with 
one treatment of approximately 2 gray (Gy) given daily 5 days per week for a total of 
approximately 60 Gy over approximately 6 weeks (and no more than 7 weeks).  TMZ will be 
administered continuously from Day 1 of radiotherapy to the last day of radiation (including 
weekends and holidays) at a daily oral dose of 75 mg/m2 for a maximum of 49 days.  Subjects in 
Arm A will receive blinded ABT-414 at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 
2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen).  Subjects in Arm B will receive 
blinded placebo IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 
5 of the 6-week regimen).  Treatment in the Chemoradiation Phase must begin ≤ 7 weeks after 
surgery/biopsy.
The start of the first cycle during the Adjuvant Therapy Phase will be scheduled approximately 
28 days after the last day of radiotherapy.  During the Adjuvant Therapy Phase, all subjects will 
receive oral TMZ 150 – 200 mg/m2 once daily on Days 1 – 5 of each 28-day cycle for 6 cycles 
unless there is disease progression, unacceptable toxicity, or other reasons to discontinue.  
Subjects in Arm A will receive blinded ABT-414 1.25 mg/kg by intravenous infusion on Day 1 
and Day 15 of each 28-day cycle for 12 cycles.  Subjects in Arm B will receive blinded placebo 
IV infusion on Day 1 and Day 15 of each 28-day cycle for 12 cycles.
If after completing 12 cycles of adjuvant treatment, the subject is tolerating study drug 
(ABT-414 or placebo) and the Investigator believes the subject is continuing to benefit from 
ongoing study drug treatment, the Investigator may extend the Adjuvant Phase after consultation 
with the Neuro-Medical Oncology Chair or AbbVie Medical Monitor, as long as disease 
progression has not been determined.
Occurrence of disease progression to calculate PFS will be determined by the Investigator, based 
on local evaluation of images and other clinical information using the Response Assessment in 
Neuro-oncology (RANO) criteria (Appendix I).  Post-baseline scans will be obtained ≤ 14 days 
before Day 1 of each odd-numbered cycle (Cycles 1, 3, 5, etc.) of the Adjuvant Phase and 
≤14 days before each visit (approximately every 8 weeks) of the Follow-Up Phase.  MR images 
will also be reviewed centrally by an independent blinded reviewer for radiographic evidence of 
disease progression.  When study drug (ABT-414/placebo) is discontinued for any reason, a 
Final Study Drug Visit will be conducted.  All subjects will have a 35-Day and 49-Day 
Follow-Up Visit (± 3 days) after the last dose of ABT-414/placebo.  The 49-Day Follow-Up 


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Visit will focus on evaluation of ongoing adverse events.  Overall survival will be assessed 
quarterly after study discontinuation.
Neurocognitive testing and patient-reported outcomes will be assessed approximately every 
8 weeks during the Adjuvant and Follow-Up Phases, and then at disease progression.


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Table 1.  Study Activities –
Chemoradiation Phase
Screeninga
Chemoradiation Phaseb
Activity
Screening 1
Screening 2
Day 1 Wk 1 
(Fraction 1 
of RT)
Day 1 of 
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 4
Day 1 of 
Wk 5
Day 1 of 
Wk 6
Day 1 of 
Wk 7
Informed Consent
X
Medical and Oncologic History
X
Physical Exam (Including Weight and 
Karnofsky Performance Status)c
X
X
X
X
Vital Signs
X
X
X
X
Ophthalmology Exam
X
Xd
Xd
ECGe
X
Serum Pregnancy Test
X 
Xf
Chemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
Coagulation
X
MRI With and Without Contrast
Xk
Submit Tissue Sample for Confirmation of 
GBM, testing of EGFR amplification, 
EGFRvIII and MGMT
X
Adverse Event Assessment/Concomitant 
Medications/Supportive Care
X
X
X
Radiation Therapyg
X
Temozolomide Administration
Xh
ABT-414 or Placebo Administration
X
X
X
Prophylactic Eye Drop Administration
Xi
Xi
Xi
Randomization
X
EORTC-QLQ-C30/BN20
Xj
MDASI-BT
Xj
NEI VFQ-25
Xj


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Table 1.  Study Activities –
Chemoradiation Phase
Screeninga
Chemoradiation Phaseb
Activity
Screening 1
Screening 2
Day 1 Wk 1 
(Fraction 1 
of RT)
Day 1 of 
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 4
Day 1 of 
Wk 5
Day 1 of 
Wk 6
Day 1 of 
Wk 7
Neurocognitive Function
(HVLT-R, COWA-FAS)
Xj
EQ-5D-5L and EQ-5D-VAS
Xj
Wk = Week; F/U = Follow-up; RT= Radiation Therapy; KPS = Karnofsky Performance Status; EORTC-QLQ-C30/BN20 = EORTC Quality of Life Questionnaire, Cancer and Brain 
modules; MDASI-BT = MD Anderson Symptom Index for Brain Tumors;  NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire – 25; 
HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association (FAS form); EQ-5D-5L = EuroQoL 5 Dimensions; VAS = Visual analog scale
a.
Screening procedures may be conducted before or after results of EGFR amplification are received.
b.
Chemoradiation Phase will be approximately 6 weeks (up to 7 weeks) of treatment with RT, TMZ, and ABT-414.
c.
Height will be assessed at Screening only.  Weight will be collected at all visits.  Complete physical examination will be performed at Screening only.  Symptom directed physical 
examination will be performed at all other designated visits as clinically indicated.
d.
Ophthalmology exams are to be performed 7 to 14 days after the 2nd and 3rd infusions of ABT-414/placebo and must be completed prior to the next infusion of ABT-414/placebo.
e.
ECG will be performed at screening, final visit and when clinically indicated.
f.
For female subjects of childbearing potential, a serum pregnancy test will be performed within 21 days before Day 1 of chemoradiation.  A urine or serum pregnancy test will be 
done on Day 1 Week 1 if a serum pregnancy test was performed more than 7 days before Day 1.
g.
During Chemoradiation Phase, radiation therapy will begin on Day 1, Week 1 (Fraction 1).  60 Gy will be administered in ~30 fractions over 6 weeks (up to 49 days) per the local 
prescribing information or local institutional guidelines.
h.
During Chemoradiation Phase, temozolomide (75 mg/m2) will be given once per day, continuously (including weekends), from Day 1, Week 1 until completion of radiotherapy 
(up to 49 days).
i.
Prophylactic eye drops will be administered for 7 days, from 2 days before until 4 days after, each dose of study drug (ABT-414 or placebo), as described in Section 5.5.
j.
Baseline measure can be done at any time during Screening, up to and including Day 1 of Chemoradiation Phase, but preferably after EGFR amplification has been confirmed.  
The assessments will be translated into the local languages.
k.
A brain MRI scan with and without contrast, performed at any time after diagnostic biopsy/resection but prior to randomization, is required to serve as a baseline scan for RANO 
tumor response assessments.  If a subject starts chemoradiation more than 28 days after surgery, the baseline MRI is to be performed no more than 21 (but preferably fewer) days 
prior to Day 1 Week 1 of Chemoradiation Phase and should allow sufficient time to revise the radiation therapy plan if needed due to a significant change in tumor since surgery.


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Table 2.  Study Activities –
Adjuvant Phase
Adjuvant Phase – 28-Day Cyclesa
Activity
Day 1 of 
Every 
Cycle 
(1, 2, 3 
etc.)
Day 1 of 
Odd-
Numbered 
Cycles 
(1, 3, 5, 
etc.)
Day 1 
of 
Cycle 2
Day 15 
of 
Every 
Cycleb
Day 22 
of 
Every 
Cyclec
Final 
Study 
Drug 
Visitd
35-Day 
F/Ue
49-Day 
F/U
Follow-Up 
Phase (Every 
8 Weeks 
Until Disease 
Progression)f
At 
Progression
Survival
Physical Exam (Including Weight and 
Karnofsky Performance Status)g
X
X
Xd
X
X
Vital Signs
X
X
X
X
Ophthalmology Examh
X
X
Xi
ECG
X
Chemistry
X
X
X
Hematology
X
X
X
X
MRI and Clinical Disease Progression 
Assessment
Xj
Xd,k
Xj
Adverse Event 
Assessment/Concomitant 
Medications/Supportive Care
X
X
X
X
Xr
Temozolomide Administration
Xl
ABT-414 or Placebo Administration
Xm
Xm
Prophylactic Eye Drop Administration
Xn
Xn
NEI VFQ-25o
X
X
EORTC-QLQ-C30/BN20o
X
X
Xp
MDASI-BTo
X
X
Xp
Neurocognitive Function (HVLT-R, 
COWA)o
X
X
Xp
EQ-5D-5L and EQ-5D-VASo
X
X
Xp
Treatment Satisfaction Question
X
X
Xp


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Table 2.  Study Activities –
Adjuvant Phase
Adjuvant Phase – 28-Day Cyclesa
Activity
Day 1 of 
Every 
Cycle 
(1, 2, 3 
etc.)
Day 1 of 
Odd-
Numbered 
Cycles 
(1, 3, 5, 
etc.)
Day 1 
of 
Cycle 2
Day 15 
of 
Every 
Cycleb
Day 22 
of 
Every 
Cyclec
Final 
Study 
Drug 
Visitd
35-Day 
F/Ue
49-Day 
F/U
Follow-Up 
Phase (Every 
8 Weeks 
Until Disease 
Progression)f
At 
Progression
Survival
Survival Assessmentq
X
Wk = Week; F/U = Follow-up; RT = Radiation Therapy; KPS = Karnofsky Performance Status; EORTC-QLQ-C30/BN20 = EORTC Quality of Life Questionnaire, Cancer and Brain 
modules; MDASI-BT = MD Anderson Symptom Index for Brain Tumors; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire – 25; 
HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association (FAS form); EQ-5D-5L = EuroQoL 5 Dimensions; VAS = Visual Analog Scale
a.
Assessments in the Adjuvant Phase will be based on 28-day treatment cycles, with the first cycle starting approximately 4 weeks after completion of radiation therapy.  Subjects 
will receive concomitant TMZ and study drug (placebo or ABT-414) for the first 6 cycles,and study drug monotherapy for an additional 6 cycles or until disease progression or 
study drug discontinuation.  Subjects demonstrating continued benefit and no unacceptable toxicity from adjuvant TMZ can continue adjuvant TMZ to a maximum of 12 cycles at 
the discretion of the Investigator if this is considered an acceptable standard of care per local regulations.  For subjects demonstrating continued benefit and no unacceptable 
toxicity with ABT-414/placebo after 12 cycles, the Adjuvant Phase may be extended at the discretion of the Investigator in discussion with the Neuro-Medical Oncology Chair or 
AbbVie Medical Monitor, with continued ABT-414/placebo treatment until disease progression is confirmed.
b.
Day 15 visit will not be performed after discontinuation of study drug (ABT-414/placebo) treatment.
c.
As per TMZ prescribing information, during the 28-day cycle of TMZ, a blood count for ANC and platelets should be performed 21 days (± 2 days) after the start of each TMZ 
cycle.  If the ANC falls below 1,500/µL or if the platelet count falls below 100,000/mm3, then blood counts should be performed weekly until recovery to these levels before 
TMZ dosing. A certified local lab may be used instead of central lab; if so, ANC and platelet results should be reported in the eCRF.  Day 22 testing may be omitted for cycles in 
which TMZ is not administered or if local prescribing information allows for a different testing schedule for ANC and platelets.
d.
Final Study Drug Visit to be performed approximately 14 days after last dose of ABT-414/placebo.  The physical examination and MR imaging from the first visit of the 
Follow-Up Phase will be used for the Final Study Drug Visit if these visits coincide (e.g., if the subject completes 12 cycles of Adjuvant Phase).
e.
To be performed 35 days (± 3 days) after the last dose of study drug (placebo or ABT-414).  If the Final Study Drug Visit is more than 35 days after the last dose of study drug, 
then 35-day safety follow-up procedures will not be performed.
f.
Visits in Follow-Up Phase to occur every 8 weeks, beginning 8 weeks after Day 1 of the last odd-numbered cycle in the Adjuvant Phase.
g.
Height will be assessed at Screening only.  Weight will be collected at all visits.  Complete physical examination will be performed at Screening only.  Symptom directed physical 
examination will be performed at all other designated visits as clinically indicated.
h.
Ophthalmology exam to be performed prior to ABT-414/placebo dosing on Day 1 (or up to 7 days prior to Day 1) of Cycle 1, Cycle 2, and every odd-numbered cycle thereafter 
(Cycles 3, 5, 7, etc.).  Ophthalmology exam for Cycle 1 Day 1 may be omitted if the subject had no corneal microcysts or ocular adverse events during or after the 
Chemoradiation Phase.  Ophthalmology exams may be discontinued if the subject has been on Level 1 eye drops with no ocular toxicity for 2 consecutive eye exams.
i.
Ophthalmology exam at Day 35 Follow-Up Visit to be done only if subject had corneal microcysts or other ocular findings related to ABT-414 or ocular steroids on previous 
exam and repeated at least every 8 weeks until satisfactory resolution of eye toxicities. 
j.
MRI to be performed ≤ 14 days before the start of each odd-numbered cycle or follow-up visit, starting at Cycle 1.  If the subject discontinues study drug prior to disease 
progression, MRIs should continue to be obtained approximately every 8 weeks until disease progression is confirmed.


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k.
MRI to be performed, if not performed within last 3 weeks, if subject withdraws from study prior to disease progression.
l.
TMZ will be administered once daily on Days 1 through 5 of each 28-day cycle for 6 cycles per the local prescribing information.
m.
ABT-414 or placebo infusion will be administered on Day 1 and Day 15 of each 28-day cycle for 12 cycles.  For subjects demonstrating continued benefit and no unacceptable 
toxicity with ABT-414/placebo after 12 cycles, the Adjuvant Phase may be extended at the discretion of the Investigator in discussion with the Neuro-Medical Oncology Chair or 
AbbVie Medical Monitor, with continued ABT-414/placebo treatment until disease progression is confirmed.
n.
Prophylactic eye drops will be administered daily for 7 days with each dose of ABT-414/placebo, from 2 days before until 4 days after each dose of study drug (ABT-414 or 
placebo), as described in Section 5.5.
o.
These assessments should be completed prior to study drug administration and any other study procedures being performed at these visits, and prior to discussing with the subject 
whether disease progression has occurred.
p.
To be assessed at the time of disease progression (as soon as possible), regardless of the study phase in which disease progression occurred, or upon study withdrawal for any 
other reason.
q.
Survival will be assessed quarterly after treatment discontinuation until death.
r.
If the subject is unable to return to the site for the Day 49 Follow Up Visit, a phone call may be conducted to obtain AE and concomitant medication information.


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Table 3.  Blood Samples for Biomarker and Pharmacokinetic Schedule of Assessments*
Chemoradiation Phase
Activity
Day 1 Wk 1 
(Fraction 1 of RT)
Day 1 of Wk 2
Day 1 of Wk 3
Day 1 of Wk 4
Day 1 of Wk 5
Plasma Markers
0 hour (pre-dose)
Serum Markers
0 hour (pre-dose)
PK – ABT-414 and Total 
ABT-806 Assays
0 hour (pre-dose) & within 
30 min post-dose
Anytime from 4 days 
before (preferred) to 
1 day after the scheduled 
visits 
0 hour (pre-dose) & 
within 30 min post-dose
Anytime from 4 days 
before (preferred) to 
1 day after the scheduled 
visits
0 hour (pre-dose) & within 
30 min post-dose
PK – CysmcMMAF assay
0 hour (pre-dose) & within 
30 min post-dose
Anytime from 4 days 
before (preferred) to 
1 day after the scheduled 
visits
within 30 min post-dose
Anytime from 4 days 
before (preferred) to 
1 day after the scheduled 
visits
within 30 min post-dose
PK – Antidrug Antibody
0 hour (pre-dose)
0 hour (pre-dose)
0 hour (pre-dose)
Pharmacogenomic sample
0 hour (pre-dose)
Adjuvant Phase (28-Day Cycles) and Post-Progression
Activity
Day 1 of Cycle 1
Day 1 of Cycles 2 – 12 
(Every Cycle)
Day 1 of Cycle 14 and 
Every Other Cycle (14, 
16, 18, etc.) while 
ABT-414/Placebo 
Treatment is Ongoing
Final Study Drug Visit
Post-Progression**
Plasma Markers
0 hour (pre-dose)
0 hour (pre-dose)
Serum Markers
0 hour (pre-dose)
Relapse Biopsy collection
yes
PK – ABT-414 and Total 
ABT-806 Assays
0 hour (pre-dose) & within 
30 min post-dose on Day 1 
of Cycle 1 
0 hour (pre-dose)
0 hour (pre-dose)
PK – Antidrug Antibody
0 hour (pre-dose)
0 hour (pre-dose)
0 hour (pre-dose)
*
For subjects in the hepatic sub-study the Biomarker and Pharmacokinetic Schedule of Assessments can be found in Appendix IX.  Additional blood for PK can be collected at the 
discretion of the investigator in discussion with the Sponsor.
**
For subjects who undergo tumor surgery (biopsy or resection) for medically directed reasons at any time during treatment or post-progression, a portion of the tumor tissue can be 
submitted for biomarker-related research.


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4.2
Study Procedures
The study procedures outlined in Table 1 and Table 2 are discussed in detail in this section with 
the exception of the monitoring of treatment compliance (Section 5.10) and the collection of 
adverse event information (Section 7.0).  All study data will be recorded on electronic case 
report forms (eCRFs), with the exception of pregnancy reporting forms and the neurocognitive 
function tests.
Procedures performed at Screening will serve as baseline, unless repeated prior to dosing; in 
which case the latter will serve as baseline.  Unless otherwise noted, subsequent study 
procedures should be performed within 3 days prior to the scheduled study visit date when 
possible.  Subjects who are not randomized will be considered a screen failure and will not be 
included in any intent-to-treat analyses.
Informed Consent
The informed consent for tissue and other pre-screening and for activities in the main study may 
be used separately or combined as a single informed consent document where allowed by local 
regulation and the IEC/IRB.
The IEC/IRB-approved informed consent must be signed and dated by each subject or the 
subject's legally acceptable representative prior to the submission of tumor tissue for screening, 
undergoing any study procedures or before any prohibited medications are withheld from the 
subject in order to participate in this study.  Separate informed consent documents will also be 
required for the optional substudies in this protocol:  for the collection of pharmacogenetic 
samples and the collection of tumor tissue post-treatment after disease progression, Section 15.3.
Tumor tissue testing will be conducted to confirm GBM diagnosis (central review of tumor 
histopathology), determination of EGFR amplification, EGFRvIII mutation and MGMT
methylation status are all required for subject randomization.  All clinical screening procedures 
should proceed simultaneously while tissue testing results are pending and should not be delayed 
until after EGFR amplification status is obtained.
For details on obtaining and documenting informed consents, Section 15.3.
Medical and Oncologic History
The following will be collected during the Screening Visit:
Demographic information, including age, sex, and ethnicity.  Ethnicity will include whether 
a subject is first generation Han Chinese.


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Complete medical history, including documentation of any clinically significant medical 
condition.
History of tobacco and alcohol use.
Detailed oncologic history including:
Date of primary cancer diagnosis;
Histology at the time of study entry;
Date and extent of surgical resection;
Neurologic deficits, if any, at the time of enrollment;
At each visit, the subject's medical history will be reviewed, and any changes from baseline will 
be recorded in the source documents and on the adverse event eCRF.  On Day 1, any changes 
observed from the Screening Visit will be recorded in the subject's medical history.
Physical Examination
A complete physical examination (PE), including body weight and height, will be performed at 
Screening.  A symptom directed physical examination will be performed at all other designated 
visits as clinically indicated.  Weight will be collected at all visits and a PE will be performed as 
clinically indicated as outlined in Table 1.  Clinically significant changes from baseline will be 
documented in the source documentation and electronic case report forms (eCRFs) as adverse 
events.
ABT-414-Targeted Ophthalmologic Examinations (ABT-414-TOE)
The ABT-414 Targeted Ophthalmologic Examination (ABT-414 TOE) was designed for this 
study to systematically identify and grade objective findings of ABT-414-related eye toxicity and 
to assess for adverse effects potentially related to ocular steroid use.  The ABT-414 TOE will be 
provided as study specific start up materials.  Changes in the steroid potency of prophylactic eye 
drops to be used with ABT-414/placebo dosing will be based on corneal findings from the 
ABT-414-TOE assessments performed throughout the study, as described below in Table 4.
Subjects will undergo ophthalmologic examinations as follows:
Screening:  prior to starting chemoradiation

Any clinically significant abnormal findings at Screening ophthalmologic examination 
are to be documented as part of the subject's medical history.
Chemoradiation Phase:  within 7 days to 14 days after the 2nd and 3rd infusions of 
ABT-414/placebo


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Adjuvant Phase:  within 7 days prior to ABT-414/placebo dosing on Day 1 of Cycle 1, 
Cycle 2, and all odd-numbered cycles thereafter (Cycles 3, 5, 7, etc.) and at the 
35-DayFollow-Up Visit.
Additional eye exams may be performed as needed throughout the study, including 
additional exams if evidence of microcystic keratopathy persists after the 35-Day Follow-Up 
Visit to monitor reversibility.  A subset of sites will be asked to provide ophthalmic 
photography (e.g., slit lamp, confocal microscopy, Heidelberg Retina Tomographer [HRT3], 
etc.) of corneal abnormalities.
Ophthalmologic exams may be discontinued for subjects who have no evidence of eye toxicity on 
2 consecutive examinations after being decreased to Level 1 eye drops.
Qualified medical personnel will perform the ophthalmologic examination, which will include 
assessments of visual acuity, intra-ocular pressure, funduscopic examination (at Screening,  35 
DayFollow-Up Visit only), and slit lamp examination according to standard procedures of the 
ophthalmologist.  The corneas will be evaluated via slit lamp at every exam to identify potential 
pathological changes.  Grading on the ABT-414-TOE findings for "microcysts/edema" and 
"superficial punctate keratopathy" will be used to inform potential changes in the level of 
prophylactic steroid eye drops to be used with ABT-414/placebo dosing, as described in 
Section 5.5.  Grading for these two items is as follows:
Microcysts/Edema
0
=
None
+0.5 (Trace)
=
Trace, localized epithelial haze
+1 (Mild)
=
Dull glass appearance that may include fine individual microcystic 
changes
+2 (Moderate)
=
Dull glass appearance of epithelium with large number of vacuoles 
with or without stromal edema
+3 (Severe)
=
Epithelial bullae and/or whorl keratopathy, localized or diffuse, 
with or without stromal striae


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Superficial Punctate Keratopathy
0
=
None
+0.5 (Trace) 
=
Trace (1 – 5 puncta)
+1 (Mild)
=
Mild (6 – 20 puncta)
+2 (Moderate)
=
Moderate (> 20 puncta, but countable)
+3 (Severe)
=
Severe (too many puncta to count)
Table 4:  Ophthalmology Examination Schedule
STUDY VISIT/PERIOD*
EXAM REQUIRED?
COMMENTS
Screening
Yes
Establishes baseline assessment for 
corneal exam and visual acuity
Chemoradiation Phase
Day 1, Week 5 (≤ 7 days before 
Week 5 ABT-414/placebo dose)
Yes
Do not decrease Level of eye drops until 
after the subject has received at least 
2 eye exams
Day 1, Week 7 (7 – 14 days after 
Week 5 ABT-414/placebo dose)
Yes
--
Recovery Period
No ophthalmology exam required
No
As-needed basis only
Adjuvant Phase
Day 1, Cycle 1**
No
Exam not required if the subject had no 
corneal microcysts or ocular adverse 
events during or after the 
Chemoradiation Phase
Day 1, Cycle 2*
Yes
--
Day 1 of Cycles 3, 5, 7, etc.*
Yes***
Continue while subject is taking study 
drug (ABT-414/placebo)
35-Day Follow-Up Visit
Yes
Ophthalmology exams required as scheduled for subjects on Level 2 – 4 eye drops.
*
Additional eye exams may be performed as needed.  For eye toxicity considered by the investigator to be related to 
ABT-414, ophthalmology exams will be repeated until symptoms related to eye toxicity have resolved.
**
Scheduled ophthalmology exams may be done at any time, up to 7 days before the scheduled date, prior to the scheduled 
infusion of ABT-414/placebo.
***
Eye exams may be discontinued for subjects who have no findings of ocular toxicity on 2 consecutive scheduled exams
while on Level 1 (non-steroid) drops.
Adverse Event Reporting of ABT-414-TOE Findings
ABT-414-TOE reports will be reviewed by the Investigator (or medically qualified delegate).  
Examination records should be retained in the subject's source file.  With the exception of the 
corneal findings described below, decisions on which findings, if any, from the ophthalmologic 


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examination or ABT-414-TOE report to be reported as adverse events will be made according to 
the Investigator's judgment.  Adverse events will be graded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0 criteria, as 
discussed in Section 7.2 and not according to the ABT-TOE grading system.
To ensure consistent reporting of microcystic keratopathy, which is characteristic of ABT-414 
but for which there is no Medical Dictionary for Regulatory Activities (MedDRA) preferred term 
or CTCAE adverse event term, any abnormal finding on the "corneal epithelium" and/or 
"superficial punctate keratopathy" fields of the ABT-414-TOE will be recorded as an adverse 
event, using the term "microcystic keratopathy."  These events will be graded as shown in 
Table 5, which is based on CTCAE criteria for "keratitis."
Table 5.  Adverse Event Reporting in eCRF for Corneal Findings from the ABT-414-TOE
Corneal finding from 
ABT-414-TOE
Adverse Event Report for eCRF
Adverse Event 
Verbatim Term
CTCAE Grade
Microcysts/Edema
OR
Superficial punctate 
keratopathy
Microcystic 
keratopathy
1 – Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
2 – Symptomatic; medical intervention indicated (e.g., topical 
agents); limiting instrumental ADL
3 – Decline in vision (worse than 20/40 but better than 20/200); 
limiting self care ADL
4 – Perforation or blindness (20/200 or worse) in the affected eye
Vital Signs
Vital sign determinations of sitting blood pressure, heart rate and body temperature will be 
measured at all visits, as outlined in Table 1.  If possible, blood pressure and heart rate 
measurements should not immediately follow scheduled blood collections.
Blood pressure and pulse rate should be measured after the subject has been sitting for at least 
3 minutes.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed for all subjects as outlined in Table 1 and Table 2.
Each ECG will be printed and evaluated by an appropriately qualified physician (in consultation 
with a cardiologist if necessary) at the study site.  A qualified physician will determine if any 
findings outside normal physiological variation are clinically significant, document the presence 


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or lack of findings and the clinical significance (if any) on the ECG report and then sign and date 
the ECG report.
The ECG tracings will be retained as source documentation in the subject's records at the study 
site.  The baseline (Screening) ECG will be used to document baseline status of the subject so 
that safety comparisons can be made if necessary.  Repeat ECGs will be performed whenever 
clinically necessary.
Karnofsky Performance Status
Karnofsky Performance Status (KPS)5 will be evaluated at the same time as the physical 
examinations.  The status will be determined as:
100 – normal, no complaints, no signs of disease
90 – capable of normal activity, few symptoms or signs of disease
80 – normal activity with some difficulty, some symptoms or signs
70 – caring for self, not capable of normal activity or work
60 – requiring some help, can take care of most personal requirements
50 – requires help often, requires frequent medical care
40 – disabled, requires special care and help
30 – severely disabled, hospital admission indicated but no risk of death
20 – very ill, urgently requiring admission, requires supportive measures or treatment
10 – moribund, rapidly progressive fatal disease processes
0 – death
Pregnancy Test
For female subjects of childbearing potential, a serum pregnancy test will be performed 
≤21 days before Day 1 of chemoradiation.  A urine or serum pregnancy test will be done on 
Day 1 Week 1 if a serum pregnancy test was performed most recently more than 7 days before 
Day 1.
The test may be repeated at the discretion of the investigator at any time during the study.  A 
lactating or pregnant female will not be eligible for participation in this study.
Clinical Laboratory Tests
All subjects will have the laboratory analyses performed as outlined in Table 6.  Laboratory 
samples will be assessed using a certified central laboratory, and these data will be used for all 


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data analysis.  The central laboratory for this study will provide instructions regarding the 
collection, processing, and shipping of samples.
Clinical chemistry, hematology, and urinalysis labs will be collected according to the schedule 
shown in Table 1 and Table 2 (± 3 days).  Screening labs will be performed within 21 days prior 
to Day 1 of the Chemoradiation Phase, and results must be reviewed by the Investigator or 
designee prior to dosing on Day 1.  Screening labs may be repeated if clinically indicated to 
confirm eligibility.
The Principal Investigator or designee as noted on the delegation of authority log will review, 
initial and date all laboratory results.  Any laboratory value outside the reference range that is 
considered clinically significant by the Investigator will be followed as appropriate.  Clinically 
significant laboratory values will be recorded as adverse events if they meet the criteria as 
specified in Section 7.
A certified local reference laboratory may perform laboratory testing as needed for immediate 
subject management.  For laboratory results that are required per protocol to make study 
treatment decisions (e.g., to determine eligibility to continue TMZ), results from a certified local 
lab may be used if central results may not be available prior to dosing.  However, the sample for 
central laboratory analysis should be drawn and sent as per the protocol schedule to be used in 
the data analysis.  In the case of contradictory results, in which the local lab result supports 
eligibility or treatment decision that would be prohibited based on the central lab result, the local 
laboratory result must be recorded in the eCRF to be included in the data analysis.  Other local 
laboratory values should not be captured in the eCRF.  The appropriate documents will be 
collected for both the central and local laboratories, as needed.
For Day 22 hematology assessments during the Adjuvant Phase (performed when adjuvant TMZ 
treatment is ongoing) a certified local laboratory may be used alone without central testing.  If a 
central laboratory result is not available for the Day 22 lab, the local lab results for platelet count 
and absolute neutrophil count (ANC) will be recorded in the eCRF.


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Table 6.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Absolute platelet count
Mean corpuscular volume (MCV)
Coagulation (screening Only)
Prothrombin time (PT)
Activated PartialThromboplastin 
Time (aPTT)
International normalized ratio 
(INR)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase (GGT)
Sodium
Potassium
Calcium
Inorganic phosphorus
Glucose
Cholesterol
Triglycerides
Total protein
Uric Acid
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination if 
dipstick results are positive
For any laboratory test value outside the reference range that the Investigator considers to be 
clinically significant:

The Investigator will follow the out-of-range value to a satisfactory clinical 
resolution.

A laboratory test value that requires a subject to be discontinued or interrupted from 
any study treatment agent (ABT-414, TMZ or RT) or from the study, or requires a 
subject to receive treatment (medical intervention) will be recorded as an adverse 
event.
MRI and Clinical Assessment for Disease Progression
A brain MRI scan with and without contrast, performed at any time after diagnostic surgery or 
biopsy but prior to randomization, is required to serve as a baseline scan for RANO tumor 
response assessments.  The most recent scan done prior to randomization will be used as the 
baseline scan.  A baseline MRI must include the image sequences (T1 with and without contrast 
and T2 FLAIR) required for making RANO assessments.  If a subject starts chemoradiation 
≤28 days after surgery, the post-operative MRI scan (including an intraoperative or 
post-operative MRI scan) performed as part of standard care prior to Screening may be used as 


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the baseline scan for RANO assessments; if so, this scan must be included with the submission 
of scans for central imaging reviews.  If the subject starts chemoradiation more than 28 days 
after surgery, then the baseline MRI must be performed within 21 (preferably fewer) days prior 
to Day 1 Week 1 of Chemoradiation and must allow sufficient time to revise the radiation 
therapy plan if needed due to a significant change in tumor since surgery.
Post-baseline MRIs with contrast will be obtained ≤ 14 days before Day 1 of each odd-numbered 
cycle (Cycles 1, 3, 5, etc.) of the Adjuvant Therapy Phase; approximately every 8 weeks of the 
Follow-Up Phase (≤ 14 days before each Follow-Up Visit), and at the Final Study Drug Visit (if 
the subject withdraws from the study prior to disease progression and has not had an MRI with 
contrast within the previous 3 weeks).  At the discretion of the Investigator, MRI with contrast 
may be performed at additional times as clinically indicated or as needed to assess whether there 
has been progression of disease.  If the subject discontinues study drug prior to disease 
progression, every effort should be made to acquire MRIs according to the same schedule while 
the subject is willing.
Scheduled tumor assessments are not affected by delays in therapy or drug holidays.  Subjects 
will continue to be monitored by the same techniques as at baseline.  Ideally, subjects should be 
imaged on the same MRI scanner, or at least with the same magnet strength, for the duration of 
the study to reduce difficulties in interpreting changes.  The Standardized Brain Tumor Imaging 
Protocol should be used wherever technically feasible at the site.6
Changes in measurable lesions over the course of therapy and changes in systemic corticosteroid 
dose and clinical status will be assessed, and the assessment of disease progression will be 
determined by the Investigator using the updated Response Assessment in Neuro-Oncology 
(RANO) criteria7 (Appendix I).  MRI images will also be reviewed centrally by an independent 
blinded reviewer for radiographic evidence of disease progression.
Scan Submission Quality Assurance and Quality Control in Imaging
The designated central imaging vendor will track all scans of all subjects received from the sites 
and will request/query missing/incomplete scans.  Scan submissions should include pre-study 
(pre-surgical and post-surgery) scans and all on-study scans.  Furthermore, if the scans arrive in 
unacceptable quality or in a non-acceptable format, the site will be informed to provide substitute 
scans.


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Scans may be uploaded by the participating centers via a central imaging platform.  Please refer 
to the imaging guidelines/manual for more details regarding submission of images, qualification 
of sites, and imaging QA/QC level description.
Assignment of Subject Numbers
All screening activities must be completed and reviewed prior to randomization.  Subjects who 
meet the eligibility criteria will proceed to randomization via the IRT system.  Randomization 
may be registered in IRT up to 3 days prior to Day 1 Week 1 of chemoradiation.
Screening numbers will be unique 5-digit numbers and will begin with 10101 with the 
first 3 digits representing the investigative site, and the last 2 digits representing the subjects at 
that site.  Randomized subjects will keep their screening number as their subject number.  
Subjects will be randomized on Day 1 as described in Section 5.9 and will receive a separate 
unique 6 digit randomization number that will be recorded automatically in the eCRF through the 
IRT system.  This randomization number will be used only by the Sponsor for loading the 
treatment schedule into the database.
Systemic Corticosteroid Use
Systemic corticosteroid dates of use, dosing, and frequency will be recorded as concomitant 
medications beginning from 7 days prior to the start of chemoradiation and throughout the study.
Neurocognitive Function – Verbal Memory and Executive Function
Two brief, sensitive, repeatable, highly standardized, and objective tests will be used to assess 
neurocognitive changes across time; the Hopkins Verbal Learning Test-Revised (HVLT-R) and 
COWA-FAS verbal fluency test.  The COWA test form used in this trial (which includes the 
letters F, A, and S in English and frequency-matched letters in other languages) is different than 
the two forms used as part of the Multilingual Aphasia Exam (MAE) which use C, F, and L or P, 
R, and W.  Several previous studies of neurocognitive function in subjects with GBM or 
metastatic brain tumors have used the MAE COWA test as part of a multi-domain assessment
called the Clinical Trial Battery (CTB).8,9  The FAS and CFL forms of the COWA test may vary 
in difficulty, which could in turn influence subject performance.10  The Trail Making Test 
(TMT), which is also included as part of the CTB will not be used in this study because 
treatment-related changes in visual acuity may confound the interpretation of neurocognitive 
outcomes measured by this assessment.  Administration of the HVLT-R and COWA-FAS verbal 
fluency test is practical in terms of burden on the subject.11,12  Neurocognitive function has been 


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demonstrated to predict tumor progression13 and to independently predict survival for subjects 
with central nervous system tumors.14-17
The neurocognitive tests are administered by certified test administrators at each site, and the 
total time for the cognitive testing is approximately 30 minutes, as follows:
Cognitive Domain
Test
Administration Time 
(minutes)
Memory
Hopkins Verbal Learning Test-Revised18
5 
Executive Function
FAS verbal fluency10
5
The healthcare professional (e.g., nurse, psychologist) at each study site who is responsible for 
test administration in this study must be trained and pre-certified.  Training materials and testing 
forms are produced, distributed and collected by VeraSci (formerly NeuroCog Trials) 
(http://www.verascience.com).  See the VeraScitesting materials for additional details regarding 
administration and scoring of these assessments.
Subjects will complete the neurocognitive testing as outlined in Table 1 and Table 2.  
Neurocognitive testing should be completed prior to study drug administration and any other 
study procedures being performed at these visits, and prior to discussing with the subject that 
their disease has progressed.
Health-Related Quality of Life (HRQoL)
Health-related quality of life will be assessed with the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 320
and with the EORTC Brain Cancer module (QLQ-BN20) module.21  The QLQ-C30 is 30-item 
patient self-report questionnaire composed of both multi-item and single scales, including 
five functional scales (physical, role, emotional, social, and cognitive), three symptom scales 
(fatigue, nausea and vomiting, and pain), a global health status/HRQoL scale, and six single 
items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).  
Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much."  The 
QLQ-C30 was developed and validated for use in a cancer patient population, and its reliability 
and validity is highly consistent across different language-cultural groups.20
The QLQ-BN20 is a 20-item patient self-report questionnaire that was developed specifically as 
a module for subjects with brain cancer.  It consists of four domain scores, including future 
uncertainty, visual disorder, motor dysfunction, and communication deficit, as well as 
seven individual symptom items (headache, seizures, drowsiness, hair loss, itching, difficulty 


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with bladder control, and weakness of both legs).  Subjects rate items on a four-point scale, with 
1 as "not at all" and 4 as "very much."  A retrospective validation study has been conducted 
confirming its psychometric validity.22
Subjects will complete the EORTC QLQ-C30/BN20 as outlined in Table 1 and Table 2.  These 
assessments should be completed prior to study drug administration and any other study 
procedures being performed at these visits, and prior to discussing with the subject that their 
disease has progressed.
MD Anderson Symptom Inventory – Brain Tumor
The MD Anderson Symptom Inventory brain tumor module (MDASI-BT) is a patient self-report 
or interviewer-administered measure used to assess the severity of multiple brain tumor-related 
symptoms and the impact of these symptoms on daily functioning in the last 24 hours.23  It was 
developed and validated specifically for use in patients with primary brain tumors.  The 
MDASI-BT consists of the core 13 symptom items (pain, fatigue, nausea, disturbed sleep, 
distress, shortness of breath, lack of appetite, drowsiness, dry mouth, sadness, vomiting, 
difficulty remembering, and numbness or tingling), and 6 interference items (general activity, 
mood, walking ability, normal work, relations with other people, and enjoyment of life and 
9 brain tumor-specific symptom items: weakness on one side of the body, difficulty 
understanding, difficulty speaking, seizures, difficulty concentrating, vision, change in 
appearance, change in bowel pattern (diarrhea or constipation), and irritability.  MDASI-BT 
items are rated from 0 to 10, with 0 indicating that the symptom is either not present or does not 
interfere with the patient’s activities and 10 indicating that the symptom is "as bad as you can 
imagine" or "interfered completely" with the patient's life.  Symptoms can be grouped into 
measured domains including neurologic, cognitive, affective, constitutional, general, and 
gastrointestinal.  The interference items can be grouped into activity- and mood-related 
interference domains.
Subjects will complete the MDASI-BT as outlined in Table 1 and Table 2.  These assessments 
should be completed prior to study drug administration and any other study procedures being 
performed at these visits, and prior to discussing with the subject that their disease has 
progressed.
EuroQol 5 Dimensions (EQ-5D-5L) and EuroQol 5 Dimension Value Sets ( EQ-5D-VAS)
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations. The EQ-5D-5L has five dimensions:  mobility, self-care, 


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usual activities, pain/discomfort and anxiety/depression. These dimensions are measured on a 
five level scale: no problems, slight problems, moderate problems, severe problems, and extreme 
problems.  The EQ-5D-5L also contains a visual analog scale (VAS) to assess the subject's 
overall health.24
Subjects will complete the EQ-5D-5L and EQ-5D-VAS as outlined in Table 1 and Table 2.  
These assessments should be completed prior to study drug administration and any other study 
procedures being performed at these visits, and prior to discussing with the subject that their 
disease has progressed.
NEI VFQ-25
Visual functioning will be assessed with the National Eye Institute Visual Functioning 
Questionnaire – 25-item version questionnaire (NEI-VFQ-25), a reliable and valid 25-item 
version of the 51-item National Eye Institute Visual Function Questionnaire (NEI-VFQ).  The 
NEI-VFQ-25 evaluates visual function and limitations in daily activities related to impaired 
visual function as well as the impact of ocular disease on patients' lives.  The NEI VFQ-25 is a 
patient self-report questionnaire consisting of 25 questions, with a total score and subscale scores 
ranging from 0 – 100.  In this questionnaire, the score of 0 corresponds to the lowest and of 100 
to the highest vision-related quality of life.  There are 12 subscales, each consisting of one or 
more questions, including general health, general vision, ocular pain, near activities, distance 
activities, vision specific social functioning, vision specific mental health, vision specific role 
difficulties, vision specific dependency, driving, color vision and peripheral vision.
The NEI VFQ-25 will be assessed as outlined in Table 1 and Table 2.
Treatment Satisfaction Question
A single treatment satisfaction question will be used to assess the subject's treatment experience.
The following question asks about your treatment experience.  Please choose the response that 
best describes how you feel about the study treatment.


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1. Based on your experience in this study, would you choose to receive the study treatment 
again?
(Circle One)
Definitely would
1
Probably would
2
Unsure
3
Probably would not
4
Definitely would not
5
Survival Assessment
Overall survival will be assessed quarterly after treatment discontinuation until death.  This can 
be conducted remotely such as by phone or other means.
Blood Biomarker Sample Collection
The collection, processing and storage should be performed as described in the study-specific
laboratory manual.
Collection for Plasma Markers
Approximately 12 mL of blood will be collected pre-dose at time points outlined in Table 3.  
The collection, processing and storage should be performed as described in the study-specific 
laboratory manual.
Blood Collection for Serum Markers
Approximately 5 mL of blood will be collected pre-dose as outlined in Table 3.  The 
collection should be performed as described in the study-specific laboratory manual.
Collection of Tumor Tissue
Subjects must consent to provide a tissue sample.  Tissue blocks should be submitted as 
described in the study-specific laboratory manual.  Tissue blocks can be returned upon request.  
Collection and submission of the samples should be performed as described in the study-specific
laboratory manual.  If permission is granted to submit slides, instructions will be provided to the 
sites at that time.
Subjects should have at least 1 block of tumor tissue; submission of 2 blocks is strongly 
encouraged to maximize the chances of eligibility.  The size of tumor on the submitted block(s) 
should be sufficient to represent at least 1 square centimeter of viable glioblastoma tumor when a 


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section is cut onto a slide.  In rare circumstances, alternative forms of tissue submission may be 
considered on a case by case basis in discussion with the Neuro-Medical Oncology Chair and 
Study Neuro-Pathologist.
Relapse Tissue Collection
For all subjects in the study who undergo tumor surgery for medically directed reasons upon 
suspected disease progression or for other medical reasons during treatment, biopsy/resection 
material can be made available for biomarker analysis.
Blood Samples for ABT-414 and Total ABT-806 Drug Concentration Measurements
A single blood draw at the specified time points will allow for ABT-414 and Total ABT-806 
pharmacokinetic analysis.  Samples will be collected into appropriately labeled evacuated serum 
collection tubes without a gel separator at the time points specified in Table 3.
Pharmacokinetic (PK) samples should not be drawn from the same arm in which study drug 
(ABT-414 or placebo) is infused.  Samples collected immediately after infusion should be 
collected after the full infusion procedure is complete.
Approximately 3.0 mL of blood will be collected to provide approximately 1.5 mL serum at each 
time point for both ABT-414 and Total ABT-806 determination (approximately 0.75 mL 
required for each assay).
The time that each serum sample is collected will be recorded to the nearest minute in the source 
documents and in the appropriate eCRFs.  The date and start/end time of each ABT-414/placebo 
infusion shall also be recorded, in the appropriate eCRFs, to the nearest minute on days when 
pharmacokinetics sampling is performed.
ADA and Neutralizing ADA (nADA) Assays
Approximately 3.0 mL of blood for ADA/nADA analysis will be collected into appropriately 
labeled serum collection tubes at the time points specified in Table 3.  It is important that serum, 
and not plasma, be harvested.
ADA/nADA samples should not be drawn from the same arm in which study drug is infused.
Approximately 3.0 mL of blood will be collected to provide approximately 1.5 mL serum at each 
time point for both ADA and nADA determination (approximately 0.75 mL required for each 


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assay).  Samples for the nADA assay will be analyzed upon request.  Pharmacokinetics and 
ADA samples collected may also be used for future assay development and validation activities.
The time that each serum sample is collected will be recorded to the nearest minute in the source 
documents and in the appropriate eCRFs.
Blood Samples for Unconjugated Cys-mcMMAF Assay
Blood samples for unconjugated Cys-mcMMAF for pharmacokinetic analysis will be collected 
in evacuated potassium edetic acid (ethylenediaminetetraacetic acid) K2EDTA-containing 
collection tubes at the time points specified in Table 3.  The time that each sample is collected 
will be recorded to the nearest minute in the source documents and in the appropriate eCRFs.
The collection, processing and storage should be performed as described in the study-specific 
laboratory manual.
Plasma concentration of unconjugated Cys-mcMMAF will be determined using validated 
methods under the supervision of Drug Analysis Department at AbbVie.
Blood Samples for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected on Day 1 from each subject 
who consents to provide a sample for pharmacogenetic analysis.  If the sample is not collected 
on Day 1, it may be collected at any time throughout the study.
Samples will be processed and shipped to AbbVie or a designated laboratory for 
deoxyribonucleic acid (DNA) extraction and long-term storage. Instructions for the preparation 
and shipment of pharmacogenetic samples will be provided in the study specific lab manual.
Abbvie will store the DNA samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on ABT-414 (or drugs of this class) 
continues but no longer than 20 years.
4.3
Definition of Disease Assessments
Progression Free Survival
Time to progression-free survival (PFS) will be defined as the number of days from the date of 
randomization to the date of earliest disease progression based on RANO criteria or to the date of 
death, if disease progression does not occur.  All disease progression will be included regardless 
of whether the event occurred while subject was taking the study drug or had previously 


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discontinued the study drug.  All events of death will be included for subjects who had not 
experienced disease progression.  Subjects for whom neither death nor progression have been 
documented will be right-censored on the date of the last adequate assessment of disease.  PFS 
will be analyzed by the Kaplan-Meier method.
The phenomenon of pseudoprogression should be considered when determining if there is 
disease progression, particularly during the first 3 months after radiotherapy.  Pseudoprogression 
refers to the occurrence of "early delayed radiation reactions" that occur usually within the 
first 3 months post radiation treatment.  These transient adverse signs and symptoms may 
spontaneously improve without therapy or with supportive care such as corticosteroids.  Thus, 
care should be taken in making the diagnosis of tumor progression or recurrence (Appendix I).
Overall Survival
Overall survival (OS) will be defined as the number of days from the date of randomization to 
the date of death due to any cause.  Subjects for whom death has not been documented will be 
right-censored at the last date the subject is documented to be alive.  OS will be analyzed by the 
Kaplan-Meier method.
Karnofsky Performance Status
Changes from baseline will be summarized for each scheduled post-baseline visit and for the 
Final Study Drug Visit for Karnofsky performance status.  The baseline will be defined as the 
last measurement collected before randomization.  The post-baseline visit will include those 
occurring within 49 days of the last dose of study drug.  The Final Study Drug Visit will be 
defined as the last post-baseline measurement collected within 49 days of the last dose of study 
drug (ABT-414, or placebo).


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5.0
TREATMENT PLAN
Treatment must begin ≤ 7 weeks after brain tumor biopsy/resection.
5.1
Treatment Plan Overview
During the Chemoradiation Phase, all subjects will undergo focal RT, with one treatment given 
daily 5 days per week over approximately 6 weeks (and no more than 7 weeks).  TMZ will be 
administered 75 mg/m2 orally once daily continuously from Day 1 of radiotherapy to the last day 
of radiation for a maximum of 49 days.  Subjects in Arm A will receive ABT-414 at 2.0 mg/kg 
IV infusion once every 2 weeks (on Day 1 of Weeks 1, 3, and 5) during this period.  Subjects in 
Arm B will receive placebo IV infusion once every 2 weeks (on Day 1 of Weeks 1, 3, and 5) 
during this period.  Treatment in the Chemoradiation Period must begin ≤ 49 days after surgery 
diagnosing GBM.  Occasionally, a subject might require a staged or two-surgery approach; for 
such cases, subjects will still be considered eligible for this study if the latest surgery was 
performed within 30 days after the initial surgery/biopsy diagnosing GBM and if all screening 
procedures are completed and chemoradiation treatment begins ≤ 49 days after the latest surgery.
The start of the first cycle during the Adjuvant Phase will be scheduled approximately 28 days 
after the last day of chemoradiation.  The AbbVie Medical Monitor or RTOG Neuro-Oncology 
should be notified if Adjuvant Phase treatment is to be started more than 42 days after the last 
day of chemoradiation.  During the Adjuvant Phase, all subjects will receive oral TMZ 
150 – 200 mg/m2 once daily on Days 1 – 5 of each 28-day cycle for 6 cycles.  Subjects in Arm A 
will receive ABT-414 at 1.25 mg/kg on Day 1 and Day 15 of each 28-day cycle for a total of 
12 cycles.  Subjects in Arm B will receive placebo IV infusion on Day 1 and Day 15 of each 
28-day cycle for a total of 12 cycles.  Adjuvant treatment will be discontinued upon 
determination of tumor progression as defined by RANO criteria, unacceptable toxicity, or 
refusal to continue study treatment.
Duration of Adjuvant TMZ
Subjects demonstrating continued benefit and no unacceptable toxicity from adjuvant TMZ can 
continue TMZ to a maximum of 12 cycles at the discretion of the Investigator if this is 
considered an acceptable standard of care per local regulations.
Subjects in Arm A will receive ABT-414 on Day 1 and Day 15 of each 28-day cycle.  Subjects in 
Arm B will receive placebo IV infusion on Day 1 and Day 15 of each 28-day cycle.  Subjects 
who discontinue TMZ for TMZ-related toxicity will continue ABT-414/placebo treatment.  
Subjects who discontinue ABT-414 or placebo due to ABT-414-related or placebo-related 


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toxicity prior to completion of the Adjuvant Therapy Phase will continue TMZ treatment as 
scheduled.
Duration of Adjuvant ABT-414 or Placebo
If after completing 12 cycles of adjuvant ABT-414/placebo, the subject is tolerating treatment 
and the Investigator believes the subject is continuing to benefit from ongoing study drug 
treatment, the Investigator may extend the Adjuvant Phase with ABT-414/placebo after 
consultation with the Neuro-Medical Oncology Chair or AbbVie Medical Monitor.  The 
ABT-414/placebo will continue at the same dosing schedule, as long as disease progression has 
not been determined.
5.2
Radiation Therapy
Chemoradiation treatment must begin within 7 WEEKS after biopsy/resection.
The schema at the beginning of the protocol should be followed.
Within 3 months after site initiation, assessment of specific technology requirements is required 
for this study; please refer to the study-specific radiation manual for detailed instructions.  
Pneumocystis (jirovecii) pneumonia (PCP) prophylaxis should be per local regulation guidelines 
during the radiation phase (Section 5.8).
5.2.1
Treatment Technology
This protocol requires photon treatment. 3D-CRT and IMRT are allowed.  Any of the methods of 
IMRT, including fixed gantry IMRT, helical tomotherapy, or volumetric arc therapy (VMAT) 
may be used, subject to protocol localization and dosimetry constraints.  Computerized 
tomography (CT)-based treatment planning is necessary to assure accuracy in the selection of 
field arrangements.  MRI-fusion for accurate target delineation is strongly recommended.
Treatment shall be delivered with megavoltage (MV) machines of a minimum energy of 6 MV 
photons.  Selection of the appropriate photon energy(ies) should be based on optimizing the 
radiation dose distribution within the target volume and minimizing dose to non-target normal 
tissue.  Source skin distance for SSD techniques or source axis distance for SAD techniques must 
be at least 80 cm.  Electron, particle, or implant boost is not permissible.  IMRT delivery will 
require megavoltage radiation therapy machines of energy ≥ 6 MV.
Treatment may be performed using a sequential boost to the contrast-enhanced region of the 
target; otherwise treatment may be delivered straight through without sequential boost detailed 


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in Section 5.2.4.  Any institution can choose any one technique, but once selected, should remain 
consistent through the completion of this protocol.  Subject specific QA (Section 5.2.10) is 
highly recommended prior to start of treatment and is described in the study specific radiation 
manual.
5.2.2
Immobilization and Simulation
Immobilization
Proper immobilization is critical for this protocol.  Subject setup reproducibility must be 
achieved using appropriate clinical devices.
Subjects shall be treated in a supine position and immobilized with a thermoplastic mask and 
headrest.  Additional immobilization devices such as a bite block and/or knee-wedge are 
permitted.  In rare instances, based on tumor location and patient anatomy, prone set-up is 
permissible.
Simulation Imaging
A planning CT scan of the cranial contents with 3.0 mm slice thickness or less will be required 
which will be fused with the pre- and post-operative MRI scans.  Rigid registration is permitted, 
but deformable fusion is not permitted.
5.2.3
Imaging for Structure Definition, Image Registration/Fusion and Follow-Up
Rigid image registration must be used for the protocol.  Deformable fusion is not allowed.  
Post-operative MRI with T2/fluid attenuated Inversion recovery (FLAIR) and contrast enhanced 
T1 sequences is required and must be obtained after surgical resection.  Additionally, if a subject 
starts chemoradiation more than 28 days after surgery, the subject will have a brain MRI with 
T2/FLAIR and contrast enhanced T1 sequences included no more than 21 (but preferably fewer) 
days prior to Day 1 Week 1 of Chemoradiation Phase to be used as the baseline MRI scan for 
efficacy analyses; the timing of the MRI must allow sufficient time to revise the radiation 
therapy plan if needed due to a significant change in tumor since surgery.  Radiotherapy planning 
is recommended to be completed as soon as reasonably feasible, but in all cases, chemo-
radiotherapy MUST begin NO LATER than 7 weeks after initial biopsy or latest tumor resection.
The scans used for planning MUST be submitted as a complete series along with the treatment 
plan as well.  If a pre-operative MRI scan is not available for fusion, fusion with only the 
post-operative MRI scan is permitted.  It is recommended, not required, to obtain the 
pre-operative MRI scan to assist in treatment planning.  Target volume delineation will be based 
on a contrast enhanced MRI scan obtained after surgery, ideally obtained within 72 hours after 
surgery although that timing is not mandatory.  Pre-operative imaging should be used to guide 


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identification of target delineation, but critical structures are best contoured on the post-operative 
MRI and/or CT, as there is expected structural shift between the pre- and post-operative scans.
5.2.4
Definition of Target Volumes and Margins
Differences exist in methods utilized for GTV/CTV/PTV definitions; this protocol 
accommodates and permits two key philosophical concepts, labeled the "RTOG" and the 
"EORTC" approaches; each institution will be required to declare upfront which approach they 
will pursue, and will be required to adhere to that single approach during the conduct of this 
protocol.
The main "RTOG" approach describes a sequential boost or cone-down radiotherapy technique 
which is described below.  However, this approach is less widely used in Europe. As such, the 
radiotherapy technique for sites wishing to follow the "EORTC" approach is also defined below 
as an alternative straight through or single phase technique, designed to reflect the broad 
overall tenets of radiotherapy practices for glioblastoma treatments in EORTC institutions.  
Although many individual variations on the themes exist, in this multi-institutional international 
study, these two concepts, as specifically defined within the protocol are permitted, and other 
variations, unless approved by one of the Radiation Oncology co-chairs, will be considered a 
major protocol violation.  As mentioned in Section 5.2.1, any institution can choose either of 
the two techniques, but once selected, must remain consistent through the completion of 
this protocol for all patients enrolled under this amendment or later by that institution (a 
site that used the RTOG approach prior to Amendment may switch to the EORTC 
approach, as long as that approach is maintained until the end of the study).  An institution 
may not choose both techniques, and may not use different techniques for different 
patients, or different techniques for different physicians within the same institution.  
Additionally, if an institution starts a patient's treatment with a sequential boost approach 
using a certain fraction size (e.g., 1.8 GY per fraction), they are expected to complete the 
cone down with the same fraction size.  Institutions must also send a composite plan 
showing the final accumulated dose distribution.  The composite dose distribution will be 
used to score the plans for critical structure dose.  Exceedingly rare exceptions on a case-
by-case basis will only be permissible if approved in writing by a Radiation Oncology study 
chair.
Note:  All structures must be named for digital RT data submission as listed as in the table 
below.  The structures marked as "Required" in the table must be contoured and submitted when 
applicable.  Resubmission of data may be required if labeling of structures does not conform to 
the standard DICOM name listed.  Capital letters, spacing and use of underscores must be 


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applied exactly as indicated, to ensure appropriate, timely, accurate, and reproducible QA 
process application to all cases.
Target Structured Labeling:  Option 1:  RTOG Approach – Sequential Boost
Standard Name
Description
Validation
Required/Required When 
Applicable/Optional
GTV1
GTV to receive 45 or 46 Gy
Required
CTV1
CTV to receive 45 or 46 Gy
Required
PTV1
PTV to receive 45 or 46 Gy
Required
GTV2
GTV to receive 59.4 or 60 Gy
Required
CTV2
CTV to receive 59.4 or 60 Gy
Required
PTV2
PTV to receive 59.4 or 60 Gy
Required
Details Specifications
Target volumes will be based upon post-operative-enhanced MRI.  Pre-operative imaging should 
be used for correlation and improved identification.
GTV1 – Either the T2 or the FLAIR abnormality on the post-operative MRI scan, inclusive of all 
contrast-enhancing T1 abnormality on the post-operative MRI and the surgical cavity.  Areas of 
vascular infarction or compromise of normal brain should be excluded if they are deemed to not 
be part of the original pre-operative tumor volume, and a comparison of the pre- and 
post-operative scans will assist in this process.
CTV1 – Is defined as the GTV1 plus a margin of 2 cm, which may be reduced around natural 
barriers to tumor growth such as the skull, ventricles, falx, etc. to as low as 0 mm to "fixed" 
barriers, i.e., bone, and falx and as low as 3 – 5 mm to “non-rigid” barriers such as brain stem, 
ventricles, etc.  If no surrounding edema is present (i.e., the FLAIR and/or T2 MR images do not 
demonstrate any significant abnormality), the CTV 1 in those instances should include the 
post-operative MRI enhancement and the surgical resection cavity plus a 2 cm margin, with 
reduction permitted as described above.
GTV2 – Contrast enhancing T1 abnormality and the surgical cavity on the post-operative MRI 
scan.  Areas of vascular infarction or compromise of normal brain should be excluded if they are 
deemed to not be part of the original pre-operative tumor volume, and a comparison of the 
pre- and post-operative scans will assist in this process.  The exception to this is the polar tumor, 
e.g., temporal lobe, frontal lobe, or occipital lobe tip, where a gross total resection is achieved, 
and no post-operative "cavity" remains, consequential to the partial or total lobectomy.  For these 


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uncommon patients, GTV2 will be defined as either the T2 or the FLAIR abnormality on the 
post-operative MRI scan, i.e., in these cases, GTV1 = GTV2.
CTV2 – Is defined as the GTV2 plus a margin of 2 cm.  The CTV2 margin may be reduced 
around natural barriers to tumor growth such as the skull, ventricles, falx, etc. to as low as 0 mm 
to "fixed" barriers, i.e., bone, and falx and as low as 3 – 5 mm to "non-rigid" barriers such as 
brain stem, ventricles, etc.
PTV1 and PTV2 – In general the PTV is the CTV plus a geometric 5 – 7 mm expansion in all 
dimensions.  This can be reduced to 4 mm if daily volumetric (3D) or non-volumetric (2D) 
IGRT is utilized.  PTV may extend beyond bony margins and the skin surface.
Target Structure Labeling:  Option 2:  EORTC Approach – Single Phase
Standard Name
Description
Validation
Required/Required When 
Applicable/Optional
GTV
GTV to receive 59.4 or 60 Gy
Required
CTV
CTV to receive 59.4 or 60 Gy
Required
PTV
PTV to receive 59.4 or 60 Gy
Required
Detailed Specifications
Target volumes will be based upon the post-operative-enhanced MRI.  Pre-operative imaging 
should be used for correlation and improved identification.
GTV – Contrast enhancing T1 abnormality and the surgical cavity on the post-operative MRI 
scan.  Areas of vascular infarction or compromise of normal brain should be excluded if they are 
deemed to not be part of the original pre-operative tumor volume, and a comparison of the 
pre- and post-operative scans will assist in the process.  The exception to this is the polar tumor, 
e.g., temporal lobe, frontal lobe, or occipital lobe tip, where a gross total resection is achieved, 
and no post-operative "cavity" remains, consequential to the partial or total lobectomy.  For these 
uncommon patients, GTV will be defined as either the T2 or the FLAIR abnormality on the 
post-operative MRI scan.
CTV – Is defined as the GTV plus a margin of 2 cm, which may be modified in two respects:  
1) The CTV margin may be reduced around natural barriers to tumor growth such as the skull, 
ventricles, falx, etc., to as low as 0 mm to "fixed" barriers, i.e., bone, and falx and as low as 
3 – 5 mm to "non-rigid" barriers such as brain stem, ventricles, etc., and 2) in all areas of 
persisting edema on FLAIR (preferred) or T2-weighted MRI images, the CTV will be expanded 
beyond 2 cm to include these regions.


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PTV – In general the PTV is the CTV plus a geometric 5 mm expansion in all dimensions.  This 
can be reduced to 4 mm if daily volumetric (3D) or non-volumetric (2D) IGRT is utilized.  
PTV may extend beyond bony margins and up to the skin surface.
5.2.5
Definition of Critical Structures and Margins
Note:  For either "RTOG" or "EORTC" approaches, all structures must be named for digital RT 
data submission as listed in the table below.  The structures marked as "Required" in the table 
must be contoured and submitted with the treatment plan.  Structures marked as "Required when 
applicable" must be contoured and submitted when applicable.
Resubmission of data may be required if labeling of structure does not conform to the standard
Digital Imaging and Communications in Medicine (DICOM) name listed.  Capital letters, 
spacing and use of underscored must be applied exactly as indicated.
All structures should be contoured on the planning CT, using the post-operative MRI for 
guidance.  Due to variance in eye position between the CT and MRI, if possible, the lenses, 
retina, and optic nerves should be contoured using the CT dataset only.
Special consideration should be given to avoid doses greater than the prescription dose within the 
scalp as well as limiting exit dose through the oral cavity and mucosa.


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Organs-at-Risk Structure Labeling:  Option 1 and 2:  RTOG and EORTC Approaches
Standard Name
Description
Validation
Required/Required When 
Applicable/Optional
Lens_L
Left lens
Required
Lens_R
Right Lens
Required
Retina_L
Left retina
Required
Retina_R
Right retina
Required
OpticNrv_L
Left optic nerve
Required
OpticNrv_R
Right optic nerve
Required
OptNrv_PRV_L
Left optic nerve planning risk volume
Required
OptNrv_PRV_R
Right optic nerve planning risk volume
Required
OpticChiasm
Optic chiasm
Required
OptChiasm_PRV
Optic chiasm planning risk volume
Required
BrainStem
Brainstem
Required
SpinalCord
Spinal cord
Required
Brain
Whole brain parenchyma
Required
Glnd_Lacrimal_L
Left lacrimal gland
Required
Glnd_Lacrimal_R
Right lacrimal gland
Required
Cochlea_L
Left cochlea
Optional
Cochlea_R
Right cochlea
Optional
Detailed Specifications
Please refer to the organs at risk contouring guidelines and supplement published in 
Radiotherapy and Oncology:  http://www.thegreenjournal.com/article/S0167-8140(15)00080-
8/pdf.
Lens_L, Lens_R, Retina_L, Retina_R, OpticNrv_L, OpticNrv_R:  Due to variance in eye 
position between the CT and MRI, if possible, the structures should be contoured using the CT 
dataset only.  The retina is defined as the innermost of the three layers that form the wall of the 
eyeball.  Please contour 5 mm posterior wall of the eye.  Please refer to supplemental figure 
V:Va-Vg in the organs at risk contouring guidelines.
OptNrv_PRV_L:  Left optic nerve should be expanded by a volumetric expansion of 3 mm.
OptNrv_PRV_R:  Right optic nerve should be expanded by a volumetric expansion of 3 mm.
OpticChiasm:  Located above the pituitary fossa, the optic chiasm includes both anterior and 
posterior limbs.  It is best visualized on post-operative T2/FLAIR MRI Sequence, but should be 
confirmed on CT dataset due to potential variation in CT/MRI fusion.


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OptChiasm_PRV:  Optic chiasm should be expanded by a volumetric expansion of 3 mm.
BrainStem:  Brainstem contour should include all three components:  midbrain, pons, and 
medulla.  The brainstem is bordered superiorly by the tentorial incisures and inferiorly by the 
foramen magnum.  It can be visualized on post-operative MRI sequence, but should be 
confirmed on CT dataset due to potential variation in CT/MRI fusion.
SpinalCord:  Spinal cord should be contoured, wherever possibly, on the CT dataset only.
Brain:  Whole brain parenchyma includes all intracranial contents, inclusive of target volumes.  
Because some volumetric change could have occurred in the whole brain parenchyma due to 
evolving post-operative changes, it is recommended, whenever possible to contour the whole 
brain parenchyma using the CT dataset only.
Cochlea_L, Cochlea_R:  Although not mandated, it is recommended that the left and right 
cochlea be contoured using the CT dataset on bone window.
Glnd_Lacrimal_L, Glnd_Lacrimal_R:  The lacrimal gland is located supero-laterally to the 
extraconal portion of the orbit, medial to the zygomatic process of the frontal bone and is 
superior to the lateral rectus muscle and lateral to the superior rectus muscle.  Please refer to 
supplementary figure V:Vd-Vh in the organs at risk contouring guidelines paper.
5.2.6
Dose Prescription
Note:  The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priority table should be used 
during dose optimization.  It is important to remember that ideal plans might not be achievable in 
all cases.  Thus the Compliance Criteria table could be different than the information given here.  
Cases will be scored using the Compliance Criteria table.
Option 1:  RTOG Approach – Sequential Boost
Target Standard 
Name
Dose (Gy)
Fraction Size (Gy)
# of Fractions
Dose Specification Technique
PTV1
44 – 46
2
23
≥ 95% of PTV receives 46 Gy
Optional:PTV1
45
1.8
25
≥ 95% of PTV receives 45 Gy
PTV2
60
2
30
95% of PTV should receive 
≥60 Gy
Optional:PTV2
59.4
1.8
33
95% of PTV should receive 
≥59.4 Gy


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Option 2:  EORTC Approach – Single Phase
Target Standard 
Name
Dose (Gy)
Fraction Size (Gy)
# of Fractions
Dose Specification Technique
PTV
60
2
30
95% of PTV should receive 
≥60 Gy
Optional:PTV
59.4
1.8
33
95% of PTV should receive 
≥59.4 Gy
5.2.7
Compliance Criteria
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table.  The Per Protocol and Variation Acceptable categories are both considered 
to be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation 
Acceptable category can include more challenging plans that do not fall at or near the ideal 
results.
Normalization of Dose:  95% of the PTV (D95%) should be covered by 100% of the prescription 
dose.
Option 1:  RTOG Approach – Sequential Boost
Target Volume Constraints and Compliance Criteria
Name of Structure
Dosimetric Parameter
Per Protocol
Variation Acceptable
PTV1
D95%(%)*
100% of prescribed dose (PD)
at least 95% of PD
PTV2
D95%(%)*
100% of prescribed dose (PD)
at least 95% of PD
D10%(%)*
≤ 105% of PD
≤ 110% of PD
D0 03cc(%)*
≤ 106% of PD
≤ 112% of PD
*
Dose is normalized to prescription dose (PD) in Gy.
Variation Acceptable ranges exclude those from Per Protocol.


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Option 2:  EORTC Approach – Single Phase
Target Volume Constraints and Compliance Criteria
Name of Structure
Dosimetric Parameter
Per Protocol
Variation Acceptable
PTV
D95%(%)*
100% of prescribed dose (PD)
at least 95% of PD
D10%(%)*
≤ 105% of PD
≤ 110 of PD
D0 03cc(%)*
≤ 106% of PD
≤ 112% of PD
*
Dose is normalized to prescription dose (PD) in Gy.
Variation Acceptable ranges exclude those from Per Protocol.
Normal Structure Constrains and Compliance Criteria for Both RTOG and EORTC 
Approaches
Name of Structure
Dosimetric Parameter
Per Protocol
Variation Acceptable
SpinalCord
D0 03cc
≤ 50 Gy
Brainstem
D0 03cc
≤ 55 Gy
≤ 60 Gy
OpticChiasm_PRV
D0 03cc
≤ 55 Gy
≤ 60 Gy
OptNrv_PRV_L or 
OptNrv_PRV_R
D0 03cc
≤ 55 Gy
≤ 60 Gy
Retina_L or Retina_R
D0 03cc
≤ 45 Gy
≤ 50 Gy
Brain
D5%
≤ 65 Gy
≤ 67 Gy
Lens_L or Lens_R
D0 03cc
≤ 7 Gy
≤ 10 Gy
Glnd_Lacrimal_L or 
Glnd_Lacrimal_R
D0 03cc
≤ 40 Gy
≤ 45 Gy
Cochlea_L or Cochlea_R
Mean dose
≤ 45 Gy
≤ 50 Gy
Note:  A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable.  Plan falling in this category are 
considered to be suboptimal and additional treatment planning optimization is recommended.
Exceptions:
1. SpinalCord does not have a Variation Acceptable; Deviation Unacceptable occurs when 
SpinalCord dose limit for Per Protocol is not met.
2. Deviation Unacceptable occurs when dose limits for Variation Acceptable are not met for 
both OptNrv_PRV_L and OptNrv_PRV_L; or OptNrv_PRV_L  if the subject does not 
have a serviceable vision in the right eye; or OptNrv_PRV_R  if the subject does not have 
a serviceable vision in the left eye.
3. Deviation Unacceptable occurs when dose limits for Variation Acceptable are not met for 
both Retina_L and Retina_R; or Retina_L if the subject does not have serviceable vision 
in the right eye; or Retina_R if the subject does not have serviceable vision in the left eye.


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4. Exceeding the dose limits for Variation Acceptable for Lens_L or Lens_R will not be 
scored as Deviation Unacceptable.
Delivery Compliance Criteria
Per Protocol
Variation Acceptable
Start date
≤ 7 weeks after surgery
None
Interruptions
≤ 4 days
5 – 7 days
5.2.8
Treatment Planning Priorities
Critical Structure and Target priorities must be listed in order of decreasing importance.
1. SpinalCord
2. BrainStem
3. OptChiasm_PRV
4. OptNrv_PRV_L and OptNrv_PRV_R
5. PTV1
6. PTV2 (If using the EORTC technique, PTV1 and PTV2 should be replaced by PTV)
7. Brain
8. Retina_L and Retina_R
9. Glnd_Lacrimal_L and Glnd_Lacrimal_R
10. Lens_L and Lens_R
In the event that an OAR with higher priority that PTV2 or PTV (depending on which approach 
is taken e.g., "RTOG" or "EORTC") is in immediate proximity to PTV2 or PTV such that dose 
to the OAR cannot be constrained within Unacceptable Deviation limits, then D95% for PTV2 or 
PTV should be lowered to Varian Acceptable range to ensure that the OAR with higher priority 
does not exceed Unacceptable Deviation limits.  If this approach does not constrain the OAR 
with higher priority than PTV2 or PTV within Unacceptable Deviation limits, then D95% for 
PTV2 or PTV can be further lowered to below but as close as possible to Variation Acceptable 
range to ensure that the OAR with higher priority does not exceed Unacceptable Deviation 
limits; this will be scored as an Unacceptable Deviation for PTV2 or PTV.


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5.2.9
Dose Calculations
Required algorithms
Acceptable choices of algorithm are listed at 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf.  Any algorithm used for this study must be credentialed 
by IROC Houston.
Plan Review and Evaluation
Traditional DVHs and dose distribution displays will be used for plan review and evaluation 
DVHs will also be used for retrospective outcome analysis.
Dose matrix resolution
Dose matrix grid size must be 3 mm × 3 mm × 3 mm or smaller
5.2.10
Subject-Specific QA
For photon IMRT plans, subject specific QA is highly recommended.  QA is performed by 
delivering the plan onto a phantom and measuring the dose using an ion chamber array or other 
2D/3D device.  Measured dose distribution will be compared to planned dose distribution using a 
Gamma criterion of 3% dose difference and 3 mm distance to agreement.  For plans with highly 
modulated dose distributions a 5% dose difference and 3mm distance to agreement criterion may 
be used.  The pass rate should be at least 90% measured for the entire plan.
Subject-specific QA data should be kept on record at each institution but will not be centrally 
collected or reviewed by RTOG.
5.2.11
Daily Treatment Locations/IGRT
Imaging should be performed at least once per week.  Daily image-guided radiation therapy 
(IGRT) is optional for this protocol, and image-guidance is per individual institutional standards 
and the margins stated in Section 5.2.4.  The RTOG defines IGRT as a computer assisted 
process.  That is, image handling together with calculation of shift and rotations (if available) 
must be determined with computer assistance.  Acceptable non-volumetric or two-dimensional 
IGRT systems include:  1) Orthogonal or near-orthogonal 2D imaging that is integrated with the 
functioning of the delivery device.  These systems can use the treatment beam or special kV 
x-ray head(s) positioned at a known position in the treatment room.  Acceptable volumetric or 
three-dimensional IGRT systems include:  1) A diagnostic quality CT scanner positioned with a 
known geometry in the treatment room.  2) Volumetric cone-beam devices that use either MV or 
kV x-ray beam.  3) Tomotherapy technology that uses a fan-beam imaging approach.


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For this study, the cranium is used for image registration.  It is important to include as much of 
the anatomy of this structure as possible to ensure correct alignment of the head.  Caution 
should be taken to avoid excess repeat imaging on a given treatment day to minimize 
subject dose outside the treatment region, and steps to control subject position to less than 
3 mm should not be taken.
5.2.12
Case Review
These reviews will be ongoing and performed remotely by the Radiation Oncology study chair or 
his/her designee.
Digital RT Data Submission to RTOG Using the TRIAD Portal
RTOG will provide sites with the American College of Radiology Imaging Network's image 
acquisition and management software, Transmission of Imaging and Data (TRIAD), via 
electronic installation.  TRIAD-OA offers a web-based, software solution allowing institutions to 
submit DICOM data securely through electronic transmission.  Internal to the site, TRIAD 
allows the site to "DICOM push" from the site's Treatment Planning System (TPS), thus 
eliminating the need to burn physical media.  Once the institution has transferred the RT data 
onto a TRIAD workstation, the software will anonymize, encrypt, and submit the DICOM RT 
data via secure internet to the RTOG image archive.  For more information please visit the 
TRIAD web site at https://triad.acr.org.
TRIAD technical assistance may be requested by e-mailing TRIAD-Support@acr.org.  Please 
always include the institution name and trial number when requesting TRIAD technical 
assistance.
Summary of Dosimetry Digital Data Submission 
Item
Due
Preliminary Dosimetry Information
Digital data submission includes the following:
Within 1 week of start of RT

DICOM Items:

DICOM Post-Op MR ENTIRE Post-Op Series must be submitted along with the 
RT data

DICOM CT Data Set

DICOM Dose – Initial

DICOM Dose – Boost

DICOM Dose – Composite


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
DICOM RT Plan – Initial

DICOM RT Plan – Boost
5.2.13
Radiation Therapy Adverse Events
Acute
Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or soreness 
of the scalp.  Potential acute toxicities include nausea and vomiting as well as temporary 
aggravation of brain tumor symptoms such as headaches, seizures, and weakness.  Reactions in 
the ear canals and on the ear should be observed and treated symptomatically; these reactions 
could result in short-term hearing impairment.  Dry mouth or altered taste have been 
occasionally reported.
Early Delayed
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1 – 3 months after radiotherapy treatment.
Late Delayed
Possible late delayed effects of radiotherapy include radiation necrosis, endocrine dysfunction, 
and radiation-induced neoplasms.  In addition, neurocognitive deficits, which could lead to 
mental slowing and behavioral change, are possible.  Permanent hearing impairment and visual 
damage are rare.  Cataracts can be encountered.
5.3
Temozolomide (TMZ)
Because TMZ as prescribed in this study is considered the standard-of-care (SOC) treatment for 
this indication, commercial sources will be used for TMZ drug supply, unless otherwise 
mandated by the country.  AbbVie may provide or reimburse for TMZ to participating sites as 
required based upon availability or local regulations.
5.3.1
TMZ Administration
5.3.1.1
Chemoradiation
TMZ will be administered continuously from Day 1 of radiotherapy to the last day of radiation at 
a daily oral dose of 75 mg/m2 (for a maximum of 49 days).  The timing of each daily dose will be 
at the discretion of the Investigator.
The dose will be determined using actual body surface area (BSA) as calculated in square meters 
at the beginning of the concomitant treatment.  The BSA will be calculated from the height 


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obtained at the screening visit and the weight obtained at the visit immediately before the 
first day of treatment.  The dose of TMZ does not have to be adjusted unless there has been at 
least a 10% change in body weight; recalculation of dose for < 10% weight changes is allowed at 
the discretion of the Investigator.  Recalculations for subsequent changes in height are 
permissible but not required.  The dose will also not be capped for those that are overweight.  
The daily dose will be rounded to the nearest 5 mg.  The exact dose administered should be 
recorded in the eCRF.  Each daily dose should be given with the least number of capsules.
Subjects should be instructed to swallow the capsules whole, in rapid succession, without 
chewing them.  If vomiting occurs during the course of treatment, no re-dosing of the subject is 
allowed before the next scheduled dose.  The capsules should be taken on an empty stomach, 
therefore a minimum of 2 hours after eating and with no food consumption for at least 1 hour 
after TMZ administration.
Antiemetic prophylaxis is usually not required for the continuous daily dosing schedule (during 
radiation).  However, prophylaxis with a 5-hydroxytryptamine3 (5-HT3) antagonist is 
recommended prior to administration of the first few TMZ doses and should be administered 
orally 30 to 60 minutes before TMZ treatment.  Most subjects report optimal nausea control with 
the use of a 5-HT3 antagonist.  Routine use of antiemetics is recommended during the adjuvant 
phase of treatment.
IV temozolomide (as per local institutional standard) may be used instead of oral TMZ if there is 
a change in the subject's social situation (e.g., move to a nursing home or changes in drug 
reimbursement) after treatment TMZ initiation such that oral dosing of temozolomide is no 
longer possible.
5.3.1.2
Adjuvant Treatment
TMZ will be administered orally once per day for 5 consecutive days (Days 1 – 5) of a 28-day 
(+/– 3 day) cycle.  The starting dose for the first cycle will be 150 mg/m2/day, with a single dose 
escalation to 200 mg/m2/day in subsequent cycles if no treatment-related adverse events > Grade 
2 are noted.  The timing of each daily dose will be at the discretion of the Investigator.
The start of the first cycle will be scheduled approximately 28 days after the last day of 
radiotherapy.  The start of all subsequent cycles (Cycles 2 – 12) will be scheduled every 4 weeks 
(28 days ± 3 days) after the first daily dose of TMZ of the preceding cycle.
The dose will be determined using the BSA calculated at the beginning of each treatment cycle.  
The BSA will be calculated from the height obtained at the screening visit and from the weight 


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obtained at the visit immediately before each cycle.  More frequent assessment and use of height 
and/or weight and calculation of BSA are permitted throughout the study.  The dose of TMZ 
does not have to be adjusted unless there has been at least a 10% change in body weight; 
recalculation of dose for < 10% weight changes is allowed at the discretion of the Investigator.  
The dose will also not be capped for those that are overweight.  The daily dose will be rounded 
to the nearest 5 mg (where dosage strengths are available to accommodate rounding to 5 mg).  
The exact dose administered should be recorded in the eCRF.  Each daily dose should be given 
with the least number of capsules.
Prior to each treatment cycle with TMZ a complete blood count (CBC) will be obtained (within 
72 hours prior to dosing).  Subjects should be instructed to fast at least 2 hours before and 1 hour 
after TMZ administration.  Water is allowed during the fast period.  Subjects will be instructed to 
swallow the capsules whole, in rapid succession, without chewing them.
If vomiting occurs during the course of treatment, no re-dosing of the subject is allowed before 
the next scheduled dose.
Antiemetic prophylaxis with a 5-HT3 antagonist is strongly recommended and should be 
administered 30 to 60 minutes before TMZ administration (Section 5.8).
IV temozolomide (as per local institutional standard) may be used instead of oral TMZ if there is 
a change in the subject's social situation (e.g., move to a nursing home or changes in drug 
reimbursement) after treatment TMZ initiation such that oral dosing of temozolomide is no 
longer possible.
Subjects will be treated with post-radiation TMZ for 6 cycles unless there is evidence of tumor 
progression (RANO) or treatment-related toxicity (Section 8.3).
Subjects demonstrating continued benefit and no unacceptable toxicity from adjuvant TMZ may 
continue TMZ for an additional 6 cycles (12 cycles in total) at the discretion of the investigator if 
this is considered an acceptable standard of care per local regulations.  TMZ treatment for more 
than 12 cycles will not be allowed.
5.3.2
Chemotherapy Review
Chemotherapy reviews will be ongoing and performed by the Neuro-Oncology/Medical 
Oncology study chair or his/her designee.


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5.4
ABT-414 / Placebo Treatment
During the Chemoradiation Phase, subjects in Arm A will receive blinded ABT-414 at 2.0 mg/kg 
IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week 
regimen).  Subjects in Arm B blinded placebo IV infusion over 30 – 40 minutes once every 
2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen).  The dosing interval must be at 
least 12 days after the previous dose of ABT-414/placebo, and the doses must be administered no 
later than the last day of radiation treatment.
During the Adjuvant Therapy Phase, subjects in Arm A will receive blinded ABT-414 at 
1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 – 40 minute 
infusion, and subjects in Arm B will receive blinded placebo IV infusion on Day 1 and Day 15 of 
each 28-day cycle for 12 cycles.  If, after completing 12 cycles of study drug, the subject is 
tolerating the drug and the Investigator believes the subject is continuing to benefit from ongoing 
study drug treatment, the Adjuvant Phase may be extended following consultation with the 
Neuro-Medical Oncology Chair or AbbVie Medical Monitor.  ABT-414/placebo will continue 
according to the same dosing schedule at the discretion of the Investigator as long as disease 
progression has not been determined.
The mg/kg dose will be determined from the weight on Day 1 of the Chemoradiation Phase and 
need not change during the Chemoradiation Phase unless there is a weight change by more than 
10% from Week 1 Day 1.  Recalculation of dose for < 10% weight changes is allowed at the 
discretion of the Investigator.  There will be no cap on the weight of the subject or on the number 
of milligrams administered for overweight subjects.  More frequent assessment and use of height 
and/or weight and calculation of BSA are permitted throughout the study.
If TMZ treatment is discontinued due to intolerance during either the Chemoradiation Phase or 
Adjuvant Phase, subjects will continue receiving study drug (ABT-414 or placebo) infusions 
according to the same study schedule.
The ABT-414 (active and placebo) will be provided as a lyophilized powder in vials.  Each 
100 mg vial of ABT-414 and placebo will be reconstituted with 5.0 mL of sterile water for 
injection to provide a 20 mg/mL ABT-414 active or a placebo solution.  Each 20 mg vial of 
ABT-414 and placebo will be reconstituted with 1.0 mL of sterile water for injection to provide a 
20 mg/mL ABT-414 active or a placebo solution.  The ABT-414 is dosed as a fixed dose [or] 
based on body weight.  The contents of two or more reconsitituted vials may be diluted to 
accomplish the desired dose.  The total volume administered will be dependent upon the 
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ABT-414 and placebo solution(s) will be administered via intravenous (IV) infusion.  Specific 
dose preparation and documentation details will be provided to the site pharmacy outside of this 
protocol.
Guidelines for ABT-414 dose preparation, volume, and rate of infusion will be supplied by 
AbbVie to study site staff, within the study manual.
The dosing schedule for the hepatic impairment sub-study can be found in Appendix IX.
5.5
Eye Drops for Prophylactic Treatment of ABT-414 Eye Toxicity
Eye drops are to be used regardless of any systemic (oral/IV) corticosteroids that the subject may 
be taking concurrently.
All subjects will receive prophylactic eye drops with each dose of ABT-414/placebo for 
7 consecutive days, starting from 2 days prior to infusion and continuing until 4 days after 
infusion.  The eye drop formulations recommended for the study, ranked by steroid potency from 
Level 1 (non-steroid artificial tears) to Level 4 (high-potency steroid where available), and 
dosing schedule for each are listed in Table 7.  Alternatives may be discussed with the sponsor in 
cases where the recommended formulation(s) for one or more levels are not available locally.  
All subjects will begin on a Level 3 (moderate-potency) steroid at the initiation of the 
Chemoradiation Phase.  Subjects will be monitored with regular ophthalmologic examinations 
(with additional symptom-driven examinations as needed) using the ABT-414-TOE 
(Section 4.2).  The potency of the eye drop formulation given with subsequent ABT-414/placebo 
doses will be adjusted upward or downward, as needed, based on corneal findings from the 
ABT-414-TOE, as shown by the decision algorithm in Table 8.  To minimize unnecessary risks 
associated with prolonged administration of ocular steroids (including potential for infection, 
glaucoma, and cataracts), the algorithm requires a step-down in the level of eye drop potency for 
subjects with Grade 1 or no eye toxicity who have no evidence of corneal microcysts on 
ophthalmic examination.  The rationale for this approach is described in further detail in 
Section 5.12.4.
Though not well understood, ocular steroids may slow down the turn-over of transient 
amplifying cells in the eye and thereby protect them from damage caused by the MMAF toxin 
portion of ABT-414 that targets cells in rapid division.  Although early use has shown that 
steroid eye drops may reduce the severity of symptoms related to microcyst formation, they 
generally do not prevent them completely.  Because steroid eye drops are used to protect 
transient amplifying cells during exposure to MMAF, the best time to administer them is around 


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the time of infusion when the levels of MMAF are at their peak.  Prolonged use of steroid eye 
drops outside of the time when there is MMAF exposure is not recommended, as they may cause 
other side effects and prevent the healing process.
Table 7:  Eye Drop Recommended Dosing Regimen
All subjects will start on Level 3 eye drop regimen.  The choice of specific prophylactic eye drop 
formulation is at the Investigators discretion.
LEVEL
PRIMARY CHOICE
ALTERNATIVE CHOICES
DOSE SCHEDULE
Level 1
Artificial Tears
(non-steroid)
Dexpanthenol
Visine
Thera Tears
Refresh
Systane
1 – 2 drops (gtts) in each eye (OU) 
TID for 7 days, starting 48 hours 
before each infusion
Level 2
0.12% prednisolone
acetate suspension
0.1% fluorometholone
1% rimexolone suspension
0.25% desonide solution
Medrysone
0.2% Ioteprednol
Hydrocortisone sodium 
phosphate
1 – 2 drops (gtts) in each eye (OU) 
TID** for 7 days, starting 48 hours 
before each infusion
Level 3
(Initial
Strategy^)
1% prednisolone
acetate suspension*
0.1% dexamethasone 
phosphate solution
0.5% Ioteprednol etabonate
Dexamethasone sodium 
phosphate
Betamethasone
1 – 2 drops (gtts) in each eye (OU) 
TID** for 7 days, starting 48 hours 
before each infusion
Level 4
0.05% difluprednate 
emulsion
(if locally available)
1 – 2 drops (gtts) in each eye (OU) 
TID** for 7 days, starting 48 hours 
before each infusion
*
1% prednisolone is the preferred steroid for Level 3.  TID = three times daily.
**
Dosing more frequently than TID is allowed at investigator discretion.
^
Level 3 is the starting level for all subjects.




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
General or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the Investigator

Subject become pregnant while on study
Subjects unable to continue either TMZ or ABT-414/placebo due to excessive drug-specific 
toxicity will be allowed to continue therapy with the other, tolerated therapy components until 
one of the other criteria above is met.
Subjects discontinuing therapy in the absence of progression should not receive any other cancer 
treatment before their disease progresses, unless this is clearly not in the interest of the subject.
ABT-414 treatment may be continued at the investigator's discretion if for any reason there is 
uncertainty about whether true disease progression has occurred.  As anecdotal cases of drug-
related pseudoprogression have been reported, which were associated with both initial clinical 
and radiological deterioration and appeared to have a different temporal course and 
characteristics to traditional radiotherapy-related pseudoprogression, investigators may consider 
biopsy prior to study drug discontinuation.  If, after treatment discontinuation, there is additional 
clinical information leading the investigator to conclude that the reason for discontinuation is no 
longer valid, the subject may resume study treatment as long as no other chemotherapy, 
radiotherapy, immunotherapy, NovoTTF, or other treatment with antineoplastic intent has been 
received, with the exception of surgical intervention that yields histology not demonstrative of 
tumor progression.
After progression, the treatment will be left to the discretion of the Investigator.  Any anti-cancer 
therapy other than the study drug will not be considered as part of the protocol treatment.  
However, treatments will be recorded.
The protocol or any portion of the protocol may also be discontinued or placed on hold by 
AbbVie due to unacceptable toxicity events, inadequate drug supply, or other reasons after the 
study sites have been notified in writing.
If subject withdraws consent, the type of withdrawal should be specifically indicated (further 
treatment with TMZ, ABT-414/placebo, any follow up for progression, or any follow-up of 
toxicity, or any follow up for survival).  In any case, data collected until the date of withdrawal 
will remain available for study analysis.


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5.7
Integral Assay/Biomarker
EGFR Amplification Testing
Subjects must consent to provide tumor tissue, a portion of which will be used to assess EGFR
amplification status, MGMT promoter methylation, and EGFRvIII.  Only subjects with tumors 
that demonstrated EGFR gene amplification by centralized testing using the study designated 
EGFR FISH assay as well as sufficient tissue for MGMT testing will be eligible for enrollment.  
Tissue should be prepared and shipped to central lab as described in the study specific laboratory 
manual.  Sites will be provided with EGFR amplification results.
EGFRvIII Mutation Testing
Subjects tumors will be assessed for EGFRvIII mutation status by centralized testing using a 
designated RT-PCR assay.  EGFRvIII testing will be performed at the same time as EGFR
amplification testing to reduce delay and will be used to determine stratification for subject 
randomization.  Tissue should be prepared and shipped to central lab as described in the study 
specific laboratory manual.  Study sites will be provided with EGFRvIII results.
MGMT Testing
Subjects tumors will be assessed for MGMT methylation status by centralized testing using a 
PCR assay.  MGMT methylation status will be assessed in parallel with EGFR amplification 
testing to reduce delay and will be used to determine stratification for subject randomization.  
Tissue should be prepared and shipped to central lab as described in the study specific laboratory 
manual.  Study sites will be provided with MGMT results.
If the subject has a previously available valid result from an approved vendor such as LabCorp, 
Laboratory Corporation of America, or Covance which use the same central assay (or in limited 
cases local MGMT testing performed for clinical or research purposes if, upon review of the local 
MGMT testing methodology, approval is granted by RTOG or AbbVie), then those MGMT
results will be accepted for eligibility and stratification in this study.  If the MGMT results tested 
as part of this study (central results) are or become available prior to randomization, then the 
central results will be used for stratification UNLESS the central results obtained are 
"insufficient tissue," indeterminate, or invalid, in which case the valid result from the approved 
non-central MGMT assay will be used for stratification.


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Other
Remaining tissue, serum, plasma and whole blood will be retained to conduct exploratory
research to investigate biomarkers where allowed by local regulations.  If local regulations do 
not allow for tissue shipment or storage, the tissue will be returned or destroyed immediately 
after eligibility testing.  Types of biomarkers analyzed may include (but are not limited to):  
nucleic acids, proteins, transcriptome profile, or metabolites.  Evaluation may include 
biomarkers related to pathway(s) targeted by drug, those believed to be related to the disease or 
to drug response.  The samples may be analyzed as part of a multi-study assessment of factors 
involved in the response to therapy or the disease state.  The information learned from these 
collected samples may be used to investigate factors influencing response to treatment, scientific 
questions related to cancer, and/or in the development of new therapies and diagnostic tests.  The 
results of exploratory biomarker testing may not be included with the study summary.
AbbVie (or people or companies working with AbbVie) will store and analyze the samples in a 
secure space with adequate measures to protect confidentiality.  The samples will be retained for 
analysis while research on ABT-414, or drugs of this class, or GBM (or related oncology 
diseases), continues up to, but no longer than, 20 years from the end of the study, or per local 
requirements.
Pharmacogenetic Testing
DNA samples may be sequenced and data analyzed for genetic factors contributing to the disease 
or to the subject's response to ABT-414, or other study treatment in terms of pharmacokinetics, 
efficacy, tolerability, and safety.  Such genetic factors may include genes for drug metabolizing 
enzymes, drug transport proteins, genes within the target pathway, genes believed to be related to 
the disease or to drug response.  Some genes currently insufficiently characterized or unknown 
may be understood to be important at the time of analysis.  The samples may be analyzed as part 
of a multi-study assessment of genetic factors involved in the response to ABT-414, drugs of this 
class, or the disease state.  The samples may also be used for the development of diagnostic tests 
related to ABT-414, drugs of this class, or the disease state.  The results of pharmacogenetic 
analyses may not be reported with the study summary.
5.7.1
Availability of Results
Sites will be provided with EGFR amplification, EGFRvIII, and MGMT results, but not other 
pharmacodynamics, pharmacogenetic, or exploratory results.


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5.8
General Concomitant Medication and Supportive Care Guidelines
Any medication or vaccine (including over-the-counter, prescription medicines, vitamins and/or 
herbal supplements) that the subject is receiving at the time of enrollment, receives during the 
study, and continuing for 49 days following the last dose of study drug must be recorded in 
source documents and electronic case report forms (eCRFs).  The reason for use, date(s) of 
administration (e.g., start, ongoing, and end date), dosage information, including dose and 
frequency must be entered into the database.
Non-pharmacologic supportive care measures for ocular toxicities (e.g., use of bandage contact 
lenses, punctal plugs, sunglasses, etc.) that the subject is receiving at the time of enrollment, 
receives during the study, and continuing for 49 days following the last dose of study drug must 
be recorded in source documents and electronic case report forms (eCRFs), including the reason 
for use and date(s) of administration (e.g., start, ongoing, and end date), must be entered into the 
database.
Both corticosteroid therapy and continuous TMZ therapy induce lymphocytopenia.  Subjects 
receiving either of these drugs or both concomitantly are at an increased risk for opportunistic 
infections.  Therefore, a prophylaxis against Pneumocystis (jirovecii) pneumonia (PCP) for all 
subjects receiving TMZ during radiation therapy such as trimethoprim-sulfamethoxazole 
(Bactrim forte®, Bactrim DS®), monthly pentamidine inhalations, dapsone, or as required by 
local regulation guidelines for TMZ administration.  Prophylaxis during adjuvant TMZ is at the 
discretion of the Investigator per the local prescribing information for TMZ.
Best supportive care and treatment should be given as appropriate to each subject (antibiotics, 
transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, etc.).
5.8.1
Permitted Supportive/Ancillary Care and Concomitant Medications
Antiemetic prophylaxis with a 5-HT3 antagonist is strongly recommended and should be 
administered 30 to 60 minutes before TMZ administration for at least the first few doses during 
the Chemoradiation Phase and all doses of the Adjuvant Phase.
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the treating Investigator.  The locally approved product label, institutional 
guidelines, local practice, or applicable Summary of Product Characteristics (SmPC) should be 
referenced for any concomitant therapy guidelines.


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5.8.2
Prohibited Therapies

Growth factors and transfusions are permissible for routine supportive care in treatment 
of patients with chemotherapy per local prescribing regulations and Investigator 
discretion.  However, they are not permitted to induce elevations in neutrophil, 
hemoglobin, hematocrit or platelet count for the purposes of:  (1) protocol eligibility; or 
(2) administration of TMZ on the scheduled dosing interval without delay when a delay 
would otherwise be required by cytopenias; (3) allowing treatment with TMZ at a higher 
dose; or (4) avoiding interruption of the treatment during concomitant radiotherapy that 
would otherwise be required for cytopenias.

Dacarbazine hypersensitivity is a contraindication for TMZ administration.  No other 
investigational anti-neoplastic drugs will be allowed during the study.  Subjects who 
come off study after progression of disease may be allowed to use other investigational 
drugs.  Every effort should be made to document the use of post-progression therapies.

Use of other types of surgery, chemotherapy, immunotherapy or biologic therapy during 
study treatment (prior to disease progression) as an anticancer therapy is prohibited.  Any 
medication or vaccine (including over-the-counter, prescription medicines, vitamins 
and/or herbal supplements) used for antineoplastic intent is prohibited.  Further, 
additional stereotactic boost radiotherapy during study treatment (prior to disease 
progression) is not allowed. If any of these treatments are required, the subject will not 
receive further therapy with TMZ and ABT-414 or placebo according to this protocol; 
however, the subject will continue to be followed for disease progression and survival 
information.  All therapy after study treatment discontinuation is at the Investigator's 
discretion, but should be recorded in the eCRF.
5.8.3
Unblinding Procedure
AbbVie, the RTOG, the investigator, the study site personnel and subject will remain blinded to 
each subject's treatment with ABT-414 or placebo throughout the course of the study, except in 
two situations:

rare cases where the sponsor has determined that unblinding is necessary for subject 
safety, or

after unequivocal disease progression has been documented, where knowledge of the 
study drug treatment assignment is necessary to determine the subject's eligibility for a 
subsequent clinical trial or is necessary, in the judgment of the investigator, for 
appropriate management of the subject.


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The IRT will provide access to blinded subject therapy information for an individual subject in 
the case of a medical emergency or if necessary, after confirmed disease progression, to 
determine eligibility for a subsequent clinical trial or to appropriately manage the subject.  In the 
event the investigator believes that knowledge of study treatment is required, every effort must 
be made to contact the Neuro-Medical Oncology Chair or the AbbVie Medical Monitor (or 
qualified designee) listed at the top of the study protocol prior to contacting the IRT for 
unblinding (as long as subject safety is not compromised).  In the case of unblinding for reasons 
other than safety (e.g., to determine eligibility for another clinical trial), eCRFs confirming the 
date and criteria for establishing disease progression must be completed prior to performing 
unblinding.  The date and reason that the blind was broken must be conveyed to AbbVie and 
recorded on the appropriate eCRF.  In the event the AbbVie Clinical Project Team should break 
the blind, the reason will be documented in a note to study file and on the appropriate eCRF.
5.9
Method of Assigning Subjects to Treatment Groups
At the Screening Visit, all subjects will be assigned a unique subject number through the use of 
IRT.  For subjects who do not meet the study selection criteria, the site personnel must contact 
the IRT system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number, assigned at the Screening Visit, 
throughout the study. For enrollment of eligible subjects into the study, the study site will utilize 
the IRT system in order to receive unique study drug kit numbers and a unique randomization 
number.  Subjects will be randomized to either Arm A or Arm B in a 1:1 ratio.  The 
randomization will be stratified, as described in Section 3.1.  The randomization number will be 
used only by AbbVie for loading the treatment assignments into the database.  The study drug kit 
numbers and randomization numbers will be assigned according to schedules 
computer-generated before the start of the study by the AbbVie Statistics Department.  Upon 
receipt of study drug, the study site will acknowledge receipt in the IRT system.
5.10
Treatment Compliance
The Investigator or his/her designated and qualified representatives will administer study drug 
only to subjects enrolled in the study in accordance with this Protocol M13-813.  The study drug 
must not be used for reasons other than that described in the protocol.  Subjects will be 
supervised at the time of study drug administration.


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5.11
Drug Accountability
The Investigator or designee will verify that study drug supplies are received intact at the 
appropriate temperature and in the correct amounts.  This will be documented by signing and 
dating the Proof of Receipt or similar document or via direct recording in the IRT.  An accurate 
(running) inventory of study drug will be kept by the site, and will include the lot number, Proof 
of Receipt number(s), kit numbers, the number of vials dispensed, subject initials, initials of 
person who administered the drug and the date study drug was administered for each subject.  An 
overall accountability of the study drug will be performed and verified by AbbVie monitor 
throughout the study and at the study site closeout visit.
After verification of drug accountability, used vials must be destroyed at the site according to 
local regulations governing hazardous waste.  Disposal of used study supplies must be 
documented in IRT.  All study drug must be inventoried, accounted for, and returned to AbbVie 
or destroyed per instructions from AbbVie and according to local regulations.  A copy of the 
Return Shipment Form, in accordance with instructions provided by the AbbVie monitor, will 
also be included in the shipment.
Labels must remain attached to the containers.  If pre-arranged between AbbVie and the site, 
destruction of the study drug may be performed at the site.
5.12
Discussion and Justification of Study Design
5.12.1
Discussion of Study Design and Choice of Control Groups
The background treatment regimen for the current study—6 weeks of concomitant radiation and 
TMZ treatment, followed by 6 cycles of adjuvant TMZ therapy (dosed on Days 1 – 5 of each 28-
day cycle) is currently an established standard-of-care treatment for newly diagnosed GBM.25  
Consistent with other recent or ongoing trials of experimental therapies (bevacizumab, Opdivo, 
and NovoTTF) in this indication, ABT-414 will be prescribed as add-on treatment to the 
RT/TMZ standard of care.  The study will be placebo-controlled and double-blind, which is the 
gold standard for assessing efficacy.  The original design was a seamless Phase 2b/3 that allowed 
early termination of the study and reduced unnecessary subject exposures to an ineffective 
treatment if the Phase 2b results demonstrated futility.  However, rapid acceleration in the 
enrollment rate of INTELLANCE-1 suggested that the Phase 3 portion of the study would likely 
be finished enrolling before results of the planned PFS-based futility analysis would be available.  
In addition, recent information gathered from the INTELLANCE-2 trial, suggesting an OS 
benefit of the ABT-414/TMZ combination in recurrent GBM and a safety profile consistent with 


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previous Phase 1 results, provide increased confidence that the addition of ABT-414 to standard 
frontline therapy would demonstrate a statistically significant and clinically relevant benefit for 
OS, as well as an acceptable safety profile, in newly diagnosed subjects in the INTELLANCE-1 
study.  For these reasons, the study design has been modified to eliminate the PFS-based 
Phase 2b interim futility analysis and to complete the study as a Phase 3 study based on the gold 
standard efficacy endpoint of OS.
5.12.2
Appropriateness of Measurements
OS, the primary efficacy endpoint for the study, is widely accepted as the most clinically 
relevant endpoint for oncology trials.  PFS is a clinically relevant endpoint but does not always 
correlate with OS.  PFS will be studied as a secondary endpoint.  Standard pharmacokinetic, 
statistical, clinical and laboratory procedures will be utilized in this study.
5.12.3
Suitability of Subject Population
The study population is restricted to subjects with newly diagnosed GBM whose tumors exhibit 
EGFR amplification (including that subset of the population with EGFRvIII mutation).  Selective 
efficacy for the EGFR-amplified population is consistent with the understood mechanism of 
ABT-414, as the antibody selectively targets EGFR-amplified tumors, and is strongly supported 
by clinical data from the ongoing Phase 1 Study M12-356.  As of April 2015, there have been 
6 subjects with confirmed objective responses to ABT-414, all of whom have tested positive for 
EGFR amplification.  There have been no subjects who have tested negative for EGFR
amplification with a confirmed objective response.
5.12.4
Selection of Doses in the Study
Radiotherapy and TMZ Treatment
Radiation and drug doses for the background treatment in this study, consisting of 6 weeks of 
concomitant radiotherapy (~60 Gy over 30 fractions) and TMZ (at 75 mg/m2 daily), followed by 
6 cycles of adjuvant TMZ (at 150 – 200 mg/m2 for 5 days of each 28-day cycle) is the 
established standard of care for treatment of newly diagnosed GBM.25  TMZ will be prescribed 
as per local guidelines.
ABT-414 Dose Selection
For the Chemoradiation Phase, the recommended ABT-414 dose of 2.0 mg/kg infused once 
every 2 weeks was selected based on results from Arm A of Study M12-356, in which all 
subjects received ABT-414 combined with concomitant radiation and TMZ treatment.  During 


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dose escalation at this level, no Grade 3 or higher toxicities were observed.  Higher doses were 
associated with at least 1 dose-limiting toxicity event and were not well tolerated.  Compared to 
dosing with TMZ alone, ABT-414 appears to be better tolerated when given with concomitant 
RT and TMZ.
For the Adjuvant Phase, the recommended ABT-414 dose of 1.25 mg/kg infused once every 
2 weeks was selected based on results from Arm B of Study M12-356, in which all subjects 
received ABT-414 along with maintenance TMZ.  During dose escalation at this level (and with 
steroid prophylaxis) during maintenance TMZ cycles, 2/10 subjects had ocular DLTs, but only 
1 was attributable to ABT-414.  Since the 1.25 mg/kg dose was chosen for an expanded safety 
cohort added to that study, this dose level has been generally well tolerated, only approximately 
20% of subjects developing ocular adverse events (Grade 3 or greater) requiring a dose 
reduction.
As previously mentioned, the ocular manifestations of microcystic keratopathy to date have been 
reversible after withholding ABT-414, usually after 4 to 6 weeks.  Subjects who restart ABT-414 
at lower doses (~1.0 mg/kg) have less severe toxicities and can generally tolerate further therapy.
Prophylactic Eye Drop Dosing Strategy
The strategy for dosing prophylactic eye drops to manage the eye toxicity associated with 
ABT-414 in this study, which starts all subjects (including those assigned to placebo instead of 
ABT-414) on moderate potency ocular steroid drops, was designed to help preserve the study 
blind needed to conduct a successful controlled study while minimizing the risk associated with 
prolonged use of ocular steroids.  Placebo subjects unblinded to their treatment assignment in 
this study population are expected to have unacceptably high dropout rates, leading to systematic 
bias and increased risk of a failed study due to a loss of statistical power.  A recent trial 
evaluating the efficacy of rindopepimut (ACT III trial) in the same newly diagnosed GBM 
population and a similar treatment paradigm—with rindopepimut added to standard-of-care 
therapy with RT/TMZ—was originally designed as an open-label study with a standard-of-care 
treatment arm as a control group.  However, due to high attrition rates for the subjects assigned 
to the standard-of-care treatment arm, the study had to be redesigned as a single-arm trial without 
a control group.26
During Phase 1 studies, use of prophylactic steroid eye drops (for 7 days of each 14-day dosing 
interval) was deemed necessary for all subjects taking ABT-414 in order to minimize the severity 
of ocular adverse events related to microcystic keratopathy, the adverse effect characteristic of 
ABT-414.  To avoid systematic unblinding in this study, placebo subjects must receive eye drops 


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matching those given to subjects receiving ABT-414.  Using blinded placebo eye drops in this 
study was considered but found to be infeasible due to differences in the packaging and visual 
appearance of the eye drops themselves between the ocular steroid suspensions/solutions to be 
used for prophylaxis and available saline or lubricant formulations.  Therefore, all subjects in this 
study will receive moderate potency steroid eye drops (e.g., prednisolone acetate 1% suspension) 
with the first two doses of ABT-414/placebo.  Targeted ophthalmologic examinations, to assess 
and grade any objective findings characteristic of ABT-414-mediated corneal toxicity, will be 
performed regularly, starting no later than after the first two infusions ABT-414/placebo, and the 
steroid potency of the eye drops for subsequent doses will be adjusted based on these objective 
findings.  Subjects who have no evidence of microcystic keratopathy on ophthalmic examination 
are required to step down to a Level 2, low-potency steroid safer for long-term use, or in certain 
cases, to a Level 1 non-steroid solution.
Because the appearance of microcystic keratopathy seen with ABT-414 is a relatively unique and 
specific finding unlikely to occur spontaneously or with other drugs used for GBM, it is highly 
unlikely that a placebo-assigned subject would continue on a moderate-potency steroid for a 
prolonged period.
In addition to the step-down in steroid potency required for subjects without objective findings of 
microcystic keratopathy, risks related to prolonged steroid use are further reduced by a) the fact 
that subjects are off steroid drops for 7 days of each 14-day dosing interval, and b) the 
requirement for scheduled ophthalmologic examinations (including assessments for 
steroid-related effects such as increased intraocular pressure/glaucoma or cataract formation) at 
least every 4 weeks during the Chemoradiation Phase and first 2 cycles of the Adjuvant Phase, 
followed by every 8 weeks thereafter, or more frequently if indicated by eye symptoms.  Based 
on this dosing schedule and frequent safety monitoring for potential steroid-related effects, 
long-term term use of Level 2 (low-potency steroid) eye drops constitutes a minimal safety risk 
to subjects.  Maintaining subjects on low potency steroid eye drops is expected to improve study 
retention, because receiving active eye drops will support the subjects' belief that they may have 
been assigned to ABT-414.  (While not recommended, subjects who have no evidence of 
microcystic keratopathy may be required, on an individual site-level basis, to step down to a 
Level 1, non-steroid eye drop if that site's IRB/EC or regulatory authority has determined that 
long-term use of ocular steroids at any potency is unacceptable in such subjects.)


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6.0
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
6.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study treatment at any time.  In addition, the 
Investigator may discontinue a subject from the study at any time if the Investigator considers it 
necessary for any reason, including the occurrence of an adverse event or noncompliance with 
the protocol.
Subjects who withdraw consent to continue study therapy will be encouraged to continue 
participation with other study procedures and assessment unless unwilling to do so.  Clinical 
assessment needed for the 49-Day safety assessment after ABT-414 discontinuation and to 
determine the occurrence and timing of disease progression (for PFS) and/or death (for OS) 
should be prioritized.  Subject may withdraw from the treatment without withdrawing consent 
for follow up of PFS, OS or drug toxicities.
A subject will be withdrawn from the study treatment if any of the following occur:
1)
The subject or subject's legally acceptable representative withdraws consent.

In the event a subject withdraws from the study, stored biomarker samples will be 
retained unless the subject also withdraws consent for use of unused stored biomarker 
samples.  If the subject changes his/her consent, and the samples have already been 
tested, those results will still remain part of the overall research data.
If a subject withdraws consent or discontinues from the main study, their optional 
sub-study samples will continue to be stored and analyzed until sub-study consent is 
withdrawn as well.

Unless the withdrawal of consent specifically withdraws consent from follow up of OS, 
subjects will continue to be followed for OS, and OS will be recorded.  The opt out of OS 
follow-up must be clearly documented.  Of note, OS may still be obtainable from a query 
of publically available information unless prohibited by local regulations.
2)
The subject experiences radiographic disease progression per RANO (Appendix I).  
Progression is defined by any of the following:

at least 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (compared with baseline if no decrease) on stable or increasing doses of 
corticosteroids;

a significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy, 
not due to comorbid events;

the appearance of any new lesions;

clear progression of nonmeasurable lesions;


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
definite clinical deterioration not attributable to other causes apart from the tumor, or to 
decrease in corticosteroid dose;

Failure to return for evaluation as a result of death or deteriorating condition.
The phenomenon of pseudoprogression should be considered when determining if there is 
disease progression, particularly during the first 3 months after radiotherapy.  
Pseudoprogression refers to the occurrence of "early delayed radiation reactions" that occur 
usually within the first 3 months post radiation treatment.  These transient adverse signs and 
symptoms may spontaneously improve without therapy or with supportive care such as 
corticosteroids.  Thus, care should be taken in making the diagnosis of tumor progression or 
recurrence (Appendix I).
Clinical Progression and Other Factors
Note that increase in corticosteroid dose alone, in the absence of clinical deterioration related to 
tumor, will not be used as a determinant of progression.  Subjects with stable imaging studies, 
whose corticosteroid dose was increased for reasons other than clinical deterioration related to 
tumor, do not qualify for stable disease or progression.  Subjects should be observed closely.  If 
their corticosteroid dose can be reduced back to baseline, they will be considered as having 
stable disease; if further clinical deterioration related to tumor becomes apparent, they will be 
considered to have progression.  The date of progression should be the first time point at which 
corticosteroid increase was necessary.
The definition of clinical deterioration is left to the discretion of the Investigator, but it is 
recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS of at least 
20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration unless attributable to comorbid events or changes in 
corticosteroid dose.
Subjects with nonmeasurable enhancing disease whose lesions have significantly increased in 
size and become measurable (minimal bidirectional diameter of at least 10 mm and visible on at 
least two axial slices that are preferably, at most, 5 mm apart with 0-mm skip) will also be 
considered to have experienced progression.  The transition from a nonmeasurable lesion to a 
measurable lesion resulting in progression can theoretically occur with relatively small increases 
in tumor size (e.g., a 9 × 9 mm lesion [nonmeasurable] increasing to a 10 × 11 mm lesion 
[measurable]).  Ideally, the change should be significant (at least 5 mm increase in maximal 
diameter or at least 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions).


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In general, if there is doubt about whether the lesion has progressed, continued treatment and 
close follow-up evaluation will help clarify whether there is true progression.  If there is 
uncertainty regarding whether there is progression, the subject may continue on treatment and 
remain under close observation (e.g., evaluated at 4-week intervals).  If subsequent evaluations 
suggest that the subject is in fact experiencing progression, then the date of progression should 
be the time point at which the issue was first raised.
Note:  During the first 12 weeks after completing chemoradiation:  progression can only be 
defined using diagnostic imaging if there is new enhancement outside of the radiation field 
(beyond the high-dose region or 80% isodose line) or if there is unequivocal evidence of viable 
tumor on histopathologic sampling (e.g., solid tumor areas [i.e., more than 70% tumor cell nuclei 
in areas], high or progressive increase in MIB-1 proliferation index compared with prior biopsy, 
or evidence for histologic progression or increased anaplasia in tumor).  Note:  Given the 
difficulty of differentiating true progression from pseudoprogression, clinical decline alone, in 
the absence of radiographic or histologic confirmation of progression, will not be sufficient for 
definition of progressive disease in the first 12 weeks after completion of concurrent 
chemoradiotherapy.  In addition, subjects who remain clinically stable and/or are suspected to 
have pseudoprogression based on metabolic or vascular imaging should continue with their 
current therapy (Appendix I).
3)
The subject experiences unacceptable toxicity with ABT-414 in combination with TMZ.
4)
The subject requires a dose modification for ABT-414 below 0.5 mg/kg.
5)
The subject requires other anti-cancer treatment, such as surgery or alternate anti-cancer 
agents, during the study period.
6)
The subject experiences a ≥ Grade 3 allergic reaction.
7)
Significant noncompliance with the protocol that could impact subject safety or data 
integrity.
8)
The Investigator believes it is in the best interest of the subject.
9)
The subject has a positive pregnancy test result.
If, after treatment discontinuation, there is additional clinical information leading the Investigator 
to conclude that the reason for discontinuation is no longer valid, the subject may resume study 
treatment as long as no other chemotherapy, radiotherapy, immunotherapy, NovoTTF, or other 
treatment with antineoplastic intent has been received, with the exception of surgical intervention 
that yields histology not demonstrative of tumor progression.  


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6.1.1
Discontinuation of Temozolomide
Subjects should discontinue TMZ if any of the criteria for discontinuation, as described in the 
guidelines provided in local approved regulatory prescribing information are met.
6.1.2
Discontinuation of ABT-414 or Placebo
Study drug (ABT-414/placebo) will be continued as discussed above in Section 5.4 unless 
toxicities prohibit further use.  Severe allergic reactions (Grade 3 or Grade 4) require the 
immediate interruption of ABT-414/placebo and discontinuation from the study.
6.1.3
Discontinuation of Radiation
Subjects should discontinue radiation if any of the criteria for discontinuation, as described in the 
institutional guidelines or local approved regulatory prescribing information are met.
6.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable cause, 
after providing written notice to AbbVie in advance of the intended termination.  Advance notice 
is not required by either party if the study is stopped due to safety concerns.  If AbbVie 
terminates the study for safety reasons, AbbVie will immediately notify the Investigator by 
telephone and subsequently provide written instructions for study termination.
If the study is prematurely discontinued to due safety or futility reasons, study drug will no 
longer be provided once the entire study is discontinued.  When possible, AbbVie and the 
Investigator will develop a plan to provide ABT-414/placebo as required by local regulations.


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7.0
ADVERSE EVENTS
7.1
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to 
the physical characteristics, identity, quality, purity, potency, durability, reliability, safety, 
effectiveness, or performance of a product after it is released for distribution.  The investigational 
product in this trial contains biologic compound(s).
7.2
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of adverse events 
(AE) on a routine basis throughout the study.  The Investigator will assess and record any 
adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, 
severity, time course (end date, ongoing, intermittent), relationship of the adverse event to study 
drug, and any action(s) taken.  For serious adverse events considered as having "no reasonable 
possibility" of being associated with study drug, the Investigator will provide an Other cause of 
the event.  For adverse events to be considered intermittent, the events must be of similar nature 
and severity.  Adverse events, whether in response to a query, observed by site personnel, or 
reported spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
Adverse event reporting is required for all protocol treatment modalities:  ABT-414/placebo, 
TMZ, and radiation therapy.
The NCI CTCAE v.4 will be used for adverse event reporting/grading of event severity.
All ophthalmology exam reports will be reviewed by the Investigator (or medically qualified 
delegate).  With the exception of the corneal findings described below, decisions on which
findings from ophthalmologic examinations, if any, will be reported as adverse events, as well as 
the grading of any such events, will be made according to the Investigator's judgment.  These 
events will be graded according to NCI CTCAE v.427 criteria, and not according to the grading 
system used for the ophthalmology examinations.
To ensure consistent reporting of the corneal findings characteristic of ABT-414 that are 
not well described by the MedDRA preferred terms or CTCAE grading, any abnormal 
finding on either the "Microcysts/Edema" or "Superficial Punctate Keratopathy" field of 


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the ABT-414-TOE must be recorded as an adverse event of "microcystic keratopathy" 
with severity grading as shown in Table 5 (see Section 4.2 for additional details).
7.2.1
Definitions
7.2.1.1
Adverse Event
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event is 
considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as 
from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a 
pre-existing condition or illness is considered an adverse event.  Worsening in severity of a 
reported adverse event should be reported as a new adverse event.  Laboratory abnormalities and 
changes in vital signs are considered to be adverse events only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, meet protocol specific criteria 
(regarding toxicity management, (Section 8)) or if the Investigator considers them to be adverse 
events.  When Grade 3 or higher elevations in glucose, cholesterol or triglycerides is reported 
under non-fasting conditions, the Investigator may choose not to report the abnormality as an 
adverse event until it has been confirmed by repeated testing under fasting conditions.  Repeat 
testing for such confirmation may be done at the next scheduled laboratory visit or earlier.  An 
elective surgery/procedure scheduled to occur during the study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure is being 
done will be considered an adverse event.
7.2.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a serious 
adverse event (SAE) within 24 hours of the Investigator being made aware of the serious adverse 
event:
Death of Subject
An event that results in the death of a subject.


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Life-Threatening
An event that, in the opinion of the Investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay. This 
does not include an emergency room visit or admission to an 
outpatient facility, hospitalization for respite care, or 
hospitalization due solely to progression of the underlying 
cancer.  This does not include hospitalization for elective or 
diagnostic procedures.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
7.2.1.3
Adverse Events Expected Due to Study Related Endpoints
7.2.1.3.1
Deaths
For this study, mortality is an efficacy endpoint.  Deaths that occur during the protocol specified 
adverse event reporting period (Section 7.3) that are more likely related to disease progression 
will therefore be an expected adverse event and will not be subject to expedited reporting.


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Death should be considered an outcome and not a distinct event.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF.  Generally, only one such event should be reported.  The term "sudden 
death" should only be used for the occurrence of an abrupt and unexpected death due to 
presumed cardiac causes in a subject with or without preexisting heart disease, within 1 hour of 
the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the 
subject was last seen alive and stable.   If the cause of death is unknown and cannot be 
ascertained at the time of reporting, "unexplained death" should be recorded on the Adverse 
Event eCRF.  If the cause of death later becomes available (e.g., after autopsy), "unexplained 
death" should be replaced by the established cause of death.
7.2.1.3.2
Expected Adverse Events Due to Glioblastoma
Adverse Events that may be expected due to the subject's underlying glioblastoma or its standard 
therapy include headache, seizure, neutropenia and progression of underlying GBM, and 
progression of GBM leading to death, etc.  These events are considered expected AEs for this 
study regardless of ABT-414 treatment.  As such, individual subject cases of these events, when 
considered serious, will not be reported in expedited fashion as individual cases, but will be 
evaluated during aggregate reviews by the IDMC.  Appendix III includes a complete list of the 
adverse events that will be considered as expected for reporting purposes, based on events 
commonly related to underlying glioblastoma or complications from glioblastoma standard 
therapy.
7.3
Adverse Event Severity
The Investigator will rate the severity of each adverse event according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0)27
For adverse events not captured by the Common Terminology Criteria, the following should be 
used:


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Grade 1
The adverse event is transient and easily tolerated by the subject 
(mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating (severe).
Grade 4
Life threatening; urgent intervention.
Grade 5
The adverse event resulted in death of the subject (severe).
Relationship to Protocol Treatment
The Investigator will use the following definitions to assess the relationship of the adverse event 
to the use of protocol treatment, with separate assessments for each component of therapy 
(ABT-414/placebo, TMZ and radiation therapy):
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there 
is insufficient evidence (information) to suggest a causal relationship.
Reasonable possibility is defined such that the specific treatment (ABT-414/placebo, TMZ, or 
radiation therapy) is more likely to be the cause of the event than any other reason, whereas no 
reasonable possibility is defined as the Other cause of the event is more likely.  For causality 
assessments, events assessed as having a reasonable possibility of being related to protocol 
treatment will be considered "associated."  Events assessed as having no reasonable possibility of 
being related to protocol treatment will be considered "not associated."  In addition, when the 
Investigator has not reported a causality or deemed it not assessable, AbbVie will consider the 
event associated.
If an Investigator's opinion of no reasonable possibility of being related to protocol treatment is 
given, an Other cause of event must be provided by the Investigator for the serious adverse 
event.
7.4
Adverse Event Collection Period
All protocol related serious adverse events and non-serious adverse events must be reported as 
follows:


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
From time the study-specific informed consent is signed, but prior to the initial 
administration of component therapy, will only be collected if they are considered by the 
Investigator to be causally related to the study-required procedures.

From first day of component therapy administration until 49 days after last administered 
dose of ABT-414.
Adverse event information will be collected as shown in Figure 1.
Figure 1.
Adverse Event Collection
Protocol Related 
Serious and
Non-Serious AEs*
Serious and Non-Serious AEs
Elicited and/or Spontaneously Reported




Consent 
Signed
RT, TMZ, 
ABT-414
Start
ABT-414 
Stopped
49 Days After 
ABT-414 
Stopped
*
Only if considered by the Investigator to be causally related to study required procedures.
7.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with protocol treatment or not, the 
Investigator will notify  AbbVie Clinical Pharmacovigilance within 24 of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the electronic 
data capture (EDC) system.  Serious adverse events that occur prior to the site having access to 
the EDC or EDC is not operable should complete the SAE Non-CRF paper forms and be faxed 
to  AbbVie Clinical Pharmacovigilance within 24 hours of being made aware of the serious 
adverse event.
Email to
FAX to: 


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For serious adverse event concerns, contact the AbbVie Oncology Safety Team at:
Oncology Safety Management 
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Contact Information:
Safety Line:
Email:
Fax:
For any subject safety concerns, please contact the RTOG physician listed below:
For questions that need to be addressed by the study sponsor, please contact the AbbVie 
physician below:
Primary Clinical Monitor:
AbbVie
Telephone Contact Information:
Mobile:
Email:


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Primary Medical Monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Telephone Contact Information:
Office:
Mobile:
Fax:
Email:
In emergency situations involving study subjects when the primary Medical Monitor is not 
available by phone, please contact the 24-hour AbbVie Medical Escalation Hotline where your 
call will be re-directed to a designated backup Medical Monitor MD.
Phone:  
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) 
reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the European 
Union (EU) countries will be the most current version of the Investigator's Brochure for 
ABT-414 or Summary of Product Characteristics for TMZ.
Serious adverse events which are considered expected due to the underlying disease of GBM28 as 
described in Appendix III would not be expedited as individual safety case reports to regulatory 
authorities.
7.6
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue protocol therapy 
and must be discontinued from the study.  The Investigator must report the positive pregnancy 
test to the appropriate contact listed in protocol Section 7.4 within 1 working day of the site 
becoming aware of the pregnancy.
All subjects should be informed that contraceptive measures should be taken throughout the 
study and for 6 months after discontinuing study drug.  Information regarding a pregnancy 
occurrence in a study subject and the outcome of the pregnancy will be collected.  The 
Investigator must follow the pregnancy to completion and provide an update to AbbVie after 
delivery.


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Male subjects should be informed that contraceptive measures should be taken by their female 
partners.  If the subject's partner should become pregnant during the study, this should also be 
reported and data may be collected.  In the event of pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the partner 
must be obtained prior to the collection of any pregnancy-specific information and the pregnancy 
will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for either 
mother or infant, meeting any serious criteria including elective or spontaneous abortion, is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the site 
becoming aware of the event.


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8.0
TOXICITY MANAGEMENT AND DOSE MODIFICATIONS
For the purpose of medical management, all adverse events and laboratory abnormalities that 
occur during the study must be evaluated by the Investigator.  The table of clinical toxicity 
grades modified from the NCI CTCAE Version 4.0 (available on the CTEP home page 
http://ctep.cancer.gov) is to be used in the grading of adverse events and laboratory abnormalities 
that are reported as adverse events, each of which will be followed to satisfactory clinical 
resolution.
A drug-related toxicity is an adverse event or laboratory value outside of the reference range that 
is judged by the Investigator or AbbVie as having a reasonable possibility of being related to 
protocol treatment.  A toxicity is deemed "clinically significant" on the basis of the Investigator's 
medical judgment.
Dose reductions or delays should be made for the likely causative agent.  If one of the agents 
should be stopped for any reason other than disease progression, the subject can continue on the 
other single agent alone at the same dose and schedule.
8.1
ABT-414/Placebo Toxicity Management
Subjects will be closely monitored for treatment-related adverse events, especially allergic 
reactions, during all infusions.  For the initial ABT-414/placebo infusion, pre infusion vital signs 
will be taken and direct observation is required for the first 15 minutes of the infusion.  Also for 
the initial ABT-414/placebo infusion, subjects must remain at the site for monitoring for 
60 minutes post infusion.  For subsequent infusions, post-infusion monitoring is not required; 
however, pre-infusion vital signs should still be taken.  Longer observation periods and more 
frequent vital sign checks may be required in subjects who experience infusion reactions.
Institutional standards should be used to treat all allergic reactions.
Based upon results from the first clinical and preclinical safety pharmacology evaluation of 
ABT-414, experience with other inhibitors of EGFR, and experience with MMAF ADCs, 
potential toxicities may include fatigue, vomiting, thrombocytopenia, allergic reactions, rash, eye 
complaints, and liver function test abnormalities.
8.1.1
Dose Modifications for ABT-414/Placebo
For all observed toxicities, subjects should be assessed for inter-current illness or other causes
and treated as appropriate.


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Starting doses and suggested dose level reductions are shown in Table 9, and subsequent 
subsections discuss when dose reductions should be considered or are required.  More aggressive 
dose reductions are always allowed if the Investigator believes that it is in the best interest of the 
subject.
With the exception of ophthalmologic toxicities as described in Section 8.1.2 and hepatic 
laboratory abnormalities as described in Section 8.1.6, all dose reductions are permanent unless a 
toxicity initially attributed as potentially related to ABT-414/placebo is later re-attributed as not 
potentially related and discussed with the Neuro-Medical Oncology study chair, AbbVie Medical 
Monitor or their designee.
Table 9.  ABT-414/Placebo Dose Modification Table during Chemoradiation and Adjuvant 
Phase
Dose Level
Dose
Chemoradiation Phase
Adjuvant Phase
Starting Dose
2.0 mg/kg
1.25 mg/kg*
1st Reduction
1.5 mg/kg
1.0 mg/kg
2nd Reduction
1.0 mg/kg
0.75 mg/kg
3rd Reduction
-
0.5 mg/kg
-
Discontinue
*
If CTCAE Grade 3 eye toxicity is observed during the Chemoradiation Phase, then 1.0 mg/kg is recommended, but not 
required, as the starting dose for the Adjuvant Phase.
8.1.2
Ophthalmologic Toxicities
Microcystic keratopathy is a very common adverse effect of ABT-414, occurring in over 50% of 
subjects.  Key elements in the overall management of microcystic keratopathy include subject 
education, use of prophylactic eye drops to reduce severity, supportive care measures, and 
careful ophthalmological monitoring to identify microcystic changes or steroid-related adverse 
effects and guide supportive treatment.
8.1.2.1
Ophthalmologic Monitoring and Prophylactic Eye Drop Use
As described in Section 4.2, subjects will receive ophthalmological examinations at regular 
intervals throughout the study, and additional examinations may be done as needed.  The 
ABT-414-TOE examinations are intended to systematically identify and grade objective findings 
of ABT-414-related eye toxicity and to assess for adverse effects potentially related to ocular 
steroid use.


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Administration of prophylactic eye drops for 7 days is required with each administration of 
ABT-414/placebo, from 2 days prior until 4 days after drug infusion.  A description of the 
steroid-potency levels and dosing schedule for each, as well as considerations for adjusting 
prophylactic eye drop levels or frequency based on ophthalmologic findings, is described in 
Section 5.5.
Prophylactic and symptomatic use of cold compresses over the eyes and ophthalmologic 
vasoconstrictors around the time of ABT-414 infusions is allowed, as it may reduce drug uptake 
in the cornea.
8.1.2.2
Treatment of Ophthalmologic Toxicity Once Symptoms Occur
Supportive care measures (e.g., lubricating eye drops, therapeutic bandage contact lenses, 
punctal plugs, antibiotic drops, etc.) play a pivotal role in ABT-414 treatment, as they can 
provide considerable relief for symptoms of ABT-414-related eye toxicity, including 
photophobia, blurry vision and eye discomfort.  Therefore, supportive care measures 
should be used early and extensively to minimize the need for ABT-414 dose interruptions 
and dose reductions.
Once corneal microcysts have formed, there are no known therapies that can remove them from 
the cornea.  Thus, only therapies that can control symptoms and promote healing are indicated.  
Use of steroid eye drops outside the prescribed prophylactic period is allowed but may not be the 
best strategy, as it may inhibit the healing process.  Supportive care measures should be actively 
considered and fully utilized when symptoms of ABT-414-related eye toxicity occur, as they are 
the most effective way to manage eye symptoms and maximize ABT-414 dosing.
Use of supportive care measures should be individually tailored for each subject based on 
frequent monitoring by an ophthalmologist to inform the best treatment for the subject.  The 
choice and timing of supportive care measures is not restricted by the study protocol, and all 
choices are at the discretion of the study investigator in consultation with the ophthalmologist as 
needed.  Supportive measures can be used throughout the treatment cycle, including days on 
which prophylactic eye drops are used, and they may be initiated prior to the onset of symptoms 
at the discretion of the investigator.
Lubricating eye drops may be used liberally throughout treatment and are commonly prescribed 
prior to onset of eye symptoms.
Feedback from ophthalmologists with experience managing ABT-414 ocular toxicity suggest 
that use of therapeutic bandage contact lenses can have a major impact on improving eye 


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symptoms, including photophobia, blurred vision and various forms of eye discomfort, and thus 
minimize the need for ABT-414 dose interruptions and dose reductions.  Therefore, use of 
therapeutic bandage contact lenses should be strongly considered whenever toxicity suggesting 
the need for ABT-414 dose modification is present, and they may also be used for lower grade 
symptoms.
8.1.2.3
Discussions with Subjects
It is important that subjects understand this toxicity and the importance of following the 
recommendations for the prophylactic eye drops and supportive care measures, as well as the 
rapid reporting of their symptoms.  It is also important to let them know that at this time, in all of 
the subjects, symptoms have improved over time and there is no evidence to suggest that there is 
any permanent damage done to the cornea.  It does take some time, however, for symptoms to 
resolve and thus an immediate reversal of symptoms should not be promised.  At least 
3 – 4 weeks must take place for the regeneration of the cornea; this is an approximate timeline 
for when symptoms should improve and corneal healing should take place.  Tumor responses to 
ABT-414 have been sustained in subjects who require treatment holds for 4 or more weeks.
8.1.2.4
ABT-414 Dose Adjustment for Ophthalmologic Toxicity
Guidelines for ABT-414/placebo dose modifications for ophthalmologic toxicities considered by 
the investigator to be related to ABT-414 are shown in Table 10.  Decisions on dose adjustments 
will be based on CTCAE grades assigned by the Investigator (not on the ABT-414-TOE grades).  
Re-treatment at a lower dose of ABT-414 has generally resulted in less severe toxicities.  
However, it is important to fully utilize supportive measures as needed in order to minimize the 
need for dose interruptions and dose reductions.
If, after a dose reduction for ocular symptoms, changes in supportive care interventions lead to 
significant improvement in ocular symptoms for subsequent ABT-414/placebo doses, the 
ABT-414/placebo dose may be re-escalated to the previous higher dose at the discretion of the 
investigator after discussion with the Neuro-Medical Oncology study chair or his/her designee.


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Table 10.  Guidelines for ABT-414/Placebo Dose Interruption and Re-Initiation During 
Chemoradiation and Adjuvant Phase for Ophthalmologic Toxicities
Ocular Adverse Event
CTCAE Grade^
ABT-414 / Placebo Dosing Modifications
Dose Interruption*
Dose Reduction*
1 – Asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated^

Not indicated

Not indicated
2 – Symptomatic; medical 
intervention indicated (e.g., topical 
agents); limiting instrumental ADL^

Not indicated, but allowed at 
investigator's discretion

Investigator should fully 
utilize supportive care 
measures** as needed to 
manage ocular findings

Not indicated, but allowed at 
investigator's discretion

Investigator should fully utilize 
supportive care measures** as 
needed to manage ocular findings
3 – Decline in vision (worse than 
20/40 but better than 20/200); 
limiting self-care ADL^

Recommended but not 
required; at investigator’s 
discretion to interrupt study 
drug until AE resolves to at 
least Grade 2

Investigator should fully 
utilize supportive care 
measures** as needed to 
manage ocular findings

Recommended but not required; 
at investigator's discretion unless 
otherwise noted

Investigator should fully utilize 
supportive care measures** as 
needed to manage ocular 
findings
4 – Perforation or blindness (20/200 
or worse) in the affected eye^

Interrupt study drug until AE 
resolves to at least Grade 2 
(required)

Investigator should fully 
utilize supportive care 
measures** as needed to 
manage ocular findings

Required if Grade 4 toxicity 
present despite full utilization of 
supportive care measures**
^
Grading criteria shown are for the term "microcystic keratopathy."  For other ocular adverse events considered by the 
investigator to be related to ABT-414, use the applicable CTCAE grading criteria for that term.
*
If use of supportive measures reduces severity of eye toxicity, the lower CTCAE grade severity (the grade in the presence of 
ongoing supportive measures) may be used to guide potential dose modifications.   
**
Supportive care measures include but are not limited to lubricant drops, bandage contact lens, antibiotic drops, ointments, 
punctal plugs and sunglasses.
8.1.3
Severe Allergic Reactions (Grade 3 or Grade 4)
These require the immediate interruption of ABT-414/placebo treatment and discontinuation 
from the study.  Appropriate medical therapy including epinephrine, systemic corticosteroids, 
intravenous antihistamines, bronchodilators, and oxygen should be available for use in the 
treatment of such reactions.  Subjects should be carefully observed until the complete resolution 
of all signs and symptoms.


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8.1.4
Moderate Allergic Reactions (Grade 1 or Grade 2)
These will also require the immediate interruption of ABT-414/placebo infusion.  Once 
symptoms have resolved, retreatment is allowed with an infusion over 60 to 70 minutes.  All 
subsequent infusions will also be administered over 60 to 70 minutes.
8.1.5
Dermatologic Toxicities
Subjects developing dermatologic toxicities while receiving ABT-414/placebo should be 
monitored for the development of inflammatory or infectious sequelae, and appropriate treatment 
of these symptoms initiated.  In subjects with mild and moderate (Grade 1 or Grade 2) skin 
toxicity, treatment should continue without dose delay or modification.  Treatment with topical 
and/or oral antibiotics should be considered.
If a subject experiences severe (Grade 3 or Grade 4) acneiform rash, ABT-414/placebo treatment 
adjustments should be made based on a discussion between the Investigator, the RTOG 
Neuro-Medical Oncology Study Chair and AbbVie Medical Monitor.
Subjects who experience a grade 3 or higher dermatological toxicity will be treated as following:  
The subject will require a dose interruption and ABT-414/placebo may be reintroduced at a 
reduced dose (per the guidance previously stated above) if the toxicity returns to ≤ grade 1 within 
4 weeks.
8.1.6
Hepatic Laboratory Abnormalities (ABT-414/Placebo)
Guidelines for ABT-414/placebo dose modifications related to hepatic laboratory abnormalities 
are presented in Table 11.


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Table 11.  ABT-414/Placebo Dose Modification Guidelines for Hepatic Laboratory 
Abnormalities
Hepatic Laboratory Abnormality
ABT-414/Placebo
ALT or AST > 5 × ULN* but 
≤ 20 × ULN (and TBL ≤ 2 × ULN)

Hold drug regardless of assessed relationship to drug.  See 
Section 8.4 for guidelines on repeat testing (ALT, AST, ALP, 
TBL) and evaluation. 

Dosing may not be resumed until ALT and AST have 
recovered to ≤ 5 × ULN*

Dosing may be resumed at the same dose if ALT or AST was 
elevated >5 × ULN* for less than 2 weeks.  Additionally, dosing 
may be resumed at the same dose if another likely cause has 
been identified.

Dosing must be resumed at a reduced dose (see Table 9)** if 
ALT or AST was elevated > 5 × ULN* for more than 2 weeks 
and no other likely cause has been identified.

Following dose reduction, if ALT and AST remain ≤5 × ULN* 
after 2 doses at the reduced dose level, then re-escalation to the 
previous dose is allowed at the investigator's discretion.

If a subsequent dose reduction is required due to hepatic 
laboratory abnormalities, then re-escalation is not allowed.
ALT or AST > 20 × ULN
or 
ALT or AST > 3 × ULN and 
TBL > 2 × ULN
Hold drug regardless of assessed relationship to drug.  See 
Section 8.4 for guidelines on repeat testing (ALT, AST, ALP, TBL) 
and evaluation.
If another clear cause has been identified, drug may be resumed 
when ALT and AST ≤ 5 × ULN and TBL ≤ 2 × ULN
In general, if no other cause has been identified, drug should be 
permanently discontinued, and rechallenge not attempted.  
Rechallenge can be considered after consultation with the sponsor if
all of the following are met:

the subject has shown important benefit from the drug and other 
options are not available,

ALT and AST have recovered to ≤ 5 × ULN and TBL has 
recovered to ≤ 2 × ULN,

the subject has been informed of the potential risk and has 
consented to the rechallenge,

close follow-up of the subject is feasible.
ALP = alkaline phosphatase, ALT = alanine transferase, AST = aspartate transferase, TBL = total bilirubin
*
If elevated at baseline, either 5 × the baseline value or 8 × ULN, whichever is lower.
**
Unless the next planned dose is already a lower dose per the protocol (i.e., start of the adjuvant phase).
8.1.7
Other Toxicities
For all other toxicities considered by the investigator to be potentially related to 
ABT-414/placebo, the general guidelines to be used for dose interruptions and/or dose reductions 
are shown in Table 12.


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Table 12.  General Guidelines for ABT-414/Placebo Dose Interruptions and Re-Initiation 
During Chemoradiation and Adjuvant Phase (Except Ophthalmologic, Allergic, 
Dermatologic Toxicities and Hepatic Laboratory Abnormalities)
CTCAE Grade
ABT-414
Dose Interruption
Dose Reduction
Grade 1
Not indicated
Not indicated
Grade 2
Not indicated
Not indicated, but at investigator's 
discretion
Grade 3
Interrupt study drug until AE resolves to 
at least Grade 1 (or baseline if higher than 
Grade 1)
Recommended but not required; at 
investigator's discretion
Grade 4
Interrupt study drug until AE resolves to 
at least Grade 1 (or baseline if higher than 
Grade 1)
Required
8.2
Ocular Steroid Toxicity Management
Adverse effects related to ocular steroid use should be managed as clinically indicated in
consultation with the ophthalmologist.  The decision whether to continue prophylactic eye drops 
at the same steroid potency level should weigh both the potential benefits and risks of continuing 
treatment.  As described in Section 5.5, prophylactic eye drops must be reduced to Level 1 
(non-steroid drops) if there is evidence of ocular steroid-related toxicity in the complete absence 
of any corneal epithelial abnormalities on the ABT-414-TOE.
8.3
Temozolomide Toxicity Management
TMZ should be administered per the local prescribing regulations.  If local prescribing 
information and the instructions in Section 8.3.1 or Section 8.3.2 conflict, then either local 
prescribing information or protocol language can be used at the discretion of the investigator.
See Section 8.4 for guidelines on repeat testing and evaluation of hepatic laboratory 
abnormalities regardless of the assessed relationship to study treatments.
8.3.1
Temozolomide During Concomitant Radiation Therapy
Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) should be per local regulation 
guidelines for all subjects receiving concomitant TMZ and radiotherapy.


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No TMZ dose reduction will be made, but delay or discontinuation of TMZ administration will 
be decided weekly according to hematologic and non-hematologic adverse events (AEs), as 
specified below.
If the administration of TMZ has to be interrupted, the radiotherapy will proceed normally.  
Missed doses of TMZ will not be made up at the end of radiotherapy.  The total number of days 
and total dose of TMZ will be recorded on the eCRFs.
If one or more of the following are observed:
ANC ≥ 0.5 and < 1.5 × 109/L
Platelet count ≥ 10 and < 100 × 109/L
Grade 2 non-hematologic AE considered possibly related to TMZ (except alopecia, nausea 
and vomiting while on maximal antiemetic therapy, and fatigue)
then treatment with concomitant TMZ will be withheld until all of the following conditions are 
met:
ANC ≥ 1.5 × 109/L
Platelet count ≥ 100 × 109/L
Grade ≤ 1 non-hematologic AE (except alopecia, nausea and vomiting, and fatigue)
In case of hematologic AE as defined above, a complete blood count (CBC) should be performed 
at least twice weekly.  In case of non-hematologic AE, the subject should be assessed at least 
weekly with relevant laboratory test(s).  As soon as all of the above conditions are met, the 
administration of TMZ will resume at the same dose as used initially.
If one or more of the following are observed:
ANC < 0.5 × 109/L (Grade 4)
Platelet count < 10 × 109/L (Grade 4)
Grade 3 or 4 non-hematologic AE considered possibly related to TMZ (except alopecia, 
nausea and vomiting unless the subject has failed maximal antiemetic therapy, and 
fatigue)
then treatment with concomitant TMZ should be stopped.
If the duration of radiotherapy exceeds 7 weeks, then concomitant treatment with TMZ should be 
stopped after 49 days of TMZ treatment.


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Summary of Temozolomide Delay or Discontinuation During Concomitant Radiation 
Therapy
AE
Value
Action
ANC
≥ 0.5 and < 1.5 × 109/L
Delay temozolomide until:
---ANC ≥ 1.5 × 109/L
---Platelet ≥ 100 × 109/L
---Non-hem AE ≤ Grade 1
Platelet count
≥ 10 and < 100 × 109/L
Non-hematologic (except alopecia, 
nausea/vomiting unless on maximal 
antiemetic therapy)
NA
ANC
< 0.5 × 109/L
Stop concomitant temozolomide
Platelet count
< 10 × 109/L
Non-hematologic (except alopecia, 
nausea/vomiting)
NA
8.3.1.1
Concomitant Temozolomide, if Radiotherapy Is Interrupted
If radiotherapy has to be temporarily or permanently interrupted for technical or medical reasons 
unrelated to the TMZ administration, then treatment with daily TMZ should continue.
8.3.2
Post-Radiation (Adjuvant) Temozolomide
Continued dosing administration is based on adverse events (AEs) during the prior treatment 
cycle.  If multiple AEs are seen, the dose administered should be based on the dose reduction 
required for the most severe grade of any single AE.
Dose Level
Temozolomide Dose, 
mg/m2/day
Remarks
–1
100
Reduction if prior AE
0
150
Starting dose cycle 1 (adjuvant)
+1
200
Escalated dose at cycle 2, for cycles 2 – 12 in 
absence of AE
Delay
On Day 1 of each cycle (within the prior 72 hours), ANC ≥ 1.5 × 109/L, platelet count 
≥100 × 109/L and all treatment-related grade 3 or 4 non-hematologic AEs (except alopecia, 
nausea, and vomiting) must have resolved (to grade ≤ 1).
If AEs persist, treatment should be delayed by 2 weeks for up to 4 consecutive weeks, so that the 
TMZ dosing can coincide with the administration of the ABT-414 or placebo.  If, after 4 weeks 
of delay, all AEs have still not resolved, then any further adjuvant treatment with TMZ should be 
stopped.  When possible, TMZ treatment when resumed should start on either Day 1 or Day 15 
of a cycle so that it may coincide with ABT-414/placebo treatment.


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Dose Escalation
If, during the first cycle, all non-hematologic AEs observed were grade ≤ 2 (except alopecia, 
nausea and vomiting) and with platelets ≥ 100 × 109/L and ANC ≥ 1.5 × 109/L, then the TMZ 
dose should be escalated to dose level 1 and this dose should be used as the starting dose for 
subsequent cycles.  If treatment after cycle 1 has to be delayed because of ongoing non-
hematologic AEs of grade ≥ 2, then no escalation is possible.  If the dose was not escalated at 
cycle 2, then the dose should not be escalated in further cycles (Cycles 3 – 6).
Dose Reductions
If any non-hematologic AE observed was grade > 2 (except alopecia, nausea and vomiting) 
and/or if platelets < 50 × 109/L and/or ANC < 1 × 109/L, then the dose should be reduced by 
one dose level.  For subjects who would require dose reductions to a dose level 
< 100 mg/m2/day, TMZ will be stopped.  Also, if any of the same non-hematologic grade 3 AE 
recurs (except alopecia, nausea and vomiting) after reduction for that AE, then TMZ will be 
stopped.
If any treatment-related non-hematologic AE observed was grade 4 (except alopecia, nausea and 
vomiting) then adjuvant TMZ treatment should be stopped.
Subsequent cycles (Cycles 3 – 12):  Any dose reductions of TMZ will be determined according 
to (1) non-hematologic AE during the preceding treatment cycle, as well as (2) the nadir 
(lowest/worst) ANC and platelet counts observed.  No dose escalation should be attempted.  The 
same dose reductions as for the second cycle should be applied.
Important:  If the dose was reduced or delayed for adverse events, there will be no dose 
escalation.
The reason(s) for dose reduction and/or delay must be documented in the eCRF.


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Summary of Dose Modification or Discontinuation During Post-Radiation Temozolomide
Worst Non-Hematologic AE (Except Alopecia, Nausea and Vomiting)
During the Previous Cycles
Grade
Dose Modification
0 – 2
No dose modifications for non-hematologic AEs.  Dose escalations (only for cycle 2) or 
reductions based on ANC and platelet counts are applicable.
3
Reduce by one dose level (except alopecia, nausea and vomiting).  Dose modifications 
(escalations or reductions) based on ANC and platelet counts are not applicable.  No further 
escalation is possible.  If the same non-hematologic grade 3 AE recurs (except alopecia, nausea 
and vomiting) after reduction for that AE, then stop temozolomide.
4
Stop temozolomide (except for alopecia, nausea and vomiting).  Dose modifications (escalations 
or reductions) based on ANC and platelet counts are not applicable.
Nadir Values
ANC
Action
≥ 1.5 × 109/L
Escalation to DL 1 (cycle 2 only)
≥ 1 & < 1.5 × 109/L
Dose unchanged
< 1 × 109/L
Reduce by 1 dose level
Platelets
≥ 100 × 109/L
Escalation to DL 1 (cycle 2 only)
50 – 99 × 109/L
Dose unchanged
< 50 × 109/L
Reduce by 1 dose level
Note:  A complete blood count must be performed on Day 22 (+/– 3 days) of each adjuvant treatment cycle.
Hematologic AE on Day 1 of Each Cycle (Within 72 Hours Before)
AE
Delay
ANC < 1.5 × 109/L and/or 
Platelet count < 100 × 109/L
Delay up to 4 weeks until all resolved.  If unresolved after 4 weeks then stop 
temozolomide.  If resolved, dose delay/reductions based on non-hematologic 
AEs are applicable.  If treatment has to be delayed for AEs, then no escalation 
is possible.
Non-Hematological AE (Except for Alopecia, Nausea and Vomiting) on Day 1 of Each 
Cycle (Within 72 Hours Before)
Grade
Delay 
2 – 3
Delay up to 4 weeks until all resolved (to grade ≤ 1).  If unresolved after 4 weeks, then stop 
temozolomide.  If resolved, dose delay/reductions based on ANC and platelets are applicable.  
If treatment has to be delayed for AEs, then no escalation is possible. 


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8.4
Hepatic Laboratory Abnormalities
This section provides information on safety monitoring, evaluation of potential causes, and 
appropriate documentation for subjects with hepatic laboratory abnormalities suggesting 
potential drug-induced liver injury (DILI).  It was adapted with modifications from the FDA 
Guidance for Industry, Drug-Induced Liver Injury:  Premarketing Clinical Evaluation 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM174090.pdf) in consultation with a hepatologist with expertise in DILI.
Information derived from the scientific literature and public databases on liver injury attributable 
to prescription and nonprescription medications, herbals and dietary supplements can be found at 
the LiverTox database (https://livertox.nlm.nih.gov).
If a subject develops one of the following laboratory abnormalities, hepatic laboratory 
abnormalities should be confirmed by repeat testing, and the subject should be monitored and 
evaluated as described in this section, regardless of the assessed relationship to the study 
treatments:

ALT or AST > 3 × ULN and TBL > 2 × ULN, or

ALT or AST > 5 × ULN (or > 5 × the baseline value if elevated) or > 8 × ULN, 
whichever is lower
Confirmation of Liver Test Abnormalities
For subjects meeting either of the criteria above, confirmation of hepatic laboratory 
abnormalities should be done as follows: 

Repeat testing of all four of the usual measures (ALT, AST, alkaline 
phosphatase, and TBL) should be performed within 3 days of the initial 
abnormality to confirm the abnormalities and to determine if they are increasing or 
decreasing.
o
Serum transaminases may rise and fall quite rapidly, and waiting a week or two 
before obtaining confirmation of elevations may lead to a false conclusion that 
the initially observed abnormality was spurious.
o
The need for prompt repeat testing is especially great if AST or ALT is 
> 3 × ULN and TBL > 2 × ULN.
o
If the subject is unable to return to the trial site promptly, the subject should be 
retested locally, with results and normal laboratory ranges recorded in the CRFs.


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
Inquire about concurrent new or escalating symptoms (e.g., right upper quadrant 
pain or tenderness, fever, rash).  Although non-specific in the setting of GBM 
treatment, fatigue nausea, and vomiting should also be assessed as clinical symptoms 
potentially associated with liver injury.
It is appropriate to initiate close observation (described below) to determine whether the 
abnormalities are improving or worsening and to consider whether the subject meets 
criteria for stopping study drug if symptoms suggestive of liver injury persist or if repeat 
testing shows:

ALT or AST > 5 × ULN (or > 5 × baseline if elevated or > 8 × ULN, whichever is 
lower) or

ALT/AST > 3 × ULN and total bilirubin > 2 × ULN.
Close Observation
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI (as described above), and not to wait until the next scheduled visit or 
monitoring interval.  The primary goal of close observation is to determine as quickly as possible 
whether observed abnormal findings are transient and will resolve spontaneously or will progress
to marked serum aminotransferase elevation or evidence of functional impairment, as indicated 
by rising bilirubin or INR, which represent substantial liver injury.
Close observation includes:

Repeating liver enzyme and serum bilirubin tests two or three times weekly.  If 
total bilirubin is elevated, obtain direct bilirubin.  Frequency of retesting can 
decrease to once a week or less if abnormalities stabilize or drug has been 
discontinued and the subject is asymptomatic.

Obtaining additional tests, as appropriate, to evaluate liver function, 
(e.g., international normalized ratio [INR]); diagnostic measures (e.g., 
ultrasound of the liver), serum ammonia, etc.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
Update the appropriate eCRFs (if applicable).

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.  Update the appropriate eCRFs (if applicable).

Ruling out other immediately apparent possible causes of aminotransferase (ALT or 
AST) elevation and hyperbilirubinemia, as described below.


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
Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
Relevant supplemental information must be collected and entered in the appropriate eCRF(s),
Evaluating Data for Alternative Causes
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes:

Acute viral hepatitis.  The usual onset of hepatocellular DILI is indistinguishable 
from acute viral hepatitis A or B. Hepatitis C is much less often acute in its onset and 
tends to be insidious, but it sometimes can resemble acute DILI.  The presence of 
acute viral hepatitis A, B, and C should be evaluated by serological markers.  Viral 
hepatitis D (requires concomitant hepatitis B infection) and E are relatively rare in the 
United States.  Hepatitis E is more common in developing countries, including 
Southeast Asia, and should be considered in recent travelers to those countries and in 
patients in trials conducted in those countries.  Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, 
toxoplasmosis, varicella, and parvovirus, although these infections are seen more 
typically in immuno-suppressed individuals.  Adolescent and young adult patients 
with possible DILI should be tested for Epstein-Barr virus.  Hepatitis is common 
among transplant patients with cytomegalovirus disease.

Alcoholic and autoimmune hepatitis.  Acute alcoholic hepatitis usually is recurrent, 
with a history of binging exposure to alcohol preceding episodes, and it has some 
characteristic features, such as associated fever, leukocytosis, right upper quadrant 
pain and tenderness, hepatomegaly, and AST > ALT, that may help distinguish it 
from other causes of liver injury.  Other features of the physical examination may 
include the presence of stigmata of cirrhosis, such as spider nevi, palmar erythema, 
estrogenic changes in males, and Dupuytren's contractures.  Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and 
laboratory testing, including serologic testing (e.g., antinuclear or other antibodies).

Hepatobiliary disorders.  Biliary tract disease, such as migration of gallstones or 
intrahepatic lesions, more often causes cholestatic injury initially and should be 
investigated with gall bladder and ductal imaging studies, especially if alkaline 
phosphatase is increased.  Malignant interruption of the biliary tract also should be 
considered.

NASH.  NASH may be seen in obese, hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels, and hepatic and 


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sometimes splenic enlargement.  It is sometimes associated with cirrhosis and portal 
hypertension.

Cardiovascular causes.  Cardiovascular disease, especially right heart failure and 
hypotension or any cause of impaired oxygenation of the liver, may cause acute 
centrilobular hypoxic cell necrosis (ischemic hepatitis) with rapid and sometimes 
spectacular increases of serum transaminases (e.g., ALT or AST > 10,000 U/L).  
Cardiovascular dysfunction or impaired liver oxygenation, including hypotension or 
right heart failure, should be assessed by physical examination and history.

Concomitant treatments.  It is critical to discover concomitant treatments, including 
exposure to nonprescription and dietary supplement products that might be 
responsible for injury.  The possible exposure to potentially toxic herbal or dietary 
supplement mixtures (sometimes of unknown composition), nonprescription 
medications such as acetaminophen, or to occupational chemical agents may not be 
volunteered unless subjects are specifically questioned.
Follow-Up to Resolution
All subjects showing hepatic laboratory abnormalities suggestive of possible DILI should be 
followed until satisfactory resolution of the laboratory abnormalities).  DILI may develop or 
progress even after the causative drug has been stopped.  Local lab results should be recorded on
appropriate eCRFs. 
Dose Modifications for Study Drugs
See the dose modification guidelines for each respective drug.


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9.0
DRUG INFORMATION
9.1
TMZ
Study sites must refer to the TMZ package insert for detailed pharmacologic and safety 
information.
See Section 5.3 for TMZ administration instructions.  Refer to the current package insert/SmPC 
provided with each drug and the site-specific pharmacy for toxicity information and instructions 
for drug preparation, handling, and storage.
9.1.1
TMZ Supply
TMZ is commercially available.
9.2
ABT-414
9.2.1
Identification of Investigational Product(s)
Information about ABT-414 formulations to be used in this study is presented in Table 13.
Table 13.  Identification of Investigational Product(s)
Study Drug
Formulation
Dosage Form
Strength (mg)
Manufacturer
ABT-414
Sucrose, histidine, 
polysorbate 80
Sterile lyophilisate in 
a vial (to be 
reconstituted and 
further diluted for IV 
infusion)
100 mg
20 mg
AbbVie
Placebo for 
ABT-414
Sucrose, histidine, 
polysorbate 80
Sterile lyophilisate in 
a vial (to be 
reconstituted and 
further diluted for IV 
infusion)
100 mg
20 mg
AbbVie
9.2.2
Packaging and Labeling of Blinded ABT-414/Placebo
Vials containing ABT-414 lyophilized powder or placebo will be packaged in cartons in a 
blinded fashion.  Vials containing ABT-414 lyophilized powder designated for the hepatic 
impairment sub-study will be packaged in cartons in an open-labeled fashion.  Each vial and 
carton will be labeled per country requirements.


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9.2.3
Storage and Disposition of ABT-414/Placebo
The ABT-414 and placebo lyophilisate for injection must be stored refrigerated at 2°C to 
8°C/36°F to 46°F, protected from light, and must not be frozen.
The reconstituted ABT-414 or Placebo should be refrigerated at 2°C to 8°C/36°F to 46°F, for no 
more than 20 hours.  After storage at 2°C to 8°C/36°F to 46°F, the solution can be allowed to 
come to room temperature and be administered within 4 hours.  From start to reconstitution until 
the infusion is completed, a total of 24 hours should not be exceeded.  If maintained at room 
temperature, the solution should be used within 4 hours.
Storage temperature logs will be maintained to document proper storage conditions.  The 
refrigerator temperature must be recorded on a daily basis on the temperature logs to record 
proper function.  Temperature excursions must be reported to AbbVie immediately.
The investigational products are for investigational use only and are to be used only within the 
context of this study.  The study drug supplied for this study must be maintained under adequate 
security and stored under the conditions specified on the label until dispensed for subject use or 
returned to AbbVie.
9.2.4
Preparation/Reconstitution of Dosage Form
ABT-414/placebo Study Medication Preparation Guidelines will be provided as a separate 
document outside of this protocol.
9.2.5
Product Complaint
9.2.5.1
Definition
A Product Complaint is any Complaint related to the biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or packaging, 
product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), missing 
components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined directly 
above should be captured.


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9.2.5.2
Reporting
Product Complaints concerning the investigational product must be reported to the Sponsor 
within 24 hours of the study site's knowledge of the event via the Product Complaint form.  
Product Complaints occurring during the study will be followed-up to a satisfactory conclusion.  
All follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor.  Product Complaints associated with adverse 
events will be reported in the study summary.  All other complaints will be monitored on an 
ongoing basis.
Product Complaints may require return of the product with the alleged complaint condition. In 
instances where a return is requested, every effort should be made by the Investigator to return 
the product within 30 days.  If returns cannot be accommodated within 30 days, the site will need 
to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.


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10.0
PATHOLOGY/BIOSPECIMENS
Tumor tissue for EGFR assessment should be prepared and sent to central lab as described in the 
study specific laboratory manual and outlined in Section 4.2.


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11.0
DATA AND RECORDS
11.1
Source Documents
Source documents are defined as original documents, data and records.  These may include 
hospital records, clinical and office charts, laboratory data/information, subject diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
Source document data may be transcribed onto electronic case report forms (eCRFs) as required.  
Data collected during this study must be recorded on the appropriate source document.
For all adverse events, the onset date and event description will be captured in source documents.  
Other adverse event data points required for eCRF completion can be entered directly in the 
eCRF and may serve as the source document and should be printed, signed and dated by the 
Investigator.
The Investigator/institution will permit study-related monitoring, audits, IEC/IRB review, and 
regulatory inspection(s), providing direct access to source data documents.
11.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this study.  
These forms will be used to transmit information collected during the study to AbbVie and 
regulatory authorities, as applicable.  The CRF data for this study are being collected with an 
electronic data capture (EDC) system called Rave® provided by the technology vendor Medidata 
Solutions Incorporated, NY, USA.  The EDC system and the study-specific electronic case report 
forms (eCRFs) will comply with Title 21 CFR Part 11.  The documentation related to the 
validation of the EDC system is available through the vendor, Medidata, while the validation of 
the study-specific eCRFs will be conducted by AbbVie and will be maintained in the Trial 
Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject files will 
serve as source data for the study.  All eCRF data required by this protocol will be recorded by 
investigative site personnel in the EDC system with the exception of the ePRO information 
which will be integrated into the eCRFs electronically.  All data entered into the eCRF will be 
supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any necessary 
corrections to the eCRF.  All change information, including the date and person performing the 


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corrections, will be available via the audit trail, which is part of the EDC system.  For any 
correction, a reason for the alteration will be provided.  The eCRFs will be reviewed periodically 
for completeness, legibility, and acceptability by AbbVie personnel (or their representatives).  
AbbVie (or their representatives) will also be allowed access to all source documents pertinent to 
the study in order to verify eCRF entries.  The principal Investigator will review the eCRFs for 
completeness and accuracy and provide his or her electronic signature and date to eCRFs as 
evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from Investigator 
sites at the end of the site's participation in the study.  Data from the EDC system will be 
archived on appropriate data media (CD-ROM, etc.) and provided to the Investigator at that time 
as a durable record of the site's eCRF data.  It will be possible for the Investigator to make paper 
printouts from that media.


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12.0
QUALITY ASSURANCE REVIEWS FOR DRUG AND RADIATION 
THERAPY
Drug and radiation therapy reviews will be performed by the Neuro-Medical Oncology and 
Radiation Therapy study chairs or their designees.  The goal of these reviews is to evaluate 
protocol treatment compliance within each of these areas.  These reviews will be ongoing and are 
contingent on timely submission of treatment data.




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14.0
STATISTICAL CONSIDERATIONS
14.1
Study Design
This is a Phase 3 study.  The primary objective of the study is to assess whether ABT-414 in 
combination with concomitant TMZ/RT followed by combination of ABT-414 with adjuvant 
TMZ improves overall survival (OS) compared to concomitant TMZ/RT + adjuvant TMZ in 
subjects with EGFR-amplified GBM.  A total of 640 evaluable subjects will be randomized.
14.2
Statistical Methods
This is a comparative randomized, placebo controlled, double-blinded Phase 3 trial.  All efficacy 
analyses will be performed in the Full Analysis Set (defined below).  OS (primary efficacy 
endpoint for the overall study) and PFS (secondary efficacy endpoint) will be compared between 
treatment Arms A and B using stratified log-rank test statistics or a weighted version of this test 
(to be pre-specified in the Statistical Analysis Plan document (the SAP)), adjusting for the study 
stratification factors.  PFS is defined as time from randomization to progression of disease (per 
RANO criteria) or death, whichever occurs first.
Randomization and Stratification
MGMT methylation status and RPA (referenced in Appendix VI) are demonstrated to be 
prognostic of survival for newly diagnosed GBM subjects.  For this study, subjects will be 
stratified by MGMT methylation status (methylated versus unmethylated), RPA class (III versus 
IV versus V), region of the world (US/Canada versus other) and EGFRvIII mutation status 
(mutated versus other), where EGFRvIII other is defined as wild type, indeterminate due to test 
failure, invalid, or insufficient tissue.  EGFRvIII is a stratification factor because it is potentially 
prognostic and because it is related to the mechanism of action of ABT-414 which binds to both 
activated wild type EGFR and EGFRvIII.  After stratification, subjects will be randomized to 
either Arm A or Arm B in a 1:1 ratio.
Analysis Sets
The following analysis sets will used for analysis of safety and primary and secondary efficacy 
endpoints of the study:

Full Analysis Set (FAS) will comprise all randomized subjects regardless of whether they 
received study treatment.  Subjects will be classified according to the treatment they were 
assigned at the time of randomization.  The FAS will be the primary analysis set for the 
analysis of efficacy endpoints.


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
Safety Analysis Set (SAS) will comprise all randomized subjects who receive at least 
one dose of study treatment (either RT, TMZ or ABT-414).  Subjects will be classified 
according to treatment received.  Thus a subject randomized to Arm A who receives 
RT+TMZ but does not receive ABT-414 will be considered in the control group (Arm B) 
for safety analysis.

Per-protocol Set (PPS) will comprise all randomized subjects excluding those with major 
deviation from study inclusion and exclusion criteria, compliance with procedures.  
Subjects will be classified according to treatment assigned.  The PPS will be used for 
supportive analysis of efficacy endpoints.
14.3
Primary Endpoints Study Design
14.3.1
Primary Endpoint
The primary endpoint for this study is OS, defined as time from randomization to death from any 
cause.  For subjects who are not reported to have died at the time of an analysis, OS will be right-
censored at the last date the subject is documented to be alive.
14.3.2
How Primary Endpoint Will Be Analyzed
Efficacy analysis for the overall study will be performed in the FAS which includes all 
randomized subjects regardless of whether or not they received study treatment.  The PPS will be 
used for supportive analysis of efficacy endpoints.  The primary endpoint for the overall study is 
overall survival (OS).  To meet the primary objective, OS will be compared between treatment 
Arms A and B for the FAS and PPS using stratified log-rank test statistics or a weighted version 
of the test, adjusting for the study stratification factors and additional independent prognostic 
factors as deemed appropriate, to be specified in the SAP.  If a weighted version is considered to 
be more appropriate in view of potentially delayed treatment effect, it will be pre-specified in the 
SAP prior to conducting any unblinded analysis of study data.  The hazard-ratio of OS for 
ABT-414 Arm A compared to placebo Arm B will be estimated by fitting Cox-proportional 
hazards regression models adjusting for the main-effects of the stratification factors and 
additional independent prognostic factors as deemed appropriate, to be specified in the SAP.
Type I Error Control
To maintain overall type I error control for the overall study, each secondary endpoint will be 
tested in the order listed if the primary endpoint (OS) and all preceding secondary endpoints 
show statistically significant results at the one-sided 0.025 level of significance.


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The O'Brien-Fleming method will be implemented to protect the one-sided type I error of 0.025.  
Specifically, a nominal alpha level of 0.00965 will be used for the interim efficacy analysis for 
OS.  For the final analysis, the primary efficacy endpoint will be tested at the one-sided nominal 
alpha level of 0.0221 after adjusting for the interim looks at efficacy data.
14.3.3
Sample Size and Power Calculations
The sample sizes are calculated based on the approach of doing the primary endpoint analyses 
(OS) using the FAS.
A total of 640 evaluable subjects are expected to be randomized.  With 441 deaths, there will be 
approximately 85% power to detect a 25% reduction in the hazard of death (HR = 0.75) using a 
log-rank test at a one-sided 2.5% level of significance.  Median OS of 16 months is expected in 
the control arm.
14.4
Study Monitoring of Primary Objectives
Interim Reporting for the DMC
The Independent Data Monitoring Committee (IDMC), as coordinated by RTOG Foundation, 
will review the study at least twice a year with respect to subject accrual, pretreatment 
characteristics of accrued subjects, the frequency and severity of toxicities and morbidity.  The 
IDMC is also available to review the study on an "as needed" basis.
Safety
AbbVie will assess adverse events, laboratory data and vital signs throughout the study.  
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that start or 
worsen on or after the day of the first dose of study drug.  Adverse event severity and laboratory 
evaluation changes will be assessed by utilizing National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  Adverse events will be 
summarized by preferred terms within a System and Organ Class according to the most current 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Changes from baseline will 
be analyzed for each scheduled post-baseline visit and for the final visit for blood chemistry and 
hematology parameters, as well as urinalysis and vital sign parameters.  Shifts in laboratory 
values from baseline NCI CTCAE grades to maximum and final post-baseline grades will be 
assessed.


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Interim Superiority and Futility Analysis of Efficacy Data
An interim superiority and futility analysis of efficacy data will be performed when 75% (332) of 
the 441 required maximum number of deaths are observed.  The analysis will be performed using 
the Full Analysis Set, with all randomized cases being included in the treatment arm to which 
they were randomized regardless of what treatment the subjects actually received.  The primary 
endpoint of OS will be compared between treatment Arms A and B using stratified log-rank test 
statistics (or, a weighted version, as pre-specified in the SAP) adjusting for the study 
stratification factors and additional independent prognostic factors as deemed appropriate, to be 
specified in the SAP.  The hazard-ratio of OS for ABT-414 Arm A compared to placebo Arm B 
will be estimated by fitting Cox-proportional hazards regression models adjusting for the main-
effects of the stratification factors and additional independent prognostic factors as deemed 
appropriate, to be specified in the SAP.  Adjustment of the level of significance (alpha) for 
multiple testing will be made using the O'Brien-Fleming group sequential spending function for 
early rejection of the null hypothesis to declare superiority.  Superiority will therefore be 
assessed at a one-sided significance level of 0.00965, which is corresponding to a Z-score 
superiority boundary at –2.34.  The trial may also be stopped for futility following this interim 
analysis if the estimated Cox hazard ratio of ABT-414 Arm A to placebo Arm B at interim 
analysis exceeds 0.9.
The unblinded interim results will first be reviewed by the IDMC, and the trial will be 
considered for early stopping if the IDMC makes such a recommendation after consideration of 
the OS results and all supportive evidence including all secondary endpoints and safety.  For the 
final analysis, the primary efficacy endpoint will be tested at the one-sided nominal alpha level 
of 0.0221 after adjusting for the interim looks at efficacy data.  Details for the interim efficacy 
analysis will be provided in the IDMC charter.
14.5
Accrual/Study Duration Considerations
Subjects will be accrued for a total of 640 evaluable subjects randomized in the study.  Once the 
target accrual is met, subjects will then be followed for another 18 months following 
randomization of the last subject to observe 441 deaths overall  for comparison of OS.  The total 
study duration and accrual duration is thus projected to be 48 months and 29 months, 
respectively.


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14.6
Secondary or Exploratory Endpoints (Including Correlative Science Aims)
14.6.1
Secondary Hypotheses and Endpoints
The secondary efficacy endpoints include PFS, OS for the MGMT unmethylated and methylated 
subgroups , time to deterioration in symptom severity score (MDASI-BT), time to deterioration 
in symptom interference score (MDASI-BT), time to deterioration in verbal memory (HVLT-R) 
total recall score, OS for the EGFRvIII mutated tumor subgroup, and PFS for the EGFRvIII
mutated tumor subgroup.
14.6.2
Definitions of Secondary Endpoints and How These Will Be Analyzed
Each secondary endpoint will be tested in the order listed only after the superiority of treatment 
Arm A with respect to the primary efficacy endpoint (OS) is established. .  To protect overall 
Type I error across primary and all the secondary endpoints, “overall hierarchical” testing 
strategy34 will be used for testing the primary and secondary endpoints.  Unless otherwise 
specified, the secondary time-to-event type efficacy endpoints (OS, PFS and time to 
deterioration) will be compared between treatment Arms A and B using stratified log-rank test 
statistics or a weighted version of this test (to be pre-specified in the Statistical Analysis Plan 
document), adjusting for the study stratification factors and additional independent prognostic 
factors as deemed appropriate, to be specified in the SAP.  The hazard ratio for ABT-414 Arm A 
compared to placebo Arm B will be estimated by fitting Cox proportional hazards regression 
models adjusting for the main-effects of the stratification factors and additional independent 
prognostic factors as deemed appropriate, to be specified in the SAP.
Progression Free Survival (PFS)
PFS is defined as time from randomization to progression of disease (per RANO criteria) or 
death, whichever occurs first.  For subjects who are not documented to have experienced a PFS 
event at the time of an analysis, PFS will be right-censored on the date of their last adequate 
radiographic assessment of disease.  PFS will be analyzed in similar way to OS.  That is, PFS 
will be compared between treatment Arms A and B for the FAS using stratified log-rank test 
statistics or a weighted version of this test (to be pre-specified in the Statistical Analysis Plan 
document, adjusting for the study stratification factors and additional independent prognostic 
factors as deemed appropriate, to be specified in the SAP.  The hazard-ratio of PFS for ABT-414 
Arm A compared to placebo Arm B will be estimated by fitting Cox-proportional hazards 
regression models adjusting for the main-effects of the stratification factors and additional
independent prognostic factors as deemed appropriate, to be specified in the SAP.


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A sensitivity analysis will be conducted to evaluate the robustness of the results, as exploratory 
and supportive of the primary PFS analysis.  Accounting for subjects who died or progressed 
after more than one (> 1) missed visit, the following sensitivity analysis will be performed:  
Considering the date of the earliest missed radiological assessment following the last adequate 
radiological assessment prior to a subject's progression or death, as a date of progression.
No imputation will be used for subjects with no more than one missed visit in the sensitivity 
analysis.  Details for the sensitivity analysis will be provided in the SAP.
Overall Survival for the MGMT Methylated, MGMT Unmethylated and 
EGFRvIII-Mutated Tumor Subgroups
OS analysis will be performed in the subgroup of patients with MGMT methylated MGMT 
unmethylated and EGFRvIII-mutation.   The same methodology as for the primary OS analysis 
in the FAS will be applied.
Progression Free Survival for the EGFRvIII-Mutated Tumor Subgroup
PFS analysis will be performed in the subgroup of patients with EGFRvIII-mutation.  The same 
methodology as for the PFS analysis in the FAS will be applied.
Time to Deterioration in Verbal Memory (HVLT-R)
In the Phase 3 part of the study, time to deterioration in verbal memory, based on the HVLT-R 
Total Recall, will be analyzed as a separate secondary endpoint.  Other individual components 
and outcome from HVLT-R and FAS verbal fluency will be analyzed on an exploratory basis.
The HVLT-R Total Recall score will be computed by summing the total number of words 
recalled across 3 trials.  Standardized scores (mean = 0, SD = 1) for each test are calculated using 
published normative data from a healthy population.  At each assessment, change in the HVLT-R 
total recall score relative to baseline will be calculated and verbal memory performance will be 
categorized as declined or not using the reliable change index (RCI) criterion based on the raw 
scores.
The deterioration is defined as satisfying the deterioration criteria without further improvement 
within 8 weeks or occurrence of death.  TTD endpoints will be derived as follows:
TTD = Date of first occurrence of first deterioration event or censoring – date of randomization 
+ 1.


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Time to deterioration in verbal memory will be assessed using the standard log-rank test.  The 
hazard-ratio for ABT-414 Arm A compared to placebo Arm B will be estimated by fitting the 
Cox PH models with stratification factors included as the covariates.
Time to Deterioration in Symptom Severity and Symptom Interference (MDASI-BT)
In the Phase 3 part of the study, the symptom severity and the symptom interference scores of the 
MDASI-BT will be used as the outcome of interest for this analysis.  Data will be scored 
according to the MDASI user manual.  A change of ≥ 1 point on a 10-point scale at follow-up 
assessment with respect to baseline will be considered as clinically relevant.  The scores for 
symptom severity and symptom interference are calculated by averaging the scores of the 
symptom severity- and symptom interference-related questions, respectively.  Changes in 
symptom severity score and symptom interference score at each time point will be classified into 
3 categories:  improved (≤ –1), stable (> –1 and < 1), and deteriorated (≥ 1).
Time to deterioration in overall symptom burden and interference will be analyzed using the 
similar approach for time to deterioration in neurocognitive failure.
14.7
Exploratory Hypothesis and Endpoints
OS at 1 year
OS at 2 years
PFS at 1 year
PFS at 2 years
OS for non-EGFRvIII subjects (comparison between arms)
PFS for non-EGFRvIII subjects (comparison between arms)
PFS for the MGMT unmethylated and methylated sub-groups
OS and PFS for Total EGFR expressions levels
To compare change from baseline in neurocognitive functioning (HVLT-R and 
COWA-FAS)
To evaluate changes from baseline in HRQoL based on the EORTC QLQ-C30/BN20
To evaluate changes from baseline in performance status based on KPS scores
To compare median time that KPS score was maintained at 70 or higher
Change from baseline in Vision item on the MDASI-BT and EORTC BN20
EGFR amplification and EGFRvIII prognostic value
Changes in EGFR molecular profile during therapy among subjects who undergo additional 
surgery as part of routine care
Change from baseline in symptom severity factor groupings (MDASI-BT neurologic, 


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cognitive,  treatment and symptom interference (activity-related, mood-related))
Pharmacokinetics of ABT-414, total ABT-806, and unconjugated cys-mcMMAF
To evaluate changes from baseline in average daily corticosteroid dosing during post-
treatment period.
OS and PFS at 1 year and 2 years will be summarized and reported by treatment arm.
For the endpoint on the OS and PFS comparison for non-EGFRvIII EGFR amplified subjects, the 
treatment group differences will be evaluated using the similar methodology as for analyses in 
the FAS.  Analysis details will be provided in the Statistical Analysis Plan.
Scoring for the EORTC QLQ-C30, QLQ-BN20, MDASI-BT will be based on their 
corresponding user manuals.31-33  Summary statistics of the EORTC QLQ-C30, QLQ-BN20, 
MDASI-BT, HVLT-R, COWA-FAS, and KPS including their changes from baseline will be 
calculated at each assessment time point for both study arms.  Analysis details will be provided 
in the Statistical Analysis Plan.
Pharmacokinetic:
Peak and trough concentrations (maximum observed plasma concentration [Cmax] and Ctrough) of 
ABT-414 and total ABT-806 antibody will be summarized from the observed concentration data.  
Population pharmacokinetic parameters of ABT-414, total ABT-806 and cys-mcMMAF such as 
clearance and volume of distribution will be estimated using a nonlinear mixed effect modeling 
analysis.


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15.0
ETHICS
15.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent and all other forms of subject information related 
to the study (e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, informed 
consent and subject information and/or advertising, as relevant, will be obtained prior to the 
authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation of any 
changes made to the study design.  The Investigator will be required to submit, maintain and 
archive study essential documents according to ICH GCP.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies as required by local 
regulations.  During the conduct of the study, the Investigator should promptly provide written 
reports (e.g., ICH Expedited Reports or any additional reports required by local regulations) to 
the IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects.  Written documentation of the submission to the IEC/IRB should also be provided to 
AbbVie.
15.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing clinical 
study conduct and ethical principles that have their origin in the Declaration of Helsinki.  
Responsibilities of the clinical Investigator are specified in Appendix V.
15.3
Subject Information and Consent
Prior to the initiation of any screening or study-specific procedures, the Investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions 
regarding this study.  Subjects who provide optional samples for analysis will also sign an 
informed consent regarding the collection of these samples (i.e., pharmacogenetic [PG] blood 
sample and tissue samples).  Each informed consent will be reviewed, signed and dated by the 
subject, the person who administered the informed consent, and any other signatories according 


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to local requirements.  A copy of each informed consent will be given to the subject and each 
original will be placed in the subject's medical record.  An entry must also be made in the 
subject's dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
Post-treatment tissue collection and analysis will only be performed if the subject has voluntarily 
signed and dated a separate post-treatment tissue informed consent (or indicated consent within 
the main study informed consent form), approved by an IRB/IEC, after the nature of the testing 
has been explained and the subject has had an opportunity to ask questions.  The post-treatment 
tissue informed consent must be signed before the tissue collection and analysis is performed.  If 
a subject does not consent to the post-treatment tissue collection and analysis, it will not impact 
the subject's participation in the study.
A sample for pharmacogenetic analysis will only be collected if the subject has voluntarily 
signed and dated a separate pharmacogenetic informed consent (or indicated consent within the 
main study informed consent form), approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The pharmacogenetic 
informed consent must be signed before the pharmacogenetic testing is performed.  If the subject 
does not consent to the pharmacogenetic testing, it will not impact the subject's participation in 
the study.
In the event a subject withdraws from the study stored biomarker samples will also be destroyed 
upon request (samples will not be stored for more than 20 years from the time the Clinical Study 
Report is completed).  In the event that destruction is not possible, they will no longer be linked 
to the subject.  If the subject changes his/her consent, and the samples have already been tested, 
those results will still remain part of the overall research data.


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16.0
DATA QUALITY ASSURANCE
Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie 
personnel, the Investigator(s), and the study coordinators/project manager(s).  This meeting will 
include a detailed discussion and review of the protocol and essential documents, performance of 
study procedures, case report form completion and specimen collection methods.
The AbbVie monitor will monitor the study site throughout the study.  Source document review 
will be made against entries on the case report forms and a quality assurance check will be 
performed to ensure that the Investigator is complying with the protocol and regulations.  In 
addition, after the case report forms are retrieved, a review of the data will be conducted by a 
physician or representative at AbbVie.
All data hand entered in the database will be verified at AbbVie.  Any discrepancies will be 
reviewed against the hard-copy case report form and corrected on-line.  After completion of the 
entry process, computer logic and manual checks will be created to identify such items as 
inconsistent study dates.  Any necessary corrections will be made to the database via the 
appropriate change form/electronic CRF.
Routine hematology, serum chemistry and serology, and urinalysis tests will be conducted using 
a certified clinical laboratory.  Laboratory reference ranges will be obtained prior to the initiation 
of the study.  A review of all laboratory results will be conducted by the AbbVie monitor, the 
Investigator and other appropriate personnel from AbbVie.


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17.0
USE OF INFORMATION
All information concerning ABT-414 and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of ABT-414.  This 
information may be disclosed as deemed necessary by AbbVie to other clinical Investigators, 
other pharmaceutical companies, and to governmental agencies.  To allow for the use of the 
information derived from this clinical study and to ensure complete and thorough analysis, the 
Investigator is obligated to provide AbbVie with complete test results and all data developed in 
this study and to provide direct access to source data/documents for study-related monitoring, 
audits, IEC/IRB review, and regulatory inspection.
This confidential information shall remain the sole property of AbbVie, shall not be disclosed to 
others without the written consent of AbbVie, and shall not be used except in the performance of 
this study.
The Investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone number and 
emergency contact information.  This list will be maintained at the study site with other study 
records under adequate security and restricted access, and will not be retrieved by AbbVie.
Any pharmacogenetic and exploratory biomarker research that may be done using DNA samples 
from this study will be experimental in nature and the results will not be suitable for clinical 
decision making or subject management.  Hence, neither the Investigator, the subject, nor the
subject's physician (if different from the Investigator) will be informed of individual subject 
results should analyses be performed, nor will anyone not directly involved in this research.  
Correspondingly, researchers will have no access to subject identifiers.  Individual results will 
not be reported to anyone not directly involved in this research other than for regulatory 
purposes.  Aggregate pharmacogenetic and exploratory biomarker information from this study 
may be used in scientific publications or presented at medical conventions.  Pharmacogenetic 
and exploratory biomarker information will be published or presented only in a way that does not 
identify any individual subject.


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COMPLETION OF STUDY
The Investigator will conduct the study in compliance with the protocol and complete the study 
within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by both the 
Investigator and AbbVie.  The Investigator will provide a final report to the IEC/IRB following 
conclusion of the study, and will forward a copy of this report to AbbVie or their representative.
The Investigator must retain any records related to the study according to local requirements.  If 
the Investigator is not able to retain the records, he/she must notify AbbVie to arrange alternative 
archiving options.
AbbVie will select the signatory coordinating Investigator from the Investigators who participate 
in each multi-center study.  Selection criteria for this signatory Investigator will be based on 
level of participation, and significant knowledge of the clinical research, investigational drug, 
and study protocol.  The signatory Investigator for the study will review and sign the final study 
report in accordance with the European Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end of study is defined as the date of the last subject's last visit.


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INVESTIGATOR'S AGREEMENT
1.
I have received and reviewed the Investigator's Brochure for ABT-414.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable regulations 
and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a handwritten 
signature and will be legally binding.
Protocol Title:
A Randomized, Placebo Controlled Phase 3 Study of ABT-414 with 
Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects 
with Newly Diagnosed Glioblastoma (GBM) with Epidermal Growth 
Factor Receptor (EGFR) Amplification (Intellance1)
Protocol Date: 
26 May 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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20.0
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Mason WP, Del Maestro R, Eisenstat D, et al.  Canadian recommendations for the 
treatment of glioblastoma multiforme.  Curr Oncol.  2007;14(3):110-7.
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Schag CC, Heinrich RL, Ganz PA.  Karnofsky performance status revisited:  reliability, 
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Ellingson BM, Bendszus M, Boxerman, et al.  Consensus recommendations for a 
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Wen PY, Macdonald DR, Reardon DA.  Updated response assessment criteria for 
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Wefel JS, Saleeba AK, Buzdar AU, et al.  Acute and late onset cognitive dysfunction 
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Meyers CA, Smith JA, Bezjak A, et al.  Neurocognitive function and progression in 
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Barry D, Bates ME, Labouvie E.  FAS and CFL forms of verbal fluency differ in 
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Gilbert MR, Dignam JJ, Armstrong TS, et al.  A randomized trial of bevacizumab for 
newly diagnosed glioblastoma.  N Engl J Med.  2014;370(8):699-708.
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Meyers CA, Smith JA, Bezjak A, et al.  Neurocognitive function and progression in 
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Meyers CA, Hess KR.  Multifaceted end points in brain tumor clinical trials:  cognitive 
deterioration precedes MRI progression.  Neuro Oncol.  2003;5:89-95.


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14.
Meyers CA, Hess KR, Yung WK, et al.  Cognitive function as a predictor of survival in 
patients with recurrent malignant glioma.  J Clin Oncol.  2000;18:646-65.
15.
Klein M, Postma TJ, Taphoorn MJ, et al.  The prognostic value of cognitive functioning in 
the survival of patients with high-grade glioma.  Neurology.  2003;61:1796-8.
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Johnson DR, Sawyer AM, Meyers CA, et al.  Early measures of cognitive function predict 
survival in patients with newly diagnosed glioblastoma.  Neuro Oncol.  
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17.
Armstrong TS, Wefel JS, Wang M, et al.  Net clinical benefit analysis of Radiation 
Therapy Oncology Group 0525:  a phase III trial comparing conventional adjuvant 
temozolomide with dose-intensive temozolomide in patients with newly diagnosed 
glioblastoma.  J Clin Oncol.  2013;31(32):4076-84.
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Benedict RH, Schretten D, Groninger L, et al.  Hopkins verbal learning test-revised:  
normative data and analysis of inter-form and test-retest reliability.  Clin Neuropsychol.  
1998;12:43-55.
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Tombaugh TN, Kozak J, Rees L.  Normative data stratified by age and education for 
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1999;14(2):167-77.
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Aaronson NK, Ahmedzai S, Bergman B, et al.  The European Organization for Research 
and Treatment of Cancer QLQ-C30:  a quality-of-life instrument for use in international 
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21.
Osoba D, Aaronson NK, Muller M, et al.  The development and psychometric validation 
of a brain cancer quality-of-life questionnaire for use in combination with general 
cancer-specific questionnaires.  Qual Life Res.  1996;5(1):139-50.
22.
Taphoorn MJ, Claassens L, Aaronson NK et al.  An international validation study of the 
EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of 
life and symptoms in brain cancer patients.  Eur J Cancer.  2010;46(6):1033-40.
23.
Armstrong TS, Mendoza T, Gning I, et al.  Validation of the M.D. Anderson Symptom 
Inventory Brain Tumor Module (MDASI-BT).  J Neurooncol.  2006;80(1):27-35.
24.
EQ-5D-5L and EQ-5D-VAS:  http://www.euroqol.org.
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Stupp  R, Mason WP, van den Bent MJ, et al.  Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma.  N Engl J Med.  2005;352(10):987-96.
26.
Schuster J, Lai, RK, Recht LD, et al.  A phase II, multicenter trial of rindopepimut 
(CDX-110) in newly diagnosed glioblastoma:  the ACT III study.  Neuro Oncol.  
2015;0:1-8.


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27.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, 
DHHS. 28 May 2009 [cited 13 April 2011].  Available from:  
http://evsnci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010 06 
14_QuickReference_8.5x11.pdf.
28.
Dresemann G, Weller M, Rosenthal MA, et al.  Imatinib in combination with hydroxyurea 
versus hydroxyurea alone as oral therapy in patients with progressive pretreated 
glioblastoma resistant to standard dose temozolomide.  J Neurooncol.  
2010;96(3):393-402.
29.
Pintilie M.  Dealing with competing risks: testing covariates and calculating sample size, 
Statistics in medicine, 2002;21(22):3317-3324.
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Fayers P, Aaronson, N, Bjordal K et al.  The EORTC QLQ-C30 scoring manual.  2nd ed.  
Brussels:  the European Organisation for Research and Treatment of Cancer, 1999.
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Cleeland CS, Mendoza TR, Wang XS, et al.  Assessing symptom distress in cancer 
patients:  the MD Anderson Symptom Inventory.  Cancer.  2010:89(7):1634-46.
32.
Mangione CM.  (2000) NEI-VFQ Scoring Algorithm.  Version 2000.
33.
AbbVie.   ABT-414 Investigator’s Brochure Edition 5.  01 July 2016.
34.
Glimm E, Maurer W, Bretz F.  Hierarchical testing of multiple endpoints in group-
sequential trials.  Stat Med.  2010;29(2), 219-28.


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APPENDIX I
SUMMARY OF RANO RESPONSE CRITERIA
Tumor assessments will be assessed using the RANO criteria as outlined below according to 
Wen, et al, "Updated Response Assessment Criteria for High-Grade Gliomas:  Response 
Assessment in Neuro-Oncology Working Group."
Table 1.
Criteria for Determining First Progression Depending on Time from Initial 
Chemoradiotherapy
First Progression
Definition
Progressive disease 
< 12 weeks after completion 
of chemoradiotherapy
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 
80% isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling (e.g., solid tumor areas [i.e., > 70% tumor cell nuclei 
in areas], high or progressive increase in MIB-1 proliferation index compared 
with prior biopsy, or evidence for histologic progression or increased anaplasia 
in tumor).
Note:  Given the difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of radiographic or 
histologic confirmation of progression, will not be sufficient for definition of 
progressive disease in the first 12 weeks after completion of concurrent 
chemoradiotherapy.
Progressive disease 
≥12 weeks after 
chemoradiotherapy 
completion
1.
New contrast-enhancing lesion outside of radiation field on decreasing, 
stable, or increasing doses of corticosteroids.
2.
Increase by ≥ 25% in the sum of the products of perpendicular diameters 
between the first post-radiotherapy scan, or a subsequent scan with smaller 
tumor size, and the scan at 12 weeks or later on stable or increasing doses 
of corticosteroids.
3.
Clinical deterioration not attributable to concurrent medication or 
comorbid conditions is sufficient to declare progression on current 
treatment but not for entry onto a clinical trial for recurrence.
4.
For patients receiving anti-angiogenic therapy, significant increase in 
T2/FLAIR non-enhancing lesion may also be considered progressive 
disease.  The increased T2/FLAIR must have occurred with the patient on 
stable or increasing doses of corticosteroids compared with baseline scan 
or best response after initiation of therapy and not be a result of comorbid 
events (e.g., effects of radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects).
FLAIR = fluid-attenuated inversion recovery
Pseudoprogression and Radiation Effects
The proposed new response criteria suggest that within the first 12 weeks of completion of 
radiotherapy, when pseudoprogression is most prevalent, progression can only be determined if 
the majority of the new enhancement is outside of the radiation field (for example, beyond the 
high-dose region or 80% isodose line) or if there is pathologic confirmation of progressive 
disease.  It is recognized that the proposed histologic criteria have important limitations, but they 


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provide guidance on the type of findings that are suggestive of progressive disease.  For patients 
in whom pseudoprogression cannot be differentiated from true tumor progression, enrollment 
onto trials for recurrent gliomas should not be permitted.  Patients who remain clinically stable 
and/or are suspected to have pseudoprogression based on metabolic or vascular imaging should 
continue with their current therapy.
Enhancement as a Result of Surgery and Other Therapies
Increased enhancement often develops in the wall of the surgical cavity 48 to 72 hours after 
surgery.  To avoid interpretation of post-operative changes as residual enhancing disease, a 
baseline MRI scan should ideally be obtained within 24 to 48 hours after surgery and no later 
than 72 hours after surgery.  The inclusion of diffusion weighted imaging in the immediate 
post-operative MRI scan can be helpful in determining whether new enhancement developing in 
the subsequent weeks or months is caused by sequelae of ischemia or by tumor recurrence.  In 
addition, a transient increase in enhancement that can be difficult to distinguish from recurrent 
disease can also occur after locally administered therapies.  These include chemotherapy wafers, 
immunotoxins delivered by convection enhanced delivery, regionally administered gene and 
viral therapies, immunotherapies, and focal irradiation with brachytherapy and stereotactic 
radiosurgery.  Imaging modalities such as perfusion imaging, magnetic resonance spectroscopy, 
and positron emission tomography scans may sometimes be helpful in differentiating treatment 
effects from recurrent tumor.  However, no imaging modality currently has sufficient specificity 
to conclusively differentiate recurrent tumor from treatment effects, and surgical sampling may 
occasionally be needed to obtain a definitive diagnosis.
Definition of Clinical Deterioration
The definition of clinical deterioration is left to the discretion of the treating physician, but it is 
recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS of at least 
20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration unless attributable to comorbid events or changes in 
corticosteroid dose.  Similarly, a decline in the Eastern Cooperative Oncology Group and WHO 
performance scores from 0 or 1 to 2 or 2 to 3 would be considered neurologic deterioration.
For those subjects who have measurable disease post resection, RANO criteria for assessment of 
CR, PR, SD and PD can be applied.  See the below tables for the definitions to be used.


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Definition of Radiographic Response
Radiographic response should be determined in comparison to the tumor measurement obtained 
at pretreatment baseline for determination of response, and the smallest tumor measurement at 
either pretreatment baseline should be used for determination of progression.  The criteria for 
radiographic changes after therapy are listed in Table 1.  In the event that the radiographic 
changes are equivocal and it is unclear whether the patient is stable or has developed progressive 
disease, it is permissible to continue treatment and observe the patient closely, for example at 
4-week intervals.  If subsequent imaging studies demonstrate that progression has occurred, the 
date of progression should be the date of the scan at which this issue was first raised.  The 
determination of radiographic response after treatment with agents that affect vascular 
permeability is particularly difficult.  In these patients, consideration should be given to 
performing a second scan at 4 weeks to confirm the presence of response or stable disease.  All 
measurable and nonmeasurable lesions should be assessed using the same techniques as at 
baseline.  Ideally, patients should be imaged on the same MRI scanner, or at least with the same 
magnet strength, for the duration of the study to reduce difficulties in interpreting changes.
Patients with nonmeasurable enhancing disease whose lesions have significantly increased in 
size and become measurable (minimal bidirectional diameter of ≥ 10 mm and visible on at least 
two axial slices that are preferably, at most, 5 mm apart with 0 mm skip) will also be considered 
to have experienced progression.  The transition from a nonmeasurable lesion to a measurable 
lesion resulting in progression can theoretically occur with relatively small increases in tumor 
size (e.g., a 9 × 9 mm lesion [nonmeasurable] increasing to a 10 × 11 mm lesion [measurable]).  
Ideally, the change should be significant (> 5 mm increase in maximal diameter or ≥ 25% 
increase in sum of the products of perpendicular diameters of enhancing lesions).  In general, if 
there is doubt about whether the lesion has progressed, continued treatment and close follow-up 
evaluation will help clarify whether there is true progression.  If there is uncertainty regarding 
whether there is progression, the patient may continue on treatment and remain under close 
observation (e.g., evaluated at 4-week intervals).  If subsequent evaluations suggest that the 
patient is in fact experiencing progression, then the date of progression should be the time point 
at which this issue was first raised.


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Table 2.
Summary of the Proposed RANO Response Criteria
Criterion
CR
PR
SD
PD
T1 gadolinium enhancing disease
None
≥ 50% ↓
< 50% ↓ but < 25% ↑
≥ 25% ↑*
T2/FLAIR
Stable or ↓
Stable or ↓
Stable or ↓
↑*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or ↓
Stable or ↓
NA**
Clinical status
Stable or ↑
Stable or ↑
Stable or ↑
↓*
Requirement for response
All
All
All
Any*
RANO = Response Assessment in Neuro-Oncology; CR = complete response; PR = partial response; SD = stable disease; 
PD = progressive disease; FLAIR = fluid-attenuated inversion recovery; NA = not applicable
*
Progression occurs when this criterion is present.
**
Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent 
clinical deterioration.


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APPENDIX II
RTOG 3508/ABBVIE STUDY M13-813 PROTOCOL SYNOPSIS
AbbVie Inc.
Protocol Number:  M13-813
Name of Study Drug:  ABT-414
Phase of Development:  3
Name of Active Ingredient:  ABT-414
Date of Protocol Synopsis:  26 May 2019
Protocol Title:  A Randomized, Placebo Controlled Phase 3 Study of ABT-414 with Concurrent Chemoradiation 
and Adjuvant Temozolomide in Subjects with Newly Diagnosed Glioblastoma (GBM) with Epidermal Growth 
Factor Receptor (EGFR) Amplification (Intellance1)
Primary Objective:
To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ 
prolongs Overall Survival (OS) among subjects with newly diagnosed GBM harboring EGFR amplification.
Secondary Objectives:  To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ 
plus adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR
amplification for the following endpoints:

PFS

OS for the MGMT unmethylated tumor subgroup

OS for the MGMT methylated tumor subgroup

Time to deterioration in symptom severity score  (MDASI-BT)

Time to deterioration in symptom interference score (MDASI-BT)

Time to deterioration in neurocognitive functioning on the Hopkins Verbal Learning Test Revised 
(HVLT-R) total recall score

OS for the EGFRvIII-mutated tumor subgroup

PFS for EGFRvIII-mutated tumor subgroup
Safety:

Assessment of comparative safety
Tools:
Symptom Inventory:  MD Anderson Symptom Index for Brain Tumors (MDASI-BT).
Neurocognitive Functioning:  The Hopkins Verbal Learning Test-Revised (HVLT-R) for memory; and COWA-
FAS verbal fluency test for executive function.
Quality of Life:  (Exploratory Objective) European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire (EORTC QLQ-C30 with EORTC-QLQ-BN20 (brain tumor module) and EQ-5D-5L
Investigators:
Multicenter, multi-national
Study Sites:
Approximately 200
Study Population:
Newly diagnosed GBM subjects with EGFR amplification.
Number of Subjects to be Enrolled:
Approximately 640


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Mechanism of Action:
ABT-414 is a newer generation ADC consisting of:  (1) a veneered "humanized" recombinant IgG1κ antibody 
that has binding properties specific to a unique epitope of human EGFR with (2) non-cleavable maleimido-
caproyl linkers each attached to (3) a potent antimicrotubule agent, monomethylauristatin F (MMAF).  The 
antibody binds to the activated EGFR epitope (even in the absence of the EGFRvIII mutation), is internalized, 
and then intracellular enzymes release the toxin leading to inhibition of microtubule function, the disruption of 
critical cellular processes, and cell death.  Importantly, ABT-414 binds to an epitope that is available 
predominantly on tumor cells with either the EGFRde2-7 (EGFRvIII) deletion mutant or on tumor cells with 
activated wild-type EGFR (i.e., with EGFR amplification).  The epitope is largely inaccessible when EGFR is 
expressed at normal physiological levels; thus, ABT-414 has limited binding to non-activated, wild-type EGFR
expressed on normal tissues.  These properties, therefore, favor limited effects of the toxin on normal tissues 
while maintaining a high degree of activity on EGFR-amplified tumor cells.
Methodology:
This is a Phase 3 randomized double-blind, placebo-controlled trial comparing the efficacy and safety of 
ABT-414 versus placebo, each as concurrent treatment with standard-of-care therapy of radiation/TMZ plus 
adjuvant TMZ and followed by ABT-414/placebo monotherapy, in subjects with newly diagnosed GBM.
The study comprises a Screening Period of up to 7 weeks from surgery; a 6-week concomitant Chemoradiation 
Phase; an Adjuvant Phase beginning approximately 4 weeks after completion of chemoradiation, and a 
Follow-Up Phase.  The Adjuvant Phase is comprised of 28-day cycles, with subjects receiving concomitant TMZ 
and study drug (ABT-414/placebo) for the first 6 cycles, and study drug (ABT-414/placebo) monotherapy for the 
following 6 cycles.  Subsequent cycles will start approximately 28 days from the start of the previous cycle, and 
the cycle schedule will not be affected by delays or interruptions in TMZ or ABT-414/placebo dosing.  Adjuvant 
treatment will be discontinued once disease progression has been determined.  A Final Study Drug Visit will be 
performed upon discontinuation of study drug (ABT-414/placebo) for any reasons, followed by a 35-Day and 
49-Day Follow-up Visits (± 3 days).  Subjects who are unable to attend the 49 Day Follow-up will be phoned to 
obtain adverse event and concomitant medication information.  In the Follow-Up Phase, subjects who complete 
adjuvant treatment or discontinue study drug prior to disease progression will continue to undergo MR imaging 
and assessment of neurocognitive functioning and patient reported outcomes (PRO) approximates every 8 weeks 
up to and including at the time of disease progression, starting 8 weeks after the last scheduled PRO assessments 
in the Adjuvant Phase.  After disease progression, overall survival will continue to be assessed quarterly.
A sample of pre-treatment tumor tissues will be collected and sent to central laboratories to confirm diagnosis of 
GBM (required to enroll in the trial) and test for EGFR amplification (required to enroll in the trial), MGMT
promoter methylation (a stratification factor), EGFRvIII mutation (a stratification factor) and other biomarkers 
prior to starting chemoradiation.  If a subject has a repeat surgery before initiating treatment, then the tissue from 
either biopsy/resection may be used for histologic and EGFR amplification, EGFRvIII mutation and MGMT
promoter methylation testing.  If molecular results are discordant between multiple specimens from the same 
patient, then the results that permit eligibility will be used.  Remaining sample tissue will be retained for other 
exploratory molecular analysis where allowed by local regulations.  If local regulations do not allow tissue 
shipment or storage, the tissue will be immediately returned or destroyed after eligibility testing.
Screening procedures must be completed prior to Day 1 of the Chemoradiation Phase.  Screening procedures will 
include signing of a study consent form, medical history, Karnofsky Performance Scale (KPS) assessment and 
recursive partitioning analysis (RPA) classification, baseline ECG, physical, ophthalmologic and neurological 
examinations, Patient Reported Outcomes (PRO) and neurocognitive assessments, laboratory tests (≤ 21 days 
from treatment start), and pregnancy test (≤ 7 days from treatment start) if applicable.  If a subject starts 
chemoradiation more than 28 days after surgery, the subjects will have a brain MRI 21 (but preferably fewer) 
days prior to Day 1 Week 1 of the Chemoradiation Phase to be used as the baseline for efficacy analyses; the 
timing of the MRI should allow sufficient time to revise the radiation therapy plan if needed due to a significant 
change in tumor since surgery.  Safety-related evaluations will be conducted within 14 or fewer days prior to Day 
1 of the Chemoradiation Phase.  Subjects who screen positive for EGFR amplification in the tumor tissue may 
enter the study if all inclusion/exclusion criteria are met.


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Methodology (Continued):
Upon study entry, subjects will be stratified according to the following 4 factors:  region of the world (US/Canada 
or other), RPA classes (III, IV or V), MGMT methylation (methylated or unmethylated), and EGFRvIII status 
(mutated or other).  Subjects will be randomized within each stratum on a 1:1 ratio to receive either ABT-414 
Arm A or Placebo Arm B during the Chemoradiation and Adjuvant therapy phases.
During the Chemoradiation Phase, all subjects will undergo focal RT, with one treatment of approximately 2 gray 
(Gy) given daily 5 days per week for a total of approximately 60 Gy over approximately 6 weeks (and no more 
than 7 weeks).  TMZ will be administered continuously from Day 1 of radiotherapy to the last day of radiation 
(including weekends and holidays) at a daily oral dose of 75 mg/m2 for a maximum of 49 days.  Subjects in 
Arm A will receive blinded ABT-414 at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 2 weeks (Day 1 
of Weeks 1, 3, and 5 of the 6-week regimen).  Subjects in Arm B will receive blinded placebo IV infusion over 
30 – 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen).  Treatment in the 
Chemoradiation Phase must begin ≤ 7 weeks after biopsy/surgery.
The start of the first cycle during the Adjuvant Therapy Phase will be scheduled approximately 28 days after the 
last day of radiotherapy.  During the Adjuvant Therapy Phase, all subjects will receive oral TMZ 150 – 200 
mg/m2 once daily on Days 1 – 5 of each 28-day cycle for 6 cycles unless there is disease progression, 
unacceptable toxicity, or other reasons to discontinue.  Subjects in Arm A will receive blinded ABT-414 at 1.25 
mg/kg by intravenous infusion on Day 1 and Day 15 of each 28-day cycle for 12 cycles.  Subjects in Arm B will 
receive blinded placebo IV infusion on Day 1 and Day 15 of each 28-day cycle for 12 cycles.
If, after completing 12 cycles of adjuvant treatment, the subject is tolerating study drug (ABT-414 or placebo) 
and the Investigator believes the subject is continuing to benefit from ongoing study drug treatment, the 
Investigator may extend the Adjuvant Phase after consultation with the Neuro-Medical Oncology Chair or 
AbbVie Medical Monitor, as long as disease progression has not been determined.
Occurrence of disease progression to calculate PFS will be determined by the Investigator, based on local 
evaluation of images and other clinical information using the Response Assessment in Neuro oncology (RANO) 
criteria.  Post-baseline scans will be obtained ≤ 14 days before Day 1 of each odd-numbered cycle (Cycles 1, 3, 5, 
etc.) of the Adjuvant Phase and ≤ 14 days before each visit (approximately every 8 weeks) of the Follow-Up 
Phase.  MR images will also be reviewed centrally by an independent blinded reviewer for radiographic evidence 
of disease progression.  When study drug is discontinued for any reason, a Final Study Drug Visit will be 
conducted.  All subjects will have a 35-Day and 49-Day Follow-Up Visits (± 3 days) after the last dose of 
ABT-414/placebo.  Overall survival will be assessed quarterly after study discontinuation.
All subjects will receive prophylactic eye drops with each dose of ABT-414/placebo for 7 consecutive days, 
starting from 2 days prior to infusion and continuing until 4 days after infusion.  The eye drop formulations 
recommended for the study are ranked by steroid potency from Level 1 (non-steroid artificial tears) to Level 4 
(high-potency steroid where available.  Subjects will be monitored with regular ophthalmologic examinations 
(with additional symptom-driven examinations as needed).  The potency of the eye drop formulation given with 
subsequent ABT-414/placebo doses will be adjusted upward or downward based on corneal findings.  To 
minimize unnecessary risks associated with prolonged administration of ocular steroids there is a step-down in 
the level of eye drop potency for subjects who have received at least 2 doses of ABT-414/Placebo and with Grade 
1 or no eye toxicity who have no evidence of corneal microcysts on 2 consecutive ophthalmic examinations.


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Methodology (Continued):
During chemoradiation, subjects should receive antiemetic prophylaxis and antibiotics should be per local 
regulation guidelines to prevent Pneumocystis (jirovecii) pneumonia (PCP) while receiving TMZ.  Supportive 
care including systemic corticosteroid use is allowed.  Anti-cancer agents, other investigational anti-neoplastic 
drugs and some uses of growth factors are prohibited during the study.  Any other type of chemotherapy, 
immunotherapy, biologic therapy, medication (including over the counter) or vaccine used for antineoplastic 
intent are also prohibited.
An open-label, single-group sub-study of ABT-414 use in newly diagnosed GBM subjects with mild to moderate 
hepatic impairment is included in Appendix IX.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Histologically confirmed de novo Grade IV glioma (GBM, gliosarcoma or other subvariants) confirmed 
by central pathology tissue screening.
2.
EGFR amplification in tumor tissue confirmed by central assessment.
3.
Inclusion Criteria removed in Amendment 5.
4.
The subject must have recovered from the effects of surgery, post-operative infection, and other 
complications before enrollment including suture/staple removal from brain surgery and sufficient wound 
healing before randomization.
5.
≥ 18 years of age.
6.
Karnofsky performance status ≥ 70 at assessment ≤ 14 days prior to randomization.
7.
Results for required stratification factors (EGFRvIII status, MGMT methylation status, Recursive 
Partitioning Analysis (RPA) class, and region of world) available prior to randomization.
8.
Subject has adequate bone marrow, renal, and hepatic function ≤ 21 days prior to randomization as 
follows:

Absolute neutrophil count (ANC) ≥ 1,500/mm3.

Platelets ≥ 100,000/mm3.

Hemoglobin (Hgb) ≥ 9.0 g/dL (Note:  The use of transfusion or other intervention to achieve Hgb 
≥9.0 g/dL is acceptable.).

Renal function:  calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula.

Hepatic function:  Total bilirubin ≤ 1.5 times upper limit of normal (ULN), Aspartate 
Aminotransferase (AST), and Alanine Aminotransferase (ALT) ≤ 3 times upper limit of normal 
(ULN).  Subjects with Gilbert's syndrome documented in medical history may be enrolled if total 
bilirubin is < 3 times ULN.
9.
Electrocardiogram (ECG) without evidence of acute cardiac ischemia ≤ 21 days prior to randomization.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
10.
Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year or 
surgically sterile by bilateral salpingectomy, bilateral oophorectomy or hysterectomy) should practice at 
least one accepted method of birth control listed below during study entry, for the entire duration of the 
study and for at least 6 months after treatment with ABT-414 and TMZ treatment has ended.  Male 
subjects should practice at least one of the accepted methods of birth control during study and for at least 
6 months after ABT-414 and TMZ.  If using a condom, practice at least one other methods of birth 
control listed below during the study and for at least 6 months after ABT-414 and TMZ:

Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal) associated with the inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1;

Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of 
ovulation, initiated at least 1 month prior to Study Day 1;

Bilateral tubal occlusion/ligation;

True abstinence:  Refraining from heterosexual intercourse when this is in line with the preferred and 
usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable];

A vasectomized male subject or a vasectomized partner of a female subject;

Intrauterine device, IUD (females);

Intrauterine hormone-releasing system, IUS (females);

Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal 
jellies or cream) unless not deemed acceptable as highly effective contraception by local regulations.
11.
Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days 
prior to randomization.
12.
Must voluntarily sign and date informed consent form, for tumor tissue biomarker testing and for study 
participation, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), 
prior to the initiation of any screening or study-specific procedures.
Main Exclusion:
1.
Subject has multifocal GBM, defined as discrete sites of disease without contiguous T2/FLAIR 
abnormality that require distinct radiotherapy ports.

Note that satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the 
main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are 
permitted.  For any questions, please contact the Sponsor.
2.
Exclusion criteria removed in Amendment 5.
3.
Subject has recurrent GBM.
4.
Exclusion criteria removed in Amendment 5.
5.
Subject has metastatic GBM.
6.
Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior 
chemotherapy for a different cancer is allowable, except prior TMZ.
7.
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation 
fields.
8.
Any prior therapy for glioblastoma except surgery (intra-operative techniques to guide resection are 
allowed as are experimental imaging techniques).
9.
Prior invasive malignancy (except for non-melanomatous skin cancer; carcinoma in situ of the breast, oral 
cavity, or cervix) unless disease free for ≥ 2 years.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
10.
Prior, concomitant, or planned concomitant treatment with anti-neoplastic intent including but not limited 
to Novo Tumor Treatment Fields (Novo TTF, EGFR-targeted therapy (including EGFRvIII-directed 
therapy), bevacizumab, Gliadel wafers or other intratumoral or intracavitary anti-neoplastic therapy, or 
other experimental therapeutics intended to treat the tumor.  Diagnostic or imaging studies, quality of life, 
biomarker or epidemiological studies; surgery and operative guides to improve extent of resection are 
allowed.
11.
Subject has had major immunologic reaction to an IgG-containing agent.
12.
Subject has had LASIK (laser-assisted in situ keratomileusis) procedure within the last 1 year or cataract 
surgery within the last 3 months.
13.
Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or excipients, and 
dacarbazine (contraindication for TMZ).
14.
Subject is unsuitable for receiving ocular steroids:

Subject has any active viral disease of the cornea or conjunctiva, including epithelial herpes simplex 
keratitis (dendritic keratitis), vaccinia, and varicella; mycobacterial infection of the eye; fungal 
diseases of ocular structures; or any other contraindication for ocular steroid use.

Subject has a known or suspected hypersensitivity to any ocular steroid.

Subject has primary open angle glaucoma or a history of steroid-induced intraocular pressure 
elevation.
15.
Subject is a lactating or pregnant female.
16.
Severe, active co-morbidity, defined as follows:

Severe hepatic impairment (Child-Pugh category C or higher [score of 10 or higher (Appendix VII)]):  
Subjects with mild or moderate hepatic impairment (Child-Pugh score of 5 – 9) may be eligible for 
treatment, as described in Appendix IX.

Unstable angina and/or congestive heart failure within the last 6 months.

Transmural myocardial infarction within the last 6 months.

Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of ≥2 mm 
using the analysis of an EKG performed within 21 days prior to enrollment.

New York Heart Association grade II or greater congestive heart failure requiring hospitalization 
within 12 months prior to enrollment (Appendix IV).

History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months.

Serious and inadequately controlled cardiac arrhythmia.

Acute bacterial or fungal infection requiring intravenous antibiotics at the time of enrollment.

Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of enrollment.

Subjects with clinically defined Acquired Immune-Deficiency Syndrome (AIDS)-defining illness.  
This is necessary to ensure subjects are likely to be able to receive the full TMZ regimen.

Active connective tissue disorders, such as lupus or scleroderma that in the opinion of the 
Investigator may put the subject at high risk for radiation toxicity.

Any other major medical illnesses or psychiatric impairments that in the Investigator's opinion will 
prevent administration or completion of protocol therapy.
17.
Subjects treated on any other therapeutic clinical protocols within 30 days prior to study entry or during 
participation in the study except intra-operative therapy to guide resection or experimental imaging 
without therapeutic intent.
18.
Inability to undergo contrast-enhanced MRI scans.


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Background Therapy:
All subjects will receive standard-of-care treatment for newly diagnosed glioblastoma, per local prescribing 
information and local institutional guidelines, as background therapy.
Chemoradiation Phase:  All subjects will undergo focal radiotherapy, 60 Gy in 30 fractions (or 59.4 Gy in 
33 fractions) over approximately 6 weeks (and no more than 7 weeks).  TMZ will be administered continuously 
from Day 1 of radiotherapy to the last day of radiation (including weekends and holidays) at a daily oral dose of 
75 mg/m2 for a maximum of 49 days.
Adjuvant Phase:  During the Adjuvant Therapy Phase, all subjects will receive oral TMZ 150 – 200 mg/m2 once 
daily on Days 1 – 5 of each 28-day cycle for 6 cycles unless there is disease progression, unacceptable toxicity, or 
other reasons to discontinue.  The start of the first cycle during the Adjuvant Therapy Phase will be scheduled 
approximately 28 days after the last day of radiotherapy.
Investigational Product:
ABT-414
Doses:
20 mg and 100 mg vials
sterile lyophilisate to be reconstituted and further diluted for IV infusion
Mode of Administration:
Intravenous (IV) infusion administered over 30 to 40 minutes.
Reference Therapy:
Placebo solution
Doses:
To match 20 mg and 100 mg vials
sterile lyophilisate to be reconstituted and further diluted for IV infusion
Mode of Administration:
Intravenous (IV) infusion administered over 30 to 40 minutes
Reference Therapy:
Temozolomide (TMZ)
Doses:
Daily Day 1 to maximum 49 days in chemoradiation phase
Daily Days 1 – 5 every 28 days in adjuvant phase
Mode of Administration:
Oral
Duration of Treatment:
In the absence of treatment delays due to adverse event(s), treatment may continue as specified in the Treatment 
Plan Overview, Section 5.1, or until one of the following criteria applies:
The subject experiences disease progression
The subject experiences intercurrent illness that prevents further administration of treatment
The subject experiences excessive toxicity precluding further therapy with either ABT-414 or TMZ, 
according to the Investigator
Subject decides to withdraw consent for participation in the study
General or specific changes in the subject's condition render the subject unacceptable for further treatment 
in the judgment of the Investigator
Subject becomes pregnant while on study
Subjects unable to continue either TMZ or ABT-414/placebo due to excessive drug-specific toxicity will be 
allowed to continue therapy with the other, tolerated therapy components until one of the other criteria above is 
met.


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Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint will be OS.
Secondary endpoints are as follows:

PFS

OS for the MGMT unmethylated tumor subgroup

OS for the MGMT methylated tumor subgroup

Time to deterioration in symptom severity score (MDASI-BT)

Time to deterioration in symptom interference score (MDASI-BT)

Time to deterioration neurocognitive functioning on the Hopkins Verbal Learning Test-Revised 
(HVLT-R) total recall score

OS for EGFRvIII-mutated tumor subgroup

PFS for EGFRvIII-mutated tumor subgroup
Safety:

Assessment of comparative safety
Tools:
Symptom Inventory:  MD Anderson Symptom Index for Brain Tumors (MDASI-BT).
Neurocognitive Functioning:  HVLT-R for verbal memory, and COWA-FAS for executive function.
Quality of Life:  European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30) with the EORTC-QLQ-BN20 (brain tumor) module, EQ-5D-5L and EQ-5D-VAS for health 
status; National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) for visual function and impact on 
daily activities.
Pharmacokinetic:
Blood samples for assay of ABT-414, total ABT-806, anti-drug antibodies (ADA), neutralizing anti-drug 
antibodies (nADA) and unconjugated cys-mcMMAF will be collected at designated time points throughout the 
study.
Pharmacodynamic:
Plasma and serum will be collected at designated time points throughout the study.  Tumor tissues obtained 
during biopsy or surgery will also be used for pharmacodynamic studies.
Safety:
Adverse events, laboratory profiles, physical exams, ECGs, and vital signs will be assessed throughout the study.  
Eye examinations will be assessed at baseline and throughout the study.
Statistical Methods
Analysis Sets:
The following analysis sets will used for analysis of safety and primary and secondary efficacy endpoints of the 
study:

Full Analysis Set will comprise all randomized subjects regardless of whether they received study 
treatment.  Subjects will be classified according to the treatment they were assigned at the time of 
randomization.  The Full Analysis Set will be the primary analysis set for the analysis of efficacy 
endpoints.

Safety Analysis Set (SAS) will comprise all randomized subjects who receive at least 1 dose of study 
treatment (either RT, TMZ, or ABT-414).  Subjects will be classified according to treatment received.  
Thus, a subject randomized to Arm A who receives RT + TMZ but does not receive ABT-414 will be 
considered in the control group (Arm B) for safety analysis.

Per-protocol Set (PPS) will comprise all randomized subjects excluding those with major deviation from 
study inclusion and exclusion criteria and compliance with procedures.  Subjects will be classified 
according to treatment assigned.  The PPS will be used for supportive analysis of efficacy endpoints.


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Statistical Methods (Continued):
Efficacy Analysis:
Analysis of OS and PFS:
The primary efficacy endpoint for the study is OS and PFS is considered as one of the secondary efficacy 
endpoints.  Overall survival is defined as time from randomization to death.  For subjects who are not reported to 
have died at the time of an analysis, OS will be right-censored at the last date the subject is documented to be 
alive.  PFS is defined as time from randomization to progression of disease (per RANO criteria) or death, 
whichever occurs first.  For subjects who are not documented to have experienced a PFS event at the time of an 
analysis, PFS will be right-censored on the date of their last adequate radiographic assessment of disease.  To 
meet the primary and secondary objectives, OS and PFS will be compared between treatment arms A and B using 
stratified log-rank test statistics or a weighted version of this test (to be pre-specified in the Statistical Analysis 
Plan document (the SAP), adjusting for the study stratification factors and additional independent prognostic 
factors as deemed appropriate, to be specified in the SAP.  The hazard-ratio of OS and PFS for ABT-414 Arm A 
compared to placebo Arm B will be estimated by fitting Cox-proportional hazards regression models adjusting 
for the main-effects of the stratification factors and additional independent prognostic factors as deemed 
appropriate, to be specified in the SAP.
Interim Analysis
An interim superiority and futility analysis of efficacy data will be performed when 75% (332) of the 
441 required maximum number of deaths are observed.  The analysis will be performed using the Full Analysis 
Set, with all randomized cases being included in the treatment arm to which they were randomized regardless of 
what treatment the subjects actually received.  The primary endpoint of OS will be compared between treatment 
Arms A and B using stratified log-rank test statistics or a weighted version, as pre-specified in the SAP, adjusting 
for the study stratification factors and additional independent prognostic factors as deemed appropriate, to be 
specified in the SAP.  The hazard-ratio of OS for ABT-414 Arm A compared to placebo Arm B will be estimated 
by fitting Cox-proportional hazards regression models adjusting for the main-effects of the stratification factors 
and additional independent prognostic factors as deemed appropriate, to be specified in the SAP.  Adjustment of 
the level of significance (alpha) for multiple testing will be made using the O'Brien-Fleming group sequential 
spending function for early rejection of the null hypothesis to declare superiority.  In addition, futility analysis 
will be carried at same time.  If the estimated Cox HR exceeds 0.90 then trial may be stopped for futility.
The unblinded interim results will first be reviewed by the IDMC, and the trial will be considered for early 
stopping if the IDMC makes such a recommendation after consideration of the OS results and all supportive 
evidence including all secondary endpoints and safety.


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Statistical Methods (Continued):
Sample-Size Justification:
The sample sizes are calculated based on the approach of doing the primary endpoint analyses (OS) using the 
FAS.
A total of 640 evaluable subjects are expected to be randomized.  With 441 deaths there will be 85% power to 
detect a 25% reduction in the hazard of death (HR = 0.75) using a log rank test at a one-sided 2.5% level of 
significance.  Median OS of 16 months is expected in the placebo arm.
Type I Error Control:
To maintain overall type I error control for the overall study, each secondary endpoint will be tested in the order 
listed if the primary endpoint (OS) and all preceding secondary endpoints show statistically significant results at 
the 1-sided 0.025 level of significance.  The O'Brien-Fleming method will be implemented to protect the 
one-sided type I error of 0.025.  A nominal alpha level of 0.00969 will be used for the interim efficacy analysis 
for OS.  For the final analysis, the primary efficacy endpoint will be tested at the one-sided nominal alpha level of 
0.0221 after adjusting for the interim look at efficacy data.
Pharmacokinetic:
Peak and trough concentrations (Cmax and Ctrough) of ABT-414 and total ABT-806 antibody will be summarized 
from the observed concentration data.  Population pharmacokinetic parameters of ABT-414, total ABT-806 and 
cys-mcMMAF such as clearance and volume of distribution will be estimated using a nonlinear mixed effect 
modeling analysis.
Safety Analysis:
AbbVie will assess adverse events, laboratory data, and vital signs throughout the study.  Analyses of adverse 
events will include only "treatment-emergent" events, i.e., those that start or worsen on or after the day of the 
first dose of study drug.  Adverse events severity and laboratory evaluation changes will be assessed by utilizing 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
Adverse events will be summarized by preferred terms within a System and Organ Class according to the most 
current Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Changes from baseline will be 
analyzed for each scheduled post-baseline visit and for the final visit for blood chemistry and hematology 
parameters, as well as urinalysis and vital sign parameters.  Shifts in laboratory values from baseline NCI 
CTCAE grades to maximum and final post-baseline grades will be assessed.


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APPENDIX III
ADVERSE EVENTS EXPECTED DUE TO GBM OR PROGRESSION 
OF GBM
Tinnitus
Diplopia
Dysphagia
Hypoaesthesia oral
Paraesthesia oral
Facial pain
Disease progression
Pyrexia
Subdural haematoma
Subdural haemorrhage
Abnormal loss of weight
Decreased appetite
Dehydration
Anaplastic astrocytoma
Glioblastoma
Glioblastoma multiforme
Malignant glioma
Malignant neoplasm progression
Neoplasm progression
VIIth nerve paralysis
Oculofacial paralysis
Facial nerve disorder
Facial paresis
Facial neuralgia
Hypoaesthesia
Burning sensation
Paralysis
Dementia
Dysarthria
Agnosia
Prosopagnosia
Apraxia
Hemiapraxia
Gait apraxia
Dyspraxia
Agraphia
Alexia
Cerebral haemorrhage
Cerebral haematoma
Hyperaesthesia
Ataxia
Cerebellar ataxia
Cerebral ataxia
Myoclonus
Post-anoxic myoclonus
Amnesia


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Ataxia
Atonic seizures
Balance disorder
Brain compression
Brain oedema
Cerebrospinal fluid retention
Cerebrospinal thrombotic tamponade
Cervicogenic headache
Clonic convulsion
Clumsiness
Cluster headache
Convulsion
Convulsions local
Coordination abnormal
Cranial nerve disorder
Cranial nerve palsies multiple
Cranial nerve paralysis
Epilepsy
Epileptic aura
Exertional headache
Fumbling
Headache
Hemianopia
Hemiparesis
Hemiplegia
IIIrd nerve paralysis
IIIrd nerve paresis
Incoherent
Intracranial pressure increased
IVth nerve paresis
Language disorder
Lethargy
Loss of consciousness
Memory impairment
Movement disorder
Myoclonic epilepsy
Paraesthesia
Paresis cranial nerve
Partial seizures
Partial seizures with secondary generalisation
Postictal headache
Postictal state
Preictal state
Quadranopia
Sedation
Seizure like phenomena
Slow speech
Somnolence
Speech disorder


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Status epilepticus
Stupor
Tension headache
Tonic clonic movements
Tonic convulsion
Tonic posturing
Tunnel vision
Typical aura without headache
Vascular headache
Vertigo CNS origin
VIIIth nerve lesion
Visual field defect
Affect lability
Agitation
Anxiety
Anxiety disorder
Anxiety disorder due to a general medical condition
Depressed mood
Distractibility
Elevated mood
Executive dysfunction
Hyposomnia
Impaired reasoning
Inappropriate affect
Initial insomnia
Insomnia
Mood altered
Mood swings
Incontinence
Urinary incontinence
Intracerebral haematoma evacuation
Subdural haematoma evacuation
Drain of cerebral subdural space
Deep vein thrombosis
Thrombosis


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APPENDIX IV
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION
The NYHA classifies heart failure into classes based on functional limitations and severity
Class
Patient Symptoms
Class I
(Normal)
Few observable symptoms, no limitation in ordinary physical activity.
Class II
(Mild)
Mild observable symptoms and slight limitation during ordinary activity.  
Comfortable at rest.
Class III
(Moderate)
Marked limitation in physical activity due to symptoms even during 
less-than-ordinary activity.  Comfortable only at rest.
Class IV
(Severe)
End-stage heart failure.  Severe limitations.  Experience symptoms even 
while at rest.


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APPENDIX V
RESPONSIBILITIES OF THE CLINICAL INVESTIGATOR
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices (GCP) 
and local regulations and guidelines governing the study at the site location. In signing the 
Investigator Agreement in Section 19.0 of this protocol, the Investigator is agreeing to the 
following:
1.
Conducting the study in accordance with the relevant, current protocol, making changes in 
a protocol only after notifying AbbVie, except when necessary to protect the safety, rights 
or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees [e.g., independent ethics committee (IEC) or institutional 
review board (IRB)] review and approval of the protocol and amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to AbbVie 
and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, including 
the instructions for use and the potential risks and side effects of the investigational 
product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study 
about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those 
records available for inspection by representatives of AbbVie and/or the appropriate 
regulatory agency, and retaining all study-related documents until notification from 
AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the 
initial clinical investigation and all amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others, to the appropriate individuals 
(e.g., Coordinating Investigator, Institution Director) and/or directly to the ethics 
committees and AbbVie.


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10. Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate hazards to 
human subjects.


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APPENDIX VI
RPA CLASSIFICATION CRITERIA
RPA Class
Criteria
Class III
Age < 50 and KPS 90 – 100
Class IV
Age < 50 and KPS < 90:  OR age ≥ 50 and KPS 70 – 100 and 
partially or total resected with no worse than minor neurofunction 
impairment
Class V
Age ≥ 50 and KPS 70 – 100 and underwent prior partial or total 
tumor resection with worse than minor neurofunction impairment:  
OR age ≥ 50 and KPS 70 – 100 and underwent prior tumor biopsy 
only
If a subject has a repeat surgery prior to randomization, the extent of surgical resection after the 
repeat surgery (biopsy-only vs. partial/total resection) will be used for determining RPA class.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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APPENDIX VII CHILD-PUGH SCORE
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, µmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Slight
Moderate to severe
Hepatic encephalopathy*
None
Grade 1 or 2
(or suppressed with 
medication)
Grade 3 or 4
(or refractory)
*
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves.
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity.
The Child-Pugh classification is defined in terms of the sum of the scores for the five parameters, as shown in Appendix VII.

A score of 5 or 6 indicates Child-Pugh Category A (mild hepatic impairment).

A score of 7, 8, or 9 indicates Child-Pugh Category B (moderate hepatic impairment).


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APPENDIX VIII LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviations
ADC
Antibody Drug Conjugate
AE
Adverse Event
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CBC 
Complete Blood Count
CTB
Clinical Trial Battery
CNS 
Central Nervous System
COWA
Controlled Oral Word Association
CR
Complete Response
CT
Computerized tomography
CUSA
Cavetron Ultrasonic Aspirator
D
Day
Depatux-M
Depatuxizumab Mafodotin (ABT-414)
DICOM
Digital Imaging and Communications in Medicine
DLT
Dose Limiting Toxicities
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eCRFs
Electronic Case Report Forms
EGFR
Epidermal Growth Factor Receptor
EORTC
European Organization for Research and Treatment of Cancer
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
EQ-5D
EuroQol 5 Dimensions
EQ-5D-VAS
EuroQol 5 Dimensions Value Sets
EU
European Union
FAS
Full Analysis Set
FFPE
Formalin-fixed Paraffin Embedded
FLAIR
Fluid Attenuated Inversion Recovery
GBM
Glioblastoma
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase


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GTT
Eye drop(s)
Gy
Gray
Hgb
Hemoglobin
HRQoL
Health Related Quality of Life
HVLT-R
Hopkins Verbal Learning Test-Revised
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC 
Independent Ethics Committee
IGRT
Image-guided Radiation Therapy
IMRT
Intensity-modulated Radiation Therapy
IMP 
Investigational Medicinal Product
INR
International Normalized Ratio 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
K2EDTA
Potassium Edetic acid (ethylenediaminetetraacetic acid)
KPS
Karnofsky Performance Status
LDH
Lactate Dehydrogenase
mAbs
monoclonal antibodies
MCV
Mean Corpuscular Volume
MDASI-BT
M.D. Anderson Symptom Inventory Brain Tumor Module
MedDRA
Medical Dictionary for Regulatory Activities
MGMT
O6-methylguaninemethlytransferese
MMAF
monomethylauristatin F
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MV
Megavoltage
NCIC
National Cancer Institute of Canada
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NEI-VFQ-25
National Eye Institute Visual Functioning Questionnaire – 25
NOVOTTF
NovoTumor Treatment Fields
OU
Each Eye
OS
Overall Survival
PCP
Pneumocystis jirovecii pneumonia
PD
Progressive Disease
PE 
Physical Exam
PFS
Progression-Free Survival
PG
Pharmacogenetic
PK
Pharmacokinetics
PPS
Per-protocol Set
PRO
Patient-Reported Outcomes


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PR
Partial Response
PT
Prothrombin Time
RANO
Response Assessment in Neuro Oncology
RT
Radiation Therapy
RBC
Red Blood Cell Count
RPA
Recursive Partitioning Analysis
RTOG
Radiation Therapy Oncology Group 
SAD
Source Axis Distance
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Safety Analysis Set
SD
Stable Disease
SGPT
Serum glutamic-pyruvic transaminase
SGOT
Serum glutamic-oxaloacetic transaminase 
SmPC
Summary of Product Characteristics
SOC
Standard of Care
SUSAR
Suspected Unexpected Serious Adverse Reactions
SSD
Source Skin Distance
TOE
Targeted Ophthalmologic Examination
TPS
Treatment Planning System
TMZ
Temozolomide
TRIAD
Transmission of Imaging and Data
ULN
Upper Limits of Normal
VMAT
Volumetric Arc Therapy
WBC
White Blood Cell Count
5-HT3
5-hydroxytryptamine3
Pharmacokinetic and Statistical Abbreviations
Cmax
Maximum observed plasma concentration
Cmin
Minimum observed plasma concentration


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APPENDIX IX. SUBJECTS WITH MILD TO MODERATE HEPATIC IMPAIRMENT
This appendix outlines the ABT-414 sub-study in subjects with hepatic impairment.  The revised 
schedule of assessments for the hepatic impairment sub-study is provided in Table 3H below.
Sub-Study Objective
To assess the pharmacokinetics, safety and tolerability of ABT-414 in subjects with newly 
diagnosed EGFR-amplified GBM who have mild or moderate hepatic impairment.
Overview
This is a Phase 1, open-label, multicenter sub-study.  Approximately 6 subjects with mild hepatic 
impairment and 6 subjects with moderate hepatic impairment will be enrolled if they meet all 
inclusion criteria and do not meet any of the exclusion criteria.
All subjects with hepatic impairment will be assigned to active treatment with ABT-414 during 
the Chemoradiation and Adjuvant Phases of treatment.  Radiation therapy and TMZ therapy will 
be administered to hepatically impaired subjects the same way as those with normal hepatic 
function.  The pharmacokinetics of TMZ in patients with mild-to-moderate hepatic impairment 
have been shown to be similar to those observed in normal hepatic function.  Caution should 
only be exercised when TMZ is administered to patients with severe hepatic impairment.  The 
visit schedule and study procedures will be the same as for other study subjects unless described 
otherwise in this appendix.
After meeting the selection criteria for subjects with hepatic impairment, as shown below, 
approximately 6 subjects will be assigned to each of the two cohorts according to their hepatic 
function as shown in Table 1H.  Within each cohort, the first 3 subjects will be assigned to dose 
level 1.  If the dose level 1 was tolerated, the subsequent subjects may be assigned to dose 
level 2.
Table 1H.
Cohorts of Subjects with Hepatic Impairment and Treatment
Cohorts
Hepatic 
Function
Dose Level
Chemoradiation 
Phase
Adjuvant Phase
(Cycles 1 – 2)
Maintenance Phase
(Cycle 3 and After)
A
Child-Pugh A
1a
1.0 mg/kg
1.0 mg/kg
1.0 mg/kg
2
2.0 mg/kg
1.25 mg/kg
1.25 mg/kg
B
Child-Pugh B
1b
1.0 mg/kg
0.5 mg/kg
1.0 mg/kg
2
2.0 mg/kg
1.25 mg/kg
1.25 mg/kg


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For subjects with hepatic impairment, pharmacokinetic assays will be performed as samples are 
received on an ongoing basis to inform dose selection for subsequent subjects throughout the 
study.  Prior to proceeding with dose level 2 in each cohort, safety data and pharmacokinetic data 
for the subjects at dose level 1 within that cohort will be assessed by the sponsor and the 
Neuro-Medical Oncology Chair.  The doses to be given for dose level 2 in each cohort may be 
reduced if indicated by safety and/or pharmacokinetic data from prior subjects.
Selection Criteria
Because reducing variability for efficacy evaluations is not necessary for the pharmacokinetic 
and safety objectives for these cohorts, eligibility criteria are only restricted to those ensuring the 
subject has EGFR-amplified GBM and those to ensure safety for subjects taking ABT-414 and 
ocular steroids.
Inclusion Criteria
A subject cannot be considered eligible for this study unless ALL of the following 
conditions are met.
Subjects may only be randomized if the additional criteria below are met:
1.
Histologically confirmed de novo Grade IV glioma (GBM, gliosarcoma or other 
subvariants) confirmed by central pathology tissue screening.
2.
EGFR amplification in tumor tissue confirmed by central assessment.
3.
Not applicable to this substudy.
4.
The subject must have recovered from the effects of surgery, post-operative infection, 
and other complications before enrollment including, suture/staple removal from brain 
surgery and sufficient wound healing before registration.
5.
≥ 18 years of age.
6.
Not applicable to this substudy.
7.
Not applicable to this substudy.
8.
Subject has adequate bone marrow and renal function ≤ 21 days prior to randomization 
and has mild-to-moderate hepatic impairment as follows:
a.
Absolute neutrophil count (ANC) ≥ 1,500/mm3;
b.
Platelets ≥ 100,000/mm3;


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c.
Hemoglobin (Hgb) ≥ 9.0 g/dL (Note:  The use of transfusion or other intervention to 
achieve Hgb ≥ 9.0 g/dL is acceptable.);
d.
Renal function:  calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault 
formula;
e.
Hepatic function (for subjects participating in the hepatic impairment 
sub-study only): The subject has chronic liver disease and/or cirrhosis documented 
by the presence of at least 1 of the following:

Liver biopsy with histologic findings consistent with cirrhosis

Computerized tomographic or ultrasonographic evidence of liver disease

Physical examination, clinical or laboratory evidence of chronic liver disease

Colloid shift on a liver-spleen scan
And the subject has mild-to-moderate hepatic impairment, including Category A 
(score of 5 or 6) and Category B (score of 7, 8, or 9) impairment according to the 
Child-Pugh classification (see Table 2H for scoring), with no clinical history of 
liver decompensation based on clinical laboratory values and clinical findings 
assessed within 14 days prior to the start of Chemoradiation.

Patients with biliary obstruction for which a shunt has been placed are eligible, 
provided the shunt has been in place for at least 10 days prior to the first dose of 
the study drug and the liver function has stabilized.  Two measurements at least 2 
days apart that put the patient in the same hepatic dysfunction stratum will be 
accepted as evidence of stable hepatic function.  There should be no evidence of 
biliary sepsis.  Electrocardiogram (ECG) without evidence of acute cardiac 
ischemia ≤ 21 days prior to randomization. 
9.
Female subjects of childbearing potential (i.e., those who are not postmenopausal for at 
least 1 year or surgically sterile by bilateral salpingectomy, bilateral oophorectomy or 
hysterectomy) and their male partners should practice at least one accepted method of 
birth control listed below during study entry, for the entire duration of the study and for at 
least 6 months after treatment with ABT-414 and TMZ treatment has ended.  Male 
subjects and their female partners of childbearing potential should practice at least one of 
the accepted methods of birth control during study and for at least 6 months after 
ABT-414 and TMZ.  In addition to the use of a condom, male subjects and their female 
partners of childbearing potential should practice at least one of the methods of birth 
control listed below during the study and for at least 6 months after ABT-414 and TMZ:

Total abstinence from sexual intercourse beginning at least one complete menstrual 
cycle prior to study drug administration (of note:  sexual abstinence as a method of 


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contraception should be limited to those cases where it is already established as the 
pre-existing lifestyle choice of the subject);

A vasectomized male subject or a vasectomized partner of a female subject;

Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior 
to study drug administration;

Intrauterine device (females);

Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring 
with spermicidal jellies or cream) unless not deemed acceptable as highly effective 
contraception by local regulations.
10.
Women of child-bearing potential must have a negative pregnancy test (urine or serum) 
within 7 days prior to randomization.
11.
Must voluntarily sign and date informed consent form, for tumor tissue biomarker testing 
and for study participation, approved by an Independent Ethics Committee (IEC)/ 
Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures.
Exclusion Criteria
Subjects with one or more of the following conditions are NOT eligible for this study.
Randomization Criteria
1.
Not applicable to this substudy.
2.
Not applicable to this substudy.
3.
Subject has recurrent GBM.
4.
Not applicable to this substudy.
5.
Subject has metastatic GBM.
6.
Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that 
prior chemotherapy for a different cancer is allowable, except prior temozolomide.
7.
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap 
of radiation fields.
8.
Any prior therapy for glioblastoma (intra-operative techniques to guide resection are 
allowed as are experimental imaging techniques).
9.
Prior invasive malignancy (except for non-melanomatous skin cancer; carcinoma in situ 
of the breast, oral cavity, or cervix) unless disease free for ≥ 2 years.


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10.
Prior, concomitant, or planned concomitant treatment with NovoTumor Treatment Fields 
(Novo TTF), EGFR-targeted therapy (including EGFRvIII-directed therapy), 
bevacizumab, Gliadel wafers or other intratumoral or intracavitary anti-neoplastic 
therapy, or other experimental therapeutics intended to treat the tumor; the exceptions are 
diagnostic or imaging studies, quality of life, biomarker or epidemiological studies; and 
operative guides to improve extent of resection.
11.
Subject has had major immunologic reaction to an IgG-containing agent.
12.
Subject has had LASIK (laser-assisted in situ keratomileusis) procedure within the last 
1 year or cataract surgery within the last 3 months.
13.
Subject has a history of hypersensitivity to TMZ or excipients, ABT-414 components or 
excipients, and dacarbazine (contraindication for TMZ).
14.
Subject is unsuitable for receiving ocular steroids:

Subject has any active viral disease of the cornea or conjunctiva, including epithelial 
herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella; mycobacterial 
infection of the eye; fungal diseases of ocular structures; or any other contraindication 
for ocular steroid use.

Subject has a known or suspected hypersensitivity to any ocular steroid.

Subject has primary open angle glaucoma or a history of steroid-induced intraocular 
pressure elevation.
15.
Subject is a lactating or pregnant female.
16.
Severe, active co-morbidity, defined as follows:

Subject has severe hepatic impairment (Child-Pugh score of 10 or higher; see 
Table 2H)

Unstable angina and/or congestive heart failure within the last 6 months;

Transmural myocardial infarction within the last 6 months;

Evidence of recent myocardial infarction or ischemia by the findings of 
S-T elevations of ≥ 2 mm using the analysis of an EKG performed within 14 days 
prior to enrollment;

New York Heart Association grade II or greater congestive heart failure requiring 
hospitalization within 12 months prior to enrollment (Appendix IV);

History of stroke, cerebral vascular accident (CVA) or transient ischemic attack 
within 6 months;

Serious and inadequately controlled cardiac arrhythmia;


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
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
enrollment;

Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of enrollment;

Subjects with clinically defined Acquired Immune-Deficiency Syndrome 
(AIDS)-defining illness.  This is necessary to ensure subjects are likely to be able to 
receive the full TMZ regimen;

Active connective tissue disorders, such as lupus or scleroderma, that in the opinion
of the Investigator may put the subject at high risk for radiation toxicity;

Any other major medical illnesses or psychiatric impairments that in the Investigator's 
opinion will prevent administration or completion of protocol therapy;
17.
Subjects treated on any other therapeutic clinical protocols within 30 days prior to study 
entry or during participation in the study except intra-operative therapy to guide resection 
or experimental imaging without therapeutic intent.
18.
Inability to undergo contrast-enhanced MRI scans.
Criteria for Cohort Assessment
The Child-Pugh classification presented in Table 2H will be used to categorize the degree of 
hepatic impairment for assignment into the mild and moderate hepatic impairment groups.
Table 2H.
Child-Pugh Scale for the Assessment of Hepatic Impairment
Parameter
Points Assigned for Observed Findings
1
2
3
Total bilirubin, µmol/L (mg/dL)
< 34.2
(< 2)
34.2 – 51.3
(2 – 3)
> 51.3
(> 3)
Serum albumin, g/L (g/dL)
> 35
(> 3.5)
28 – 35
(2.8 – 3.5)
< 28
(< 2.8)
INR
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Slight
Moderate to severe
Hepatic encephalopathy*
None
Grade 1 or 2
(or suppressed with 
medication)
Grade 3 or 4
(or refractory)
*
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
Grade 2:  lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4:  unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity
The Child-Pugh classification is defined in terms of the sum of the scores for the five parameters, as shown in Table 2H.

A score of 5 or 6 indicates Child-Pugh Category A (mild hepatic impairment).

A score of 7, 8, or 9 indicates Child-Pugh Category B (moderate hepatic impairment).


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Table 3H.
Tables of Activities for Hepatic Sub Study
Table 1.  Study Activities –
Chemoradiation Phase
Screeninga
Chemoradiation Phaseb
Activity
Screening 1
Screening 2
Day 1 Wk 1 
(Fraction 1 
of RT)
Day 1 of 
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 4
Day 1 of 
Wk 5
Day 1 of 
Wk 6
Day 1 of 
Wk 7
Informed Consent
X
Medical and Oncologic History
X
Physical Exam (Including Weight and 
Karnofsky Performance Status)c
X
X
X
X
Vital Signs
X
X
X
X
Ophthalmology Exam
X
Xd
Xd
ECGe
X
Serum Pregnancy Test
X
Xf
Chemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
Coagulation
X
MRI With and Without Contrast
Xk
Submit Tissue Sample for Confirmation of 
GBM, testing of EGFR amplification, 
EGFRvIII and MGMT
X
Adverse Event Assessment/Concomitant 
Medications/Supportive Care
X
X
X
Radiation Therapyg
X
Temozolomide Administration
Xh
ABT-414 or Placebo Administration
X
X
X
Prophylactic Eye Drop Administration
Xi
Xi
Xi
Enrollment
X
Wk = Week; F/U = Follow-up; RT= Radiation Therapy; KPS = Karnofsky Performance Status
a.
Screening procedures may be conducted before or after results of EGFR amplification are received.


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b.
Chemoradiation Phase will be approximately 6 weeks (up to 7 weeks) of treatment with RT, TMZ, and ABT-414.
c.
Height will be assessed at Screening only.  Weight will be collected at all visits.  Complete physical examination will be performed at Screening only.  Symptom directed physical 
examination will be performed at all other designated visits as clinically indicated.
d.
Ophthalmology exams are to be performed 7 to 14 days after the 2nd and 3rd infusions of ABT-414/placebo and must be completed prior to the next infusion of ABT-414/placebo.
e.
ECG will be performed at screening, final visit and when clinically indicated.
f.
For female subjects of childbearing potential, a serum pregnancy test will be performed within 21 days before Day 1 of chemoradiation.  A urine or serum pregnancy test will be 
done on Day 1 Week 1 if a serum pregnancy test was performed more than 7 days before Day 1.
g.
During Chemoradiation Phase, radiation therapy will begin on Day 1, Week 1 (Fraction 1).  60 Gy will be administered in ~30 fractions over 6 weeks (up to 49 days) per the local 
prescribing information or local institutional guidelines.
h.
During Chemoradiation Phase, temozolomide (75 mg/m2) will be given once per day, continuously (including weekends), from Day 1, Week 1 until completion of radiotherapy 
(up to 49 days).
i.
Prophylactic eye drops will be administered for 7 days, from 2 days before until 4 days after, each dose of study drug (ABT-414 or placebo), as described in Section 5.5.
j.
Baseline measure can be done at any time during Screening, up to and including Day 1 of Chemoradiation Phase, but preferably after EGFR amplification has been confirmed.  
The assessments will be translated into the local languages.
k.
A brain MRI scan with and without contrast, performed at any time after diagnostic biopsy/resection but prior to randomization, is required to serve as a baseline scan for RANO 
tumor response assessments.  If a subject starts chemoradiation more than 28 days after surgery, the baseline MRI is to be performed no more than 21 (but preferably fewer) days 
prior to Day 1 Week 1 of Chemoradiation Phase and should allow sufficient time to revise the radiation therapy plan if needed due to a significant change in tumor since surgery.


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Table 2.  Study Activities – Adjuvant 
Phase
Adjuvant Phase – 28-Day Cyclesa
Activity
Day 1 of 
Every 
Cycle 
(1, 2, 3 
etc.)
Day 1 of 
Odd-
Numbered 
Cycles 
(1, 3, 5, 
etc.)
Day 1 
of 
Cycle 2
Day 15 
of 
Every 
Cycleb
Day 22 
of 
Every 
Cyclec
Final 
Study 
Drug 
Visitd
35 
Day 
F/Ue
49 Day 
F/U
Follow-Up 
Phase (Every 
8 Weeks 
Until Disease 
Progression)f
At 
Progression
Survival
Physical Exam (Including Weight and 
Karnofsky Performance Status)g
X
X
Xd
X
X
Vital Signs
X
X
X
X
Ophthalmology Examh
X
X
Xi
ECG
X
Chemistry
X
X
X
Hematology
X
X
X
X
MRI and Clinical Disease Progression 
Assessment
Xj
Xd,k
Xj
Adverse Event Assessment/Concomitant 
Medications/Supportive Care
X
X
X
X
Xp
Temozolomide Administration
Xl
ABT-414 or Placebo Administration
Xm
Xm
Prophylactic Eye Drop Administration
Xn
Xn
Survival Assessmento
X
Wk = Week; F/U = Follow-up; RT = Radiation Therapy; KPS = Karnofsky Performance Status; EORTC-QLQ-C30/BN20 = EORTC Quality of Life Questionnaire, Cancer and Brain 
modules; MDASI-BT = MD Anderson Symptom Index for Brain Tumors; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire – 25; 
HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association (FAS form); EQ-5D-5L = EuroQoL 5 Dimensions; VAS = Visual Analog Scale
a.
Assessments in the Adjuvant Phase will be based on 28-day treatment cycles, with the first cycle starting approximately 4 weeks after completion of radiation therapy.  Subjects 
will receive concomitant TMZ and study drug (placebo or ABT-414) for the first 6 cycles,and study drug monotherapy for an additional 6 cycles or until disease progression or 
study drug discontinuation.  Subjects demonstrating continued benefit and no unacceptable toxicity from adjuvant TMZ can continue adjuvant TMZ to a maximum of 12 cycles at 
the discretion of the Investigator if this is considered an acceptable standard of care per local regulations.  For subjects demonstrating continued benefit and no unacceptable 
toxicity with ABT-414/placebo after 12 cycles, the Adjuvant Phase may be extended at the discretion of the Investigator in discussion with the Neuro-Medical Oncology Chair or 
AbbVie Medical Monitor, with continued ABT-414/placebo treatment until disease progression is confirmed.
b.
Day 15 visit will not be performed after discontinuation of study drug (ABT-414/placebo) treatment.


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c.
As per TMZ prescribing information, during the 28-day cycle of TMZ, a blood count for ANC and platelets should be performed 21 days (± 2 days) after the start of each TMZ 
cycle.  If the ANC falls below 1,500/µL or if the platelet count falls below 100,000/mm3, then blood counts should be performed weekly until recovery to these levels before 
TMZ dosing. A certified local lab may be used instead of central lab; if so, ANC and platelet results should be reported in the eCRF.  Day 22 testing may be omitted for cycles in 
which TMZ is not administered or if local prescribing information allows for a different testing schedule for ANC and platelets.
d.
Final Study Drug Visit to be performed approximately 14 days after last dose of ABT-414/placebo.  The physical examination and MR imaging from the first visit of the 
Follow-Up Phase will be used for the Final Study Drug Visit if these visits coincide (e.g., if the subject completes 12 cycles of Adjuvant Phase).
e.
To be performed 35 days (± 3 days) after the last dose of study drug (placebo or ABT-414).  If the Final Study Drug Visit is more than 35/49 days after the last dose of study 
drug, then 35-day safety follow-up procedures will not be performed.
f.
Visits in Follow-Up Phase to occur every 8 weeks, beginning 8 weeks after Day 1 of the last odd-numbered cycle in the Adjuvant Phase.
g.
Height will be assessed at Screening only.  Weight will be collected at all visits.  Complete physical examination will be performed at Screening only.  Symptom directed physical 
examination will be performed at all other designated visits as clinically indicated.
h.
Ophthalmology exam to be performed prior to ABT-414/placebo dosing on Day 1 (or up to 7 days prior to Day 1) of Cycle 1, Cycle 2, and every odd-numbered cycle thereafter 
(Cycles 3, 5, 7, etc.).  Ophthalmology exam for Cycle 1 Day 1 may be omitted if the subject had no corneal microcysts or ocular adverse events during or after the 
Chemoradiation Phase.  Ophthalmology exams may be discontinued if the subject has been on Level 1 eye drops with no ocular toxicity for 2 consecutive eye exams.
i.
Ophthalmology exam at Day 35 Follow-Up Visit to be done only if subject had corneal microcysts or other ocular findings related to ABT-414 or ocular steroids on previous 
exam and repeated at least every 8 weeks until satisfactory resolution of eye toxicities.
j.
MRI to be performed ≤ 14 days before the start of each odd-numbered cycle or follow-up visit, starting at Cycle 1.  If the subject discontinues study drug prior to disease 
progression, MRIs should continue to be obtained approximately every 8 weeks until disease progression is confirmed.
k.
MRI to be performed, if not performed within last 3 weeks, if subject withdraws from study prior to disease progression.
l.
TMZ will be administered once daily on Days 1 through 5 of each 28-day cycle for 6 cycles per the local prescribing information.
m.
ABT-414 or placebo infusion will be administered on Day 1 and Day 15 of each 28-day cycle for 12 cycles.  For subjects demonstrating continued benefit and no unacceptable 
toxicity with ABT-414/placebo after 12 cycles, the Adjuvant Phase may be extended at the discretion of the Investigator in discussion with the Neuro-Medical Oncology Chair or 
AbbVie Medical Monitor, with continued ABT-414/placebo treatment until disease progression is confirmed.
n.
Prophylactic eye drops will be administered daily for 7 days with each dose of ABT-414/placebo, from 2 days before until 4 days after each dose of study drug (ABT-414 or 
placebo), as described in Section 5.5.
o.
Survival will be assessed quarterly after treatment discontinuation until death.
p.
If the subject is unable to return to the site for the Day 49 Follow-Up Visit, a phone call may be conducted to obtain AE and concomitant medication information.


Protocol Number RTOG 3508/AbbVie M13-813
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Pharmacokinetic Evaluation
For all subjects in this sub-study, blood samples for PK and immunogenicity evaluation will be 
collected according to the schedule described in Table 4H.  PK samples should be processed 
according to the guidelines in Section 4.2 and the laboratory manual.
Values for the pharmacokinetic parameters of ABT-414, Total ABT-806 and cys-mcMMAF, 
including the maximum observed plasma concentration (Cmax), the time to Cmax (peak time, 
Tmax), the terminal phase elimination rate constant and the area under the plasma concentration 
time curve (AUC) from time 0 to the time of the last measurable concentration (AUCt) and from 
time 0 to infinite time (AUC∞), will be determined using noncompartmental methods.  
Confirmed positive ADA results will be reported in Titer units.  Additional parameters may be 
calculated if useful in the interpretation of the data.
Plasma or serum concentrations and pharmacokinetic parameter values of each analyte will be 
tabulated for each subject and each dose level, and summary statistics will be computed for each 
sampling time and each parameter by hepatic impairment category.
An analysis of covariance (ANCOVA) will be performed for dose-normalized AUCt and Cmax.  
The factor of primary interest is hepatic function category.  Body weight, sex, age and other 
variables will be considered as possible covariates.  Covariates such as age, gender, and perhaps 
others that might explain some of the variability in the population will be included in the model 
initially.  However, a covariate may be dropped from the model if the regression coefficient is 
not significant at level 0.10.  The natural logarithmic transformation will be employed for AUC 
and Cmax unless the data clearly indicate that other transformation or the untransformed variable 
provides more nearly symmetric probability distributions and/or more nearly homogenous 
variances across dose levels.  Additional analyses will be performed if useful and appropriate.


Protocol Number RTOG 3508/AbbVie M13-813
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Table 4H.
Schedule of Pharmacokinetic Sampling for Subjects with Hepatic 
Impairment
Chemoradiation Phase
Activity
Day 1 Wk 1 
(Fraction 1 of 
RT)
Day 2 of
Wk 1
Day 3 of
Wk 1
Day 5 of
Wk 1
Day 1 of
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 5
PK –
ABT-414 
and Total 
ABT-806 
Assays
0 hour (pre-dose),  
0.5 hour 
(immediately after 
infusion), and 4 
hour after start of 
infusion
Sample at 
24-hour 
post-dose
(within 
± 4 hour)
Sample at 
48-hour 
post-dose
(within 
± 4 hour)
Sample at 
96-hour 
post-dose
(within 
± 4 hour)
Sample at 
168-hour 
post-dose
(within 
± 4 hour)
0 hour 
(pre-dose) 
and within 
30 min 
post-dose
0 hour 
(pre-dose) and 
within 30 min 
post-dose
PK – Cys-
mcMMAF 
assay
0 hour (pre-dose), 
0.5 hour 
(immediately after 
infusion), and 4 
hour after start of 
infusion
Sample at 
24-hour 
post-dose
(within ±
4 hour)
Sample at 
48-hour post-
dose
(within ±
4 hour)
Sample at 
96-hour post-
dose
(within ±
4 hour)
Sample at 
168-hour 
post-dose
(within ±
4 hour)
0 hour 
(pre-dose) 
and within 
30 min 
post-dose
0 hour 
(pre-dose) and 
within 30 min 
post-dose
PK –
Antidrug 
Antibody
0 hour (pre-dose)
0 hour 
(pre-dose)
0 hour 
(pre-dose)
Adjuvant Phase 
– 28-day Cycles
Activity
Day 1 of Cycle 1
Day 1 of Cycles 2 – 12 
(Every Cycle)
PK –
ABT-414 and 
Total 
ABT-806 
Assays
0 hour (pre-dose) and within 
30 min post-dose on Day 1 of 
Cycle 1
0 hour (pre-dose)
PK – Antidrug 
Antibody
0 hour (pre-dose)
0 hour (pre-dose)
Radiation Therapy and Temozolomide Administration
Radiation therapy and temozolomide therapy will be administered as described in the main 
protocol.
ABT-414 Administration
At the Screening Visit, all subjects will be assigned a unique subject number that will indicate 
the subject is enrolling into the open label hepatic impairment sub-study.  The subjects in this 
sub-study will be stratified by their Child-Pugh scores (mild or moderate impairment) as 
described in Table 2H.
Subjects will receive ABT-414 by IV infusion over 30 – 40 minutes once every 2 weeks during 
the Chemoradiation Phase (on Day 1 of Weeks 1, 3, and 5 of the 6-week regimen) and during the 


Protocol Number RTOG 3508/AbbVie M13-813
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177
Adjuvant Phase (on Day 1 and Day 15 of each 28-day cycle for 12 cycles).  If, after completing 
12 cycles of ABT-414 in the Adjuvant Phase, the subject is tolerating the drug and the 
Investigator believes the subject is continuing to benefit from ongoing ABT-414 treatment, the 
Adjuvant Phase may be extended following consultation with the Neuro-Medical Oncology 
Chair.  ABT-414 will continue according to the same dosing schedule at the discretion of the 
Investigator as long as disease progression has not been determined.
The mg/kg dose for each dose will be as described in Table 1H.  The mg/kg dose will be 
determined from the weight on Day 1 of the Chemoradiation Phase and need not change during 
subsequent treatment unless there is a weight change by more than 10% from baseline.  
Recalculation of dose for < 10% weight changes is allowed at the discretion of the Investigator.  
There will be no cap on the weight of the subject or on the number of milligrams administered 
for overweight subjects.
If TMZ treatment is discontinued due to intolerance during either the Chemoradiation Phase or 
Adjuvant Phase, subjects will continue receiving ABT-414 infusions according to the same study 
schedule.
ABT-414 Toxicity Management and Individual Subject Dose Modifications
Subjects will be closely monitored for treatment-related adverse events during all infusions.  For 
the initial ABT-414 infusion, pre infusion vital signs should be taken and direct observation is 
required for the first 15 minutes of the infusion.  Also for the initial ABT-414 infusion, subjects 
must remain at the site for monitoring for 60 minutes post-infusion.  For subsequent infusions, 
post-infusion monitoring is not required; however, pre-infusion vital signs should still be taken.  
Longer observation periods and more frequent vital sign checks may be required in subjects who 
experience infusion reactions.
Recommendations for dose reductions (either as required by protocol or at the discretion of the 
investigator) are as follows:  For a current dose of 1.5 – 2.0 mg/kg, it is recommended that the 
dose be reduced by 0.5 mg (or more, at the investigators discretion).  For a current dose of 
0.75 – 1.25 mg/kg, it is recommended that the dose be reduced by 0.25 mg (or more, at the 
investigators discretion).


Protocol Number RTOG 3508/AbbVie M13-813
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APPENDIX X
SUBJECTS CONTINUING PARTICIPATION AFTER MAIN STUDY
This appendix outlines the modifications to the study procedures and ABT-414 dosing in 
subjects who are currently receiving ABT-414 and who choose to continue ABT-414 treatment 
after the results from the pre-planned interim efficacy analysis. Subjects who received placebo 
will be discontinued from the study.
At the time of the interim efficacy analysis, there were approximately 48 subjects who remained 
on active ABT-414 treatment.  The RTOG Steering Committee and AbbVie determined it was 
appropriate to allow subjects who are receiving ABT-414 to continue doing so based on 
investigator and subject decision.
Requirements for continuing treatment with ABT-414 after interim efficacy analysis
If the subject was receiving blinded treatment, they must be confirmed to be receiving 
ABT-414.
Must voluntarily sign and date the updated informed consent form, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB)
Study Activities
Only study activities necessary for study drug dosing, safety monitoring and adverse event
reporting will be continued.  The revised schedule of study assessments for these subjects is 
provided in Table 2b below.
 
 


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Table 2b.  Study Activities 
28-Day Cyclesa
Final Study 
Drug 
Visitd/At 
Progression
35-Day F/Ue
49-Day F/U
Activity
Day 1 of 
Every Cycle 
(1, 2, 3 etc.)
Day 1 of Odd-
Numbered Cycles 
(1, 3, 5, etc.)
Day 15 
of Every 
Cycleb
Day 22 of 
Every 
Cyclec
Symptom-directed Physical Exam
Xf
Xf
Ophthalmology Exam
Xg
Xg
Xg
Chemistry
X
X
X
Hematology
X
X
X
X
Adverse Event Assessment/Concomitant 
Medications
X
X
X
X
Xk
Temozolomide Administration
Xh
ABT-414 Administration
Xi
Xi
Prophylactic Eye Drop Administration
Xj
Xj
F/U = Follow-up
a.
Assessments will be based on 28-day treatment cycles, with the first cycle starting approximately 4 weeks after completion of radiation therapy.  Subjects will receive 
concomitant TMZ and study drug (ABT-414) for the first 6 cycles, and study drug monotherapy for an additional 6 cycles or until disease progression or study drug 
discontinuation.  
b.
Day 15 visit will not be performed after discontinuation of study drug (ABT-414) treatment.
c.
As per TMZ prescribing information, during the 28-day cycle of TMZ, a blood count for ANC and platelets should be performed 21 days (± 2 days) after the start of each TMZ 
cycle.  If the ANC falls below 1,500/µL or if the platelet count falls below 100,000/mm3, then blood counts should be performed weekly until recovery to these levels before 
TMZ dosing.  A certified local lab may be used instead of central lab; if so, ANC and platelet results should be reported in the eCRF.  Day 22 testing may be omitted for cycles in 
which TMZ is not administered or if local prescribing information allows for a different testing schedule for ANC and platelets.
d.
Final Study Drug Visit to be performed approximately 14 days after last dose of ABT-414.
e.
To be performed 35 days (± 3 days) after the last dose of study drug (ABT-414).  If the Final Study Drug Visit is more than 35 days after the last dose of study drug, then 35-day 
safety follow-up procedures will not be performed.
f.
Physical exams will be performed only as needed for safety management and adverse event reporting.
g.
Ophthalmology exams will be performed only as needed for safety management and AE/SAE reporting. The last ophthalmology exam following discontinuation of ABT-414 
may be done at the 35-Day F/U or 49-Day F/U Visit. Targeted ophthalmology exam data will not be collected by the Sponsor.
h.
TMZ will be administered once daily on Days 1 through 5 of each 28-day cycle for 6 cycles per the local prescribing information.
i.
ABT-414 infusion will be administered on Day 1 and Day 15 of each 28-day cycle for 12 cycles.  
j.
Prophylactic eye drops will be administered daily for 7 days with each dose of ABT-414, from 2 days before until 4 days after each dose of study drug (ABT-414), as described in 
Section 5.5 of the main study.  Patients will receive management of ocular side effects as per investigator discretion. In this case, ABT-414 dose interruption and/or reduction may 
be used, and any available prophylactic or supportive care measures may be employed without restriction, at the discretion of the investigator.
k.
If the subject is unable to return to the site for the Day 49 Follow Up Visit, a phone call may be conducted to obtain AE/SAE and concomitant medication information.


Protocol Number RTOG 3508/AbbVie M13-813
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180
ABT-414 Administration and Individual Subject Discontinuation
ABT-414 will be administered as described in the main protocol.
Subjects may continue receiving ABT-414 while drug supply is available as long as disease 
progression has not been determined.
ABT-414 Toxicity Management and Individual Subject Dose Modifications
Section 8.0 of the main protocol provides guidance for toxicity management and dose 
modifications.
Adverse Events and Concomitant Medications
Adverse event and concomitant medication data will be collected to support regulatory safety 
reporting requirements.


Protocol Number RTOG 3508/AbbVie M13-813
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181
APPENDIX XI
PROTOCOL AMENDMENT:  LIST OF CHANGES
Title Page
"Investigator:"
"Neurosurgery" previously read:
Has been changed to read:
Title Page
"Investigator:"
"Statistician" previously read:
Has been changed to read:


Protocol Number RTOG 3508/AbbVie M13-813
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182
Section 1.0  INTRODUCTION AND BACKGROUND
Subsection Additional Safety Information
Delete:  last paragraph
Taken together, the efficacy and safety data available to date demonstrate an acceptable
benefit/risk profile of ABT-414 in patients with EGFR-amplified GBM (see Section 1.2) and 
support continued investigation of this investigational agent in the current trial.
Section 1.0  INTRODUCTION AND BACKGROUND
Subsection Summary of Results from Pre-planned Interim Efficacy Analysis
Add:  new subsection title and text
Summary of Results from Pre-planned Interim Efficacy Analysis
An interim efficacy analysis based on a data cut of 30 April 2019 was performed by the RTOG 
Independent Data Monitoring Committee (IDMC), at which time 346 OS events had been 
observed out of 639 subjects included in the main part of the study.  The primary analysis of OS 
based on the Intent-to-Treat (ITT) population showed no difference in OS between groups, with 
a median OS of 18.9 vs. 18.7 months for ABT-414 and placebo, respectively.  The weighted (ρ = 
0, γ = 0.2) stratified log-rank test p-value (1-sided) was 0.628, and the observed hazard ratio 
(HR) (95% CI) for OS was 1.01 (0.82, 1.25).  The median PFS was 8.0 vs. 6.3 months for ABT-
414 and placebo, respectively, with a stratified log-rank test p-value (1-sided) of 0.029.  The 
observed hazard ratio (HR) (95% CI) for PFS was 0.84 (0.70, 1.02).  Preliminary analysis of 
demographic and clinical characteristics did not reveal any factors predictive of OS benefit for 
the addition of ABT-414 to standard RT/TMZ therapy.
Overall, 99.4% and 97.8% of subjects experienced at least 1 adverse event, and 87.3% and 
62.3% experienced a Grade 3 or higher AE in the ABT-414 and placebo arms, respectively.  
Overall, 94.7% and 36.1% of subjects experienced at least 1 ocular adverse event related to 
corneal epitheliopathy, 61.0% and 0.6% experienced a Grade 3 or higher AE related to corneal 
epitheliopathy, and 11.8% and 0% discontinued study drug (ABT-414 or placebo) in the ABT-
414 and placebo arms due to corneal epitheliopathy, respectively.  The most common (> 10%) 
events related to corneal epitheliopathy included keratopathy, vision blurred, photophobia, dry 
eye, eye pain, keratitis, and punctate keratitis.  Excluding events related to corneal 
epitheliopathy, events for which the incidence in the ABT-414 group was ≥ 5% greater than in 
the placebo group included thrombocytopenia, gamma-glutamyltransferase increased, aspartate 
aminotransferase increased, alanine aminotransferase increased, constipation, blood alkaline 


Protocol Number RTOG 3508/AbbVie M13-813
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183
phosphatase increased, fatigue, and platelet count decreased.  Excluding events related to corneal 
epitheliopathy, Grade 3 or higher events for which the incidence in the ABT-414 group was at 
least 5% and was ≥ 2% greater than in the placebo group included thrombocytopenia, gamma-
glutamyltransferase increased, and alanine aminotransferase increased.
The interim efficacy analysis results overall indicate no survival benefit for adding ABT-414 to 
standard RT/TMZ therapy in newly diagnosed GBM patients.  However, given that no new 
important safety risks were identified, the RTOG Steering Committee and AbbVie believe it is 
appropriate to allow subjects who are currently receiving ABT-414 to continue ABT-414 
treatment if the investigator and subject believe it is in the subject's best interest.  For those 
subjects who choose to continue ABT-414, study procedures have been modified as described in 
Appendix X.  The appendix provides guidance for study drug administration and collection of 
safety data related to AEs and SAEs.  No additional efficacy data will be collected.
APPENDIX X  SUBJECTS CONTINUING PARTICIPATION AFTER MAIN STUDY
Add:  new appendix title and text
APPENDIX X
SUBJECTS CONTINUING PARTICIPATION AFTER MAIN 
STUDY
This appendix outlines the modifications to the study procedures and ABT-414 dosing in 
subjects who are currently receiving ABT-414 and who choose to continue ABT-414 treatment 
after the results from the pre-planned interim efficacy analysis. Subjects who received placebo 
will be discontinued from the study.
At the time of the interim efficacy analysis, there were approximately 48 subjects who remained 
on active ABT-414 treatment.  The RTOG Steering Committee and AbbVie determined it was 
appropriate to allow subjects who are receiving ABT-414 to continue doing so based on 
investigator and subject decision.
Requirements for continuing treatment with ABT-414 after interim efficacy analysis
If the subject was receiving blinded treatment, they must be confirmed to be receiving 
ABT-414.
Must voluntarily sign and date the updated informed consent form, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB)
 
 


Protocol Number RTOG 3508/AbbVie M13-813
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184
Study Activities
Only study activities necessary for study drug dosing, safety monitoring and adverse event
reporting will be continued.  The revised schedule of study assessments for these subjects is 
provided in Table 2b below.


Protocol Number RTOG 3508/AbbVie M13-813
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185
Table 2b.  Study Activities 
28-Day Cyclesa
Final Study 
Drug 
Visitd/At 
Progression
35-Day F/Ue
49-Day F/U
Activity
Day 1 of 
Every Cycle 
(1, 2, 3 etc.)
Day 1 of Odd-
Numbered Cycles 
(1, 3, 5, etc.)
Day 15 
of Every 
Cycleb
Day 22 of 
Every 
Cyclec
Symptom-directed Physical Exam
Xf
Xf
Ophthalmology Exam
Xg
Xg
Xg
Chemistry
X
X
X
Hematology
X
X
X
X
Adverse Event Assessment/Concomitant 
Medications
X
X
X
X
Xk
Temozolomide Administration
Xh
ABT-414 Administration
Xi
Xi
Prophylactic Eye Drop Administration
Xj
Xj
F/U = Follow-up
a.
Assessments will be based on 28-day treatment cycles, with the first cycle starting approximately 4 weeks after completion of radiation therapy.  Subjects will receive 
concomitant TMZ and study drug (ABT-414) for the first 6 cycles, and study drug monotherapy for an additional 6 cycles or until disease progression or study drug 
discontinuation.  
b.
Day 15 visit will not be performed after discontinuation of study drug (ABT-414) treatment.
c.
As per TMZ prescribing information, during the 28-day cycle of TMZ, a blood count for ANC and platelets should be performed 21 days (± 2 days) after the start of each TMZ 
cycle.  If the ANC falls below 1,500/µL or if the platelet count falls below 100,000/mm3, then blood counts should be performed weekly until recovery to these levels before 
TMZ dosing.  A certified local lab may be used instead of central lab; if so, ANC and platelet results should be reported in the eCRF.  Day 22 testing may be omitted for cycles in 
which TMZ is not administered or if local prescribing information allows for a different testing schedule for ANC and platelets.
d.
Final Study Drug Visit to be performed approximately 14 days after last dose of ABT-414.
e.
To be performed 35 days (± 3 days) after the last dose of study drug (ABT-414).  If the Final Study Drug Visit is more than 35 days after the last dose of study drug, then 35-day 
safety follow-up procedures will not be performed.
f.
Physical exams will be performed only as needed for safety management and adverse event reporting.
g.
Ophthalmology exams will be performed only as needed for safety management and AE/SAE reporting. The last ophthalmology exam following discontinuation of ABT-414 
may be done at the 35-Day F/U or 49-Day F/U Visit. Targeted ophthalmology exam data will not be collected by the Sponsor.
h.
TMZ will be administered once daily on Days 1 through 5 of each 28-day cycle for 6 cycles per the local prescribing information.
i.
ABT-414 infusion will be administered on Day 1 and Day 15 of each 28-day cycle for 12 cycles.
j.
Prophylactic eye drops will be administered daily for 7 days with each dose of ABT-414, from 2 days before until 4 days after each dose of study drug (ABT-414), as described in 
Section 5.5 of the main study.  Patients will receive management of ocular side effects as per investigator discretion. In this case, ABT-414 dose interruption and/or reduction 
many be used, and any available prophylactic or supportive care measures may be employed without restriction, at the discretion of the investigator.
k.
If the subject is unable to return to the site for the Day 49 Follow Up Visit, a phone call may be conducted to obtain AE/SAE and concomitant medication information.


Protocol Number RTOG 3508/AbbVie M13-813
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186
ABT-414 Administration and Individual Subject Discontinuation
ABT-414 will be administered as described in the main protocol.
Subjects may continue receiving ABT-414 while drug supply is available as long as disease 
progression has not been determined.
ABT-414 Toxicity Management and Individual Subject Dose Modifications
Section 8.0 of the main protocol provides guidance for toxicity management and dose 
modifications.
Adverse Events and Concomitant Medications
Adverse event and concomitant medication data will be collected to support regulatory safety 
reporting requirements.





SAP_001.pdf: 
Depatuxizumab mafodotin (ABT-414)
M13-813 – Statistical Analysis Plan
Version 2.0 – 23 Apr 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M13-813
A Randomized, Placebo Controlled Phase 3 Study of 
ABT-414 with Concurrent Chemoradiation and 
Adjuvant Temozolomide in Subjects with Newly 
Diagnosed Glioblastoma (GBM) with Epidermal 
Growth Factor Receptor (EGFR) Amplification 
(Intellance1)
Date:  23 Apr 2019
Version 2.0
Prepared in collaboration by
AbbVie
and
 RTOG Foundation
NCT02573324


Depatuxizumab mafodotin (ABT-414)
M13-813 – Statistical Analysis Plan
Version 2.0 – 23 Apr 2019
2
Document history
Statistical Analysis Plan
Date
Original (version 1.0)
03-Dec-2018
Amendment 1 (version 2.0)
23-Apr-2019
Summary of changes in Amendment 1 (version 2.0)
●
The definition of deterioration in HVLT-R Total recall score has been updated 
to use 5-point change in raw score.
Rationale:  To match the deterioration definition used in prior RTOG studies 
(Wefel et al).
●
The censoring rule for the PFS analysis was updated to exclude any PD or 
death that occurs > 20 weeks after the previous scan date.
Rationale:  To avoid prolonging PFS estimates when there are missing RANO 
assessments.  The 20-week window was chosen to reflect 2 consecutive missed 
RANO assessments (8-week intervals) plus the 4-week assessment window 
specified in the study protocol.
●
Additional sensitivity analyses for PFS including investigator assessed PFS 
and PFS with varying censoring rule and are included.
Rationale:  These additional sensitivity analyses for centrally assessed PFS are 
included to evaluate the robustness of the primary PFS analysis.  In addition, 
investigator assessed PFS analysis is also included.
●
Visit windows for different endpoints were clarified with greater details.


Depatuxizumab mafodotin (ABT-414)
M13-813 – Statistical Analysis Plan
Version 2.0 – 23 Apr 2019
3
Rationale:  The details were added to provide appropriate information in the SAP 
for clarification purpose, including providing windows suitable for the procedure 
schedule for different endpoints.
●
Other changes:  Following changes are also implemented:
○
Editorial changes to improve consistency and clarity.
○
Analysis related to targeted ophthalmologic evaluation (TOE) endpoints 
are updated 
○
Definition of prior medication is updated to include medications that 
started before first study treatment and continue to be taken after first study 
treatment.
○
Questionnaire of COWA-FAS added in the Appendix VI.
○
Definition of baseline value for all the parameters except steroids use is
updated to include all the records with study Rx day ≤ 1 to minimize the 
number of patients with missing baseline values. The definition of 
baseline value for steroids use is updated to include all the records within 
14 days prior to the first dose of study drug. 
○
Figure 2 was updated as some of the text was not legible. 
○
Time to deterioration (TTD) is renamed as Deterioration Free Survival 
(DFS) throughout the document.
○
Sensitivity analysis for HVLT-R Total score is added.


Depatuxizumab mafodotin (ABT-414)
M13-813 – Statistical Analysis Plan
Version 2.0 – 23 Apr 2019
4
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................4
3.0
Abbreviation.............................................................................8
4.0
Introduction ...........................................................................10
5.0
Study Objectives, Design and Procedures...........................10
5.1
Objectives ................................................................................................10
5.2
Study Design............................................................................................12
5.2.1
Study Design and Design Diagram..........................................................12
5.2.2
Variables used for Stratification at Randomization.................................15
5.3
Endpoints .................................................................................................16
5.3.1
Primary Efficacy Endpoint ......................................................................16
5.3.2
Secondary Efficacy Endpoints.................................................................16
5.3.3
Exploratory Efficacy Endpoints...............................................................18
5.3.4
Safety Endpoints ......................................................................................23
5.4
Sample Size Justification .........................................................................23
5.5
Interim Analysis.......................................................................................24
5.5.1
Interim analysis for early efficacy and futility.........................................24
5.5.2
Interim reporting for the DMC ................................................................24
5.6
Multiplicity Testing Procedures for Type-I Error Control ......................24
5.6.1
Type I error control for interim analysis..................................................24
5.6.2
Type I error control for testing multiple endpoints..................................25
6.0
Analysis Populations .............................................................28
6.1
Definition of Analysis Populations..........................................................28
6.1.1
Efficacy Populations ................................................................................28
6.1.2
Safety Populations ...................................................................................29
7.0
Analysis Conventions ............................................................29
7.1
Definition of Baseline..............................................................................29
7.2
Dealing with Multiple Values on the Same Day......................................29
7.3
Definition of Treatment Emergent Observation for Safety 
Analysis....................................................................................................30
7.4
Definition of Study days and Rx Days ....................................................30


Depatuxizumab mafodotin (ABT-414)
M13-813 – Statistical Analysis Plan
Version 2.0 – 23 Apr 2019
5
7.5
Definition of Visit Windows....................................................................31
7.5.1
Definition of Visit Windows for HRQoL and Neurocognitive 
Function assessments...............................................................................31
7.5.2
Definition of Visit Windows for Laboratory assessments.......................32
7.5.3
Definition of Visit Windows for Vital signs and KPS assessments ........33
7.5.4
Definition of Visit Windows for Targeted ophthalmology exams 
(TOE) assessments...................................................................................34
7.5.5
Definition of Visit Windows for steroids dosing.....................................35
7.6
Data Handling Convention at Database Level.........................................35
8.0
Demographics, Baseline Characteristics, Medical 
History and Previous/Concomitant Medications ...............35
8.1
Demographic and Baseline Characteristics .............................................35
8.2
Medical and Surgical History ..................................................................36
8.3
Prior/Concomitant Medications (excluding protocol-required 
prophylactic eye drops)............................................................................37
8.4
Prior/Concomitant Medications (protocol-required prophylactic 
eye drops).................................................................................................38
9.0
Subject Disposition and Study Drug Exposure ..................38
9.1
Subject Disposition ..................................................................................38
9.2
Study drug exposure ................................................................................39
10.0
Efficacy Analysis....................................................................39
10.1
General Considerations............................................................................39
10.1.1
Analysis of Efficacy Endpoints by Variable Type...................................40
10.1.2
Missing Data Imputation for Efficacy Endpoints ....................................42
10.2
Primary Efficacy Analysis .......................................................................42
10.3
Secondary efficacy analysis.....................................................................45
10.4
Other efficacy analyses ............................................................................46
10.4.1
Additional analyses based on OS, centrally assessed PFS and 
local investigator assessed PFS................................................................46
10.4.2
Analyses of QLQ-C30 and QLQ-BN20 response ...................................46
10.4.3
Analysis of EQ-5D-5L index value and EQ VAS score..........................47
10.4.4
Analysis of COWA-FAS verbal fluency score........................................47
10.4.5
Additional analysis of HVLT-R scores....................................................47
10.4.6
Analysis of KPS score .............................................................................47


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10.4.7
Additional analyses for MDASI-BT symptom severity score.................48
10.4.8
Analysis of corticosteroid use data ..........................................................48
10.5
Sensitivity Analyses.................................................................................48
10.6
Subgroup Analyses ..................................................................................49
10.7
Pharmacokinetic Analyses .......................................................................50
11.0
Safety Analyses ......................................................................50
11.1
General Considerations............................................................................50
11.2
Analysis of Adverse Events.....................................................................50
11.2.1
Treatment-Emergent Adverse Events (TEAEs).......................................50
11.2.2
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................55
11.2.3
Listing of Adverse Events........................................................................55
11.3
Analysis of Depatux-M targeted ophthalmologic exam (TOE) 
results .......................................................................................................56
11.4
Analysis of Laboratory Data....................................................................57
11.4.1
Variables and Criteria Defining Abnormality..........................................58
11.4.2
Statistical Methods...................................................................................61
11.5
Analysis of Vital Signs ............................................................................61
11.5.1
Variables and Criteria Defining Abnormality..........................................61
11.5.2
Statistical Methods...................................................................................62
11.6
Analysis of ECG parameters....................................................................62
12.0
Reference................................................................................63
13.0
Appendix.................................................................................65
List of Tables
Table 1.
Visit window for HRQoL and Neurocognitive Function 
assessments ..............................................................................................32
Table 2.
Visit window for biochemistry and hematology lab parameter 
assessments in chemo-radiation phase.....................................................32
Table 3.
Visit window for hematology and biochemistry lab parameter 
assessments in adjuvant phase .................................................................33
Table 4.
Visit window for vital signs and KPS assessments in chemo-
radiation phase .........................................................................................33


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Table 5.
Visit window for vital signs and KPS assessments in adjuvant 
phase ........................................................................................................34
Table 6.
Visit window for TOE assessments in chemo-radiation phase................34
Table 7.
Visit window for TOE assessments in adjuvant phase ............................35
Table 8.
Clinical laboratory test.............................................................................58
Table 9.
Criteria for NCI CTCAE Grades for Laboratory Values 
Hematology Variables .............................................................................59
Table 10.
Criteria for NCI CTCAE Grades for Laboratory 
Values - Chemistry Variables ..................................................................60
Table 11.
Criteria for Potentially Clinically Significant vital signs Values.............62
List of Figures
Figure 1.
Schema of study design ...........................................................................15
Figure 2.
Testing procedure (all the tests are one-sided).........................................27


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3.0
Abbreviation
AE(SI)
Adverse Event (of Special Interest)
ALP
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
CI
Confidence Interval
COWA-FAS
Controlled Oral Word Association – FAS version
CTC(AE)
Common Terminology Criteria (for Adverse Events)
Depatux-M
Depatuxizumab mafodotin
DFS
Deterioration Free Survival
ECG
Electrocardiogram
eCRFs
Electronic Case Report Forms
EGFR
Epidermal Growth Factor Receptor
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
EuroQol 5 Dimensions 5 Level
EQ VAS
EuroQol Visual Analog Scale
FAS
Full Analysis Set
FH
Fleming Harrington
FLAIR
Fluid Attenuated Inversion Recovery
GBM
Glioblastoma
GGT
Gamma-glutamyl transferase
Gy
Gray
HR
Hazard Ratio
HRQoL
Health Related Quality of Life
HVLT-R
Hopkins Verbal Learning Test-Revised
IDMC
Independent Data Monitoring Committee
IRT
Interactive Response Technology
KM
Kaplan Meier
KPS
Karnofsky Performance Status
LLN
Lower Limit of Normal
MDASI-BT
M.D. Anderson Symptom Inventory Brain Tumor Module


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MedDRA
Medical Dictionary for Regulatory Activities
MGMT
O6-methylguaninemethlytransferese
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
NEI-VFQ-25
National Eye Institute Visual Functioning Questionnaire – 25
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival
PPS
Per-protocol Set
PRO
Patient-Reported Outcomes
PT
Preferred Term
QLQ-BN20
Quality of Life Questionnaire Brain Cancer Module
QLQ-C30
Quality of Life Questionnaire Core 30
QoL
Quality of Life
RANO
Response Assessment in Neuro Oncology
RCI
Reliable Change Index
ROW
Rest of the World
RT
Radiation Therapy
RPA
Recursive Partitioning Analysis
RS
Raw Score
RTOG 
RTOG Foundation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Safety Analysis Set
SGPT
Serum glutamic-pyruvic transaminase
SGOT
Serum glutamic-oxaloacetic transaminase 
SOC
Standard of Care
SS
Scale Score
TE(AE)
Treatment Emergent Adverse Event
TMZ
Temozolomide
TOE
Targeted ophthalmology exam
TTE
Time to Event
ULN
Upper Limit of Normal
WHO
World Health Organization


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4.0
Introduction
This statistical analysis plan (SAP) will provide details statistical methods for the analysis 
of efficacy and safety data collected in Study M13-813 (INTELLANCE 1) as outlined in 
Protocol Amendment 8 (dated 29 November 2018)21 and will describe analysis 
conventions to guide the statistical programming work.
Efficacy and safety analyses will be performed using SAS Version 9.3 or higher (SAS 
Institute, Inc., Cary, NC  27513) under the UNIX operating system.  The SAP will be 
signed off before any unblinded analysis is performed.
5.0
Study Objectives, Design and Procedures
5.1
Objectives
Primary objective
To determine whether the addition of Depatuxizumab mafodotin or Depatux-M 
(ABT-414) to concomitant radiotherapy (RT) and Temozolomide (TMZ) as well as to 
adjuvant TMZ prolongs Overall Survival (OS) among subjects with newly diagnosed 
glioblastoma (GBM) harboring epidermal growth factor receptor (EGFR) amplification.
Secondary objectives
To determine whether the addition of Depatux-M to concomitant RT and TMZ as well as 
to adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM 
harboring EGFR amplification in terms of the following endpoints:
●
Progression Free Survival (PFS), assessed centrally
●
OS for the MGMT unmethylated group
●
OS for the MGMT methylated group 
●
Deterioration Free Survival in M.D. Anderson Symptom Inventory Brain 
Tumor Module (MDASI-BT) symptom severity score
●
Deterioration Free Survival in MDASI-BT symptom interference score 


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●
Deterioration Free Survival in Hopkins Verbal Learning Test Revised (HVLT-
R) Total Recall score
●
OS for the EGFRvIII-mutated tumor subgroup
●
PFS for EGFRvIII-mutated tumor subgroup
Safety:
●
Assessment of comparative safety
Exploratory objectives
To determine whether the addition of Depatux-M to concomitant RT and TMZ as well as 
to adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM 
harboring EGFR amplification in terms of the following endpoints:
●
OS at 0.5, 1, 2, 2.5, 3, 4, and 5 years
●
Centrally-assessed PFS at 0.5, 1, 2, 2.5, 3, 4, and 5 years
●
Centrally-assessed PFS for the MGMT unmethylated and methylated sub-
groups
●
OS and centrally-assessed PFS for non-EGFRvIII mutated subgroup 
●
OS and centrally-assessed PFS for Total EGFR expression levels
●
Progression Free Survival (PFS), assessed by investigator 
●
EGFRvIII status as a prognostic factor independent of treatment assignment 
overall and among molecular subgroups 
●
Change from baseline in HRQoL and health status measures 
○
QLQ-C30:  Global health status, Physical Functioning, Cognitive 
Functioning, and Role Functioning scale 
○
QLQ-BN20:  Visual Disorder, Motor Dysfunction, and Communication 
Disorder scale
○
MDASI-BT:  neurologic, cognitive, treatment, symptom interference 
(activity-related, mood-related), and vision item scores 
○
COWA-FAS:  verbal fluency score


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○
HVLT-R:  Total Recall score, Delayed Recall Score, Recognition 
Discrimination Index 
○
EQ-5D-5L and EQ VAS scale scores
○
Karnofsky Performance Status (KPS)
●
Median time for which KPS score was maintained at 70 or higher
●
Deterioration Free Survival in neurocognitive functioning on Controlled Oral 
Word Association (COWA-FAS)
●
Changes in EGFR molecular profile during therapy among subjects who 
undergo additional surgery as part of routine care
●
Pharmacokinetics of Depatux-M, total ABT-806, and free cys-mcMMAF
●
Change from baseline in corticosteroid dosing 
5.2
Study Design 
5.2.1
Study Design and Design Diagram
This is a Phase 3 randomized double-blind, placebo-controlled trial comparing the 
efficacy and safety of Depatux-M versus placebo, each as concurrent treatment with 
standard-of-care therapy (comprised of concomitant RT/TMZ and adjuvant TMZ) and 
followed by monotherapy, in subjects with newly diagnosed GBM.  For this study, 
subjects will be stratified by MGMT methylation status (methylated and unmethylated), 
RPA class (III, IV, and V), region of the world (North America (includes USA and 
Canada) and rest of the world (ROW)) and EGFRvIII mutation status (mutated and wild 
type/indeterminate).  A total of 640 evaluable subjects will be randomized on a 1:1 ratio 
to receive:
●
Arm A: Depatux-M plus TMZ during the Chemoradiation and Adjuvant 
Phases.
●
Arm B: Placebo plus TMZ during the Chemoradiation and Adjuvant Phases.
The study comprises the following 4 phases/periods:  a Screening Period, followed in 
sequence by a Chemoradiation Phase, an Adjuvant Phase and a Follow-up Phase.


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Screening Period
Screening procedures must be completed prior to Day 1 of the Chemoradiation Phase.  
The baseline brain magnetic resonance imaging (MRI) will be obtained no more than 
28 (but preferably fewer) days prior to Day 1 of the Chemoradiation Phase.  Safety related 
evaluations will be conducted 14 or fewer days prior to Day 1 of the Chemoradiation 
Phase.  If a subject has a repeat surgery prior to randomization, the extent of surgical 
resection after the repeat surgery (biopsy-only vs. partial/total resection) will be used for 
determining RPA class.
Chemoradiation Phase
Treatment in the Chemoradiation Phase should begin ≤ 7 weeks after surgery/biopsy.  
During this Phase, all subjects will undergo fractionated focal radiotherapy (RT), with 
one treatment of approximately 2 gray (Gy) given daily 5 days per week for a total of 
approximately 60 Gy over approximately 6 weeks (and no more than 7 weeks).  TMZ will 
be administered continuously from Day 1 of radiotherapy to the last day of radiation at a 
daily oral dose of 75 mg/m2 for a maximum of 49 days.  Subjects will receive blinded 
Depatux-M or Placebo at 2.0 mg/kg IV infusion over 30 – 40 minutes once every 2 weeks 
(Day 1 of Weeks 1, 3, and 5 of the 6-week regimen).
Adjuvant Phase
The Adjuvant Phase is comprised of 28-day cycles.  The first cycle starts approximately 
28 days after the last day of radiotherapy.  Subsequent cycles will start approximately 
28 days from the start of the previous cycle.  Subjects receives concomitant TMZ (on 
Day 1 - 5) and Depatux-M/Placebo (on Day 1 and Day 15) for the first 6 cycles, and study 
drug (Depatux-M/Placebo) monotherapy for the following 6 cycles.  TMZ treatment for 
an additional 6 cycles (up to 12 cycles total) is allowed at investigator discretion.  If after 
completing 12 cycles of adjuvant treatment, the subject is tolerating study drug 
(Depatux-M or placebo) and the investigator believes the subject is continuing to benefit 
from ongoing study drug treatment, the investigator may extend the Adjuvant Phase after 
consultation with the Neuro-Medical Oncology Chair or AbbVie Medical Monitor, as 


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long as subject's disease has not progressed.  Adjuvant treatment will be discontinued 
once disease progression occurs.  A final study drug visit will be performed upon 
discontinuation of study drug (Depatux-M/placebo) for any reason, followed by a 49-Day 
Follow-Up Visit (± 3 days).
Follow-Up Phase
Subjects who complete adjuvant treatment or discontinue study drug prior to disease 
progression will continue to undergo MRI assessment, assessment of neurocognitive 
functioning, and assessment of PROs approximately every 8 weeks up to and including 
the time of disease progression.  After disease progression, overall survival will continue 
to be assessed quarterly.
Doses of study drug (i.e., Depatux-M/Placebo and TMZ) in chemoradiation and adjuvant 
phases can be modified or interrupted (see Protocol Section 8.1, Section 8.2 and 
Section 8.3).  Post-baseline scans will be obtained ≤ 14 days before Day 1 of each odd-
numbered cycle (Cycles 1, 3, 5, etc.) of the Adjuvant Phase and ≤ 14 days before each 
visit (approximately every 8 weeks) of the Follow-Up Phase.  OS will be assessed 
quarterly after study discontinuation. 
A schematic of the study design is shown in Figure 1.  The study activities for each visit 
in Chemoradiation and Adjuvant phases are outlined in Table 1 and Table 2 of study 
protocol, respectively.


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Figure 1.
Schema of study design
5.2.2
Variables used for Stratification at Randomization 
All screening activities must be completed and reviewed prior to randomization.  Subjects 
who meet the eligibility criteria will be stratified according to the following 4 factors:
●
MGMT methylation status:  Methylated and Unmethylated
●
RPA classes:  III, IV, and V
●
Region of the World:  North America (includes USA and Canada) and Rest of 
the World (ROW)
●
EGFRvIII status:  Mutated and Other.
EGFRvIII Other includes wild type, indeterminate due to test failure, invalid, or 
insufficient tissue.  Within each stratum, subjects will be randomized to either Arm A (i.e., 


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Depatux-M + TMZ) or Arm B (i.e., Placebo + TMZ) in a 1:1 ratio via the interactive 
response technology (IRT) system.
Screening numbers will be unique 5-digit numbers with the first 3 digits representing the 
investigative site, and the last 2 digits representing the subjects at that site.  Randomized 
subjects will keep their screening number as their subject identification number.  During 
randomization each patient will receive a separate unique 6 digit randomization number.  
This randomization number will be recorded automatically in the electronic case report 
forms (eCRFs) through the IRT system.
5.3
Endpoints
5.3.1
Primary Efficacy Endpoint
Primary efficacy endpoint is overall survival (OS).  OS is defined as time from the 
randomization to death due to any cause.  For subjects who are alive at the end of this 
study, OS will be right-censored on the last date the subject is known to be alive.
5.3.2
Secondary Efficacy Endpoints
Overall Survival (OS) related secondary endpoint
The following OS related endpoints are considered as secondary endpoints:
●
OS for the MGMT unmethylated group
●
OS for the MGMT methylated group
●
OS for the EGFRvIII-mutated tumor subgroup
Progression Free Survival (PFS) related endpoints 
PFS is defined as time from randomization to the date of progression of disease (PD) 
assessed centrally per Response Assessment in Neuro-Oncology (RANO) criteria or 
death, whichever occurs first.  Any PD or death that occurs > 20 weeks after the previous 
scan date will be excluded along with the following scans.  Subjects without an event will 
be right-censored at the date of last follow up for disease progression.  Patients with no 


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post baseline follow up for progression and who doesn't experience a death event within 
20 weeks after the randomization date will be censored at the day of randomization.  
The PFS related secondary endpoints are:
●
PFS, assessed by independent central review
●
PFS, assessed by independent central review for EGFRvIII-mutated tumor 
subgroup
MDASI-BT symptom severity and interference score
This is a validated PRO instrument used to assess the severity of brain tumor related 
symptoms and its impact on daily function in last 24 hours.  It consists of 22 symptom 
items and 6 interference items.  Each item is rated from 0 to 10, with higher score 
indicating worse symptoms/interference. 
MDASI-BT symptom severity score is defined as average over 13 core symptom items 
and 9 brain tumor symptom items.  The MDASI-BT symptom severity score will be 
obtained if more than 50% of the items (at least 12 out of 22 items) are completed on a 
given assessment using the formula: (sum of items answered) × 22/number of items 
answered.
MDASI-BT symptom interference score is defined as an average of 6 interference items.  
The MDASI-BT symptom interference score will be obtained if more than 50% of the 
items (at least four out of six items) are completed on a given assessment using the 
formula:  (sum of items answered) × 6/number of items answered.18,28
A change of ≥ 1 point on a 10-point scale at follow-up assessment with respect to baseline 
will be considered as clinically relevant.  Changes in symptom severity score and 
symptom interference score at each time point will be classified into 3 categories:  
improved (≤ –1), stable (> –1 and < 1), and deteriorated (≥ 1).


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The secondary endpoints based on this measure are as follows:
●
Deterioration Free Survival (i.e., decrease by 1 unit or death, whichever comes 
first) in MDASI-BT symptom severity score 
●
Deterioration Free Survival (i.e., decrease by 1 unit or death, whichever comes 
first) in MDASI-BT symptom interference score
HVLT-R
This standardized neurocognitive function test is used to assess change in verbal memory 
over time. This test has been validated within brain-disordered population.  The HVLT-R 
Total Recall Score will be computed by summing the total number of words across 3 trials 
(Trial 1, Trial 2 and Trial 3).  Then, the Total Recall Score will be standardized using the 
published age specific normative data from a healthy population.
A change of ≥ 5 points in raw HVLT-R total recall score with respect to baseline will be 
considered as clinically relevant.  Changes in HVLT-R total recall score at each post-
baseline time point will be classified into 3 categories:  deteriorated (≤ –5), stable (> –5 
and < 5) and improved (≥ 5) (Wefel et al., 2011). 
The secondary endpoint based on this measure is:
●
Deterioration Free Survival in HVLT-R total recall score.
5.3.3
Exploratory Efficacy Endpoints
Overall Survival (OS)
●
Survival rates at the end of 0.5, 1, 2, 2.5, 3, 4, and 5 years 
●
OS in non-EGFRvIII subjects
Progression Free Survival (PFS) 
●
Centrally-assessed PFS rates at the end of 0.5, 1, 2, 2.5, 3, 4, and 5 years


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●
Centrally-assessed PFS for the MGMT unmethylated and methylated sub-
groups
●
Centrally-assessed PFS in non-EGFRvIII subjects
●
Progression free survival (PFS), assessed by investigator 
HRQoL assessments per QLQ-C30 questionnaire developed by EORTC: 
The Quality of Life Questionnaire Core 30 (QLQ-C30) is a 30-item patient self-report 
questionnaire validated for use in a cancer patient population.  Subjects rate items 1 - 28 
on a four-point scale (1 = "not at all" to 4 a = "very much") with higher score indicating 
worse functioning/symptoms and the items 29 - 30 on 1 - 7 points scale.  It is composed 
of global health status/QoL scale; five functional scales (physical, role, emotional, 
cognitive, and social); three symptom scales (fatigue, nausea and vomiting, and pain); and 
six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). 
The following endpoints based on this measure will be analyzed:
●
Change from baseline in Global Health Status, Physical Functioning, 
Cognitive Functioning, Role Functioning
HRQoL assessments per QLQ-BN20 questionnaire developed by EORTC: 
Quality of Life Questionnaire Brain Cancer module (QLQ-BN20) is a 20-item patient 
self-report questionnaire is specifically developed for brain cancer patients.  Subjects rate 
items on a four-point scale (1 = "not at all" to 4 a = "very much") with higher score 
indicating worse symptoms.  It is composed of 11 symptom scales (7 single item scales 
and 4 multi-item scales).
The following endpoints based on this measure will be analyzed:
●
Change from baseline in symptom scales of Visual Disorder, Motor 
Dysfunction and Communication Disorder


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MDASI-BT symptom severity score
Details of MDASI-BT symptom severity score are provided in Section 5.3.2.  The 
following exploratory endpoints will be analyzed: 
●
Change from baseline in neurologic domain score (mean over seizures, 
numbness, pain, and weakness)
●
Change from baseline in cognitive domain score (mean over difficulty 
understanding, difficulty remembering, difficulty speaking, and difficulty 
concentrating)
●
Change from baseline in treatment domain score (mean over dry mouth, 
drowsiness, and appetite)
●
Change from baseline in Vision item score (one of the 9 brain tumor-specific 
items)
MDASI-BT symptom interference score
Details of MDASI-BT symptom interference score is provided in Section 5.3.2.  The 
following exploratory endpoints will be analyzed: 
●
Change from baseline in activity-related interference domain score (mean over 
general activity, work, and walking)
●
Change from baseline in mood-related interference domain score (mean over 
mood, relations with other people, and enjoyment of life)
Karnofsky Performance Status (KPS): 
●
Change from baseline in KPS score
●
Median time for which KPS score was maintained at 70 or higher
COWA-FAS verbal fluency
This standardized neurocognitive function test is used to assess change in executive 
function over time.  In this test, patients are asked to name words beginning with F, A and 


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S in English (and frequency matched letters in other languages).  The COWA-FAS verbal 
fluency score will be computed by summing the total number of unique words. 
At each post-baseline assessment, change in raw and standardized COWA-FAS verbal 
fluency score relative to baseline will be calculated and categorized as deteriorated or not 
using the reliable change index (RCI) criterion based on the standardized scores.  The 
details are provided in Appendix VII.
The endpoints based on this measure are as follows:
●
Deterioration free survival in verbal fluency score
●
Change from baseline in verbal fluency score
Neurocognitive functioning based on HVLT-R 
Details of HVLT-R score is provided in Section 5.3.2.  In addition to Total Recall Score 
(over Trials 1 - 3), the following two scores will also be evaluated:  
●
Delayed Recall Score (Trial 4) and 
●
Recognition Discrimination Index (= total number of true positives – total 
number of false positives)
The following exploratory endpoints will be analyzed: 
●
Change from baseline in Total Recall score
●
Change from baseline in Delayed Recall Score
●
Change from baseline in Recognition Discriminant Index
EQ-5D-5L Health Index and EQ-VAS
EuroQol 5 Dimensions 5 levels (EQ-5D-5L) is a validated instrument to measure generic 
health status.  It is a 5-item patient self-report questionnaire.  Subjects rate items on a 
five-point scale (1 = "no problems" to 5 a = "extreme problem") with higher score 
indicating worse health.  The EQ-5D-5L health states, defined by the EQ-5D-5L 


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descriptive system, will be converted into a single preference-weighted health utility 
index score by applying country-specific weights.  If country is not available in the look-
up table, then weights based on the United States will be applied. Scores will be 
computed according to procedures outlined in EQ-5D-5L scoring manual, available at 
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf.
In the assessment of EuroQol Visual Analog Scale (EQ VAS), subjects are asked to 
indicate their overall health status on a 0 to 100 visual analogue scale with endpoints 
labelled 'the best health you can imagine' and 'the worst health you can imagine.'  This 
information is used as a quantitative measure of health as judged by the individual 
respondents.
The endpoints based on this measure are as follows:
●
Change from baseline in EQ-5D-5L index value
●
Change from baseline in EQ VAS score.
Change from baseline in corticosteroid dosing
Average daily corticosteroid dose (dexamethasone equivalent) at baseline is defined as 
any use of systemic steroid within 14 days prior to randomization.  Post-baseline steroid 
use is defined as any use of systemic steroid on or after randomization.  Steroid doses will 
be converted to a dexamethasone equivalent dose.3
Corticosteroids (mg)
Conversion Factor*
Cortisone
0.75/25
Hydrocortisone
0.75/20
Methylprednisolone
0.75/4
Prednisolone
0.75/5
Prednisone
0.75/5
Triamcinolone
0.75/4
Betamethasone
0.75/0.6
*
Dexamethasone equivalent dose (mg) = Conversion factor × Corticosteroid dose (mg).


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Baseline steroid dose is defined as the average dose within 14 days prior to randomization. 
Post-baseline steroid dose is defined as average dose from randomization to last dosing of 
study drug + 49 days.
The endpoint based on this measure is as follows:
●
Change from baseline in average daily (dexamethasone equivalent) 
corticosteroid dosing during treatment period.
5.3.4
Safety Endpoints
Safety endpoints in this study are as follows:
●
Incidence of adverse events
●
Incidence of lab abnormalities (Chemistry, hematology, urinalysis and hepatic)
●
Change from baseline in vital signs parameters
●
Change from baseline in ECG parameters
5.4
Sample Size Justification
The primary endpoint for the study is overall survival (OS).  A total of 640 evaluable 
subjects are expected to be randomized to observe 441 deaths.  A planned interim analysis 
will be carried out at 75% OS event (i.e., 332 OS events).
It is assumed that the median OS for the placebo arm will be approximately 16 months.  
Treatment with Depatux-M is hypothesized to increase median OS to 21.3 months (i.e., a 
hazard ratio (HR) of 0.75).  With 441 deaths, there will be 85% overall power to detect a 
25% reduction in the hazard of death (i.e., HR = 0.75) using a log-rank test at a one-sided 
2.5% level of significance.  
Subjects will be accrued for a total of 640 evaluable subjects randomized in the study.  
Once the target accrual is met, subjects will then be followed to observe 441 deaths 
overall for comparison of OS between arms.


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5.5
Interim Analysis 
5.5.1
Interim analysis for early efficacy and futility
An interim efficacy analyses on OS will be performed after observing 332 deaths 
(i.e., 75% of the 441 deaths required at final analysis) for declaring early efficacy or 
futility stop.  Based on the Fleming-Harrington's version of weighted a log-rank test with 
parameters ρ = 0 and γ = 0.2, approximately 66% information will be accumulated at the 
interim analysis (see Section 5.6.1).  Interim analysis will be carried out at one-sided 
type I error of 0.0058.  Interim analysis will be carried out according to the methods 
describe in Section 10.0 and justification of type I error is given at Section 5.6.1.  The trial 
may also be stopped for futility if the estimated Cox HR of Depatux-M to Placebo at 
interim analysis exceeds 0.9.
The trial will be considered for early stopping if the Independent Data Monitoring 
Committee (IDMC) makes such a recommendation after consideration of the unblinded 
interim results.  This interim review will include results for the primary and secondary 
efficacy endpoints, safety and other supportive evidence.
5.5.2
Interim reporting for the DMC
The IDMC, as coordinated by RTOG Foundation, will review the study at least twice a 
year with respect to subject accrual, pretreatment characteristics of accrued subjects, the 
frequency and severity of toxicities and morbidity.  The IDMC is also available to review 
the study on an "as needed" basis.  Details are described in the DMC charter.
5.6
Multiplicity Testing Procedures for Type-I Error Control
5.6.1
Type I error control for interim analysis
O'Brien-Fleming method will be used to adjust for multiple testing to maintain overall 
one-sided type I error level at 2.5%.  As described in Section 10.2, Fleming-Harrington 
version of weighted log-rank test10,12 would be used for primary efficacy analyses with 
weights for the events occurring at time t as


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
M 1 3 -8 1 3 – Statistical A nal ysis Pla n
Versi o n 2. 0 – 2 3 A pr 2 0 1 9
2 5
 () =  1 −  (). w here,   (⋅) is t he K M esti mate of t he s ur vi val f u ncti o n i n t he p o ole d data. 
T he wei g ht f or    e ve nt occ urri n g at ti me  ca n be calc ulate d as
  ≡ ( ) =  1 −  ( ).      ,
a n d t he i nf or mati o n fracti o n (I F) ca n be esti mate d as ( Hase ga wa, 2 0 1 6)
I F =              
   
w here D I A a n d D F A de n ote t he pla n ne d n u m ber of e ve nts at t he i nteri m a n d fi nal a nal ys is, 
res pecti vely.  Wit h i nteri m a nal ysis pla n ne d at 3 3 2 e ve nts a n d fi nal a nal ys is pla n ne d at 
4 4 1 e ve nts, t he si m ulati o n res ults s u g gest t hat t he I F a t t he i nteri m a nalys is is esti mate d t o 
be a p pr o xi matel y  6 6 %.  Wit h t his IF at i nteri m a nal y ses, a o ne-si de d t ype I err or of 
0. 0 0 5 8 will be use d f or i nteri m a nal ys is wit h 3 3 2 e ve nts f or early efficac y, a n d fi nal 
a nal ys is will be carrie d o ut at o ne-si de d ty p e I err or of 0. 0 2 3 2 t o preser ve o verall t y pe I 
err or at o ne si de d 2. 5 %.
5. 6. 2
T y p e I err or c o ntr ol f or t e sti n g m ulti pl e e n d p oi nt s
As me nti o ne d a b o ve, t he o verall o ne -si de d ty p e I err or f or testi n g t he pri mar y a n d all 
sec o n dar y e n d p oi nts will be preser ve d at 2. 5 %.  T he pri mar y a n d sec o n dar y e n d p oi nts 
will be teste d usi n g a fi xe d -se q ue nce hierarc hical testi n g strate g y.  At eac h a nalys is 
ti me p oi nt (i.e., i nteri m a n d fi nal a nalys es), t he treat me nt effects o n pri mar y a n d sec o n dar y 
e n d p oi nts will be teste d i n t he f oll o wi n g or der.


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Testing Order 
Endpoint
1
OS
2
PFS, centrally assessed
3
OS for the MGMT unmethylated tumor subgroup
4
OS for the MGMT methylated tumor subgroup
5
Deterioration free survival in MDASI-BT symptom severity score
6
Deterioration free survival in MDASI-BT symptom interference score
7
Deterioration free survival in HVLT-R Total recall score
8
OS for the EGFRvIII-mutated subgroup
9
PFS for the EGFRvIII-mutated subgroup
To protect overall Type I error across primary and all the secondary endpoints, we will 
follow "overall hierarchical" testing strategy.11  The O'Brien Fleming alpha spending 
function will be used for the OS endpoint.  For all the secondary endpoints one-sided 
alpha of 0.02 will be allocated for the interim analysis; the alpha spend in the final 
analysis will be calculated using the group sequential design methodology and estimated 
information fraction at interim analysis.  For example, the one-sided alpha for the PFS 
endpoint in the final analysis would be 0.014 and 0.018 if the information fraction at the 
interim analysis is 0.8 and 0.9, respectively.  The interim analysis will be driven by the 
timing of observed 332 OS events. 
All endpoints will be tested for between arm differences at the interim and final analyses.  
The testing procedure displayed in Figure 2 will be used to determine statistical 
significance and thus will guide the interpretation of the results.  




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6.0
Analysis Populations
The database for Study M13-813 includes subjects for the main part of the study as well 
as patients in the China sub-study (which enrolls Chinese patients) and hepatic 
impairment sub-study.  The main part of the study targeted enrollment of 640 randomized 
subjects (i.e., not including open-label hepatic sub-study subjects).  The enrollment of the 
main part of the study was closed on 31-Mar-2018, and all subjects randomized by that 
date were to be included in the main study analysis population.  Enrollment for the 
Chinese sub-study cohort remains ongoing, and Chinese subjects enrolled after 
31-Mar-2018 will not be included in the main study analysis population.  Patients enrolled 
in the open-label hepatic impairment sub-study will not be included in the main study 
analysis population.  
A total of 639 subjects, including 2 subjects in the Chinese cohort, were enrolled by 
19-Mar-2018 and will be included in the main study analysis population.  
6.1
Definition of Analysis Populations
6.1.1
Efficacy Populations
Full Analysis Set (FAS) will comprise all randomized subjects regardless of whether they 
received study treatment satisfying the following criteria:
●
Enrollment date was on or prior to 31-Mar-2018
●
Enrolled in the main study (not in the open-label hepatic sub-study)
Subjects will be classified in the treatment groups, "Depatux-M + RT/TMZ" or 
"PBO + RT/TMZ," according to the treatment they were assigned at the time of 
randomization.  Unless otherwise specified (and except for subgroup and sensitivity 
analyses), the FAS will be the default dataset for analysis of efficacy data.
Per-protocol Set (PPS) will be comprised of a subset of patients in FAS.  Subjects 
meeting any of the following criteria will be excluded from PPS:


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●
Those entered into the study even though did not satisfy the entry criteria
●
Those who developed withdrawal criteria during the study but were not 
withdrawn
●
Those who received the wrong treatment
●
Those who received an excluded concomitant treatment
Subjects will be classified according to treatment assigned.
6.1.2
Safety Populations
Safety Analysis Set will be comprised of a subset of subjects who receive at least 
one dose of study treatment (either RT, TMZ or Depatux-M) satisfying the following 
criteria:
●
Enrollment date was on or prior to 31-Mar-2018
●
Enrolled in the main study (not in the open-label hepatic sub-study)
Subjects will be classified according to the treatment they had received (as-treated).
7.0
Analysis Conventions
7.1
Definition of Baseline
The baseline for all the parameters except the steroids use is defined as the last non-
missing measurement collected prior or on the first dose date of study drug (i.e., Study Rx 
Day ≤ 1). For steroid use, the baseline is defined as the average dose taken during Study
Day –14 to Study Day –1.
7.2
Dealing with Multiple Values on the Same Day
In cases multiple values are collected on the same day at baseline or post-baseline visit, 
either the arithmetic average (for continuous summary) or the worst value (e.g., for shift 
tables) will be used for further analyses.


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7.3
Definition of Treatment Emergent Observation for Safety 
Analysis
For safety assessments, Treatment Emergent (TE) observations are defined as all newly 
occurring or worsening safety observation with onset at or following the initiation (date 
and time) of any study drug and no later than 49 days after the last dose of Depatux-
M/Placebo.
If an incomplete onset date is collected for an AE, the AE will be assumed to be 
treatment-emergent unless there is evidence that confirms that is it not.
7.4
Definition of Study days and Rx Days
Study Day of any observation is defined for post-randomization observations as: 
Study Day = Date of observation – Date of randomization + 1,
and for observations pre-dating randomization as:
Study Day = Date of observation – Date of randomization.
Thus, the day of randomization is defined as Study Day 1, while the day prior to the 
randomization is defined as Study Day –1 (there is no Study Day 0).
Study Rx Day of any post-baseline observation is defined as the number of days from the 
day of the first dose of any study drug (RT, TMZ, and Depatux-M/Placebo) to the date of 
observation.  It is calculated for each post-treatment observation as follows:
Study Rx Day = Date of observation – Date of first dose of any study drug + 1
Adjuvant Rx Day is defined only for observations made during the Adjuvant phase and is 
defined as the number of days from the day of the first dose of any study drug (TMZ or 
Depatux-M/Placebo) in the Adjuvant Phase to the date of observation.  It is calculated for 
each observation in adjuvant and follow-up phases as follows: 


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Adjuvant Rx Day = Date of observation – Date of first dose of any study drug in 
adjuvant phase + 1
7.5
Definition of Visit Windows
Visit windows for individual endpoints will be defined according to their planned 
collection schedule. All time points and corresponding time windows will be based on 
Study Rx Days (i.e., days since first dosing in chemo-radiation phase) for the assessments 
that are scheduled to be collected after first dosing in chemo-radiation phase but before 
adjuvant phase.  For the assessments that are scheduled to be collected after first dosing in 
adjuvant phase but before adjuvant phase time windows will be based on Adjuvant Rx 
Days (i.e., days since first dosing in adjuvant phase). If more than one observation is 
included in a time window, the observation closest to the planned day should be used.  If 
there are two observations equidistant from the nominal day, the later one will be used in 
analyses. 
Per protocol, subjects receive Chemoradiation for 6 weeks (up to 7 weeks), followed by 
an approximately 4-week treatment-free period before starting Adjuvant treatment.
7.5.1
Definition of Visit Windows for HRQoL and Neurocognitive 
Function assessments
Visit windows for the HRQoL and Neurocognitive function assessments are displayed 
Table 1.  


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Table 1.
Visit window for HRQoL and Neurocognitive Function assessments
Scheduled Visit
Nominal Adjuvant Rx 
Day
Time Window
Baseline
Rx Day ≤ 1
Rx Day –21 to Rx Day 1 
Adjuvant Phase Week 1
Adjuvant Rx Day 1 
Rx Day 2 to Adjuvant Rx Day 29
Adjuvant Phase Week 9
Adjuvant Rx Day 57 
Adjuvant Rx Day 30 to Adjuvant Rx Day 85 
(i.e., Week 9 Day 1 4 weeks)
Adjuvant Phase 
Week 17
Adjuvant Rx Day 113 
Day 86 to Day 141 (i.e., Week 17 Day 1 
4 weeks)
…
Adjuvant Phase Week 
(8*X + 1)
Adjuvant Rx Day 
(56*X + 1) 
Adjuvant Rx Day 56*X + 1 - 27 to Adjuvant 
Rx Day 56*X + 1 + 28
(i.e., Week (8*X + 1) Day 1 4 weeks)
7.5.2
Definition of Visit Windows for Laboratory assessments
Visit windows for the biochemistry and hematology assessments are displayed Table 2
and Table 3.  
Table 2.
Visit window for biochemistry and hematology lab parameter 
assessments in chemo-radiation phase
Scheduled Visit
Nominal study Rx Day
Time Window (Study Rx Day Range)
Baseline
≤ 1
–21 to 1 days
Week 2
8
2 to 11 days
Week 3
15
12 to 18 days
Week 4
22
19 to 25 days
Week 5
29
26 to 32 days
Week 6
36
33 to 39 days
Week 7
43
40 to Adjuvant Rx Day –8*
*
replace Adjuvant Rx Day – 8 by end of chemo-radiation phase, if no adjuvant dosing was done.


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Table 3.
Visit window for hematology and biochemistry lab parameter 
assessments in adjuvant phase
Scheduled Visit
Nominal Adjuvant Rx 
Day
Time Window (Adjuvant Rx Day Range)
Adjuvant phase Week 1 
Day 1 
Day –7 to Day 1
Adjuvant phase Week 5 
Day 29 
Day 2 to Day 43 
Adjuvant phase Week 9 
Day 57 
Day 44 to Day 71 
…
…
…
Adjuvant phase 
Week (4*X +1)
Day (28*X + 1) 
Day 28*X + 1 - 13 to Day 28*X + 1 + 14 
(i.e., Week (4*X + 1) Day 1 2 weeks)
Final study drug visit
NA
As indicated in study visit
35-day follow-up
NA
As indicated in study visit
7.5.3
Definition of Visit Windows for Vital signs and KPS 
assessments
Visit windows for vital sign and KPS assessments are displayed Table 4 and Table 5.  
Table 4.
Visit window for vital signs and KPS assessments in chemo-
radiation phase
Scheduled Visit
Nominal study Rx Day
Time Window (Study Rx Day Range)
Baseline
≤ 1
–21 to 1 days
Week 3 
15
2 to 22 days
Week 5 
29
23 to Adjuvant Rx Day –8*
*
replace Adjuvant Rx Day –8 by end of chemo-radiation phase, if no adjuvant dosing was done.


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Table 5.
Visit window for vital signs and KPS assessments in adjuvant phase
Scheduled Visit
Nominal Adjuvant Rx 
Day
Time Window (Adjuvant Rx Day Range)
Adjuvant phase Week 1 
Day 1 
Day –7 to Day 1
Adjuvant phase Week 3 
Day 15 
Day 2 to Day 22
Adjuvant phase Week 5 
Day 29 
Day 23 to Day 36
Adjuvant phase Week 7 
Day 43 
Day 37 to Day 50
…
…
…
Adjuvant phase 
Week (2*X + 1) 
14*X +1
14*X + 1 – 6 to 14*X + 1 + 7 days
Final study drug visit
NA
As indicated in study visit
35 day follow-up
NA
As indicated in study visit
7.5.4
Definition of Visit Windows for Targeted ophthalmology 
exams (TOE) assessments
Visit windows for the TOE assessments are displayed Table 6 and Table 7.  
Table 6.
Visit window for TOE assessments in chemo-radiation phase
Scheduled Visit
Nominal study Rx Day
Time Window (Study Rx Day Range)
Baseline
≤ –1
–21 to 1 days
Week 4
22
2 to 29 days
Week 6
36
30 to Adjuvant Rx Day –8*
*
replace Adjuvant Rx Day –8 by End of chemo-radiation phase, if no adjuvant dosing was done.


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Table 7.
Visit window for TOE assessments in adjuvant phase
Scheduled Visit
Nominal Adjuvant Rx 
Day
Time Window (Adjuvant Rx Day Range)
Adjuvant phase Week 1
Day 1 
Day –7 to Day 1
Adjuvant phase Week 9
Day 57 
Day 2 to Day 85 
Adjuvant phase 
Week 17
Day 113 
Day 86 to Day 141 
(i.e., Week 17 Day 1 4 weeks)
…
Adjuvant Phase 
Week (8*X + 1) 
Day (56*X + 1) 
Day 56*X + 1 - 27 to Day 56*X + 1 + 28
7.5.5
Definition of Visit Windows for steroids dosing
For steroid use, the baseline window is defined as Study Rx Day –14 to Study Rx Day –1.
The post-baseline window is defined as Study Rx Day 1 (i.e., day of first dosing) to last 
dosing date of Depatux-M/Placebo in the study + 49 days.
7.6
Data Handling Convention at Database Level
There is no applicable data handling convention at database level.
8.0
Demographics, Baseline Characteristics, Medical 
History and Previous/Concomitant Medications
Data for demographic, baseline characteristics, medical history, prior/concomitant 
medications, and cancer history will be summarized by treatment groups using the FAS 
population.
8.1
Demographic and Baseline Characteristics
The following demographic, current disease history and baseline disease characteristics 
(including stratification variables) will be summarized by treatment groups.


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Demographic variable
Baseline disease characteristics

Age

Weight

BMI

Sex 

Race (White, Black or African American, 
Asian, American Indian or Alaskan Native, 
Native Hawaiian or Pacific Islander)

Ethnicity (Hispanic or Latino, Han Chinese, 
Other)

Age 
o
< 18, 18 - < 65, 65 - < 75, ≥ 75 yr

History of tobacco product use and alcohol 
use (current, former, never, unknown)

Region of the world (North America vs Rest 
of the world)

Histology (Glioblastoma, Gliosarcoma, Other)

Level of neurological function (worse than 
minor neurofunction impairment, no worse) 

RPA classes (III, IV, V)

MGMT methylation status (methylated, 
unmethylated, indeterminate)

EGFRvIII status (mutated or other).

Karnofsky performance status (KPS)
o
< 70, 70 - < 90, ≥ 90
Baseline disease status

Time since diagnostic GBM surgery to start of 
study treatment

Systemic corticosteroid use (yes/no)

Type of surgery (Gross total resection, partial 
resection, biopsy)
Continuous variables will be summarized with N, mean, standard deviation (SD) median, 
minimum, and maximum.  Frequencies and percentages will be used to summarize 
categorical variables.
8.2
Medical and Surgical History
Medical and surgical history data will be summarized and presented using body systems 
and conditions/diagnoses as captured on the eCRF.  The body systems will be presented 
in alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized for each arm.  Subjects reporting more than 
one condition/diagnosis within a body system will be counted only once for that body 
system. 
There will be no statistical comparison between the treatment and placebo arms.  Listing 
of medical and surgical history will be provided along with start date, CTCAE grade and 
symptomatic or requiring treatment status at study entry (Yes/No).


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8.3
Prior/Concomitant Medications (excluding protocol-required 
prophylactic eye drops)
Prior medications are any medications excluding the protocol-required prophylactic eye 
drops with start date prior to the first dose of study drug.  Concomitant medications are 
any medications excluding eye drops, other than study drug, taken after the first dose of 
study drug and within 49 days of the last dose of study drug, regardless of the start and 
stop date.  Medications taken on the day of the first dose of study drug are counted as 
concomitant medications.  For reporting purpose, the following conservative approach 
will be followed for determination of prior and concomitant medication:
Start date
End date
Prior to Study Day 1 
Prior to Study Day 1
Prior medication
Missing
Prior to Study Day 1
Prior medication
Prior to Study Day 1
Study Day 1 to Last dose + 49 day
Both prior medication and 
concomitant medication
Study Day 1 to Last dose + 49 day
Study Day 1 to Last dose + 49 day
Concomitant medication
Missing 
Study Day 1 to Last dose + 49 day
Concomitant medication
Study Day 1 to Last dose + 49 day
Missing
Concomitant medication
Missing
Missing
Concomitant medication
Prior and concomitant medications will be summarized separately by the generic name 
coded by the World Health Organization (WHO) dictionary.  Subjects reporting the same 
medication generic name two or more times will be counted only once for that generic 
name.  Subjects reporting more than one medication will be counted only once in the total 
number of subjects taking a concomitant medication.  In addition, the number of prior and 
concomitant medications will also be presented for each treatment arm.  There will be no 
statistical comparison for the prior and concomitant medications between treatment arms.


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8.4
Prior/Concomitant Medications (protocol-required 
prophylactic eye drops)
Concomitant use of eye drops from screening will be summarized by generic name.  
Listing of eye-drops used will be provided along with dosing information, start date, end 
date and investigator assessed compliance.
9.0
Subject Disposition and Study Drug Exposure
9.1
Subject Disposition
Subject disposition summary will be presented for all screened subjects by investigator 
site and overall.  The following information will be presented:  subjects screened, subjects 
randomized, subjects who received at least 1 dose of study drug, subjects who entered 
adjuvant phase, subjects who completed 6 or more TMZ cycles in adjuvant phase, 
subjects who completed 12 or more Placebo/Depatux-M cycles in adjuvant phase, and 
subjects discontinued from the study. 
In addition, a subject disposition summary will be presented on the FAS by treatment 
group and overall, including the following information
●
Subjects randomized
i.
Subjects did not receive any study drug
ii. Subjects received randomized study drug
iii. Subjects received other than randomized study drug
●
Subjects entered in Adjuvant Phase
●
Subjects entered in survival follow-up phase
●
Reason for discontinuation from study
In addition, median follow up time, number of patients alive on treatment period, number 
of patients alive in the follow-up period, and reason for study drug discontinuations will 
be summarized by treatment arms.


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9.2
Study drug exposure
Treatment duration for Depatux-M/placebo and TMZ are defined as below:
Treatment duration for Depatux-M/Placebo (in days) = last Depatux-M/Placebo dose 
date – first Depatux-M/Placebo dose date + 15.
Treatment duration for TMZ (in days) = last TMZ dose date – first TMZ dose date + 1.
Exposure to Depatux-M/Placebo and TMZ will be summarized for chemoradiation phase, 
Adjuvant phase and overall study.  Following information will be summarized:
●
Overall treatment duration for Depatux-M/Placebo and TMZ, separately
●
Percentage of patients received cumulative dose of RT < 57 Gy, 57 - 63 Gy, 
> 63 Gy  
●
Number of doses of Depatux-M/Placebo and TMZ in chemo-radiation phase, 
separately
●
Cumulative doses (mg/kg) of Depatux-M/Placebo and TMZ in chemo-
radiation phase, separately
●
Weekly dosing of Depatux-M/Placebo in chemo-radiation phase
●
Number of cycles of Depatux-M/Placebo and TMZ in adjuvant phase, 
separately
●
Number of doses of Depatux-M/Placebo in adjuvant phase
10.0
Efficacy Analysis
10.1
General Considerations
For the analysis of efficacy endpoints, the Full Analysis Set (FAS) will be the primary 
analysis set whereas the Per Protocol Set (PPS) will be used for supportive analysis only.  
Analysis for the sub-groups will be carried out in the subset of FAS meeting the sub-
group selection criteria at the enrollment.


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For Deterioration free survival of HRQoL and neurocognitive measures and change from 
baseline analysis, patients with missing baseline value will be excluded.  Descriptive 
summaries for the efficacy endpoints will be reported by treatment groups.  These 
summaries will also be reported at the individual levels of each stratification factors. 
There will be additional exploratory analyses for the HRQoL and neurocognitive data and 
the detailed analysis plan is documented in "Analysis of PRO/COA Instruments in the 
Phase 3 Intellance-1 Study" [AbbVie Project ID – HEOR - 00000880].
The statistical comparisons for the primary and secondary endpoints will be done 
according to the multiplicity adjustment plan described in Section 5.6.2 to preserve the 
familywise one-sided type 1 error rate to 0.025.  The statistical comparisons for all the 
other exploratory efficacy endpoints will be performed at a nominal one-sided 2.5% 
significance level.  Confidence intervals for parameters (e.g., median survival times, HR) 
will be constructed with 2-sided 95% confidence level, whenever applicable.  No type I 
error adjustment for multiple comparisons will be carried out for these exploratory 
endpoints.
10.1.1
Analysis of Efficacy Endpoints by Variable Type
Time to events (TTE) variables
All TTE endpoints defined in this study are concerned with only the first incidence of an 
event of interest, and recurrence of the same event is not considered for endpoint 
derivation.  An event however may be defined in a composite manner, i.e., as the 
occurrence of one among several different outcomes.  The composite event is observed 
when at least one of the component events occurs, and the time to the earliest among the 
occurring component events is considered to be the TTE for the composite event.
Follow-up time for TTE endpoints will be derived as follows: 
Date of first occurrence of an event or censoring – date of randomization + 1.


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TTE endpoints will be computed in days and converted into months 
(1 month = 30.4375 days) for analysis.  Thus, for subjects who experience the event of 
interest, time to event will be defined as the time from randomization to the 
first occurrence of the event.  When multiple assessments are needed to ascertain the 
occurrence of an event, the earliest date among all of these assessments is taken to be date 
of the event or censoring.  For a subject who does not experience an event on the study, 
time will be right censored at the time of his last available adequate post-baseline 
assessment that rules out the occurrence of the event.  If a subject had no post-baseline 
assessment and did not experience the event of interest, then TTE will be censored at the 
date of randomization and we will set TTE = 1 day, by convention. 
TTE endpoints will be summarized by number of events observed, number of subjects 
censored, and times corresponding to 25% (1st quartile), 50% (median) and 75% 
(3rd quartile) event probabilities.  Kaplan-Meier (KM) estimates15 will be calculated and 
plotted.  Comparison between treatment arms will be based on stratified weighted log-
rank tests (only for OS) or stratified log-rank tests (for other TTE endpoints) as specified.  
Measure of treatment effects will be provided in term of HR (Depatux-M + RT/TMZ to 
Placebo + RT/TMZ) from Cox proportional hazards regression model adjusting for the 
main effects of the stratification factors with HR value less than 1 representing treatment 
benefit.  
Deterioration Free Survival (DFS) variables for PRO assessments
All the DFS endpoints defined in this study are concerned with only the first incidence of 
a deterioration, and recurrence of the same event is not considered for endpoint derivation.  
The deterioration is defined as satisfying the deterioration criteria without further 
improvement (i.e., failing to satisfy deterioration criteria) within 8 weeks or occurrence of 
death.  Follow up time for all DFS endpoints will be derived as follows: 
Date of first occurrence of first deterioration event or censoring – date of randomization 
+ 1.


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In case there is no subsequent assessment within 8 weeks of first documented 
deterioration, the date of first documented deterioration will be considered as date of 
deterioration.  For time-to-deterioration endpoints, death will be considered as event. If a 
subject had no post-baseline assessment and did not experience the event of interest, then 
DFS will be censored at the date of randomization and we will set DFS = 1 day, by 
convention. Also for the subjects with missing baseline, DFS will be censored at the date 
of randomization.
Continuous variables
Summary of continuous endpoints (e.g., change from baseline) will include the mean, 
standard deviation, median and range.  In the context of change from baseline analyses, 
summary of baseline and post-baseline data will also be provided.  Change from baseline 
analyses will be analyzed by an analysis of covariance (ANCOVA) model including 
stratification factors and baseline as covariates and 95% CI for treatment group difference 
will be provided.
10.1.2
Missing Data Imputation for Efficacy Endpoints
No imputation of missing data is planned for the primary and secondary endpoints of this 
study.  For TTE, if the event of interest is not observed for a subject in the study, such as 
when the subject is lost to follow-up, the endpoint will be right censored at the last 
adequate observation time when occurrence of an event can be ruled out.  For patient 
reported outcomes (PRO) including MDASI-BT symptom score, QLQ-C30, and QLQ 
BN20, the imputation strategies will be based on the scoring manuals and no additional 
imputation will be done.
10.2
Primary Efficacy Analysis
The primary endpoint OS will be compared between treatment arms Depatux-M + 
RT/TMZ and Placebo + RT/TMZ.  Superiority of Depatux-M + RT/TMZ to Placebo + 
RT/TMZ in terms of OS will be evaluated using stratified weighted log-rank test, 
adjusting for the study stratification factors. Recently available data from the 


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
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4 3
I NT E L L A N C E -2 trial 2 7 as well as p u blis he d st u dies o n G B M patie nts 2 2 ,2 5 s u g gest 
i ncreasi n g se parati o n o ver ti me.  T o acc o u nt f or t he p ossi bilit y of late se parati o n i n O S 
(a n d c o nse q ue ntl y, n o n-pr o p orti o nal hazar ds), use of a wei g hte d l o g -ra n k test i n a pre-
s pecifie d ma n ner is c o nsi dere d t o be a m ore a p pr o priate a n d statistically efficie nt test t o 
detect statistical differe nces i n O S c o m pare d t o t he sta n dar d l o g -ra n k test.  U n der t he 
wei g hte d l o g -ra n k test, eac h e ve nt is wei g hte d differe ntly base d o n ti mi n g of t he e ve nts 
fr o m ran d o mizati o n.  T he Fle mi n g -Harri n gt o n ( F H) versi o n of wei g hte d l o g ra n k test 1 0
will be use d wit h f oll o wi n g wei g ht f u ncti o n:
 (|,  ) =    ()  1 −  () ,               ,  ≥0
w here,   (⋅) is t he K M esti mate of t he s ur vi val f u ncti o n i n t he p o ole d data.  T he e ve nts 
t hat occ ur later i n t he st u d y s h o ul d get m ore wei g hts t o acc o u nt f or late se parati o n.  T his 
ca n be ac hie ve d wit h para meters, ρ = 0 a n d γ > 0.  In t his st u d y , we pre-s pecif y ρ = 0 a n d 
γ = 0. 2 f or t he F H wei g hts i n t he wei g hte d l o g -ra n k test.
T he Fle mi n g -Harri n gt o n ( F H) versi o n of wei g hte d l o g -ra n k tests are well rec o g nize d 
statistical met h o ds t hat d o n ot i nflate t he t ype 1 err or if pr e-s pecifie d.9 ,2 4  T he hazar d -rati o 
of O S f or De pat u x - M + R T/ T M Z c o m pare d t o Place b o + R T/ T M Z will be esti mate d b y 
fitti n g C o x-pr o p orti o nal hazar ds re gressi o n m o dels a dj usti n g f or t he mai n -effects of t he 
stratificati o n fact ors.
T his F H test will be i m ple me nte d i n S A S usi n g LI F E T E S T pr oce d ure as f oll o ws:
p r o c
l i f e t e s t
m e t h o d = k m ;  
t i m e
< f o l l o w - u p  t i m e > * < C e n s o r i n g  s t a t u s > ( < c e n s o r i n g  c o d e s > ) ;
s t r a t a
< s t r a t i f i c a t i o n  f a c t o r s >  /  g r o u p = < t r e a t m e n t >     
                         t e s t = F L E M I N G ( 0 ,  0 . 2 )  t r e n d ;
r u n ;
T he hazar d -rati o of O S f or De pat u x-M + R T/ T M Z c o m pare d
t o Place b o + R T/ T M Z will 
be esti mate d b y fitti n g C o x -pr o p orti o nal hazar ds re gressi o n m o dels a dj usti n g f or t he mai n 
effects of t he stratificati o n fact ors.  Treat me nt differe nce i n restricte d mea n s ur vi val ti me 
( R M S T) u p t o 2 4 a n d 3 0 m o nt hs will als o be esti mate d.


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
M 1 3 -8 1 3 – Statistical A nal ysis Pla n
Versi o n 2. 0 – 2 3 A pr 2 0 1 9
4 4
Esti mati o n of H R
A C o x pr o p orti o nal -hazar ds re gressi o n m o del 6 wit h t he treat me nt a n d stratificati o n fact ors 
as c o variates will be use d t o esti m ate t he H R of De pat u x -M + R T/ T M Z t o Place b o
+ 
R T/ T M Z a n d its t w o -si de d 9 5 % CI:
 (|tr e at m e nt,str at u m )
=   () ⋅e x p ( ⋅tr e at m e nt + ϕ  ⋅ +   ⋅ +   ⋅ +   ⋅ )
w here, treat me nt ta kes val ue 1, if treate d wit h De pat u x - M + R T/ T M Z, ot her wise 0, f or 
Place b o + R T /T M Z.
  ,   ,   a n d   re prese nt t he c oefficie nt f or t he 4 stratificati o n 
fact ors, na mel y, re gi o n of t he w orl d, R P A class, M G M T met h ylati o n stat us, a n d 
E G F R vIII stat us.  T he esti mate d val ue of e x p(  ) re prese nts t he hazar d rati o o n De pat u x -
M +
R T/ T M Z (a dj usti n g f or t he effect of stratificati o n fact ors) c o m pare d t o Place b o + 
R T/ T M Z .  Effr o n's a p pr o xi mate met h o d ( 1 9 7 7) will be use d f or ha n dli n g ties. I n S A S, 
t he esti mate of H R will be esti mate d usi n g P H R E G pr oce d ure a n d Effr o n's met h o d 7 will
be e m pl o y e d b y usi n g TI E S = E F F R O N o pti o n i n M O D E L state me nt .2 0 T he f oll o wi n g 
S A S c o de will be use d
P R O C
P H R E G ;
  C L A S S
< t r e a t m e n t >  < s t r a t a  v a r i a b l e s > ;
  M O D E L
< f o l l o w - u p  t i m e > * < C e n s o r i n g  s t a t u s > ( < c e n s o r i n g  c o d e s > ) =
< t r e a t m e n t >  < s t r a t a  v a r i a b l e s > / T I E S = E F F R O N  R L ;
R U N ;
S u p p orti ve a nal y sis:  Differe nce i n restricte d mea n s ur vi val ti me ( R M S T) 
R M S T u p t o 2 4 m o nt hs a n d 3 0 m o nt hs will be re p orte d i n eac h treat me nt ar m se paratel y.  
Differe nce bet wee n treat me nt ar ms will als o be re p orte d.  R M S T is e x presse d as
 [mi n (O S ti m e, ∗)] =   () ∗


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where t* (24 or 30) represents the restriction.  In SAS, RMST will be calculated using 
TIMELIM option in LIFETEST procedure as follows after censoring the largest 
observation:
PROC LIFETEST TIMELIM=<24 or 30>;
  TIME <follow-up time>*<Censoring status>(<censoring codes>);
  STRATA <treatment>;
RUN;
10.3
Secondary efficacy analysis
Secondary efficacy endpoints are defined in Section 5.3.2.  Each of the following 
secondary efficacy endpoints will be analyzed in the order it is mentioned:
1.
PFS per central assessment
2.
OS for the MGMT unmethylated subgroup
3.
OS for the MGMT methylated subgroup
4.
Deterioration free survival in MDASI-BT symptom severity score
5.
Deterioration free survival in MDASI-BT symptom interference score
6.
Deterioration free survival in HVLT-R total recall score
7.
OS for the EGFRvIII-mutated tumor subgroup
8.
PFS (assessed centrally) for the EGFRvIII-mutated tumor subgroups
OS for the EGFRvIII-mutated tumor subgroup will be analyzed in the subset of FAS 
using stratified weighted log-rank test (FH (ρ = 0, γ = 0.2)) with stratification factors as 
region of the world, RPA classes and MGMT methylation status.  OS for the MGMT 
methylated subgroups will be analyzed in the subset of FAS using stratified weighted log-
rank test (FH (ρ = 0, γ = 0.2)) with stratification factors as region of the world, RPA 
classes and EGFRvIII status.  


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Remaining secondary endpoints (#1, #4, #5, #6, and #8 in the above list) will be analyzed 
in the FAS using the standard stratified log-rank test.  Standard log-rank test will be 
carried out in SAS using PHREG procedure specifying TEST = LOGRANK and TREND 
option in the STRATA statement as follows:
proc lifetest method=km; 
time <follow-up time>*<Censoring status>(<censoring codes>);
strata <stratification factors> / group=<treatment>    
                         test=LOGRANK trend;
run;
10.4
Other efficacy analyses
10.4.1
Additional analyses based on OS, centrally assessed PFS 
and local investigator assessed PFS
Kaplan-Meier (KM) estimate of OS rates and centrally assessed PFS rates at 0.5, 1, 2, 2.5, 
3, 4, and 5 years will be determined for each treatment group along with 95% confidence 
intervals (CIs) based on Greenwood's method.  Estimates will be provided both in overall 
population and for the subgroups based on stratification factors. 
PFS per local investigator assessment will be analyzed using the same statistical 
methodology as that for the centrally assessed PFS described in Section 10.3.
10.4.2
Analyses of QLQ-C30 and QLQ-BN20 response
Change from baseline in Global Health Status score, Physical Functioning, Cognitive 
Functioning, Role Functioning in QLQ-C30 questionnaire
Change from baseline in Visual Disorder, Motor Dysfunction, and Communication 
Disorder scale in QLQ-BN20 questionnaire
Baseline data along with post-baseline and change from baseline at each visit will be 
descriptively summarized.  The treatment group differences will be evaluated by 
analyzing the change from baseline to each of the post-baseline time-point and to the final 
measurement (last QoL assessment per subject) using an analysis of covariance 


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(ANCOVA) model adjusting for baseline and stratification factors.  Treatment difference 
along with 95% confidence interval will be provided.
10.4.3
Analysis of EQ-5D-5L index value and EQ VAS score
Change from baseline in EQ-5D-5L index value and EQ VAS score will be analyzed in a 
similar way to that described in "Change from baseline" in Section 10.4.2.
10.4.4
Analysis of COWA-FAS verbal fluency score
Verbal fluency score obtained from COWA-FAS verbal fluency test will be analyzed for 
change from baseline by using methods described in Section 10.4.2.
Deterioration Free Survival in verbal fluency score will be analyzed in the FAS using the 
standard stratified log-rank test with stratification factors as region of the world, RPA 
classes, MGMT methylation status, and EGFRvIII status.
10.4.5
Additional analysis of HVLT-R scores
Total Recall score, Delayed Recall score and Recognition Discrimination Index obtained 
from HVLT-R will be analyzed separately for change from baseline, by using methods 
described in Section 10.4.2.
10.4.6
Analysis of KPS score
KPS score will be analyzed for change from baseline by using methods described in 
Section 10.4.2.  Time-to- KPS < 70 will be analyzed by the standard stratified log-rank 
test with stratification factors as region of the world, RPA classes and EGFRvIII status.  
In addition, median time to KPS score was maintained at 70 or higher will be obtained for 
each treatment arm through Kaplan-Meier analysis considering death, progression, or 
KPS < 70 as event.


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10.4.7
Additional analyses for MDASI-BT symptom severity score
Following endpoint will be analyzed in a similar way to that described in "Change from 
baseline" in Section 10.4.2:
●
Change from baseline in MDASI-BT symptom severity score
●
Change from baseline in MDASI-BT symptom interference score
●
Change from baseline in neurologic domain score
●
Change from baseline in cognitive domain score
●
Change from baseline in treatment domain score
●
Change from baseline in Vision item score (one of the 9 brain tumor-specific 
items)
●
Change from baseline in MDASI-BT activity-related score
●
Change from baseline in MDASI-BT mood-related score
10.4.8
Analysis of corticosteroid use data
Change from baseline in average daily (dexamethasone equivalent) corticosteroid dosing 
during the treatment period will be analyzed in a similar way to that described in "Change 
from baseline" in Section 10.4.2.
10.5
Sensitivity Analyses
Sensitivity analyses will be conducted to evaluate the robustness of efficacy results.  PFS 
and OS will be analyzed in the PPS using the same statistical methodology. 
The primary endpoint of OS will be analyzed based on a stratified log-rank test, adjusting 
for the study for the study stratification factors. 
Two sensitivity analyses will be carried out for PFS endpoint by implementing different 
censoring rules in the definition of PFS (i.e., modified PFS endpoint).  These sensitivity 
analyses will be conducted in the FAS population using the same statistical methodology 
as that for the PFS endpoint described in Section 10.3. 


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Sensitivity analysis 1:  PFS as time from randomization to the date of progression of 
disease (PD) assessed centrally per RANO criteria or death, whichever occurs first.  
Subjects without an event will be right-censored at the date of last follow up for disease 
progression.
Sensitivity analysis 2:  PFS as time from randomization to the date of progression of 
disease (PD) assessed centrally per RANO criteria or death, whichever occurs first.  
Subjects with 2 or more consecutive missed assessments (i.e., > 20 weeks since last 
RANO assessment) without any subsequent assessment prior to the PFS event 
(i.e., progression or death) will be considered progressed at the planned date of the earliest 
missed RANO assessment (i.e., last scan date prior to event + 8 weeks). Subjects without 
an event will be right-censored at the date of last follow up for disease progression.
As a sensitivity analysis, at each post-baseline assessment, change in standardized HVLT-
R total recall score relative to baseline will be calculated and categorized as deteriorated 
or not using the reliable change index (RCI) criterion based on the raw scores. The details 
are provided in Appendix I.  Deterioration free survival in HVLT-R total recall score 
(using the RCI criterion) will be analyzed using the stratified log-rank test.
10.6
Subgroup Analyses
Efficacy endpoints (OS and PFS) will be assessed for the following subgroups on an as-
stratified basis at randomization using the similar methodologies described in Section 10.2
and Section 10.3.
●
Region of the world (North America (includes USA and Canada) and rest of 
the world (ROW))
●
RPA classes (III, IV, and V)
●
MGMT methylation (methylated and unmethylated)
●
EGFRvIII status (mutated and other)
In addition, Forest plot for OS and PFS will be generated to display the HR with 95% CI 
for the subgroups defined by stratification factors, age categories (< 65, 65 - < 75, 


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≥75 years), gender (male and female), KPS categories (< 80, 80 - 90, 100), time from 
diagnostic GBM surgery to start of study treatment (< 4, 4 - 6, > 6 weeks), and type of 
surgery (gross total resection, partial resection, biopsy).
10.7
Pharmacokinetic Analyses
Analysis of pharmacokinetics of Depatux–M, total ABT-806, and free cys-mcMMAF are 
not covered in this SAP and will be described in a separate document.
11.0
Safety Analyses
11.1
General Considerations
Safety analysis will be carried out in the safety population.  For most the safety endpoints 
(e.g., AEs, lab values, vital sign values and ECG values) except for TOE assessments, 
only the treatment emergent (TE) assessments (as defined in Section 7.3) will be included 
in the analyses.  Incidence of TEAEs and treatment emergent lab abnormalities will be 
summarized in chemo-radiation phase and adjuvant phase separately and also in the 
overall study.  A summary of continuous safety endpoints (e.g., change from baseline 
values in laboratory values, vital signs parameters) will include the mean, standard 
deviation, median and range.  In the context of change from baseline analyses, summary 
of baseline and post-baseline data will also be provided.  Categorical safety endpoints 
(e.g., incidence of AEs, incidence of potentially clinically significant values) will be 
summarized using frequencies and percentages.  All the analyses will be carried out by 
treatment groups.
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events (TEAEs)
TEAEs are defined as any AE with onset or increased severity after the first dose of study 
drug (RT/TMZ/Depatux–M or matching placebo) and no more than 49 days after the last 
dose of Depatux-M/placebo.  Incidence of TEAEs will be summarized in chemo-radiation 
phase and adjuvant phase separately and also in the overall study.


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
M 1 3 -8 1 3 – Statistical A nal ysis Pla n
Versi o n 2. 0 – 2 3 A pr 2 0 1 9
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C he m o -ra diati o n p hase is defi ne d as fr o m t he St u d y R x Da y 1 t o t he da y bef ore t he 
first a dj u va nt d osi n g.  If a dj u va nt d osi n g is missi n g t he n, last De pat u x -M/ Place b o d osi n g 
+ 4 9 d a y s w o ul d be t he e n d date of c he m o-ra diatio n p hase. A dj u va nt p hase is defi ne d as 
da y  of first a dj u va nt d osi n g t o t he last De pat u x-M/ Place b o d osi n g + 4 9 da ys.
A d verse E ve nt O ver vie w
T he n u m ber a n d perce nta ge of s u bjects e x perie nci n g T E A Es bet wee n t he treat me nt 
gr o u ps will be s u m marize d f or t he f ol l o wi n g a d verse e ve nt cate g ories.  
●
A n y  T E A E
●
A n y  T E A E p ossi bl y relate d t o a n y st u d y dr u g
●
A n y  T E A E p ossi bl y relate d t o De pat u x– M, T M Z a n d R T, se paratel y 
●
A n y  T E A E wit h C T C A E gra de 3 or hi g her 
●
A n y  T E A E wit h C T C A E gra de 4 or hi g her 
●
A n y  Gra de 3 or hi g her T E A E p ossi bl y  relate d t o a n y st u d y dr u g
●
A n y  Gra de 3 or hi g her T E A E p ossi bl y relate d t o De pat u x– M, T M Z a n d R T, 
se paratel y 
●
A n y  Gra de 4 or hi g her T E A E p ossi bl y relate d t o a n y st u d y dr u g
●
A n y  Gra de 4 or hi g her T E A E p ossi bl y relate d t o De pat u x– M, T M Z a n d R T, 
se paratel y 
●
A n y  T E seri o us A E ( S A E) 
●
A n y  T E S A E p ossi bly relate d t o a n y st u d y dr u g
●
A n y  T E S A E p ossi bly relate d t o De pat u x – M, T M Z a n d R T, se paratel y 
●
A n y  TE A E lea di n g t o disc o nti n uati o n of De pat u x – M or Place b o, T M Z a n d R T, 
se paratel y
●
A n y  T E A E lea di n g t o disc o nti n uati o n of De pat u x– M p ossi bl y  relate d t o a n y 
st u d y dr u g
●
A n y  T E A E lea di n g t o disc o nti n uati o n of De pat u x– M/ Place b o, p ossi bl y  relate d 
t o De pat u x-M 
●
A n y  T E A E lea di n g t o disc o nti n uati o n of T M Z, p ossi bl y relate d t o T M Z 
●
A n y  T E A E lea din g t o disc o nti n uati o n of R T, p ossi bl y  relate d t o R T 


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●
Any TEAE leading to dose-reduction of any study drug
●
Any TEAE leading to dose-interruption of any study drug
●
Any TEAE leading to death
●
Deaths 
This overview output will also be generated for each AESI, separately.
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing TEAEs will be tabulated according 
to the primary MedDRA system organ class (SOC) and MedDRA preferred term (PT) for 
each treatment group.  Subjects reporting more than one adverse event for a given 
MedDRA PT will be counted only once for that term.  Subjects reporting more than one 
type of adverse event within a MedDRA SOC will be counted only once for that SOC.  
Subjects reporting more than one type of adverse event will be counted only once in the 
overall total. 
AEs by Preferred Term
The number and percentage of subjects experiencing adverse events will be tabulated 
according to the MedDRA PT for each treatment group.  Subjects reporting more than 
one AE for a given MedDRA PT will be counted only once for that term.
AEs by Maximum Severity
Adverse events will be summarized by SOC, PT and maximum severity per NCI CTCAE 
v.4 grading in each treatment arm.  If a subject has an AE with unknown severity, then the 
subject will be counted in the severity category of "unknown," unless the subject does not 
have another occurrence of the same AE with a severity present.  In addition, Grade 3 or 
higher AE and Grade 4 or higher events will also be summarized by SOC and PT.
AEs by Relationship
Adverse events possibly related to Depatux–M, TMZ, and radiotherapy as assessed by the 
investigator, will be summarized separately in each treatment arm.  Following summaries 


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will be prese nte d f or t he A Es p ossi bl y  relate d t o De pat u x – M, T M Z, a n d ra di ot hera p y, 
se paratel y:
●
S u m mar y  of A E b y P T ( p ossi bl y relate d t o De pat u x– M a n d T M Z o nl y)
●
S u m mar y  of A E b y S O C a n d P T ( p ossi bl y relate d t o De pat u x– M a n d T M Z 
o nl y )
●
S u m mar y  of Gra de 3 or hi g her A E by S O C a n d P T
●
S u m mar y  of Gra de 4 or hi g her A E b y S O C a n d P T
●
S u m mar y  of S A E by S O C a n d P T
●
S u m mar y  of De pat u x– M/ Place b o disc o nti n uati o n b y  S O C a n d P T ( p ossi bl y 
relate d t o De pat u x– M o nl y )
●
S u m mar y  of T M Z disc o nti n uati o n b y S O C a n d P T ( p ossi bl y relate d t o T M Z 
o nl y )
If a s u bject has a n A E wit h u n k n o w n relati o ns hi p, t he n t he s u bject will be c o u nte d i n t he 
relati o ns hi p cate g or y of " u n k n o w n," u nless t he s u bject d oes n ot ha ve a n ot her occ urre nce 
of t he sa me A E wit h a relati o ns hi p prese nt.  
A E of s pecial i nterest ( A E SI ) 
A E SI s will be assesse d a nd s u m marize d usi n g sta n dar dise d Me d D R A q uer y  ( S M Q) or 
A b b Vie -defi ne d c o m pa n y  Me d D R A q uer y ( C M Q).  T he A E SIs bel o w i ncl u de e ve nts 
relate d t o i de ntifie d or p ote ntial ris ks of De pat u x-M (c or neal e pit heli o pat h y, 
he pat ot o xicit y ), e ve nts t hat are a ntici pate d t o occ ur i n t he st u d y  p o p ulati o n d ue t o 
u n derl y i n g G B M or R T/ T M Z treat me nt a n d i n de pe n de nt of de pat u xiz u ma b maf o d oti n 
e x p os ure (seiz ures, ve n o us t hr o m b oe m b olic e ve nts, t hr o m b oc yt o pe nia, ne utr o pe nia, 
i nfecti o n), a n d e ve nts c o m m o nl y ass ociate d wit h bi ol o gic t hera pies ( hy perse nsiti vit y  
reacti o ns).  S pecific A E SI will be i de ntifie d by t he f oll o wi n g searc h criteria:


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AESI
Search Criteriaa
Corneal Epitheliopathy
(corneal AE)
CMQ "80000184";
Preferred Terms: 
Topography corneal abnormal, Corneal abrasion, Injury corneal, 
Persistent corneal epithelial defect, Abnormal sensation in eye, 
Acquired corneal dystrophy, Conjunctival irritation, Corneal cyst, 
Corneal decompensation, Corneal defect, Corneal degeneration,
Corneal deposits, Corneal disorder, Corneal epithelial microcysts, 
Corneal epithelium defect, Corneal erosion, Corneal exfoliation, 
Corneal hypertrophy, Corneal infiltrates, Corneal irritation, Corneal 
lesion, Corneal neovascularisation, Corneal oedema, Corneal opacity, 
Corneal perforation, Corneal striae, Corneal thinning, Dry eye, 
Excessive eye blinking, Eye irritation, Eye opacity, Eye pain, 
Eye paraesthesia, Eye pruritus, Eye ulcer, Foreign body sensation in 
eyes, Glare, Keratic precipitates, Keratitis, Keratitis interstitial, 
Keratitis sclerosing, Keratopathy, Lacrimation decreased, Lacrimation 
disorder, Lacrimation increased, Limbal stem cell deficiency, 
Noninfective conjunctivitis, Ocular discomfort, Ocular hyperaemia, 
Ocular surface disease, Ocular toxicity, Photophobia, Punctate keratitis, 
Scleral oedema, Scleral thinning, Superior corneal epithelial arcuate 
lesion, Superior limbic keratoconjunctivitis, Ulcerative keratitis, 
Vision blurred, Visual acuity reduced, Visual brightness, 
Visual impairment, Xerophthalmia, Cornea verticillata,
Hepatotoxicity 
Drug related hepatic disorders - comprehensive search (Broad SMQ) –
20000006
Hepatotoxicity – severe 
events
Drug related hepatic disorders – severe events only (Broad SMQ) –
20000007
Thrombocytopenia
Haematopoietic thrombocytopenia Broad SMQ (SMQ, 20000031)
Neutropenia
Haematopoietic leukopenia Broad SMQ (SMQ 20000030)
Venous thromboembolic 
events
Embolic and thrombotic events, venous - Narrow SMQ (SMQ 
20000084)  
Infection events with 14 days 
after neutropenia events*
Infections  - CMQ (CMQ 80000018)
Hematological toxicity - neutropenia – Narrow CMQ (CMQ 80000154)
Hypersensitivity reactions
Hypersensitivity - Broad SMQ (SMQ 20000214)
Seizures
Convulsions - Narrow SMQ (SMQ – 20000079)
*
Includes only infections that start anytime from start of neutropenia to end of neutropenia + 14 days.
a.
Preferred terms are included in each CMQ are documented in ABT-414 Integrated Summary Safety (ISS) 
Statistical Analysis Plan.


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Time to the first occurrence (onset) of any corneal AEs will be assessed using Kaplan 
Meier methodology and median time to first onset of any corneal AE (along with 95% CI).  
This analysis will be repeated for Grade 2 or higher corneal AEs, Grade 3 or higher 
corneal AEs, and Grade 4 or higher corneal AEs. 
Time to onset will be measured in days relative to the date of first dose date to the start 
date of the first occurrence of corneal AE.  If a subject has not experienced an corneal AE, 
the subject will be censored on the subject's last assessment date (i.e., the day of the 
subject's last known laboratory assessment, last known vital sign assessment, last known 
physical exam, last known ocular exam, last known tumor assessment, or last known 
follow-up visit, whichever is the latest) or 49 days from the subject's last treatment 
(Depatux–M or placebo), whichever is earliest.  If the subject has not experienced a 
corneal AE and had no post-baseline assessment, the data will be censored on the day of 
first dosing date.
11.2.2
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs and AEs leading to Depatux–M/Placebo and TMZ discontinuation, dose reduction 
and dose interruption, and death will be summarized separately by SOC and PT in each 
treatment arm. Separate listings for SAEs, AEs leading to death and AEs leading to 
treatment discontinuation will also be provided.
11.2.3
Listing of Adverse Events
The following additional summaries of adverse events will be prepared.
●
Listing of treatment-emergent serious adverse events.
●
Listing of treatment-emergent adverse events that led to discontinuation of 
study drug.
●
Listing of treatment-emergent fatal adverse events.
●
Listing of Grade 3 or higher adverse events


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
M 1 3 -8 1 3 – Statistical A nal ysis Pla n
Versi o n 2. 0 – 2 3 A pr 2 0 1 9
5 6
1 1. 3
A n al y si s of D e p at u x -M t ar g et e d o p ht h al m ol o gi c e x a m ( T O E) 
r e s ult s
T he f oll o wi n g assess me nts fr o m t he T O E will be a nal yze d usi n g s hift ta ble f or eac h 
treat me nt ar m, se paratel y.
●
Vis ual ac uit y  ( 2 0/ 1 0 - 2 0/ 2 0, 2 0/ 2 5 - 2 0/ 4 0, 2 0/ 5 0 – 2 0/ 1 0 0, 2 0/ 1 2 5 - 2 0/ 1 6 0, 
2 0/ 2 0 0 O R w orse) – Best e y e a n d w orst e ye se paratel y
●
Micr oc y sts/ E de ma ( No ne/ Trace/ Mil d/ M o derate/ Se vere) – W orst e y e
●
S u perficial P u nctate Kerat o pat h y  ( N o ne/ Trace/ Mil d/ M o derate/ Se vere) – W orst 
e ye
●
P h ot o p h o bia ( N o ne/ Mil d/ M o derate/ Se vere) – W orst e y e
●
E y e Pai n ( Yes / N o) – W orst e y e
F or eac h of t he e n d p oi nts a b o ve, s u m mar y ta bles a n d s hift ta bles will be create d f or t he 
ti me p oi nts: 
F or all s u bjects i n t he safet y  p o p ulati o n:
●
baseli ne val ue
●
w orst val ue i n c he m o -ra diati o n p hase
●
w orst val ue i n w h ole st u d y
●
fi nal val ue o n treat me nt ( u p t o 4 9 da ys after last d ose)
●
last val ue i n f oll o w-u p 
F or s u bjects w h o recei ve d at least o ne a dj u va nt d ose of a n y st u d y treat me nt:
●
baseli ne val ue
●
w orst val ue i n c he m o -ra diati o n p hase
●
last val ue i n c he m o-ra diati o n p hase
●
w orst val ue i n a dj u va nt p hase
●
fi nal val ue i n a dj u va nt p hase ( u p t o 4 9 da ys after last d ose)
●
last val ue i n f oll o w-u p 


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Data will be summarized by n (%) by severity level at each of the above timepoints.  Shift 
tables will be produced for baseline to post-baseline timepoint for each of the endpoints 
above.
Chemo-radiation phase is defined as from the Study Rx Day 1 to the day before the 
first adjuvant dosing. If adjuvant dosing is missing then, last Depatux-M/Placebo 
dosing + 49 days would be the end date of chemo-radiation phase. Adjuvant phase is 
defined as day of first adjuvant dosing to the last Depatux-M/Placebo dosing + 49 days. 
Follow-up phase starts after last Depatux-M/Placebo dosing + 49 days to the study 
completion. 
In addition, selected continuous TOE endpoints will be summarized for change from 
baseline.
11.4
Analysis of Laboratory Data
The hematology and clinical chemistry lab parameters listed in Table 8 are planned to be 
collected for each subjects at baseline and scheduled post-baseline visits. The urinalysis 
lab parameters are planned to be collected at baseline only.


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Table 8.
Clinical laboratory test
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils (if detected)
Eosinophils (if detected)
Absolute platelet count
Mean corpuscular volume 
(MCV)
Coagulation (screening Only)
Prothrombin time
Activated PartialThromboplastin 
Time (aPTT)
International normalized ratio 
(INR)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase 
(GGT)
Sodium
Potassium
Calcium
Inorganic phosphorus
Glucose
Cholesterol
Triglycerides
Total protein
Uric Acid
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination if 
dipstick results are positive
11.4.1
Variables and Criteria Defining Abnormality
NCI CTCAE v. 4 grading criteria for laboratory abnormalities are shown in Table 9 and 
Table 10.


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Table 9.
Criteria for NCI CTCAE Grades for Laboratory Values 
Hematology Variables
Units
NCI CTCAE Grade ≥ 3
NCI CTCAE Grade ≥ 4
Low
High
Low
High
Hematology Variables
Hemoglobin
g/L
< 80
> ULN + 40
White blood cell count
109/L
< 2
< 1
Neutrophil count
109/L
< 1
< 0.5
Lymphocyte count
109/L
< 0.5
< 0.2
Absolute Platelet count
109/L
< 50
< 25
Coagulation Variables
INR increased
ratio
> 2.5 × ULN*
*
Or baseline if on antigoagulation.


De pat u xiz u ma b maf o d oti n ( A B T -4 1 4)
M 1 3 -8 1 3 – Statistical A nal ysis Pla n
Versi o n 2. 0 – 2 3 A pr 2 0 1 9
6 0
T a ble 1 0 .
Criteri a f or N CI C T C A E Gr a des f or L a b or at or y
V al ues - C he mistr y V ari a bles
C he mistr y 
V ari a bles
U nits
N CI C T C A E Gr a de ≥ 3
N CI C T C A E Gr a de ≥ 4
L o w
Hi g h
L o w
Hi g h
Creati ni ne
mc m ol/ L
> 3 × U L N
> 6 × U L N
T otal bilir u bi n
mc m ol/ L
> 3 × U L N
> 1 0 × U L N
Ala ni ne 
a mi n otra nsferase 
( A L T/ S G P T)
U/ L
> 5 × U L N
> 2 0 × U L N
As partate 
a mi n otra nsferase
( A S T/ S G O T)
U/ L
> 5 × U L N
> 2 0 × U L N
Al kali ne 
p h os p hatase ( A L P)
U/ L
> 5 × U L N
> 2 0 × U L N
Ga m ma gl uta m yl 
tra nsferase ( G G T)
> 5 × U L N
> 2 0 × U L N
S o di u m 
m m ol/ L
< 1 3 0 
> 1 5 5
< 1 2 0
> 1 6 0
P otassi u m
m m ol/ L
< 3
> 6
< 2. 5
> 7
Calci u m
m m ol/ L
< 1. 7 5
> 3. 1
< 1. 5
> 3. 4
Gl uc ose
m m ol/ L
< 2. 2
> 1 3. 9
< 1. 7
> 2 7. 8
C h olester ol 
m m ol/ L
> 1 0. 3 4
> 1 2. 9 2
T ri gl yceri des
m m ol/ L
> 5. 7
> 1 1. 4
Al b u mi n
g/ L
< 2 0
Ma g nesi u m
m m ol/ L
< 0. 4
> 1. 2 3
< 0. 3
> 3. 3
Defi niti o n of P ote nti all y Cli nic all y Si g nific a nt L a b or at or y V al ues
La b orat or y  val ues will be c o nsi dere d as p ote ntiall y cli nicall y si g nifica nt if t he y are 
Gra de 3 or hi g her as s h o w n i n Ta ble 4 a n d Ta ble 5 , wit h t he f oll o wi n g e xce pti o ns:
●
G G T:  Gra de 4
●
T otal bilir u bi n:  > 2 ×
U L N
●
C o nc urre nt A L T or A S T > 3 × U L N a n d t otal bilir u bi n ≥ 2 × U L N


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●
Concurrent ALT or AST > 3 × ULN, ALP < 2 × ULN and total bilirubin 
≥2 × ULN
The maximum ratio relative to the ULN will be used to determine if subjects met the 
criteria listed above.  The ALT, AST, and total bilirubin values need to be concurrent 
(i.e., collected on same date) and should be collected within 49 days following the last 
dose date of any study drug in order to meet the defined criteria.
11.4.2
Statistical Methods
Treatment emergent lab abnormalities will be summarized in chemo-radiation phase and 
adjuvant phase separately and also in the overall study.  For each of the continuous 
laboratory parameters, the following outputs will be produced for each treatment group:
●
Summary of lab measurements at each scheduled visits 
●
Summary of changes from baseline at each post-baseline visits along with 
treatment group difference
●
Shifts from baseline grades to worst post-baseline grades (only for the 
parameters where CTCAE grading is possible)
●
The number and percentage of subjects with maximum treatment-emergent 
laboratory values meeting the potentially clinically significant criteria 
(excluding hepatic tests) 
●
For hepatic tests, the number and percentage of subjects with hepatic 
laboratory values meeting several cut-off values (e.g., > 3 × ULN, > 5 × ULN, 
> 10 × ULN, etc.) specified for each test
●
Listing of laboratory values for subjects with potentially clinically significant 
values
11.5
Analysis of Vital Signs
11.5.1
Variables and Criteria Defining Abnormality
Pre-defined criteria for potentially clinically significant vital signs values are given in 
Table 11.


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Table 11.
Criteria for Potentially Clinically Significant vital signs Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant Values
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate
Low
Value ≤ 50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value ≤ 32°C
High
Value > 40°C
11.5.2
Statistical Methods
Vital sign parameters (diastolic/systolic blood pressure, pulse rate, and body temperature) 
and body weight will be descriptively summarized by treatment groups.  For each of the 
vital signs parameters, the following outputs will be produced:
●
Summary of vital signs parameters at each scheduled visit 
●
Summary of changes from baseline at each post-baseline visit along with 
treatment group difference
●
Summary of subjects with post baseline values meeting criteria for potentially 
clinically significant Vital Signs values
Change from baseline analyses will be summarized at each post-baseline visit and 
treatment group difference will be reported.
11.6
Analysis of ECG parameters
ECG will be performed at screening, final visit and when clinically indicated.  These ECG 
values will be summarized by visit and treatment group.  Change from baseline at each 
post-baseline visit will also be summarized using shift table.


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12.0
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13.0
Appendix 


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Appendix I:
Determining deterioration in HVLT-R Total Recall score and 
COWA FAS score
Raw Score will be standardized using the published age-specific normative data from a 
healthy population as follows.
At each post-baseline assessment, change in raw score relative to baseline will be 
calculated and categorized as declined or not using the reliable change index (RCI) 
criterion based on the raw scores.  The RCI is derived from the standard error of 
measurement of each test and represents the 90% confidence interval for the difference in 
raw score from baseline to the next assessment that would be expected if no real change 
occurred:2,14
RCI = 1.64(SEdiff), where SEdiff = [2(SEM2)]1/2 and SEM = SD[(1 – r)1/2]
SEdiff is the standard error of difference, SEM is the standard error of measurement, SD 
is the standard deviation, and r is the test-retest reliability statistic.  All RCI thresholds 
were rounded to the nearest whole number.  For HVLT-R total score and COWA-FAS 
score, r = 0.74 and 0.70 will be used, respectively.4  Deterioration in raw score should be 
compared against the RCI threshold to determine the meaningful deterioration.


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Appendix II:
Summary of RANO response criteria
Tumor progression will be assessed using the RANO criteria as outlined below according 
to Wen, et al,30 "Updated Response Assessment Criteria for High-Grade Gliomas:  
Response Assessment in Neuro-Oncology Working Group."  Note:  Only PFS data will be 
analyzed in this study.
Table 1.
Criteria for Determining First Progression Depending on Time 
from Initial Chemoradiotherapy
First Progression
Definition
Progressive disease 
< 12 weeks after 
completion of 
chemoradiotherapy
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region 
or 80% isodose line) or if there is unequivocal evidence of viable tumor 
on histopathologic sampling (e.g., solid tumor areas [i.e., > 70% tumor 
cell nuclei in areas], high or progressive increase in MIB-1 proliferation 
index compared with prior biopsy, or evidence for histologic progression 
or increased anaplasia in tumor).
Note:  Given the difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of radiographic 
or histologic confirmation of progression, will not be sufficient for 
definition of progressive disease in the first 12 weeks after completion of 
concurrent chemoradiotherapy.
Progressive disease 
≥12 weeks after 
chemoradiotherapy 
completion
1.
New contrast-enhancing lesion outside of radiation field on 
decreasing, stable, or increasing doses of corticosteroids.
2.
Increase by ≥ 25% in the sum of the products of perpendicular 
diameters between the first post-radiotherapy scan, or a subsequent 
scan with smaller tumor size, and the scan at 12 weeks or later on 
stable or increasing doses of corticosteroids.
3.
Clinical deterioration not attributable to concurrent medication or 
comorbid conditions is sufficient to declare progression on current 
treatment but not for entry onto a clinical trial for recurrence.
4.
For patients receiving anti-angiogenic therapy, significant increase in 
T2/FLAIR non-enhancing lesion may also be considered progressive 
disease.  The increased T2/FLAIR must have occurred with the 
patient on stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy and not be a 
result of comorbid events (e.g., effects of radiation therapy, 
demyelination, ischemic injury, infection, seizures, post-operative 
changes, or other treatment effects).
FLAIR = fluid-attenuated inversion recovery


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Pseudoprogression and Radiation Effects
The proposed new response criteria suggest that within the first 12 weeks of completion 
of radiotherapy, when pseudoprogression is most prevalent, progression can only be 
determined if the majority of the new enhancement is outside of the radiation field (for 
example, beyond the high-dose region or 80% isodose line) or if there is pathologic 
confirmation of progressive disease.  It is recognized that the proposed histologic criteria 
have important limitations, but they provide guidance on the type of findings that are 
suggestive of progressive disease.  For patients in whom pseudoprogression cannot be 
differentiated from true tumor progression, enrollment onto trials for recurrent gliomas 
should not be permitted.  Patients who remain clinically stable and/or are suspected to 
have pseudoprogression based on metabolic or vascular imaging should continue with 
their current therapy.
Enhancement as a Result of Surgery and Other Therapies
Increased enhancement often develops in the wall of the surgical cavity 48 to 72 hours 
after surgery.  To avoid interpretation of post-operative changes as residual enhancing 
disease, a baseline MRI scan should ideally be obtained within 24 to 48 hours after 
surgery and no later than 72 hours after surgery.  The inclusion of diffusion weighted 
imaging in the immediate post-operative MRI scan can be helpful in determining whether 
new enhancement developing in the subsequent weeks or months is caused by sequelae of 
ischemia or by tumor recurrence.  In addition, a transient increase in enhancement that can 
be difficult to distinguish from recurrent disease can also occur after locally administered 
therapies.  These include chemotherapy wafers, immunotoxins delivered by convection 
enhanced delivery, regionally administered gene and viral therapies, immunotherapies, 
and focal irradiation with brachytherapy and stereotactic radiosurgery.  Imaging 
modalities such as perfusion imaging, magnetic resonance spectroscopy, and positron 
emission tomography scans may sometimes be helpful in differentiating treatment effects 
from recurrent tumor.  However, no imaging modality currently has sufficient specificity 
to conclusively differentiate recurrent tumor from treatment effects, and surgical sampling 
may occasionally be needed to obtain a definitive diagnosis.


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Definition of Clinical Deterioration
The definition of clinical deterioration is left to the discretion of the treating physician, but 
it is recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS 
of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at 
least 7 days, be considered neurologic deterioration unless attributable to comorbid events 
or changes in corticosteroid dose.  Similarly, a decline in the Eastern Cooperative 
Oncology Group and WHO performance scores from 0 or 1 to 2 or 2 to 3 would be 
considered neurologic deterioration.
For those subjects who have measurable disease post resection, RANO criteria for 
assessment of CR, PR, SD and PD can be applied.  See the below tables for the definitions 
to be used.
Definition of Radiographic Response
Radiographic response should be determined in comparison to the tumor measurement 
obtained at pretreatment baseline for determination of response, and the smallest tumor 
measurement at either pretreatment baseline should be used for determination of 
progression.  The criteria for radiographic changes after therapy are listed in Table 2.  In 
the event that the radiographic changes are equivocal and it is unclear whether the patient 
is stable or has developed progressive disease, it is permissible to continue treatment and 
observe the patient closely, for example at 4 week intervals.  If subsequent imaging 
studies demonstrate that progression has occurred, the date of progression should be the 
date of the scan at which this issue was first raised.  The determination of radiographic 
response after treatment with agents that affect vascular permeability is particularly 
difficult.  In these patients, consideration should be given to performing a second scan at 
4 weeks to confirm the presence of response or stable disease.  All measurable and 
nonmeasurable lesions should be assessed using the same techniques as at baseline.  
Ideally, patients should be imaged on the same MRI scanner, or at least with the same 
magnet strength, for the duration of the study to reduce difficulties in interpreting 
changes.


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Patients with nonmeasurable enhancing disease whose lesions have significantly increased 
in size and become measurable (minimal bidirectional diameter of ≥ 10 mm and visible on 
at least two axial slices that are preferably, at most, 5 mm apart with 0 mm skip) will also 
be considered to have experienced progression.  The transition from a nonmeasurable 
lesion to a measurable lesion resulting in progression can theoretically occur with 
relatively small increases in tumor size (e.g., a 9 × 9 mm lesion [nonmeasurable] 
increasing to a 10 × 11 mm lesion [measurable]).  Ideally, the change should be 
significant (> 5 mm increase in maximal diameter or ≥ 25% increase in sum of the 
products of perpendicular diameters of enhancing lesions).  In general, if there is doubt 
about whether the lesion has progressed, continued treatment and close follow-up 
evaluation will help clarify whether there is true progression.  If there is uncertainty 
regarding whether there is progression, the patient may continue on treatment and remain 
under close observation (e.g., evaluated at 4-week intervals).  If subsequent evaluations 
suggest that the patient is in fact experiencing progression, then the date of progression 
should be the time point at which this issue was first raised.
Table 2.
Summary of the Proposed RANO Response Criteria
Criterion
CR
PR
SD
PD
T1 gadolinium enhancing disease
None
≥ 50% ↓
< 50% ↓ but < 25% ↑
≥ 25% ↑*
T2/FLAIR
Stable or ↓
Stable or ↓
Stable or ↓
↑*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or ↓
Stable or ↓
NA**
Clinical status
Stable or ↑
Stable or ↑
Stable or ↑
↓*
Requirement for response
All
All
All
Any*
RANO = Response Assessment in Neuro-Oncology; CR = complete response; PR = partial response; SD = stable 
disease; PD = progressive disease; FLAIR = fluid-attenuated inversion recovery; NA = not applicable
*
Progression occurs when this criterion is present.
**
Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration.






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Appendix IV:
Scoring manual for EORTC QLQ-C30 questionnaire
QLQ-C30
Item (Question) Numbers
Item Range*
Global health status/QoL
Global health status/QoL
29, 30
6
Functional scales
Physical functioning
1, 2, 3, 4, 5
3
Role functioning
6, 7
3
Emotional functioning
21, 22, 23, 24
3
Cognitive functioning
20, 25
3
Social functioning
26, 27
3
Symptom scales/Items
Fatigue
10, 12, 18
3
Nausea and vomiting
14, 15
3
Pain
9, 19
3
Dyspnea
8
3
Insomnia
11
3
Appetite loss
13
3
Constipation
16
3
Diarrhea
17
3
Financial difficulties
28
*
Item range is the difference between the possible maximum and the minimum responses to individual items; most 
items take values from 1 to 4, giving range = 3.
Individual questions from EORTC QLQ-C30 questionnaire are as follows:


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Appendix V:
Scoring manual for EORTC QLQ-BN20 questionnaire
QLQ-BN20
Item (Question) Numbers
Item Range
Symptom scales
Future uncertainty (FU)
1, 2, 3, 5
3
Visual disorder (VD)
6, 7, 8
3
Motor dysfunction (MD)
10, 15, 19
3
Communication deficit (CD)
11, 12, 13
3
Headaches (H)
4
3
Seizures (S)
9
3
Drowsiness (Dr)
14
3
Hair loss (HL)
16
3
Itchy skin (IS)
17
3
Weakness of legs (WL)
18
3
Bladder control (BC)
20
3


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Individual questions from EORTC QLQ-BN20 questionnaire are as follows:
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix VI:
Scoring manual for EQ-5D-5L and EQ VAS assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Appendix VII:
Scoring manual for COWA-FAS assessment
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
  
 
 
 
 
   
 
 
 
 
 


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Appendix VIII:
Study activities – Chemoradiation Phase
Chemoradiation Phase
Screeninga
Chemoradiation Phaseb
Activity
Screening 1
Screening 2
Day 1 Wk 1 
(Fraction 1 
of RT)
Day 1 of 
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 4
Day 1 of 
Wk 5
Day 1 of 
Wk 6
Day 1 of 
Wk 7
Informed Consent
X
Medical and Oncologic History
X
Physical Exam (Including Weight and 
Karnofsky Performance Status)c
X
X
X
X
Vital Signs
X
X
X
X
Ophthalmology Exam
X
Xd
Xd
ECGe
X
Serum Pregnancy Test
X
Xf
Chemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
Coagulation
X
MRI With and Without Contrast
Xk
Submit Tissue Sample for Confirmation of 
GBM, testing of EGFR amplification, 
EGFRvIII and MGMT
X
Adverse Event Assessment/Concomitant 
Medications/Supportive Care
X
X
X


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Chemoradiation Phase
Screeninga
Chemoradiation Phaseb
Activity
Screening 1
Screening 2
Day 1 Wk 1 
(Fraction 1 
of RT)
Day 1 of 
Wk 2
Day 1 of 
Wk 3
Day 1 of 
Wk 4
Day 1 of 
Wk 5
Day 1 of 
Wk 6
Day 1 of 
Wk 7
Radiation Therapyg
X
Temozolomide Administration
Xh
Depatux-M or Placebo Administration
X
X
X
Prophylactic Eye Drop Administration
Xi
Xi
Xi
Randomization
X
EORTC-QLQ-C30/BN20
Xj
MDASI-BT
Xj
NEI VFQ-25
Xj
Neurocognitive Function
(HVLT-R, COWA-FAS)
Xj
EQ-5D-5L and EQ-5D-VAS
Xj
Wk = Week; F/U = Follow-up; RT = Radiation Therapy; KPS = Karnofsky Performance Status; EORTC-QLQ-C30/BN20 = EORTC Quality of Life Questionnaire, Cancer and 
Brain modules; MDASI-BT = MD Anderson Symptom Index for Brain Tumors; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire – 25;
HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association (FAS form); EQ-5D-5L = EuroQoL 5 Dimensions; VAS = Visual analog scale


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Appendix IX:
Study Activities – Adjuvant Phase
Adjuvant Phase
Adjuvant Phase – 28-Day Cyclesa
Activity
Day 1 
of
Every 
Cycle 
(1, 2, 3 
etc.)
Day 1 of 
Odd-
Numbered 
Cycles (1, 3, 
5, etc.)
Day 1 
of 
Cycle 
2
Day 15 
of 
Every 
Cycleb
Day 22 
of 
Every 
Cyclec
Final 
Study 
Drug 
Visitd
35-
Day 
F/Ue
49 Day 
Follow 
Up
Follow-Up 
Phase (Every 
8 Weeks Until 
Disease 
Progression)f
At 
Progression
Survival
Physical Exam (Including Weight 
and Karnofsky Performance 
Status)g
X
X
Xd
X
X
Vital Signs
X
X
X
X
Ophthalmology Examh
X
X
Xi
ECG
X
Chemistry
X
X
X
Hematology
X
X
X
X
MRI and Clinical Disease 
Progression Assessment
Xj
Xd,k
Xj
Adverse Event 
Assessment/Concomitant 
Medications/Supportive Care
X
X
X
X
X
Temozolomide Administration
Xl
Depatux-M or Placebo 
Administration
Xm
Xm
Prophylactic Eye Drop 
Administration
Xn
Xn
NEI VFQ-25o
X
X


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Adjuvant Phase
Adjuvant Phase – 28-Day Cyclesa
Activity
Day 1 
of
Every 
Cycle 
(1, 2, 3 
etc.)
Day 1 of 
Odd-
Numbered 
Cycles (1, 3, 
5, etc.)
Day 1 
of 
Cycle 
2
Day 15 
of 
Every 
Cycleb
Day 22 
of 
Every 
Cyclec
Final 
Study 
Drug 
Visitd
35-
Day 
F/Ue
49 Day 
Follow 
Up
Follow-Up 
Phase (Every 
8 Weeks Until 
Disease 
Progression)f
At 
Progression
Survival
EORTC-QLQ-C30/BN20o
X
X
Xp
MDASI-BTo
X
X
Xp
Neurocognitive Function (HVLT-
R, COWA)o
X
X
Xp
EQ-5D-5L and EQ-5D-VASo
X
X
Xp
Treatment Satisfaction Question
X
X
Xp
Survival Assessmentq
X
Wk = Week; F/U = Follow-up; RT = Radiation Therapy; KPS = Karnofsky Performance Status; EORTC-QLQ-C30/BN20 = EORTC Quality of Life Questionnaire, Cancer and 
Brain modules; MDASI-BT = MD Anderson Symptom Index for Brain Tumors; NEI VFQ-25 = National Eye Institute Visual Functioning Questionnaire – 25; 
HVLT-R = Hopkins Verbal Learning Test-Revised; COWA = Controlled Oral Word Association (FAS form); EQ-5D-5L = EuroQoL 5 Dimensions; VAS = Visual Analog Scale