Phase 3b Study for Management of Ocular Side Effects in Subjects With EGFR-amplified Glioblastoma Receiving Depatuxizumab Mafodotin (ABT-414)
Phase: PHASE3
Conditions: Glioblastoma Multiforme
Sponsor: AbbVie

NCT03419403

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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO PATIENTS
9
3
STUDY OBJECTIVES AND ENDPOINTS
12
3.1
OBJECTIVES
12
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
OTHER SAFETY ENDPOINTS
13
3.5
PHARMACOKINETIC ENDPOINTS
13
3.6
HISTOPATHOLOGIC/BIOMARKER TISSUE EVALUATION ENDPOINTS
13
4
INVESTIGATIONAL PLAN
14
4.1
OVERALL STUDY DESIGN AND PLAN
14
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
19
5.1
ELIGIBILITY CRITERIA
19
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED MEDICATIONS AND THERAPY
23
5.4
PRIOR AND CONCOMITANT THERAPY
24
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
24
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
25
5.7
STUDY DRUG AND RADIATION THERAPY
26
5.8
RANDOMIZATION/DRUG ASSIGNMENT
29
5.9
PROTOCOL DEVIATIONS
29
6
SAFETY CONSIDERATIONS
30
6.1
COMPLAINTS AND ADVERSE EVENTS
30
6.2
SUSAR REPORTING
33
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6.3
TOXICITY MANAGEMENT
33
6.4
PRODUCT COMPLAINT
40
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
40
7.1
STATISTICAL AND ANALYTICAL PLANS
40
7.2
DEFINITION FOR ANALYSIS POPULATIONS
40
7.3
STATISTICAL ANALYSES FOR EFFICACY
41
7.4
STATISTICAL ANALYSES FOR SAFETY
41
8
ETHICS
41
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
41
8.2
ETHICAL CONDUCT OF THE STUDY
42
8.3
SUBJECT CONFIDENTIALITY
42
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
42
10 DATA QUALITY ASSURANCE
42
11 COMPLETION OF THE STUDY
42
12 REFERENCES
42
LIST OF TABLES
TABLE 1.
IDENTIFICATION OF INVESTIGATIONAL PRODUCT(S)
26
TABLE 2.
CORNEAL EPITHELIAL ADVERSE EVENT (CEAE) GRADING SCALE
32
TABLE 3.
DEPATUXIZUMAB MAFODOTIN DOSE MODIFICATION GUIDELINES FOR HEPATIC LABORATORY 
ABNORMALITIES
37
TABLE 4.
GENERAL GUIDELINES FOR DEPATUXIZUMAB MAFODOTIN DOSE INTERRUPTIONS AND 
RE-INITIATION (EXCEPT CORNEAL EPITHELIAL, ALLERGIC, AND DERMATOLOGIC TOXICITIES AND 
HEPATIC LABORATORY ABNORMALITIES)
38
TABLE 5.
DEPATUXIZUMAB MAFODOTIN DOSE MODIFICATION TABLE DURING CHEMORADIATION AND 
ADJUVANT PHASE
38
TABLE 6.
PRIMARY ENDPOINT PRECISION OF ESTIMATES
40
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LIST OF FIGURES
FIGURE 1.
STUDY DESIGN
16
FIGURE 2.
DEPATUXIZUMAB MAFODOTIN INTERVENTION STRATEGY FOR INADEQUATE CONTROL OF OCULAR 
SIDE EFFECTS
17
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
44
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
46
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
47
APPENDIX D.
ACTIVITY SCHEDULE
48
APPENDIX E.
SUBJECTS CONTINUING PARTICIPATION
51
APPENDIX F.
PROTOCOL SUMMARY OF CHANGES
55
APPENDIX G.
OPERATIONS MANUAL
56
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Glioblastoma (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 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  Despite 
this multimodel approach, median survival is 1 – 2 years.  There is an urgent need to develop novel 
therapeutics that can improve outcome in glioblastoma patients.
A substantial proportion of GBM tumors are characterized by Epidermal Growth Factor Receptor (EGFR) 
overexpression and amplification.  When present, EGFR amplification has been shown to be maintained 
throughout the natural history of the disease.  These features make EGFR a target for therapeutic 
intervention.  Depatuxizumab mafodotin (formerly known as ABT-414) is an antibody-drug conjugate 
(ADC) that incorporates the ABT-806 antibody, which is covalently bound to an auristatin microtubule-
disrupting toxin (mono methyl auristatin form [MMAF]) via a non-cleavable maleimido-caproyl (mc) 
linker.  Depatuxizumab mafodotin is currently being investigated in late phase clinical trials of patients 
with newly diagnosed glioblastoma with amplified EGFR.  The dose-limiting toxicities (DLTs) observed 
after depatuxizumab mafodotin exposure have been limited to ocular side effects (OSEs) with symptoms 
that manifest as a result of formation of corneal epithelial microcysts, a syndrome referred to as 
microcystic keratopathy.  It is hypothesized that depatuxizumab mafodotin is taken up into rapidly 
dividing cells of the corneal epithelium, mainly by non-selective, EGFR-unrelated mechanism; toxin is 
then released inside the cell, causing damage predominantly to the transient amplifying cells located 
within the basal cell layer, with relative sparing of the more slowly dividing corneal stem cells in the 
limbus.  This damage results in cellular death leading to the formation of epithelial microcysts.  The 
epithelial microcysts then travel towards the central cornea and are sloughed off as part of normal 
cornea regeneration.  Therefore, as the cornea regenerates, the symptoms resolve and the effects of 
depatuxizumab mafodotin should be transient after treatment discontinuation.
This is the first exploratory study evaluating prophylactic mitigation strategies and treatment options for 
OSEs associated with depatuxizumab mafodotin.
Ocular side effects are not unique to depatuxizumab mafodotin and have been observed with other 
ADCs currently in clinical development.3  For several of these ADCs, prophylactic steroid ophthalmic 
solution has been found to be effective in reducing the frequency and severity of ADC-induced OSEs.  In 
two Phase 1 dose-escalation studies, SGN-CD19A, which is a conjugate of a humanized anti-CD19 
antibody and an auristatin drug (monomethyl auristatin F [MMAF]), was administered to patients with 
hematologic malignancies and resulted in OSEs that manifested themselves as microcystic keratopathy 
on corneal examination.3  In both studies, patients experiencing ocular adverse events (AEs) were 
prescribed ophthalmic steroids and most experienced resolution or improvement to Grade 1 – 2 by last 
follow-up.  This observation prompted topical steroid prophylaxis in both trials, administered before 
each ADC dose.  At interim analysis, the authors of the latter study reported that this prophylaxis had 
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reduced the incidence of Grade 3 – 4 events.  In one Phase I study with conjugate of a humanized anti-
CD70 antibody and MMAF, SGN-75, dose dependent ocular side effects were observed in 57% of 
patients.  Artificial tears and steroid eye drops were prescribed, mitigating the duration and severity of 
ocular symptoms.  Thereafter, steroid eye drops were recommended for all patients with evidence of 
microcystic corneal epitheliopathy, even if asymptomatic.3  The steroid eye drops are thought to reduce 
the cellular turnover in the corneal epithelium and make the cells more resistant to the effects of 
chemotherapy agents that effect actively replicating cells.  Steroid ophthalmic steroids such as 
prednisolone 1% suspension and dexamethasone 0.1% solution have been required in all 
depatuxizumab mafodotin clinical trials since dose escalation in the first-in-human (FIH) study.
Supportive-care measures (e.g., lubricating eye drops, therapeutic bandage contact lenses, punctal 
plugs, etc.) can provide considerable relief for symptoms of depatuxizumab mafodotin-related eye side 
effects such as blurred vision, photophobia, and eye discomfort.  Although supportive care measures 
have been utilized in depatuxizumab mafodotin clinical trials, the selection and timing of specific 
interventions to be used were not prescribed by the study protocol, and investigators are allowed to 
utilize whatever strategies they deem appropriate as per clinical judgment.  Feedback from investigators 
and ophthalmologists experienced with use of depatuxizumab mafodotin has been particularly positive 
for the use of bandage contact lenses, with subjects reporting improvements in blurred vision and 
photophobia, as well as ocular discomfort.
An additional prophylactic treatment option proposed for this clinical trial is the use of vasoconstrictors 
and cold compresses immediately prior, during, and after the infusion.  It is hypothesized that 
vasoconstriction of the conjunctival arterioles by the combination of pharmacologic (topical 
vasoconstrictors) and physical (cold compresses) methods during and immediately after infusion would 
significantly decrease exposure of the corneal epithelial cells to depatuxizumab mafodotin, thereby 
decreasing damage to corneal epithelium.  Feedback from ophthalmologists testing this combination 
vasoconstrictor/cold compress strategy in the depatuxizumab mafodotin development program has 
been supportive of the potential efficacy of this approach.
Naphazoline HCl is available in 0.012% over the counter eye drop formulations.  Naphazoline is an 
imidazole derivative and acts as an adrenergic receptor agonist that induces vasoconstriction of 
arterioles of the conjunctiva by stimulation of α-adrenergic receptors of the vascular wall.  Short term 
(approximately 4 hours) tachyphylaxis in response to acute administration of naphazoline is mediated by 
receptor desensitization; more durable tachyphylaxis occurs after several days use and is mediated by 
receptor down regulation.  Naphazoline HCl 0.012% is approved for administration of 1 – 2 gtt into 
affected eye every 3 to 4 hours as needed.4
The ability to assess the effectiveness of prophylactic and interventional strategies for ocular side effect 
management has been limited in depatuxizumab mafodotin trials to date.  Potential improvements over 
standard steroid prophylaxis have only recently been identified, and support for them is based on 
anecdotal reports for a small number of subjects.  As important, the standard practice for recording 
spontaneously reported adverse events in clinical trials (recording the times of onset and complete 
resolution, and recording changes in severity only if there is an increase) provides limited longitudinal 
information on symptom severity for assessing effectiveness of supportive care interventions.
This exploratory safety study will systematically assess the effectiveness of different prophylactic 
strategies, as well as the effectiveness of bandage contact lens intervention for those who demonstrate 
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inadequate control of ocular side effects by pre-defined criteria.  Regular, repeated assessments of 
symptom severity and eye examinations will provide longitudinal information needed to evaluate the 
effectiveness of prophylactic regimens and interventions.
Clinical Hypothesis
Improved management of depatuxizumab mafodotin-related OSEs, through prophylactic eye treatment 
regimens and/or symptom-driven interventions, should minimize depatuxizumab mafodotin dose 
interruptions and discontinuations and allow subjects with GBM who are treated with depatuxizumab 
mafodotin to achieve the overall treatment intensity prescribed.  The use of novel prophylactic regimens 
(vasoconstrictor/cold compress [VC] and/or enhanced steroids [ES]) with depatuxizumab mafodotin 
infusions should decrease the severity of depatuxizumab mafodotin-related OSEs compared to the 
standard steroid (SS) regimen that was used in previous clinical trials.  The VC regimen includes both 
pharmacologic vasoconstriction with the adrenergic agonist naphazoline 0.012% topical solution and 
physical vasoconstriction by application of cold compresses to the eyes around the time of infusion.  The 
ES regimen includes a higher frequency of steroid eye drops than the standard steroid (6×/day versus 
3×/day), as well as addition of ocular steroid ointment at night.  This approach is intended to maximize 
the effects of steroids on corneal epithelial cell turnover, which is postulated to make them less 
susceptible to depatuxizumab mafodotin-induced OSEs.  In subjects for whom OSEs are not adequately 
managed with the initial prophylactic eye treatment regimen, intervention with bandage contact lenses 
should improve tolerability of OSEs.
2.2 Benefits and Risks to Patients
In preclinical studies, depatuxizumab mafodotin has demonstrated efficacy in a range of tumor types, 
including human GBM cell lines that have a high EGFR expression, and human tumor xenograft models.  
Depatuxizumab mafodotin also demonstrates a favorable EGFR-binding ratio of tumor to normal tissue.
Depatuxizumab mafodotin has been studied in 6 clinical trials to date.  In the randomized Phase 2 
Study M14-483 (INTELLANCE-2) in EGFR-amplified, recurrent GBM, the primary comparison of 
depatuxizumab mafodotin combined with TMZ (n = 88) vs TMZ or lomustine (n = 86) showed a 29% 
reduction in OS hazard rate (HR = 0.71; 95% CI [0.50, 1.02]) that did not reach statistical significance at 
the 0.05 two-sided level (p = 0.062).  The 1-year OS rate for the depatuxizumab mafodotin combination 
was 40% [29%, 50%] versus 28% [19%, 38%] for the TMZ/LOM group.  No OS difference was observed 
between depatuxizumab mafodotin monotherapy and TMZ/LOM (HR 1.04; 95%CI [0.73, 1.48]; p = 0.835 
two-sided).
Preliminary safety data were available for 809 subjects who received at least 1 dose of depatuxizumab 
mafodotin at the most recent IB update (version 7.0).  A total of 488 subjects have been exposed to 
depatuxizumab mafodotin in the open-label studies (i.e., Studies M12-356 [N = 202], M13-379 [N = 56],
M13-714 [N = 53], and M14-483 [N = 177, adult and pediatric]); in addition, 321 subjects were estimated 
to have received depatuxizumab mafodotin in the ongoing, blinded Study M13-813.  Pharmacokinetic 
results are available from the following studies of depatuxizumab mafodotin:  Studies M13-379 (N = 56), 
M12-356 (N = 202), M14-483 (N = 177), and M13-714 (N = 53).
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 
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20% of subjects receiving depatuxizumab mafodotin were fatigue (34.9%), vision blurred (27.3%), 
headache and keratitis (25.0% for each), dry eye (24.4%) and corneal epithelial microcysts (22.1%).  The 
majority of subjects who received depatuxizumab mafodotin (77.3%) experienced at least 1 treatment-
emergent adverse event coded to the System Organ Class of Eye Disorders.  In addition to ocular side 
effects related to corneal epitheliopathy, treatment-emergent adverse events reported by ≥10% of 
subjects in the depatuxizumab 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 depatuxizumab mafodotin/TMZ combination arm, for which the rate was similar to that of 
subjects receiving TMZ monotherapy.
In the ongoing Study M13-813 (RTOG 3508) blinded study in newly diagnosed GBM, one subject 
receiving depatuxizumab mafodotin (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 depatuxizumab mafodotin.  The sponsor also assessed that there was a 
reasonable possibility that depatuxizumab mafodotin 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 depatuxizumab mafodotin open-label or blinded studies, in which approximately 809 people 
have received depatuxizumab mafodotin to date.
Enhanced steroid treatment, proposed in the study, is commonly used for routine postoperative 
management and treatment of endothelial graft rejection.  Potential increase in intraocular pressure 
and increased risk of fungal infection, associated with intensified topical steroid administration will be 
mitigated by frequent (bi-weekly) ophthalmologic examinations.
Use of topical vasoconstrictors and cold compresses, both of which are over-the-counter treatments 
that will be used in accordance to the package insert instructions, present minimal risk to patients.  Any 
potential adverse reactions to these treatments will be addressed during bi-weekly ophthalmologic 
examinations.  Use of bandage contact lens intervention in combination with steroid treatment may 
potentially increase the risk of fungal and bacterial infection.  However, subjects in this study will 
undergo frequent routine ophthalmologic examinations, and treating ophthalmologists will have an 
option of using prophylactic topical antibiotics to prevent infections.
Summary of Results from Pre-planned Interim Efficacy Analysis for Study M13-813 (INTELLANCE-1)
Study M13-813/RTOG 3508/INTELLANCE-1 is an ongoing, Phase 3, randomized, double-blind, placebo-
controlled trial comparing the efficacy and safety of depatuxizumab mafodotin versus placebo, each as 
concurrent treatment with standard-of-care therapy of radiation therapy/TMZ plus adjuvant TMZ, in 
subjects with newly diagnosed GBM.  This ongoing study is being conducted by AbbVie in collaboration 
with the Radiation Therapy Oncology Group (RTOG) Foundation.  During the 6-week Chemoradiation 
Phase, subjects receive depatuxizumab mafodotin 2.0 mg/kg or placebo once every 2 weeks 
concurrently with standard 6-week concomitant radiation therapy/TMZ.  The Adjuvant Phase consists of 
28-day cycles, with subjects receiving concomitant TMZ (Days 1 to 5 of each cycle) and study drug 
(depatuxizumab mafodotin 1.25 mg/kg or placebo once every 2 weeks) for the first 6 cycles and study 
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drug (depatuxizumab mafodotin or placebo) monotherapy for the following 6 cycles, with the option to 
continue treatment until disease progression.
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 is 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 depatuxizumab mafodotin 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 depatuxizumab mafodotin 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 depatuxizumab 
mafodotin (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 depatuxizumab mafodotin 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 (depatuxizumab mafodotin or placebo) in the 
depatuxizumab mafodotin and placebo arms, 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 depatuxizumab mafodotin 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 depatuxizumab mafodotin group was at least 5% and was ≥ 2% greater 
than in the placebo group included thrombocytopenia, gamma-glutamyltransferase increased, and 
alanine aminotransferase increased.
The INTELLANCE-1 interim efficacy analysis results overall indicated no survival benefit for adding 
depatuxizumab mafodotin 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 believed it was appropriate to allow subjects receiving depatuxizumab mafodotin to continue 
depatuxizumab mafodotin treatment if the investigator and subject believed it is in the subject's best 
interest.
A total of 40 subjects have been enrolled in Study M16-534 (UNITE).  Based on the results from 
INTELLANCE-1, no new subjects will be enrolled into Study M16-534 (UNITE).  Subjects who are currently 
receiving depatuxizumab mafodotin will be allowed to continue depatuxizumab mafodotin treatment if 
the investigator and subject believe it is in the subject's best interest.  For those subjects who choose to 
continue depatuxizumab mafodotin, study procedures have been modified as described in Appendix 
E.  The appendix provides guidance for study drug administration and collection of only safety data 
related to AEs and SAEs.  No additional efficacy data will be collected.
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With all these changes, no statistical testing will be performed for the efficacy endpoints. Given only a 
small number of patients are enrolled in the study and most of them did not have long-term follow-up, 
all the efficacy endpoints will only be summarized, and no statistical model will be used to analyze the 
efficacy data. The statistical section remains unchanged to reflect the original analysis plan.
An abbreviated SAP will be written to document the details about the analysis plan.
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Primary Objective
1.
Estimate the percentage of subjects in each prophylactic treatment arm who require a change in 
OSE management due to inadequate control of OSEs.
Secondary Objective
2.
Assess the effects of intervention with bandage contact lenses (BCL) on visual acuity and OSE 
symptom severity for those subjects who require intervention due to inadequate control of 
OSEs.
3.2 Primary Endpoint
The primary endpoint is defined as the percentage of subjects with either a ≥ 3-line decline from 
baseline (≥ +0.3 on LogMAR scale) in visual acuity (with baseline correction) or ≥ Grade 3 OSE severity on 
the Corneal Epithelial Adverse Event (CEAE) scale, either of which will indicate inadequate control of 
OSEs requiring a change in OSE management strategy.
Unless otherwise noted, visual acuity will be measured using baseline correction, which will be 
determined at the screening ophthalmology visit and used to assess visual acuity at all remaining 
ophthalmology visits, for measuring changes in visual acuity and for determining the visual acuity 
component of the primary endpoint.  Details on determining baseline correction are provided in the 
operations manual.  The primary endpoint will be assessed over 8 weeks after initiation of 
depatuxizumab mafodotin treatment.
3.3 Secondary Endpoints
Secondary endpoints will be assessed as below over 8 weeks after initiation of depatuxizumab 
mafodotin treatment, assessed separately for the chemoradiation phase and adjuvant phase, as 
appropriate, as different doses of depatuxizumab mafodotin are used in each phase.  The effectiveness 
of the initial prophylactic strategy and of the BCL-intervention will be assessed separately, as will be 
resolution of OSEs after interruption/discontinuation of depatuxizumab mafodotin.
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Exploratory Endpoints of this study are:
Effectiveness of the prophylactic regimen with regard to symptom severity as assessed by:
1.
Individual items on the CEAE scale – degree of photophobia at each visit; impact of ocular 
discomfort on visual Activities of Daily Living (vADLs) at each visit; reading score (impact on 
blurred vision) at each visit.
2.
Visual Quality of Life (vQOL) score changes
Effectiveness of the intervention with regard to symptom severity as assessed by:
1.
Individual items on the CEAE scale – degree of photophobia at each visit; impact of ocular 
discomfort on vADLs at each visit; reading score (impact on blurred vision) at each visit.
2.
vQOL score changes
3.
% of subjects with improvement on vQOL
Overall survival (OS)
Progression free survival (PFS)
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
A schematic of the study design is shown in Figure 1.  Further details regarding study procedures are 
located in the Operations Manual, Section 3.  See Section 5.1 for information regarding eligibility 
criteria.
This is a Phase 3b open-label, randomized, exploratory study to evaluate the effect of 
3 ophthalmologic prophylactic treatment strategies for the management of OSEs in subjects with newly 
diagnosed, EGFR-amplified GBM who are being treated with depatuxizumab mafodotin in addition to 
standard frontline treatment with chemoradiation (RT/TMZ) followed by adjuvant TMZ.  Approximately 
90 subjects will be enrolled at approximately 30 research sites.
During the Chemoradiation Phase, all subjects will undergo focal RT, with one treatment of ~2 Gy given 
daily 5 days per week over approximately 6 weeks (and no more than 7 weeks), for a total of ~60 Gy.  
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.  All subjects will receive depatuxizumab mafodotin at 
2.0 mg/kg IV infusion once every 2 weeks (on Day 1 of Weeks 1, 3, and 5) during this period.
Treatment in the Chemoradiation Phase 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 last surgery.
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The start of the first cycle during the Adjuvant Phase will be scheduled approximately 28 days after the 
last day of chemoradiation.  The AbbVie Therapeutic Area Medical Director 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 – 12 cycles, depending on local standard of care.  All subjects will receive 
depatuxizumab mafodotin at 1.25 mg/kg IV infusion once every 2 weeks (on Day 1 and Day 15 of each 
28-day cycle) for 12 cycles.  Adjuvant treatment will be discontinued upon determination of tumor 
progression as defined by Response Assessment in Neuro-Oncology Working Group (RANO) criteria 
(Operations Manual, Appendix I), unacceptable toxicity, or refusal to continue study treatment.
Subjects will be randomized to 1 of 3 prophylactic eye treatment arms (1:1:1), to be administered with 
each infusion of depatuxizumab mafodotin (during both Chemoradiation Phase and Adjuvant Phase):
•
Arm A (SS) – Standard Steroids
•
Arm B (SS/VC) – Standard Steroids + Vasoconstrictor + Cold Compress
•
Arm C (ES/VC) – Enhanced Steroids + Vasoconstrictor + Cold Compress
Subjects will be monitored at regular intervals for OSEs by AE reports and by ophthalmology 
examinations (including slit lamp examination and visual acuity testing).
For subjects who demonstrate inadequate control of OSEs with the initial prophylactic strategy, 
according to predefined criteria for loss of visual acuity and/or OSE symptom severity, intervention with 
a BCL will first be employed (Figure 2).  Subjects who continue to demonstrate inadequate response to 
BCL intervention (CEAE Grade 3 or higher OSE symptom severity) will be eligible for unrestricted OSE 
management according to investigator discretion.  In this case, depatuxizumab mafodotin dose 
interruption and/or reduction may be used, and any available prophylactic (including addition of ES and 
VC regimens if not used initially) or supportive care measures may be employed without restriction, at 
the discretion of the investigator.
Subjects who complete 8 weeks of adjuvant therapy (8 weeks after the first dose of adjuvant 
depatuxizumab mafodotin) will be allowed to enter the Investigator Discretion phase regardless of CEAE 
Grade, visual acuity or BCL intervention.
Visual acuity will be measured using the LogMAR scale for visual acuity, while OSE symptom severity will 
be measured by the Corneal Epithelial AE grading scale (see Section 6.1 and Operations Manual, 
Section 4.3), which was developed by the sponsor for assessing and managing corneal epitheliopathy 
associated with ADCs.
Effectiveness of the prophylactic strategies will be assessed during the first 8 weeks of each phase of 
treatment (Chemoradiation Phase and Adjuvant Phase).  Subjects who discontinue depatuxizumab 
mafodotin for any reason will receive regular follow-up for assessment of AEs and ophthalmologic 
examinations until resolution of OSEs to evaluate the reversibility of depatuxizumab mafodotin-related 
OSEs.
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Figure 1.
Study Design
Abbreviations:  GBM = glioblastoma; RT = radiation therapy; TMZ = temozolomide
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Figure 2.
Depatuxizumab Mafodotin Intervention Strategy for Inadequate Control of 
Ocular Side Effects
4.2 Discussion of Study Design
Suitability of Subject Population
The study population of newly diagnosed GBM with amplified EGFR was selected because 
depatuxizumab mafodotin is currently being investigated in a late phase clinical trial with this subject 
population.  Ocular side effects are noted to occur at a > 80% frequency in GBM patients with doses 
currently utilized in the ongoing Phase 2b/3 clinical trial.
Choice of Frontline GBM Therapy
Concomitant RT/TMZ therapy followed by adjuvant TMZ therapy is the established standard-of-care 
treatment for newly diagnosed GBM, and the dose regimens for RT and TMZ for the current study are 
consistent with standard of care.  Addition of depatuxizumab mafodotin to this standard treatment 
regimen was generally well tolerated in a Phase 1 study, with dose-limiting toxicity restricted to OSEs, 
and efficacy is being evaluated in a large Phase 2b/3 study in EGFR-amplified, newly diagnosed GBM.
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Choice of Prophylactic Regimens and BCL Intervention
Prophylactic steroid eye drops were instituted early on during the first Phase 1 study in solid tumors to 
support continued dose escalation.  In the ongoing Phase 2b/3 clinical trial in newly diagnosed subjects, 
all subjects receive prophylactic steroid eye drops with each dose of depatuxizumab mafodotin for 
7 consecutive days, starting from 2 days prior to infusion and continuing until 4 days after infusion, 
making it the standard of care in the depatuxizumab mafodotin clinical development program.
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 depatuxizumab 
mafodotin 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 the drops is around the time of infusion when the levels of MMAF 
are at their peak.
Enhanced steroid treatment regimen will consist of the same steroid eye drops, as those used in the 
standard steroid arm, administered with the maximal frequency that can be achieved with reasonable 
expectation of patient compliance.  Steroid ointment will be instilled at night, when the patient cannot 
be expected to self-administer eye drops.  This regimen will maximize the exposure of the corneal 
epithelium to the steroids, allowing examination of the dose-effect relationship.  Safety of enhanced 
steroid treatment will be insured by frequent (every 2 – 4 weeks) targeted ophthalmologic 
examinations.
The dose of vasoconstrictor was selected based on the maximum dose and duration of treatment 
recommended for naphazoline hydrochloride 0.012%solution.4
The use of therapeutic BCLs can have a major impact on improving eye symptoms, including 
photophobia, blurred vision and various forms of eye discomfort, and thus minimize the need for 
depatuxizumab mafodotin dose interruptions and dose reductions.
Appropriateness of Measurements
The LogMAR scale will be the instrument utilized for measuring visual acuity because it is a well-
accepted validated tool used in ophthalmology clinical trials designed to evaluate change in visual 
acuity.5
The CEAE grading scale will be used to measure OSE symptom severity.  This measure was developed by 
AbbVie, based on experience with ADC-related microcystic keratopathy caused by depatuxizumab 
mafodotin, to address inadequacies of the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) system for appropriately capturing symptoms, grading, and making dose 
modifications for ADC-related corneal toxicity.
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an Independent 
Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening 
or study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old.
3. Laboratory values meeting the following criteria confirming adequate bone marrow, renal, 
and hepatic function:
•
Bone marrow
•
Absolute neutrophil count ≥ 1,500 cells/mm3
•
Platelets ≥ 100,000 cells/mm3
•
Hemoglobin (Hgb) ≥ 9.0 g/dL (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 × upper limit of normal (ULN).  Subjects with Gilbert's syndrome 
documented in medical history may be enrolled if total bilirubin is < 3 × ULN.
•
AST ≤ 3 × ULN
•
ALT ≤ 3 × ULN
•
Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5.  Subjects on anticoagulant
(such as coumadin) will have a target PT and INR as determined by the Investigator.
4. Willing or able to comply with procedures required in this protocol.
Disease Activity
5. Diagnosis of newly diagnosed GBM, histologically proven, World Health Organization (WHO) 
Grade IV GBM or WHO Grade IV gliosarcoma
6. Tumor must demonstrate EGFR amplification by central laboratory
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7. Tumor must be supratentorial in location
8. Karnofsky performance status of ≥ 70
Subject History
9. Electrocardiogram without evidence of acute cardiac ischemia ≤ 21 days prior to 
randomization.
10. Life expectancy of ≥ 3 months.
11. No history of hypersensitivity to any component of TMZ or dacarbazine (DTIC).
12. No history of prior chemotherapy or radiotherapy for cancer of the head and neck region.
13. No history of prior treatment with Gliadel wafers or any other intratumoral or intracavitary 
treatment.
14. No prior anti-cancer therapy (including chemotherapy, immunotherapy, radiotherapy, 
hormonal therapy, biologic therapy, or any investigational therapy) prior to 5 years of Study 
Day 1.
15. No history of a major immunologic reaction to any Immunoglobulin (IgG) containing agent.
16. No clinically significant uncontrolled condition(s) including but not limited to the following:
•
Active uncontrolled infection
•
Symptomatic congestive heart failure
•
Unstable angina pectoris or cardiac arrhythmia
•
Psychiatric illness/social situation that would limit compliance with the study
17. No medical condition which in the opinion of the Investigator places the subject at an 
unacceptably high risk for toxicities.
18. No other active malignancy within the past 3 years except for any cancer considered cured 
or non-melanoma carcinoma of the skin.
19. No history of herpetic keratitis.
20. No LASIK (laser-assisted in situ keratomileusis) procedure within the last 1 year or cataract 
surgery within the last 3 months.
21. No visual condition that compromises the ability to accurately measure visual acuity or 
assess visual ADLs (e.g., central tumor affecting visual pathways).
22. No infection with hepatitis B virus (i.e., hepatitis B surface antigen) or hepatitis C virus (i.e., 
positive for hepatitis C antibody).  Subjects who have a history of hepatitis C who have 
documented cures after anti-viral therapy may be enrolled.  Subjects with confirmed positive 
test result for human immunodeficiency virus (HIV), with CD4 count < 200 cells/microliter are 
excluded.
•
Note that subjects who are HIV positive are eligible, provided they are under treatment with 
highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter 
within 30 days prior to registration, as the treatments involved in this protocol may be 
significantly immunosuppressive. 
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•
Note HIV testing is not required for eligibility for this protocol unless mandated by local 
regulatory authority or ethics committee/institutional review board.
Contraception
23. For all females of childbearing potential, a negative serum pregnancy test at the screening 
visit and a negative urine pregnancy test at baseline prior to the first dose of study drug and 
monthly throughout the study.
24. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, as specified in Section 5.2, that is effective from Study Day 1 through at least 
6 months after the last dose of depatuxizumab mafodotin.  Female subjects of non-childbearing 
potential do not need to use birth control. 
25. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study or for at least 6 months after the last dose of depatuxizumab mafodotin.
26. If male, and subject is sexually active with female partner(s) of childbearing potential, he 
must agree, from Study Day 1 through the entire duration of the study and for at least 6 months 
after the last dose of depatuxizumab mafodotin, to practice the contraception specified in 
Section 5.2.
27. Male who is not considering fathering a child or donating sperm during the study or for at 
least 6 months after the last dose of depatuxizumab mafodotin. 
Concomitant Medications
28. Suitable for receiving ocular steroids and has none of the following:
•
Any active viral disease of the cornea or conjunctiva, including epithelial herpes simplex 
keratitis (dendritic keratitis), vaccinia, or varicella; mycobacterial infection of the eye; fungal 
diseases of ocular structures; or any other contraindication for ocular steroid use.
•
A known or suspected hypersensitivity to any ocular steroid.
•
Primary open angle glaucoma or a history of steroid-induced intraocular pressure elevation.
29. Subject must not anticipate the use of prohibited medications or foods during study 
participation (see Section 5.3 for additional prohibited medications or foods).
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:
•
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
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•
Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.
•
Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a Follicle Stimulating Hormone level > 40 IU/L.
•
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
•
Females, of Childbearing Potential
•
Females of childbearing potential must avoid pregnancy throughout the study including at 
least 6 months after the last dose of depatuxizumab mafodotin.  
•
Females must commit to one of the following methods of birth control:
•
Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to study Baseline Day 1.
•
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.
•
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).
•
Intrauterine device (IUD).
•
Intrauterine hormone-releasing system (IUS).
•
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).
•
Practice true abstinence, defined as:  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).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, initiated at least 30 days prior to Study Day 1.
•
Male or female condom with or without spermicide.
•
Cap, diaphragm, or sponge with spermicide.
•
A combination of male condom with cap, diaphragm, or sponge with spermicide (double-barrier 
method).
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Contraception Requirements for Males
Male subjects who are sexually active with a female partner of childbearing potential, must agree to use 
condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through 
the entire duration of the study and for at least 6 months after the last dose of depatuxizumab 
mafodotin:
•
His female partner(s) must also use at least 1 of the following methods of birth control:
•
Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days 
prior to study Baseline Day 1
•
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month prior to study Baseline Day 1
•
bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure)
•
intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)
•
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy, and is the sole sexual partner of the trial subject)
5.3 Prohibited Medications and Therapy
In addition to the medications and therapy listed in the eligibility criteria (Section 5.1, Concomitant 
Medications), the following medications are prohibited:
No other investigational antineoplastic 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.  The use of live attenuated vaccines is prohibited during the study 
and for a period of 49 days after the end of depatuxizumab mafodotin administration.  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 depatuxizumab mafodotin 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.
The uses of concomitant medications that are contraindicated per the national prescribing information 
are prohibited during the conduct of the study.
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Subjects must be able to safely discontinue any prohibited medications 5 half-lives or 4 weeks prior to 
initial study drug administration.  Subjects must be consented for the study prior to discontinuing any 
prohibited medications for the purpose of meeting study eligibility.
5.4 Prior and Concomitant Therapy
Continuous TMZ therapy induces lymphocytopenia and thrombocytopenia.  Subjects are at an increased 
risk for opportunistic infections and bleeding – please consult package insert.6
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.
Any medication or vaccine (including over the counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of enrollment or receives during the study must be 
recorded until completion of study.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie Therapeutic Area 
Medical Director.  Information regarding potential drug interactions with depatuxizumab mafodotin can 
be located in the depatuxizumab mafodotin Investigator's Brochure.7
5.5 Withdrawal of Subjects and Discontinuation of Study
Each subject has the right to withdraw from the study 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.
Each subject must be withdrawn from the study immediately if any of the following occur:
•
The subject or subject's legally acceptable representative withdraws consent.
•
The subject experiences confirmed disease progression (PD), as determined by 2017 update of 
the Response Assessment in Neuro-Oncology criteria by Ellingson et al,8 as described in 
Appendix I of the Operations Manual.
•
Clinically significant abnormal laboratory results or AEs that rule out continuation of the study 
drug, as determined by the Investigator or the AbbVie Therapeutic Area Medical Director (TA 
MD).
•
The subject requests withdrawal from the study.
•
Eligibility criteria violation was noted after the subject started study drug, and continuation of 
the study drug would place the subject at risk.
•
Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.
•
The subject becomes pregnant while on study drug.
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•
Subject is significantly non-compliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
•
Subject experiences intercurrent illness that prevents further administration of treatment
•
Subject experiences excessive toxicity precluding further therapy with depatuxizumab 
mafodotin, according to the Investigator.
•
General or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the Investigator.
A subject may also be withdrawn if:
•
The Investigator believes it is in the best interest of the subject.
Subjects unable to continue TMZ due to excessive toxicity will be allowed to continue therapy with 
depatuxizumab mafodotin until one of the other criteria above is met.
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.
If subject withdraws consent, the type of withdrawal should be specifically indicated (further treatment 
with TMZ, depatuxizumab-mafodotin, 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.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  AbbVie may terminate this study prematurely, either in its 
entirety or at any site.  The Investigator may also stop the study at his/her site if he/she has safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will promptly notify the 
Investigator.
5.6 Follow-Up for Subject Withdrawal from Study
After discontinuation of depatuxizumab mafodotin for any reason, subjects must be followed for safety 
evaluations, including follow-up of OSEs until symptom resolution, unless the subject withdraws consent 
for safety follow-up.
Unless the subject specifically withdraws consent from follow up of overall survival, subjects will 
continue to be followed for overall survival, and overall survival will be recorded.  Opting out of overall 
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survival follow-up must be clearly documented.  Of note, overall survival may still be obtainable from a 
query of publicly available information unless prohibited by local regulations.
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 study, their study 
samples will continue to be stored and analyzed until consent is withdrawn as well.
5.7 Study Drug and Radiation Therapy
Information about Depatuxizumab Mafodotin (ABT-414) formulations to be used in this study is 
presented in Table 1.
Table 1.
Identification of Investigational Product(s)
Study Drug
Mode of 
Administration
Dosage Form
Strength (mg)
Manufacturer
Depatuxizumab 
Mafodotin (ABT-414)
Intravenous (IV) 
infusion
Sterile lyophilisate 
in a vial
20 mg
30 mg
AbbVie
Administration and doses of depatuxizumab mafodotin during Chemoradiation Phase and Adjuvant 
Phase are described below.
AbbVie will not supply drug other than depatuxizumab mafodotin.  Prophylactic therapies will be 
obtained commercially, except if otherwise required by local regulation.
Depatuxizumab mafodotin vials will be packaged in cartons with quantities sufficient to accommodate 
study design.  Each kit will be labeled per local requirements and this label must remain affixed to the 
kit.  Upon receipt, study drug should be stored as specified on the label and kept in a secure location.  
Each kit will contain a unique kit number.  This kit number is assigned to a subject via interactive 
response technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  All blank spaces on the label will be completed by the site staff prior to 
dispensing to subjects.  Study drug will only be used for the conduct of this study.
Instructions for drug preparation will be provided by AbbVie.
TMZ will not be provided by AbbVie.  Study sites must refer to the TMZ package insert for detailed 
pharmacologic and safety information.
Chemoradiation Phase
Treatment in the Chemoradiation Phase must begin ≤ 7 weeks after most recent surgery/biopsy unless 
prior approval is obtained from the TA MD.  During the Chemoradiation Phase, all subjects will undergo 
fractionated focal RT, with 1 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) according to local 
standard-of-care practice.  TMZ will be administered continuously from Day 1 of radiotherapy to the last 
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day of radiation (including weekends and holidays) at a daily oral or intravenous dose of 75 mg/m2 for a 
maximum of 49 days.  Subjects will receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 
30 to 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen).
Adjuvant Phase
The start of the first cycle during the Adjuvant Phase will be scheduled approximately 28 days after the 
last day of chemoradiation; the AbbVie TA MD should be notified if Adjuvant Phase treatment is to be 
started more than 42 days after the last day of chemoradiation.  All subjects will receive oral TMZ 150 –
200 mg/m2 once daily on Days 1 – 5 of each 28-day cycle for 6 – 12 cycles (6 – 12 months) as per local 
standard prescribing practice.  Subjects receive depatuxizumab mafodotin as a 30- to 40-minute infusion 
at 1.25 mg/kg on Day 1 and Day 15 of each 28-day cycle for a total of 12 cycles (12 months).
OSE Prophylaxis
Subjects will receive OSE prophylaxis during both the Chemoradiation and Adjuvant Phases as long as 
depatuxizumab mafodotin treatment is ongoing.
Subjects will be randomized to one of the following prophylactic eye treatment arms.  Equivalent steroid 
or vasoconstrictor medications may only be used with pre-approval by the AbbVie Therapeutic Area 
Medical Director.
Arm A (Standard Steroid) 
•
Steroid Eye Drops (for example, Prednisolone acetate 1% suspension), 1 drop in each eye 
3 times per day starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 
4 days after infusion, for a total of 7 days.
•
Use of Prednisolone acetate is strongly recommended as the initial steroid eye drop due to the 
greater potency.  Alternative steroids eye drops (for example, 0.1% dexamethasone phosphate 
solution, or equivalent) may be used if prednisolone acetate is not tolerated.
Arm B (Standard Steroid/Vasoconstrictor and Cold Compress)
•
Steroid Eye Drop (for example, Prednisolone acetate 1% suspension), 1 drop in each eye 3 times 
per day starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days 
after infusion, for a total of 7 days.
•
Use of Prednisolone acetate is strongly recommended as the initial steroid eye drop due to the 
greater potency.  Alternative steroids eye drops (for example, 0.1% dexamethasone phosphate 
solution, or equivalent) may be used if prednisolone acetate is not tolerated.
•
Vasoconstrictor Eye Drop (for example, Naphazoline HCl 0.012% solution or equivalent), 1 drop 
in each eye 4 - 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of 
infusion; and 2 - 4 times during the remainder of the infusion day).  Continuing 4 - 6 times/day 
on Day 1 and Day 2 after infusion.  In cases when an alternative to Naphazoline HCl 0.012% 
vasoconstrictor eye drop is used, please refer to prescribing information for maximal frequency 
of administration.  However, duration of administration should remain constant (3 days total) in 
all cases.
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•
Steroid and Vasoconstrictor eye drops to be given at least 5 minutes apart.
•
Cold compress:  Starting 5 minutes prior to start of infusion and continuing for 30 minutes past 
end of infusion; then at least 2 hours total/day during remainder of infusion day and for 2 days 
after infusion.  The cold compress should be applied in increments no longer than 30 min (could 
be shorter if the patient is uncomfortable).
Arm C (Enhanced Steroid/Vasoconstrictor and Cold Compress) 
•
Steroid Eye Drop (for example, Prednisolone acetate 1% suspension), 1 drop in each eye 6 times 
per day starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days 
after infusion, for a total of 7 days.
•
Use of Prednisolone acetate is strongly recommended as the initial steroid eye drop due to the 
greater potency.  Alternative steroids eye drops (for example, 0.1% dexamethasone phosphate 
solution, or equivalent) may be used if prednisolone acetate is not tolerated.
•
Ophthalmic Steroid Ointment (for example, fluorometholone ophthalmic 0.1%, betamethasone 
eye ointment 0.1%, or equivalent) in each eye once daily before sleep starting 2 days prior to 
depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 
7 days.
•
Vasoconstrictor Eye Drop (for example, Naphazoline HCl 0.012% solution or equivalent), 1 drop 
in each eye 4 – 6 times on day of infusion in total (5 to 10 minutes before infusion; at end of 
infusion; and 2 - 4 times during the remainder of the infusion day).  Continuing 4 - 6 times/day 
on Day 1 and Day 2 after infusion.
•
Steroid and Vasoconstrictor eye drops to be given at least 5 minutes apart.
•
Cold compress:  Starting 5 minutes prior to start of infusion and continuing for 30 minutes past
end of infusion; then at least 2 hours total/day during remainder of infusion day and for 2 days 
after infusion.  The cold compress should be applied in increments no longer than 30 min (could 
be shorter if the patient is uncomfortable).
With the exception of care measures described below as allowed at any time, other prophylactic or 
supportive measures are not allowed during the initial prophylaxis phase, unless prior approval is 
obtained from the AbbVie Medical Monitor.
Bandage Contact Lens (BCL) Intervention
If any subject in Arm A, Arm B, or Arm C has a ≥ 3-line loss in visual acuity (≥ +0.3 change from baseline 
by LogMAR) OR a CEAE ≥ Grade 3 ocular side effect, the subject will then receive BCL intervention in 
addition to the assigned initial prophylactic regimen.
With the exception of care measures described below as allowed at any time, additional measures 
besides BCL and the original prophylactic regimen are prohibited during the BCL intervention phase, 
unless prior approval is obtained from the AbbVie Medical Monitor.
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Investigator Discretion
Subjects who have a ≥ Grade 3 CEAE event despite/after addition of BCL intervention to the initial 
prophylactic regimen will enter the Investigator Discretion phase, at which point there will be no 
restrictions on prophylactic or supportive measures used for OSE management.
Subjects who complete 8 weeks of adjuvant therapy (8 weeks after the first adjuvant dose of 
depatuxizumab mafodotin) will be allowed to enter in the Investigator Discretion phase regardless of 
CEAE Grade, visual acuity or BCL intervention.
Supportive Care Measures Allowed at Any Time
The following supportive care measures are allowed at any time, regardless of the current phase of OSE 
management:
•
Lubricant Eye Drops
•
Artificial Tears
•
Antibiotics
•
Sunglasses
Information on other allowable medications (prior to eligibility for the Investigator Discretion phase) 
may be described in the Operations Manual.
Please reference Section 5 "Study Drug" of the Operations Manual for more information on treatments 
administered in this study.
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the Interactive Response Technology 
(IRT) at the screening visit.  For subjects who rescreen, the screening number assigned by the IRT at the 
initial screening visit should be used.  The IRT will assign a randomization number that will encode the 
subject's treatment group assignment according to the randomization schedule generated by the 
statistics department at AbbVie.
Subjects will be randomized in a 1:1:1 ratio to 1 of 3 prophylactic eye treatment regimens (Arm A, 
Arm B, or Arm C), as described in Section 4.1.
5.9 Protocol Deviations
The Investigator is responsible for complying with all protocol requirements, written instructions and 
applicable laws regarding protocol deviations.  Protocol deviations are prohibited except when 
necessary to eliminate an immediate hazard to study subjects.  If a protocol deviation occurs (or is 
identified), the Investigator is responsible for notifying Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), regulatory authorities (as applicable) and AbbVie.
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6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
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/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE 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 AE 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.
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study.  All AEs will be followed to a satisfactory conclusion.
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a serious 
adverse event within 24 hours of the site being made aware of the serious adverse event:
Death of Subject
An event that results in the death of a subject.
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.
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).
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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.
All adverse events reported will be collected from the time of study drug administration until 49 days 
after last depatuxizumab mafodotin administration, whether solicited or spontaneously reported by the 
subject.  In addition, serious adverse events and protocol-related (considered by the investigator to be 
causally related to protocol-required study procedures) nonserious adverse events will be collected 
from the time the subject signs the study-specific informed consent.
For serious adverse events with the outcome of death, the date and cause of death will be recorded on 
the appropriate case report form.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects
Corneal Epithelial Adverse Events and Other Adverse Events of Special Interest
Because longitudinal assessment of corneal epithelial findings is central to the goals of this study, 
corneal epithelial adverse events will be assessed regularly, and severity will be re-graded at every 
assessment.  Adverse events related to corneal epithelial abnormalities will be reported using the term 
"corneal epitheliopathy," and associated signs and symptoms will be recorded and graded using the 
Corneal Epithelial Adverse Event eCRF.  Grading of corneal epithelial events is based on effects on visual
ADLs, as shown in Table 2.  Corneal epithelial AEs will be followed until symptom resolution or return to 
baseline. 
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Table 2.
Corneal Epithelial Adverse Event (CEAE) Grading Scale
Grading of Corneal Epithelial Adverse Events
0 – Asymptomatic
1 – Symptomatic, but no effect on visual ADLs
2 – Instrumental ADLs* affected, but can perform instrumental ADLs independently
3 – Instrumental ADLs* require assistance
4 – Self-care ADLs** require assistance
5 – Corneal perforation or corneal ulceration with impending perforation
Abbreviation:  ADL = activities of daily living
*
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
For eye disorders that are unrelated to corneal epithelial abnormalities (related to lens, retina, etc.), 
adverse events will be reported per usual practice and graded according to CTCAE criteria as described 
below. 
Additional AEs of special interest that will be monitored during the study:
•
Allergic reactions (see Section 6.3)
•
Dermatologic toxicities (see Section 6.3)
Adverse Event Severity and Relationship to Study Drug
With the exception of corneal epithelial adverse events (described previously) the table of clinical 
toxicity grades modified from the NCI CTCAE Version 4.0 (available on the Cancer Therapy Evaluation 
Program [CTEP] home page http://ctep.cancer.gov) will be used in the grading of AEs and laboratory 
abnormalities that are reported as AEs, each of which will be followed to satisfactory clinical resolution.
The investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug:
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.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day of the 
site becoming aware of the pregnancy.  The administration of depatuxizumab mafodotin must be 
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discontinued immediately in the event that a positive result is obtained on a pregnancy test for a 
subject, or a subject reports becoming pregnant during the study.  If a pregnancy occurs in a study 
subject or in the partner of a study subject, information regarding the pregnancy and the outcome will 
be collected.  In the event of pregnancy occurring in a subject's partner during the study, written 
informed consent from the partner must be obtained prior to collection of any such information.  A 
separate consent will be provided by AbbVie for this purpose.  Pregnancies in study subject's partners 
will be collected from the date of the first dose through at least 6 months following the last dose of 
study drug.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
6.2 SUSAR Reporting
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines and 
Appendix A of the Investigator Brochure will serve as the Reference Safety Information (RSI).  The RSI in 
effect at the start of a DSUR reporting period serves as the RSI during the reporting period.  For follow-
up reports, the RSI in place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be 
used to assess expectedness.
6.3 Toxicity Management
For all observed toxicities, subjects should be assessed for inter-current illness or other causes and 
treated as appropriate.
For the purpose of medical management, all AEs 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 5.0 (available on the CTEP home page http://ctep.cancer.gov) is to be used in the grading 
of all non-corneal adverse events and laboratory abnormalities that are reported as adverse events 
(corneal epithelial adverse events are to be assessed as detailed in Section 4.3 of the Operations 
Manual), 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.
Depatuxizumab Mafodotin Toxicity Management
Subjects will be closely monitored for treatment-related adverse events, especially allergic reactions, 
during all infusions.  For the initial depatuxizumab mafodotin 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 
depatuxizumab mafodotin infusion, subjects must remain at the site for monitoring for 60 minutes post 
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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 
depatuxizumab mafodotin, experience with EGFR inhibitors or antibodies, and/or experience with 
MMAF ADCs, potential toxicities may include corneal epitheliopathy, fatigue, liver transaminase 
elevations, thrombocytopenia, allergic reactions, and rash.
Corneal Epithelial Adverse Events
For more information related to corneal epithelial adverse events, refer to the Operations Manual, 
Section 3.15, Section 4.3, and Appendix H.
All supportive care measures should be recorded in appropriate eCRFs.
The following supportive care measures may be used at any time without restriction, regardless of CEAE 
grade, current prophylactic arm, or use of BCL intervention:
•
Non-steroid lubricant eye drops
•
Sunglasses (for photophobia)
•
Antibiotic eye drops
BCL Intervention After Inadequate Prophylaxis
The schematic in Figure 2 outlines the criteria and sequence of OSE management changes for subjects 
who have inadequate control of OSE with the assigned prophylactic regimen (CEAE Grade 3 or 4 or 
≥+0.3 LogMAR change in visual acuity).  Topical antibiotics may be added to reduce the risk of infection 
associated with combined BCL and steroid.
Investigator Discretion after Inadequate Response to BCL Intervention
•
Subjects who continue to experience CEAE Grade 3 or 4 OSEs for at least 2 weeks after addition 
of BCL intervention to the initial prophylactic regimen will be considered to have an inadequate 
response to BCL intervention and thus will be eligible for unrestricted OSE management 
according to investigator discretion.  In this case, any available prophylactic (including addition 
of ES and VC regimens if not used initially) or supportive care measures may be used without 
restriction, as well as depatuxizumab mafodotin dose interruption and/or reduction, at the 
discretion of the investigator.  Initiation of BCL intervention prior to meeting the above criterion 
requires approval of by the AbbVie Therapeutic Area Medical Director.  Subjects who complete 
8 weeks of adjuvant therapy (8 weeks after the first dose of depatuxizumab mafodotin in the 
adjuvant phase) will be allowed to enter in the Investigator Discretion phase regardless of CEAE 
Grade, visual acuity or BCL intervention.  Depatuxizumab mafodotin dose modifications for OSEs 
– suggested increments for dose reduction are described in Table 5; larger decreases may be 
made at the discretion of the investigator.
•
CEAE Grade 3 – Dose interruptions/dose reduction optional
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•
CEAE Grade 4 – Dose interruption required.  Resumption at a reduced dose allowed upon 
OSE resolution to CEAE Grade 2 or lower
•
If the depatuxizumab mafodotin dose is decreased during the chemoradiation phase, it is 
not required to start the adjuvant phase at a reduced dose (i.e., starting adjuvant phase at 
the target 1.25 mg/kg is allowed)
•
Once inadequate response to BCL intervention has been determined, additional supportive care 
measures may be used without restriction at the discretion of the investigator in consultation 
with the ophthalmologist.  These may include exploratory measures suggested by the 
ophthalmologist that are not described in the study protocol.
•
Treatment Options during Investigator Discretion Phase:
Enhanced Steroids (if not already part of initial regimen)
Vasoconstrictor Eye Drops and Cold Compress (if not already part of initial regimen)
Autologous Serum Eye Drops
Dilute with artificial tears
Scleral Contact Lens
Punctal Plugs
Other interventions per Investigator Discretion
If a subject experiences CEAE corneal ulceration with impending perforation (CU) or corneal perforation 
(CP) at any time, depatuxizumab mafodotin will be permanently discontinued, and the event will be 
reported as a serious adverse event, as described in the Operations Manual, Section 4.5.
If, after a dose reduction for CEAEs, changes in the prophylactic and/or supportive care regimens lead to 
significant improvement CEAEs for subsequent study drug doses, the depatuxizumab mafodotin dose 
may be re-escalated at the investigator's request if approved by the AbbVie Therapeutic Area Medical 
Director.
Allergic reactions require the following dose modifications:
•
Severe allergic reactions (CTCAE Grade 3 or Grade 4):  Immediate discontinuation of 
depatuxizumab mafodotin 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.
•
Moderate allergic reactions (CTCAE Grade 1 or Grade 2):  Immediate interruption of 
depatuxizumab mafodotin 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.
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Dermatologic toxicities dose modifications:
•
Monitor for the development of inflammatory or infectious sequelae, and initiate appropriate 
treatment of these symptoms.  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, depatuxizumab mafodotin 
treatment adjustments should be made based on a discussion between the Investigator and 
AbbVie Therapeutic Area Medical Director.  Subjects who experience a grade 3 or higher 
dermatological toxicity will be treated as following:
•
The subject will require a dose interruption and depatuxizumab mafodotin may be 
reintroduced at a reduced dose (per the guidance previously stated above) if the toxicity 
returns to ≤ grade 1 within 4 weeks.
Hepatic Laboratory Abnormalities (Depatuxizumab Mafodotin)
Guidelines for depatuxizumab mafodotin dose modifications related to hepatic laboratory abnormalities 
are presented in Table 3.  
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Table 3.
Depatuxizumab Mafodotin Dose Modification Guidelines for Hepatic 
Laboratory Abnormalities
Hepatic Laboratory Abnormality
Depatuxizumab Mafodotin
ALT or AST > 5 × ULN* but ≤ 20 × ULN 
(and TBL ≤ 2 × ULN)
•
Hold drug regardless of assessed relationship to drug.  See 
Section 4.6 of the Operations Manual 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 5)** 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 4.6 of the Operations Manual 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 5x the baseline value or 8x ULN, whichever is lower.
**
Unless the next planned dose is already a lower dose per the protocol (i.e., start of the adjuvant phase).
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Other Depatuxizumab Mafodotin toxicities (excluding corneal epithelial, allergic, and dermatologic 
toxicities and hepatic laboratory abnormalities)
General guidelines for other toxicities (excluding corneal epithelial, allergic, and dermatologic toxicities) 
are shown in Table 4, with suggested dose level reductions shown in Table 5.  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 corneal epithelial adverse events and hepatic laboratory abnormalities as 
previously described, all dose reductions are permanent unless a toxicity initially attributed as 
potentially related to depatuxizumab mafodotin is later re-attributed as not potentially related and 
discussed with the AbbVie Therapeutic Area Medical Director or their designee.
Table 4.
General Guidelines for Depatuxizumab Mafodotin Dose Interruptions and
Re-Initiation (Except Corneal Epithelial, Allergic, and Dermatologic Toxicities 
and Hepatic Laboratory Abnormalities)
CTCAE Grade
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
CU/CP
Permanently discontinue drug
N/A
CP = corneal perforation; CU = corneal ulceration with impending perforation; N/A = not applicable
Table 5.
Depatuxizumab Mafodotin Dose Modification Table during Chemoradiation 
and Adjuvant Phase
Dose Level
Chemoradiation Phase
Adjuvant Phase
Starting Dose
2.0 mg/kg
1.25 mg/kga
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
a.
If dose was reduced to 1.0 mg/kg during the chemoradiation phase, 1.0 mg/kg is the recommended starting dose for the 
Adjuvant Phase.
Temozolomide Toxicity Management
Safety monitoring for temozolomide-related toxicities, including clinical laboratory testing for 
temozolomide-related hematological toxicity, temozolomide dose modifications, and management of 
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toxicities attributable to temozolomide should be managed according to the guidelines in the local 
prescribing information or local institutional guidelines.  See Section 4.6 of the Operations Manual for 
guidelines on repeat testing and evaluation of hepatic laboratory abnormalities regardless of the 
assessed relationship to study treatments.
Temozolomide can continue if depatuxizumab mafodotin is interrupted.  Depatuxizumab mafodotin may 
continue if TMZ toxicity is observed.
Radiation Toxicity Management
Toxicities attributable to radiation should be managed according to institutional guidelines or at the 
discretion of the Investigator.
Management of Toxicities Related to Ophthalmologic Prophylactic Regimens
**Monitoring for intraocular pressure (IOP), cataracts, other steroid-related AEs in ophthalmology 
exams**
Toxicities attributable to prophylactic regimens should be managed according to or at the discretion of 
the Investigator.
Steroid Eye Drops
Monitor IOP during each ophthalmologic examination.  Qualified medical personnel will perform the 
ophthalmologic examination as outlined in Section 2.1 and Section 2.2 of the Operations Manual.  If 
increase in IOP occurs it should be controlled with IOP-lowering medication according to the investigator 
discretion.
Bacterial keratitis has been reported in patients who have received ophthalmic preparations that were 
dispensed in multi-dose containers.  This reaction most likely is due to contamination of the solution, so 
patients should be instructed not to allow the tip of the applicator to touch the eye or any other 
surfaces.  Fungal cultures should be taken when appropriate.  Prophylaxis and treatment of fungal 
infections should be implemented according to or at the discretion of the Investigator and consistent 
with the institutional standard of care.
Vasoconstrictor Eye Drops 
IOP will be monitored during each ophthalmologic examination, as outlined in Section 2.1 and 
Section 2.2 of the Operations Manual.  Other side effects should be managed according to or at the 
discretion of the Investigator and consistent with the institutional standard of care.
Study Drug Administration in Cases of Surgery 
If the subject must undergo emergency surgery, the study drug should be interrupted at the time of the 
surgery.  Elective surgery should be scheduled at least 2 weeks after the most recent depatuxizumab 
mafodotin dose.  After surgery, allow reintroduction of study drug once the physician has examined the 
surgical site and determined that it has healed and there is no sign of infection.
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6.4 Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
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 (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day of the study site's knowledge of the event.  Product complaints occurring during 
the study will be followed up to a satisfactory conclusion.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
For the primary endpoint, the focus will be the point estimate, and determination of sample size is 
based on practical consideration rather than power calculation.  It is planned to randomize a total of 
90 subjects, 30 subjects per arm.
For the point estimate, with 30 subjects per arm, the precision of the estimates of the primary endpoint 
is provided by the following 95% confidence intervals (Table 6):
Table 6.
Primary Endpoint Precision of Estimates
Sample Size
Number of Subjects Meeting 
the Primary Endpoint
Point Estimate (%)
95% Confidence Interval
30
8
26.7
(10.8, 42.5)
30
10
33.3
(16.5, 50.2)
30
12
40
(22.5, 57.5)
30
14
46.7
(28.8, 64.5)
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the interim database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The intent-to-treat (ITT) population will comprise all randomized subjects regardless of whether they 
receive study treatment (depatuxizumab mafodotin) or steroid-related OSE treatment.  Since the 
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primary endpoint is a safety endpoint, the ITT will be used only for summary of enrollment and 
randomization.
The safety population will comprise all randomized subjects who have received at least 1 dose of 
depatuxizumab mafodotin.  Subjects will be classified according to steroid-related treatment received.  
The safety population will be the primary analysis population for analysis of all endpoints including 
efficacy and safety endpoints.
7.3 Statistical Analyses for Efficacy
The efficacy endpoints for the study are OS and progression-free survival (PFS) and they are exploratory 
endpoints for the study.  The OS is 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.  The PFS is defined as time from randomization to 
progression of disease (per RANO criteria, as determined by the investigator) or death, whichever occurs 
first.
The survival distribution of OS and PFS will be estimated by the Kaplan-Meier method.  The comparisons 
between the 3 groups will be made by log-rank test.
7.4 Statistical Analyses for Safety
For the primary endpoint of the study, the percentage of subjects with either a ≥ 3-line decline from 
baseline (≥ + 0.3 on LogMAR scale) in visual acuity (with baseline correction) or ≥ Grade 3 OSE severity 
on the Corneal Epithelial Adverse Event [CEAE] scale will be calculated for each arm and associated 95% 
confidence intervals will be provided.  Comparisons between arms will be made using Chi-square test.
For secondary safety endpoints, continuous variables will be summarized with N, mean, standard 
deviation (SD), median, minimum, and maximum.  Frequencies and percentages will be computed for 
the category variables.  For time to event variables, Kaplan-Meier survival curves with median time and 
associated 95% confidence interval will be provided.
Detailed statistical analysis methods for primary and secondary safety endpoints will be provided in the 
statistical analysis plan (SAP).
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any participant is enrolled.  Any amendment to the protocol 
will require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities of 
the Investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted and data are generated, documented and reported 
in compliance with the protocol, ICH GCP and applicable regulatory requirements.
11 COMPLETION OF THE STUDY
The end of study is defined as the date of the subject's last visit. 
12 REFERENCES
1.
Preusser M, de Ribaupierre S, Wohrer A, et al.  Current concepts and management of 
glioblastoma.  Ann Neurol.  2011;70(1):9-21.
2.
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.
3.
Eaton JS, Miller PE, Mannis MJ, et al.  Ocular adverse events associated with antibody-drug 
conjugates in human clinical trials.  J Ocul Pharmacol Ther.  2015;31(10):589-604.  doi:  
10.1089/jop.2015.0064.  Epub 2015 Nov 5.  Review.
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4.
Clear Eyes Redness Relief Eye Drops (Naphazoline HCl 0.012%) Package Insert.  Prestige Brands 
Holdings, Inc.  Revised:  6/2017.
5.
Bailey IL, Lovie-Kitchin JE.  Visual acuity testing.  From the laboratory to the clinic.  Vision Res.  
2013;90:2-9.  doi:  10.1016/j.visres.2013.05.004.  Epub 2013 May 17.
6.
Temodar (temozolomide) Package Insert.  Merck & Co., Inc., Revised:  4/2017.
7.
AbbVie.  ABT-414 Investigator's Brochure Edition 7.  01 October 2018.
8.
Ellingson BM, Wen PY, Cloughesy TF.  Modified Criteria for Radiographic Response Assessment 
in Glioblastoma Clinical Trials.  Neurotherapeutics.  2017;14:307-20.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADC
Antibody-Drug Conjugate
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BCL
Bandage Contact Lens
CEAE
Corneal Epithelial Adverse Event
CP
Corneal Perforation
CU
Corneal Ulceration with impending perforation
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
EGFR
Epidermal Growth Factor Receptor
ES
Enhanced Steroids
GBM
Glioblastoma
GCP
Good Clinical Practice
Gy
Gray
HAART
Highly Active Antiretroviral Therapy
HIV
Human Immunodeficiency Virus
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LASIK
Laser-Assisted in Situ Keratomileusis
MMAF 
Mono Methyl Auristatin F
MRI
Magnetic Resonance Imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OS
Overall Survival
OSE
Ocular Side Effect
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PD
Progressive Disease
PFS
Progression Free Survival
PT
Prothrombin time
RANO
Response Assessment in Neuro-Oncology Working Group
RT
Radiation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SmPC
Summary of Product Characteristics
SS
Standard Steroid
TA MD
Therapeutic Area Medical Director
TMZ
Temozolomide
ULN
Upper Limit of Normal
vADL
Visual Activities of Daily Living
VC
Vasoconstrictor/cold compress
vQOL
Visual Quality of Life
WHO
World Health Organization
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-534:  Phase 3b Study for Management of Ocular Side Effects in Subjects with 
EGFR-amplified Glioblastoma Receiving Depatuxizumab Mafodotin (ABT-414)
Protocol Date:  28 May 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
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., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
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 protocol and all of its 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.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Program Development
Medical Writing
Global Medical Affairs
Oncology Clinical Development
Data and Statistical Sciences
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APPENDIX E. SUBJECTS CONTINUING PARTICIPATION
This appendix outlines the modifications to the study procedures and depatuxizumab mafodotin dosing 
in subjects who are currently receiving depatuxizumab mafodotin and who choose to continue 
depatuxizumab mafodotin treatment after the results from the pre-planned interim efficacy analysis for 
Study M13-813 (INTELLANCE-1).
As a result of the interim efficacy analysis for INTELLANCE-1 study, AbbVie determined it was 
appropriate to allow subjects who are receiving depatuxizumab mafodotin to continue doing so based 
on investigator and subject decision.
Subjects who decide to continue treatment with depatuxizumab mafodotin 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 the table
below.
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Study Activities 
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/At 
Progression
35-Day 
F/Ue
49-Day 
F/U
Symptom-directed Physical Exam
Xf
Xf
Ophthalmology Exams
Xg
Xg
Xg
Chemistry
X
X
X
Hematology
X
X
X
X
Adverse Event Assessment and Concomitant Medications
X
X
X
X
Xk
Temozolomide Administration
Xh
Depatuxizumab Mafodotin Administration
Xi
Xi
Treatments for OSE
Xj
Xj
F/U = Follow-up; OSE = ocular side effect
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 depatuxizumab mafodotin 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 depatuxizumab mafodotin 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 depatuxizumab mafodotin.
e.
To be performed 35 days (± 3 days) after the last dose of depatuxizumab mafodotin.  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 AE/SAE reporting.
g.
Ophthalmology exams will be performed only as needed for safety management and AE/SAE reporting.  The last ophthalmology exam following discontinuation of 
depatuxizumab mafodotin 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.
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i.
Depatuxizumab mafodotin infusion will be administered on Day 1 and Day 15 of each 28-day cycle for 12 cycles.
j.
Patient will receive management of ocular side effects as per investigator discretion. In this case, depatuxizumab mafodotin 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. Refer to Section 5.7 of the protocol.
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.
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Depatuxizumab Mafodotin Administration and Individual Subject Discontinuation
Depatuxizumab mafodotin will be administered as described in the protocol.
Subjects may continue receiving depatuxizumab mafodotin while drug supply is available, as long as 
disease progression has not been determined.
Depatuxizumab Mafodotin Toxicity Management and Individual Subject Dose Modifications
Section 6.3 of the protocol provides guidance for toxicity management and dose modifications.
Adverse Events and Concomitant Medications
Adverse event and concomitant medications data will be collected to support regulatory safety 
reporting requirements. 
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APPENDIX F. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date 
Version 1.0
18 December 2017
Version 2.0
02 July 2018
Version 2.1 (Country Specific – Germany)
07 November 2018
Version 3.0
14 December 2018
Rationale for protocol amendment:  For another depatuxizumab mafodotin study in newly diagnosed 
GBM patients, (Study M13-813 [INTELLANCE-1]), an independent review committee recently performed 
a review of early data.  This committee recommended that the Study M13-813 study be stopped 
because the results indicated no survival benefit was observed for depatuxizumab mafodotin compared 
with placebo when added to the standard first-line regimen of temozolomide and radiation.  However, 
given that no new clinically significant safety risks were identified, AbbVie believes it is appropriate to 
allow subjects who are currently receiving depatuxizumab mafodotin to continue depatuxizumab 
mafodotin treatment if the investigator and subject believe it is in the subject's best interest.
The purpose of this amendment (version 4.0) is to:
•
Add brief summary of results for the protocol-specified interim efficacy analysis for 
INTELLANCE-1 in the Introduction
•
Provide modified study procedures and instructions for depatuxizumab mafodotin dosing in 
Appendix E for those subjects who are currently receiving depatuxizumab mafodotin and who 
choose to continue depatuxizumab mafodotin.  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.
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APPENDIX G. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-534 Version 4.0
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1 CONTACTS
Sponsor/
Emergency 
Contact
1 North Waukegan Road
North Chicago, IL 60064
Email:  
EMERGENCY 24 hour Number:  
Office:
Mobile:
If not available:
Phone:
Safety Concerns
Oncology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Email:
SAE Reporting 
outside of RAVE
Email:
Fax:
Protocol 
Deviations
1 North Waukegan Road
North Chicago, IL 60064
OR
1 Waukegan Road
North Chicago, IL  60061
OR
1 Waukegan Road 
North Chicago, IL 60061
Phone:
Email:
OR
Phone:
Email:
Phone:
Email:
Certified Clinical 
Lab
Covance Central Laboratory Services 
Indianapolis (North America/Latin 
America):
8211 SciCor Drive
Indianapolis, IN
46214-2985 USA
Covance Central Laboratory Services 
Geneva (EMEA)
Rue Moïse-Marcinhes 7
CH - 1217 Meyrin/Genève
Switzerland
Phone:
+1 (317) 271 1200 (local calls)
Fax:
+1 (317) 273 4030
Phone:
+41 58 822 7901
Fax:
+41 58 822 7521
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Covance Central Laboratory Services 
Singapore (APAC)
1, International Business Park
#04-14 The Synergy
Singapore 609917
Phone:
+65 6560 8793
Fax:
+65 6565 5901
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-534 Version 4.0
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TABLE OF CONTENTS
1
CONTACTS
2
2
INVESTIGATION PLAN
7
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
7
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITES
11
3
STUDY PROCEDURES
12
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
12
3.2
MEDICAL/ONCOLOGY HISTORY
13
3.3
KARNOFSKY PERFORMANCE STATUS
13
3.4
ELIGIBILITY CRITERIA
14
3.5
OPHTHALMOLOGY EXAM
14
3.6
PHYSICAL EXAMINATION
15
3.7
HEIGHT & WEIGHT
15
3.8
VITAL SIGNS
16
3.9
12-LEAD ELECTROCARDIOGRAM
16
3.10 CLINICAL LABORATORY TESTS
16
3.11 TUMOR SAMPLES
18
3.12 PRIOR/CONCOMITANT THERAPY
18
3.13 PATIENT-REPORTED OUTCOMES
19
3.14 DISPENSE STUDY DRUG
19
3.15 CORNEAL EPITHELIAL ADVERSE EVENT ASSESSMENT
19
3.16 OTHER ADVERSE EVENT ASSESSMENT
20
3.17 DISEASE PROGRESSION AND SURVIVAL ASSESSMENTS
21
4
SAFETY MANUAL
21
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
21
4.2
DEFINITION OF ADVERSE EVENT
21
4.3
EXPECTED ADVERSE EVENTS
22
4.4
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
23
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4.5
REPORTING ADVERSE EVENTS
24
4.6
EVALUATION OF SUBJECTS WITH HEPATIC LABORATORY ABNORMALITIES
25
5
STUDY DRUG
28
5.1
TREATMENTS ADMINISTERED
28
5.2
PACKAGING AND LABELING
30
5.3
METHOD OF ASSIGNING SUBJECTS TO PROPHYLACTIC GROUPS
31
5.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
31
6
REFERENCES
31
LIST OF TABLES
TABLE 1.
BIDIMENSIONAL TO VOLUMETRIC DEFINITIONS OF RADIOGRAPHIC RESPONSE AND 
PROGRESSION
47
TABLE 2.
GUIDELINES FOR DETERMINING COMPREHENSIVE OBJECTIVE STATUS
51
LIST OF FIGURES
FIGURE 1.
RADIOGRAPHIC RESPONSE ASSESSMENT RUBRIC FOR NEWLY DIAGNOSED GLIOBLASTOMA
54
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
32
APPENDIX B.
KARNOFSKY PERFORMANCE STATUS
34
APPENDIX C.
OPHTHALMOLOGY EXAM
35
APPENDIX D.
VISUAL ACUITY EVALUATIONS FOR OPHTHALMOLOGY VISITS
39
APPENDIX E.
VISUAL QUALITY OF LIFE QUESTIONNAIRE
40
APPENDIX F.
PRO-CTCAE™VISUAL SYMPTOMS QUESTIONNAIRE
42
APPENDIX G.
PERCEPTION OF TREATMENT VALUE QUESTION
43
APPENDIX H.
CORNEAL EPITHELIAL ADVERSE EVENT ECRF
44
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APPENDIX I.
RANO CRITERIA FOR TUMOR ASSESSMENTS IN NEWLY DIAGNOSED GBM
46
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the subject has had an opportunity to ask questions.  The pre/post-treatment tissue informed consent 
must be signed before the tissue collection and analysis is performed.  If a subject does not consent to 
the pre/post-treatment tissue collection and analysis, it will not impact the subject's participation in the 
study.
Additionally, this study has optional post mortem tissue submission consent for subject's cornea after 
death.  This post mortem tissue collection and analysis will only be performed if the subject has 
voluntarily signed and dated a separate post-mortem tissue informed consent, approved by an 
Institutional Review Board (IRB)/Independent ethics committee (IEC), after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The post-mortem tissue 
informed consent must be signed before the tissue collection and analysis is performed.  If a subject 
does not consent to the post-mortem tissue collection and analysis, 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.
3.2 Medical/Oncology 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.
•
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 electronic case report form (eCRF).
3.3 Karnofsky Performance Status
Karnofsky Performance Status will be assessed at Screening, Final Visit, and Post-Treatment 35 Day and 
49 Day Follow-Up Visit (Appendix B).
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3.4 Eligibility Criteria
Eligibility Criteria will be assessed at Screening, see Protocol Section 5.1.
3.5 Ophthalmology Exam
Qualified medical personnel will perform the ophthalmologic examination as outlined in Section 2.1, 
Section 2.2, and Appendix C.  Additional exams may be performed as clinically indicated.  
Ophthalmology exams are to be performed 7 to 14 days after the 2nd and 3rd infusions of Depatux-M 
and must be completed prior to the next infusion of Depatux-M.  Exams will at a minimum include 
assessment of visual acuity (as described below, using LogMAR scale and Appendix D), intraocular 
pressure, and slit lamp examination, as well as assessment for symptoms of eye pain and photophobia, 
and results will be recorded in the corresponding CRF (Appendix C).
Visual Acuity (VA) and Best corrected visual acuity (BCVA)
Instructions for obtaining visual acuity assessments at each ophthalmology visit (including the visual 
correction to be used for VA assessments, when BCL should be in place during VA assessment, and when 
manifest refraction is to be performed to assess BCVA) are described below.  Visual acuity will be 
measured using the LogMAR scale in all cases.  Visual acuity will be captured with baseline glasses (VAcc) 
or without glasses (VAsc) if the subject does not require correction at baseline during all ophthalmology 
visits.  Best Corrected Visual Acuity (BCVA) will be assessed with manifest refraction during specified 
visits outlined in the protocol.
Baseline Ophthalmic Examination
•
VA with baseline correction (cc or sc) without BCL – OD, OS, OU
•
Record glasses prescription if applicable
•
Record without glasses if subject does not require correction at baseline
•
The same prescription will be used to measure VA (cc or sc) for all post-baseline visits
•
BCVA (with manifest refraction) – OD, OS, OU will be recorded
Post-baseline visits (prior to BCL intervention)
•
VA with baseline correction (cc or sc) without BCL – OD, OS, OU
•
If VA OU (cc or sc) has declined ≥ 0.3 LogMAR from baseline OR if CEAE Grade≥ 3, place BCL and 
obtain the following:
•
VA with baseline correction (cc or sc) with BCL – OD, OS, OU
•
BCVA (manifest refraction) with BCL – OD, OS, OU
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Post-baseline visits (if BCLs are being used)
•
VA with baseline correction (cc or sc) without BCL – OD, OS, OU – omit if BCL is not changed at 
the visit 
•
VA with baseline correction (cc or sc) with BCL – OD, OS, OU
•
If VA OU (cc or sc) with BCL decline ≥ 0.3 LogMAR from baseline remains, obtain the following:
•
BCVA (manifest refraction) over BCL – OD, OS, OU – repeat every ~8 weeks
Post-baseline visits (if BCL intervention not tolerated)
•
VA with baseline correction (cc or sc) without BCL – OD, OS, OU 
•
If VA OU (cc or sc) without BCL decline ≥ 0.3 LogMAR from baseline remains, obtain the 
following:
•
BCVA (manifest refraction) without BCL – OD, OS, OU – repeat every ~8 weeks
Ophthalmoscopic examination and dilation of the pupil are not required.  Results will be entered into 
electronic data capture (EDC) for data collection.  All adverse events involving ocular side effects (OSEs) 
must be followed until symptom resolution.
All ophthalmology exam reports will be reviewed by the Investigator (or medically qualified delegate) to 
assess for potential adverse events not identified by subject interview.
Advanced imaging techniques, where available, such as confocal microscopy, ocular coherence 
tomography (OCT), and Heidelberg Retina Tomographer (HRT3), are optional and may be performed on 
an exploratory basis to assess whether such techniques may aid in evaluation or management of OSEs.  
3.6 Physical Examination
Physical examination will be performed at the designated study visits as specified in Section 2.1 and 
Section 2.2.  A complete physical examination (PE) will be performed at Screening.  A symptom directed 
physical examination will be performed at all other designated visits as clinically indicated.
All findings, whether related to an AE or part of each subject's medical history, will be captured on the 
appropriate eCRF page.  Clinically significant changes from baseline will be documented in the source 
documentation and electronic case report forms (eCRFs) as adverse events.
3.7 Height & Weight
Height will be measured at screening only.  Body weight will be measured at scheduled visits as specified 
in Section 2.1 and Section 2.2.  The subject will wear lightweight clothing and no shoes during weighing.
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3.8 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits as specified in Section 2.1 and Section 2.2.  Blood pressure and pulse rate should be 
measured after the subject has been sitting for at least 3 minutes.
3.9 12-Lead Electrocardiogram
A 12-lead ECG will be performed at Screening as specified in Section 2.1.  The ECG should be performed 
prior to blood collection.  
The ECGs will be evaluated by an appropriately trained physician at the site ("local reader").  The local 
reader from the site will sign and date all ECG tracings and will provide his/her global interpretation as a 
written comment on the tracing using the following categories:
•
Normal ECG
•
Abnormal ECG – not clinically significant
•
Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
3.10 Clinical Laboratory Tests
All subjects will have the laboratory analyses performed as outlined in the Clinical Laboratory Tests 
Manual.  Laboratory samples will be assessed using a certified central laboratory, and these data will be 
used for all 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 in Section 2.
Screening laboratory tests will be performed within 21 days 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.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
•
For laboratory results that are required per protocol to make study treatment decisions (e.g., to 
determine eligibility to continue TMZ or depatuxizumab mafodotin), results from a certified 
local lab may be used if central results may not be available prior to dosing.
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If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:
•
repeat the test to verify the out-of-range value;
•
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 (depatuxizumab mafodotin, TMZ or radiation [RT]) or from the study, or 
requires a subject to receive treatment (medical intervention) will be recorded as an adverse 
event.
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)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Direct bilirubin
Albumin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase (GGT)
Sodium
Potassium
Calcium
Inorganic phosphorus
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Microscopic examination if dipstick 
results are positive
Coagulation
Prothrombin time (PT)
Activated Partial Thromboplastin
Time (aPTT)
International normalized ratio
(INR)
Serum Pregnancy Test
For female subjects of childbearing potential, a serum pregnancy test will be completed at Screening 
(≤21 days before Day 1 of chemoradiation).  If Week 1 Day 1 is greater than 7 days from the screening 
visit, the procedure will be repeated.
The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If the serum pregnancy test is 
borderline, it should be repeated to determine eligibility.
A lactating or pregnant female will not be eligible for participation in this study.
Pregnancy testing is not required for females of nonchildbearing potential.  Determination of 
postmenopausal status will be made during the screening period based on the subject's history.
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Local Clinical Laboratory Testing
Laboratory tests used to make dosing decisions for standard temozolomide therapy will be performed as 
usual per local standard of care by a certified local laboratory.  A certified local laboratory may perform 
laboratory testing as needed for immediate subject management.
Local laboratory results that are considered clinically significant by the Investigator will be followed as 
appropriate and reported as adverse events if they meet the criteria as specified in Section 4.2.
Local laboratory results will be entered into the EDC system only if the local result leads to a different 
eligibility, treatment, or safety-reporting decision than would have been supported based on central 
laboratory results.
Hepatitis Screen
HBV and HCV tests will be performed at screening.  The hepatitis test panel will be performed by a 
certified laboratory. 
HIV Screen
Subjects will have blood tested by a certified laboratory for the presence of HIV at screening.  The 
results of the HIV testing will be retained by the study site under confidential restriction. 
3.11 Tumor Samples
Tumor samples will be tested during the screening for EGFR amplification at a centralized testing 
laboratory.  The study specific laboratory manual will provide instructions regarding the collection, 
processing, and shipping of samples.  The tumor sample must test positive for EGFR amplification in 
order for the subject to be eligible for enrollment.
If available, optional tumor tissue samples from the subjects' initial surgery and at recurrence will be 
collected when available.  Additional, optional post-mortem tissue samples from the cornea will be 
collected.  Participation in post-mortem corneal tissue collection is not mandatory.  If collected, post-
mortem corneal tissue samples should be sent to:
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
3.12 Prior/Concomitant Therapy
Prior/concomitant therapy will be assessed at visits as specified in Section 2.1 and Section 2.2.
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3.13 Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instrument Visual Quality 
of Life Questionnaire (vQOL; when allowed per local regulatory guidelines; Appendix E) and the PRO-
CTCAE™Visual Symptoms Questionnaire (when allowed per local regulatory guidelines; Appendix F).  
Subjects will also complete the Perception of Treatment Value question (see Appendix G) at the final 
study visit and every 4 weeks during the follow-up phase until resolution of corneal epithelial adverse 
events.  Subjects should be instructed to follow the instructions provided with the instrument and to
provide the best possible response to each item.  Site personnel shall not provide interpretation or 
assistance to subjects other than encouragement to complete the tasks.  Subjects who are functionally 
unable to read any of the instruments may have site personnel read the questionnaire to them.  Site 
personnel will encourage completion of the instrument at all specified visits and will ensure that a 
response is entered for all items.
The subject should complete the questionnaire before site personnel perform any clinical assessments 
and before any interaction with site personnel has occurred to avoid biasing the subject's response.
The assessments will be translated into the local languages.
3.14 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Week 1 Day 1 and as specified in Section 2.1.  The 
first dose of study drug will be administered after all other Week 1 Day 1 procedures are completed.
3.15 Corneal Epithelial Adverse Event Assessment
Corneal epithelial adverse events (CEAEs) will be monitored on a regular basis from initiation of study 
treatment until symptom resolution after depatuxizumab mafodotin discontinuation, as specified in 
Section 2.1 and Section 2.2, using the CEAE rating scale and recorded using the CEAE electronic case 
report form (eCRF; Appendix H).  The CEAE rating scale is designed to describe the overall severity 
symptoms associated with ADC-related corneal epitheliopathy under a single CEAE grade, while 
capturing additional information about specific domains (ocular discomfort, photophobia, and blurred 
vision/visual acuity) that are commonly affected.
It is designed for routine use by the treating physician based on subject reporting without a requirement 
for formal eye examination, with the exception that a finding of corneal ulceration with impending 
perforation (CU) or corneal perforation (CP) would be diagnosed on examination by an eye care 
specialist.  To maximize collection of CEAE assessments according to the study schedule, particularly to 
assess reversibility of OSEs after drug discontinuation, the CEAE assessment may be conducted by 
telephone and may incorporate information from caregivers.
For the current study symptoms related to the corneal epithelium will be recorded in this eCRF and 
should NOT be recorded as adverse events in the standard adverse event log.
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CEAE Grade (Overall Severity of symptoms/findings related to corneal epithelial abnormalities):
•
Only the impact of corneal epithelial abnormalities should be considered in evaluating the CEAE 
grade.
•
These symptoms generally include blurred vision (decreased visual acuity), photophobia, 
and ocular discomfort (various terms may be used to describe ocular discomfort).
•
If visual ADL impairment is caused primarily by a condition unrelated to the corneal epithelium 
(e.g., central nervous system [CNS] lesion, retina, lens, optic nerve, etc.), this field should be 
recorded as "Not evaluable."
•
Examples of Instrumental ADLs include preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc.
•
Examples of self-care ADLs include bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.
Ocular Discomfort
•
Symptoms:  Specific symptoms contributing to ocular discomfort will be recorded.  Check all 
symptoms that apply; additional symptoms not included on this list should be entered as free 
text.
•
Impact of ocular discomfort on visual ADLs:  Only the impact of ocular discomfort on visual ADLs 
should be considered for this assessment (i.e., degree of ADL impairment in the absence of 
blurred vision or phobia should be estimated).
Photophobia
•
Severity of photophobia will be rated by the intensity of light that produces photophobia.
Reading (due to blurred vision)
•
The impact of blurred vision on the subject's ability to read is rated on the degree of adaptation 
needed for the subject to read.
•
If the subject's reading is impaired by factors unrelated to blurred vision, or if the subject does 
not attempt to read for reasons unrelated to blurred vision, this field should be recorded as 
"Not applicable (N/A)."
Please refer to Section 4.3 for additional details.
3.16 Other Adverse Event Assessment
Please refer to Section 4.2.
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3.17 Disease Progression and Survival Assessments
Subjects enrolled in the study will have survival assessments, including date and cause of death 
collected monthly or as requested by AbbVie to support data analysis for a period of 2 years after the 
subject's last study visit or until the subject becomes lost to follow-up or until study termination by 
AbbVie.
Clinical and neuroimaging assessments for GBM disease progression will be performed per local 
standard of care, and the date of disease progression will be determined according to the 2017 update 
of Response Assessment in Neuro-Oncology (RANO) criteria (Appendix I).
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All adverse events reported will be collected from the time of study drug administration until 49 days 
after last depatuxizumab mafodotin administration, whether solicited or spontaneously reported by the 
subject.  In addition, serious adverse events and protocol-related (considered by the investigator to be 
causally related to protocol-required study procedures) nonserious adverse events will be collected 
from the time the subject signs the study-specific informed consent.  After 49 days following completion 
of study treatment and throughout the Post-Treatment Period, only OSEs will be collected until 
symptom resolution or return to baseline; (SAEs and non-serious AEs will not be collected).
4.2 Definition of Adverse Event
An AE 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 AE.  Worsening in severity of an AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
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from the study, necessitate therapeutic medical intervention, meet protocol specified criteria (see 
Section 6.3 in the Protocol regarding toxicity management), and/or if the investigator considers them to 
be AEs.
The investigator will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  The investigator will assess and record any AE in detail including the date of 
onset, event diagnosis (if known), or sign/symptom, severity, time course (end date, ongoing, 
intermittent), relationship of the AE to study drug, and any action(s) taken.  For SAEs considered as 
having "no reasonable possibility" of being associated with study drug, the investigator will assign 
"other" as the cause of the event.  For AEs to be considered intermittent, the events must be of similar 
nature and severity.  AEs, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject, will be recorded.
All AEs will be followed to a satisfactory conclusion.
Disease progression and signs, symptoms or test abnormalities that, in the opinion of the investigator, 
are unequivocally due to disease progression should not be reported as AEs, even if serious or fatal (see 
also Section 4.3).
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure was 
preplanned before 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 AE.  Hospitalization of a 
subject who is in Post Treatment Follow-Up or Survival, following discontinuation of study drug, for 
subsequent line of therapy will not be captured as an SAE.  A treatment-emergent AE is defined as any 
AE reported by a subject with onset or worsening from the time that the first dose of study drug is 
administered until 90 days have elapsed following discontinuation of study drug administration.
4.3 Expected Adverse Events
Corneal Epithelial Adverse Events
For adverse events related to corneal epithelial abnormalities, associated signs and symptoms will be 
recorded and graded by the study investigator using the Corneal Epithelial Adverse Event eCRF, which 
was created by AbbVie, based on experience with ADC-related corneal epitheliopathy caused by 
depatuxizumab mafodotin, to address inadequacies of the CTCAE system for appropriately capturing 
symptoms, grading, and making dose modifications for ADC-related corneal epitheliopathy.  Grading of 
corneal epithelial events is based on effects on visual ADL, as shown in Table 2 of the study protocol, 
and the eCRF is detailed in Appendix H.
Events recorded in the Corneal Epithelial Adverse Event eCRF events will not be recorded in standard 
adverse event eCRFs, with the exception of a CEAE finding of CU/CP.  A CEAE CU/CP would be 
considered a serious adverse event and would be reported as such as described below.
For eye disorders that are unrelated to corneal epithelial abnormalities (related to lens, retina, etc.), 
events will be reported as adverse event per usual practice using standard eCRFs and graded according 
to CTCAE criteria.
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Deaths
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of GBM should be recorded only on the study completion eCRF with 
disease progression as the reason for discontinuation and not on the AE eCRF.  All other on-study 
deaths, regardless of relationship to study drug, must be recorded on the AE eCRF and immediately 
reported to the sponsor.
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 AE eCRF.  
Generally, only 1 such event should be reported.  The term "sudden death" should be used only for the 
occurrence of an abrupt and unexpected death because of presumed cardiac causes in a subject with or 
without pre-existing heart disease within 1 hour after 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 AE eCRF.  If the cause of death later becomes available (e.g., after autopsy), 
"unexplained death" should be replaced by the established cause of death.  During survival follow-up, 
deaths attributed to progression of GBM should be recorded only on the survival eCRF.
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the underlying disease, 
including transformation to a more aggressive histology, are also considered an expected outcome for 
this study and will NOT be recorded as AEs.  These data will be captured as efficacy assessment data 
only.  If there is any uncertainty as to whether an event is due to disease progression, the event should 
be reported as an AE.
4.4 Recording Data and Analyses of Safety Findings
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  Corneal epithelial adverse events will be assessed and recorded as described in 
Section 4.3.  Otherwise, the Investigator will assess and record any AE 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 SAEs 
considered as having "no reasonable possibility" of being associated with study drug, the Investigator 
will provide another cause of the event.  For adverse events to be considered intermittent, the events 
must be of similar nature and severity.  AEs, 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 resolution, or to improvement to Grade 1 unless the 
subject has died before this could be determined.
With the exception of the corneal epithelial adverse events as described in Section 4.3, the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4 will be used for AE 
reporting/grading of event severity.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of subjects with treatment-emergent adverse events (i.e., any event that begins 
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•
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. 
•
The need for prompt repeat testing is especially great if AST or ALT is > 3 × ULN and TBL 
> 2 × ULN. 
•
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. 
•
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 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. 
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•
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 in the Protocol.
5 STUDY DRUG
5.1 Treatments Administered
Depatuxizumab mafodotin must not be dispensed without contacting the Interactive Response 
Technology (IRT) system and may only be dispensed to subjects enrolled in the study through the IRT 
system.  At the end of the Treatment Period or at the Premature D/C visit, the site will contact the IRT 
system to provide visit date information and study drug return information for each kit.  Destruction of 
the study drug may be performed at the site if allowable per institutional guidelines.
Radiation Therapy
RT treatment planning and administration will be done as per local institutional guidelines.  Minor 
changes to the RT dose schedule described above due to logistical or safety reasons that are considered 
in the best interest of the subject are allowed and will not be considered protocol deviations.
TMZ Treatment
TMZ will be administered according to local standard of care.  Duration of TMZ treatment will be 
6 – 12 cycles in the adjuvant phase and is at the discretion of the investigator as supported by local 
standard of care.  TMZ will not be provided by the sponsor.
IV administration of TMZ is allowed for subjects who are unable to take oral TMZ for any reason.
Depatuxizumab Mafodotin Treatment
Depatuxizumab mafodotin will be given by IV infusion over 30 to 40 minutes, at the time points outlined 
in Section 2.1 beginning at baseline (Day 1).  The mg/kg dose of depatuxizumab mafodotin will be 
determined from the weight on Day 1 of the Chemoradiation Phase and need not change unless there is 
a weight change of more than 10% from the weight being used for the calculation.  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.
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Depatuxizumab Mafodotin Administration during Chemoradiation
During the Chemoradiation Phase, subjects will receive depatuxizumab mafodotin 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).  
The interval between depatuxizumab mafodotin doses may be adjusted as needed for safety or logistical 
reasons under the following limitations:
•
No more than 3 doses of depatuxizumab mafodotin are given during the Chemoradiation Phase.
•
Successive doses of depatuxizumab mafodotin must be at least 12 days apart.
•
All depatuxizumab mafodotin doses must be administered no later than the last day of radiation 
treatment.
Depatuxizumab Mafodotin Administration during Adjuvant Treatment
During the Adjuvant Therapy Phase, subjects in all arms will receive depatuxizumab mafodotin 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 
for 12 cycles.
If TMZ treatment is discontinued due to intolerance during either the Chemoradiation Phase or Adjuvant 
Phase, subjects will continue receiving depatuxizumab mafodotin infusions according to the same study 
schedule.
Steroid Eye Drops
Administration of steroid eye drops and any other eye drops should be separated by at least 5 minutes 
to ensure that there is no washout of the prior drug.  Formulations combining eye drops with another 
drug (e.g., antibiotic) is allowed.  Prophylactic use of antibiotic eye drops may be used in all treatment 
arms; however, it is especially important to use antibiotic eye drops with enhanced steroid regimens 
and bandage contact lenses in order to prevent infection.  
Standard Regimen:
1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing 
until 4 days after infusion, for a total of 7 days.
Enhanced Regimen:
1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing 
until 4 days after infusion, for a total of 7 days.
Ophthalmic Steroid Ointment
Ointment in each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion 
and continuing until 4 days after infusion, for a total of 7 days.
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Vasoconstrictor Eye Drops
One drop each eye 4 – 6 times on day of infusion in total (5 – 10 minutes before infusion; at end of 
infusion; and 2 – 4 times during the remainder of the infusion day).  Continuing 4 – 6 times/day on Day 1 
and Day 2 after each depatuxizumab mafodotin infusion.
Cold Compress
Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then 
use at least 2 hours total/day on Days 1 – 3 with each depatuxizumab mafodotin infusion.  The cold 
compress should be applied in increments no longer than 30 min (could be shorter if the patient is 
uncomfortable).
Bandage Contact Lens
For subjects who demonstrate inadequate control of OSEs with the initial prophylactic strategy, 
according to predefined criteria for loss of visual acuity and/or OSE symptom severity, intervention with 
a BCL will first be employed.
5.2 Packaging and Labeling
Vials containing depatuxizumab mafodotin lyophilized powder will be packaged in cartons.  Each vial and 
carton will be labeled per country requirements.  Refer to the Medication Preparation Guidelines 
provided for reconstitution and dilution of the lyophilized powder.
Depatuxizumab mafodotin will be provided by AbbVie as 20 mg and 30 mg vials.  The total volume 
administered will be dependent upon the assigned dose for that dosing period and/or the tolerability of 
depatuxizumab mafodotin.
The labels must remain affixed to the vial and carton.  All blank spaces should be completed by site staff 
prior to dispensing to subject.
Cold compresses will be supplied to the site by AbbVie.
Prophylactic therapies will be obtained commercially, except if otherwise required by local regulation.
Storage and Disposition of Study Drug
The depatuxizumab mafodotin 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 depatuxizumab mafodotin 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.  Evaluation of a prolonged infusion time may necessitate the 
need for depatuxizumab mafodotin to be reconstituted into two IV bags so that adequate stability 
measures may be maintained.  Reconstitution should be completed per the depatuxizumab mafodotin 
Extemporaneous Dose Preparation Guidelines.
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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.
5.3 Method of Assigning Subjects to Prophylactic Groups
This is an open-label, randomized, 3-arm study.  All eligible subjects will receive the same dosage of 
depatuxizumab mafodotin (2.0 mg/kg depatuxizumab mafodotin during chemoradiation and 1.25 mg/kg 
depatuxizumab mafodotin during adjuvant therapy) for 1 year.  Subjects will be randomized in a 
1:1:1 ratio to 1 of 3 prophylactic eye treatment regimens (Arm A, Arm B, or Arm C), as described in 
Section 4.1 of the protocol.
At the screening visit, all subjects will be assigned a unique subject number through the use of the 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.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
Contact information and user guidelines for IRT use will be provided to each site.
5.4 Selection and Timing of Dose for Each Subject
The same dose (2.0 mg/kg depatuxizumab mafodotin during chemoradiation and 1.25 mg/kg 
depatuxizumab mafodotin during adjuvant therapy) will be administered by intravenous (IV) infusion 
over 30 – 40 minutes every 2 weeks to all subjects.  Subjects will receive prophylactic eye treatment 
according to their prophylactic treatment regimen assignment as described in Section 5.7 of the 
protocol.
6 REFERENCES
1.
Schag CC, Heinrich RL, Ganz PA.  Karnofsky performance status revisited:  reliability, validity, and 
guidelines.  J Clin Oncol.  1984;2(3):187-93.
2.
Ellingson BM, Wen PY, Cloughesy TF.  Modified Criteria for Radiographic Response Assessment 
in Glioblastoma Clinical Trials.  Neurotherapeutics.  2017;14(2):307-20.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate aminotransferase
BCVA
Best Corrected Visual Acuity
BUN
Blood urea nitrogen
CEAE
Corneal Epithelial Adverse Event
CNS
Central Nervous System
CP
Corneal Perforation
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
CU
Corneal Ulceration with impending perforation
D/C
Discontinuation
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ES
Enhanced Steroids
GGT
Gamma-Glutamyl Transferase
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HRT3
Heidelberg Retina Tomographer
IEC
Independent ethics committee
IMP
Investigational Medical Product
INR
International normalized ratio
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
Lactate Dehydrogenase
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MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRI(1)
post RT MRI (baseline)
MRI(N)
scans that start after the first cycle of adjuvant therapy, but prior to suspected 
progression
MRI(N + 1)
first scan after progression is suspected
MRI(M)
additional follow-up MRI scans, if based on MRI (N + 1) suspected progression was 
deemed to be pseudoprogression
N/A
Not Applicable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OSE
Ocular Side Effect
PE
Physical Examination
PRO
Patient Reported Outcome
PT
Prothrombin Time
RANO
Response Assessment in Neuro-Oncology
RBC
Red blood cells
RT
Radiation
SAE
Serious adverse event
SD
Stable Disease
SOC
System Organ Class/Standard of Care
SS
Standard Steroids
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin
TMZ
Temozolomide
VA
Visual Acuity 
VA OU
VA OU Visual Acuity both eyes oculus uterque
VAcc
Visual Acuity with Correction 
VAsc
Visual Acuity without Correction
VA OD
Visual Acuity Right Eye
VA OS
Visual Acuity Left Eye
VC
Vasoconstrictors and Cold Compress
vQOL
Visual Quality of Life
WBC
White Blood Cell
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APPENDIX B. KARNOFSKY PERFORMANCE STATUS
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
Cross reference:  Schag 19841
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APPENDIX C. OPHTHALMOLOGY EXAM
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APPENDIX D. VISUAL ACUITY EVALUATIONS FOR 
OPHTHALMOLOGY VISITS
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APPENDIX E. VISUAL QUALITY OF LIFE QUESTIONNAIRE
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APPENDIX F. PRO-CTCAE™VISUAL SYMPTOMS 
QUESTIONNAIRE
Please rate the severity of the following ocular symptoms by circling the appropriate response for 
each of the questions below.
Abbreviations:  PRO-CTCAE™= Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events
Source:  https://healthcaredelivery.cancer.gov/pro-ctcae/measurement.html 
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APPENDIX G. PERCEPTION OF TREATMENT VALUE QUESTION
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APPENDIX H. CORNEAL EPITHELIAL ADVERSE EVENT ECRF
CEAE Grade (Overall Severity of Symptoms/Findings Related to Corneal Epithelial 
Abnormalities):
NE – Not evaluable (Severity of Visual ADL impairment is determined primarily by visual problems 
unrelated to cornea [lens, retina, optic nerve, CNS lesion, etc.])
0 – Asymptomatic
1 – Symptomatic, but no effect on visual ADLs
2 – Instrumental ADLs* affected, but can perform instrumental ADLs independently
3 – Instrumental ADLs require assistance
4 – Self-care ADLs** require assistance
5 – Corneal perforation or corneal ulceration with impending perforation
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Ocular Discomfort (Including Eye Pain, Dry Eye, Foreign Body Sensation, etc.)
Symptoms:  Record all symptoms contributing to ocular discomfort (check those that apply):
___ dry eye
___ eye pain
___ foreign body sensation
___ itching
___ other (specify) _________________
___ other (specify) _________________
___ other (specify) _________________
Impact of ocular discomfort on visual ADLs:
0 – Asymptomatic
1 – Symptomatic, but no effect on visual ADLs
2 – Instrumental ADLs affected, but can perform instrumental ADLs independently
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3 – Instrumental ADLs require assistance
4 – Self-care ADLs require assistance
Reading (Due to Blurred Vision)
N/A – Not Applicable (subject does not read for reasons unrelated to blurred vision)
1 – No difficulties reading
2 – Reading requires large fonts or magnification
3 – Unable to read due to blurred vision
Photophobia 
0 – None
1 – Mild (bright light)
2 – Moderate (ambient light)
3 – Severe (constant)
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APPENDIX I.
RANO CRITERIA FOR TUMOR ASSESSMENTS IN 
NEWLY DIAGNOSED GBM
For the current study, Response Assessment in Neuro-Oncology (RANO) criteria will be used to 
determine the time of disease progression (PD) for the purpose of determining progression-free 
survival (PFS) only; determination of complete response (CR) or partial response (PR) is not required 
and will not be recorded.
Criteria for RANO assessment of newly diagnosed GBM subjects are described below as per the 2017 
RANO update by Ellingson et al.2 as follows.
Post-Radiation MRI Examination as the Reference for Evaluating Radiographic Response in 
Newly Diagnosed GBM
For GBM patients, reliability of tumor assessment on the post-surgical MR scans can be problematic 
primarily because of the highly unpredictable, transient radiographic changes that often accompany the 
initial chemoradiation phase (i.e., external beam radiation therapy plus concurrent temozolomide) with 
or without experimental therapeutics.  Within 1 month after completion of standard chemoradiation 
therapy, approximately 50% of patients will experience radiographic changes suggestive of early tumor 
progression in reference to the post-surgical MRI exam, of which 50% are likely to have 
pseudoprogression (i.e., 25% of all patients at 1 month post-chemoradiation are estimated to have 
pseudoprogression).  This proportion of patients with both early progression and pseudoprogression 
decreases steadily during the subsequent standard adjuvant chemotherapy phase.
Additionally, post-operative MR scans are often contaminated with post-surgical changes and the timing 
may not be standardized across patients further confounding accurate tumor assessments.
Hence post-radiation examination (i.e., the first scan following completion of concurrent radiation 
therapy and chemotherapies such as temozolomide and/or experimental therapeutics) will be used as 
the baseline for response assessment.
Bidimensional and/or Volumetric Measurements
Either bidimensional or volumetric assessments of tumor size may be used, as long as they are 
consistently used within each subject.  Two-dimensional, perpendicular measurements of contrast 
enhancing tumor size, excluding the resection cavity along with any cysts or areas of central 
macroscopic necrosis, should be used for response assessment if volumetric tools are not available.  
Table 1 outlines suggested volumetric conversions from two- to three-dimensional measurements for 
consistency in response definitions.
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enhancing disease with respect to the "preliminary CR" scan, then the response is not sustained, 
noted as pseudoresponse, PsR, and is now considered "preliminary PD" (note confirmed PD 
requires at least two sequential increases in tumor volume).  If the second scan continues to 
exhibit disappearance of enhancing disease or emergence of non-measurable disease (less than 
10 mm bidimensional product), it is considered a durable CR and the patient should continue on 
therapy until confirmed PD is observed.
2.
Patients must be off corticosteroids (or on physiologic replacement doses only).
3.
Stable or improved clinical assessments (i.e., neurological examinations).
Note:  Patients with non-measurable disease only at baseline cannot have CR; the best response 
possible is stable disease (SD).  (For the current study subjects without measureable disease at 
baseline are ineligible for study entry.)
Partial Response (PR):  Requires all of the following:
1.
≥ 50% decrease in sum of products of perpendicular diameters or ≥ 65% decrease in total 
volume of all measurable enhancing lesions compared with baseline, sustained for at least 
4 weeks.  The first scan exhibiting ≥ 50% decrease in sum of products of perpendicular 
diameters or ≥ 65% decrease in total volume of all measurable enhancing lesions compared with 
baseline is considered "preliminary PR."  If the second scan exhibits PD with respect to the 
"preliminary PR" scan, then the response is not sustained, noted as pseudoresponse, PsR, and is 
now considered "preliminary PD" (note confirmed PD requires at least two sequential increases 
in tumor volume).  If the second scan exhibits SD, PR, or CR, it is considered a durable PR and the 
patient should continue on therapy until confirmed PD is observed.
2.
Steroid dose should be the same or lower compared with baseline scan.
3.
Stable or improved clinical assessments.
Note:  Patients with non-measurable disease only at baseline cannot have PR; the best response 
possible is stable disease (SD).  (For the current study subjects without measureable disease at 
baseline are ineligible for study entry.)
Progressive Disease (PD):  Defined by any of the following:
1.
At least two sequential scans separated by at ≥ 4 weeks both exhibiting ≥ 25% increase in sum of 
products of perpendicular diameters or ≥ 40% increase in total volume of enhancing lesions.  
The first scan exhibiting ≥ 25% increase in sum of products of perpendicular diameters or ≥ 40% 
increase in total volume of enhancing lesions should be compared to the smallest tumor 
measurement obtained either at baseline (if no decrease) or best response (on stable or 
increasing steroid dose) and is noted as "preliminary PD."  If the second scan at least 4 weeks 
later exhibits a subsequent ≥ 25% increase in sum of products of perpendicular diameters or 
≥40% increase in total volume of enhancing lesions relative to the "preliminary PD" scan, it is 
considered "confirmed PD" and the patient should discontinue therapy.  If the second scan at 
least 4 weeks later exhibits SD or PR/CR, this scan showing "preliminary PD" is noted as 
"pseudoprogression," PsP, and the patient should continue on therapy until a second increase in 
tumor size relative to the PsP scan is observed.  Note that any new measurable (> 10 mm × 
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10 mm) enhancing lesions should not be immediately considered PD, but instead should be 
added to the sum of bidimensional products or total volume representing the entire enhancing 
tumor burden.
2.
In the case where the baseline or best response demonstrates no measurable enhancing disease 
(visible or not visible), then any new measurable (> 10 mm × 10 mm) enhancing lesions are 
considered PD after confirmed by a subsequent scan ≥ 4 weeks exhibiting ≥ 25% increase in sum 
of products of perpendicular diameters or ≥ 40% increase in total volume of enhancing lesions 
relative to the scan first illustrating new measurable disease.  The first scan exhibiting new 
measurable disease is noted as "preliminary PD."  If the second scan at least 4 weeks later 
exhibits a subsequent ≥ 25% increase in sum of products of perpendicular diameters or ≥ 40% 
increase in total volume of enhancing lesions relative to the "preliminary PD" scan it is 
considered "confirmed PD" and the patient should discontinue therapy.  If the second scan at 
least 4 weeks later exhibits SD, CR, PR, or becomes non-measurable, this scan showing 
"preliminary PD" is noted as "pseudoprogression," PsP, and the patient should continue on 
therapy until a second increase in tumor size relative to the "preliminary PD," or PsP, scan is 
observed.  Note that any new measurable (> 10 mm × 10 mm) enhancing lesions on the 
subsequent scan following the preliminary PD scan should not be immediately considered 
confirmed PD, but instead should be added to the sum of bidimensional products or total 
volume representing the entire enhancing tumor burden.
3.
Clear clinical deterioration not attributable to other causes apart from tumor (e.g., seizures, 
medication adverse effects, therapy complications, stroke, infection) or attributable to changes 
in steroid dose.
4.
Failure to return for evaluation as a result of death or deteriorating condition.
Stable Disease (SD):  Requires all of the following:
1.
Does not qualify for CR, PR, or PD as defined above.  Note this also applies to patients that 
demonstrate PsR when the confirmation scan does not show PD or PsP when the confirmation 
scan does not show PR/CR.
2.
In the event that corticosteroid dose was increased (for new symptoms/signs) without 
confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows 
that the steroid increase was required because of disease progression, the last scan considered 
to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to 
the baseline dose.
Symptomatic Deterioration & Reporting Clinical Status
Patients with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time, and not either related to study treatment or 
other medical conditions, should be reported as PD due to "symptomatic deterioration."  Every effort 
should be made to document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration.  Neurological exam data should be provided to the independent radiologic 
facility as "stable, better, worse" in case report forms or from study sponsor.  Clinical status should be 
recorded as "worse" if the neurological exam is worse; otherwise the clinical status should be set to "not 
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worse."  In the event that necessary clinical data is not available, clinical status should be recorded as 
"not available" and that particular time point can only be reviewed for PD (otherwise "non-evaluable").  
Neurological data must be within ± 7 days of the time-point response date, otherwise the data is 
considered "not available."
Steroid Use and Dose
Steroid use should be derived from the concomitant medications on the case report forms and recorded 
as "Yes," "No," or "not available."  A value of "No" should be assigned if, at the timepoint, the subject is 
not on steroids or on physiologic replacement doses only (< 1.5 mg dexamethasone or equivalent per 
day).
Systemic steroid dose should be derived from the concomitant medications on the case report forms.  
Average steroid dose no greater than 2 mg change from baseline should be abstracted to "stable."  If 
outside this range the steroid dose should be abstracted to "increased" or "decreased" accordingly.  
Steroid data should be within ± 5 days of the time-point response date; otherwise the data is considered 
"not available."
Overall Objective Status
The overall objective status for an evaluation should be determined by combining the patient's 
radiographic response on target lesions, new disease, neurological status, and steroid dose/usage as 
defined in Table 2 for patients with measurable (> 10 mm × 10 mm) disease.  Note that patients with 
possible PsP or pseudoresponse should be given the Objective Status of "Preliminary Progression" or 
"Preliminary Response," respectively.  Once PsP, pseudoresponse, or true progression/response are 
confirmed, the Objective Status can be changed accordingly.
Detailed Modified Radiographic Response Assessment Rubric
In order to provide both clinical guidelines for continuing therapy beyond suspected radiographic 
progression if the treating physician believes there may be a therapeutic benefit and to provide criteria 
for defining progression and early drug failure while also allowing for the possibility of PsP and PsR, 
modified response rubrics should be employed, depending on whether the patient is newly diagnosed or 
enrolled in a trial for recurrent disease.  The response rubric for newly diagnosed GBM is shown in 
Figure 1 below.
It is important to note that the primary differences between conventional RANO and the proposed 
modified criteria are:  (1) use of the post-radiation time point as the baseline for response evaluation in 
newly diagnosed GBM, (2) considering only objectively defined, measurable enhancing disease in the 
definition of response and progression (i.e., exclusion of qualitatively assessed T2/FLAIR changes), and 
(3) repeating radiographic assessments to confirm disease progression if initial radiographic evidence of 
PD is identified in the absence of clinical/neurologic decline.
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Details Common to Both Newly Diagnosed and Recurrent GBM
Preliminary Radiographic Progression.  If the lesion size has increased ≥ 25% sum of bidirectional
product or ≥ 40% in volume between MRI Scan 1 and N, these patients should be categorized as 
"preliminary radiographic progression."  If the investigator believes the patient can safely continue on 
therapy, then they should continue to treat and acquire a follow-up confirmatory scan [MRI(N + 1)] at 
the next scan interval (8 weeks ± 4 weeks from MRI Scan (N) or no less than 4 weeks minimum duration 
between preliminary PD and confirmed PD scans) to verify tumor growth and progression.  For patients 
with gross-total resection (GTR) and no measurable enhancing disease, preliminary radiographic 
progression is defined as a transition from no measurable disease to nonmeasurable (but present) 
disease (< 10 mm × 10 mm) or measurable disease (> 10 mm × 10 mm).  If the investigator feels it is safe 
to keep the patient on, a confirmatory scan at MRI(N + 1) should be obtained to verify tumor 
progression.
Confirmed Progression.  If the patient has an increase ≥ 25% sum of bidirectional product or ≥ 40% in 
volume between MRI Scan N and N + 1, this is "Confirmed Progression," the patient should stop therapy 
and the date of radiographic progression is the date of suspected progression, MRI(N).  If the patient has 
SD/PR/CR on MRI(N + 1) with respect to MRI(N), PsP is confirmed and the patient should continue on 
therapy.  Patients will then continue on therapy and receive additional follow-up MRI scans [MRI(M)].  If 
the lesion size has increased ≥ 25% sum of bidirectional product or ≥ 40% in volume on MRI(M) relative 
to the smaller of Nadir or MRI(N + 1), then the patient has "Confirmed Progression," the patient should 
stop therapy (unless otherwise allowed per protocol) and the date of radiographic progression is the 
new date, MRI(M).  For patients with no measurable disease at the Post-RT baseline, "Confirmed 
Progression" will be defined as a transition from non-measurable (but present) disease (< 10 mm × 
10 mm) on MRI(N) to measurable disease (> 10 mm × 10 mm) on MRI(N + 1).  For patients with 
confirmed PsP and no measurable disease at Nadir, "Confirmed Progression" should be defined as a 
transition from no measurable disease to measurable disease (> 10 mm × 10 mm).  In all cases, patients 
with confirmed progression should stop therapy.
Preliminary & Confirmed Radiographic Response.  If a measurable lesion has decreased ≥ 50% sum of 
bidirectional product or ≥ 65% in volume between MRI(1) and MRI(N), these patients should be 
categorized as "preliminary radiographic responders" and will be monitored for an additional time point 
and/or treatment cycle.  After an additional cycle of therapy (8 weeks ± 4 weeks from MRI(N)), patients 
will receive a confirmatory MRI(N + 1).  If the lesion(s) have increased ≥ 25% sum of bidirectional 
product or ≥ 40% in volume from MRI(N) (indicating radiographic progression from MRI(N)), this is 
considered an "unsustained radiographic response" or "pseudoresponse."  The date of radiographic 
progression for these patients will be MRI(N + 1) and the patient should stop therapy.  Alternatively, if 
the lesion has not increased from MRI(N), this is considered a "durable radiographic response," the 
patient will continue on therapy, and the date of preliminary radiographic progression is the time point 
of an increase ≥ 25% sum of bidirectional product or ≥ 40% in volume (from Nadir) during the remainder 
of the study.  The investigator can then decide whether to continue safely on therapy until progression 
has been confirmed and at the subsequent time point stop therapy if they feel the patient cannot safely 
continue therapy.
Stable Disease.  If the lesion size has not increased or decreased beyond the set thresholds between 
Scan 1 and N, the patient is considered "stable."  Such patients will continue on therapy, and the date of 
preliminary progression is the time point of an increase ≥ 25% sum of bidirectional product or ≥ 40% in 
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volume (from Nadir) during the remainder of the study.  Upon preliminary progression the investigator 
can choose to either continue therapy and confirm progression or discontinue therapy. For cases with 
significant neurologic decline at the time of imaging progression as determined from MRI(N), a 
confirmatory scan at time point MRI(N + 1) may not be possible or necessary.  For these cases, it is 
appropriate to define MRI(N) as the progression time point.
Open Access.  The guidelines provided for this study protocol are adapted, with protocol-specific 
clarifications, from Ellingson et al (2017).  The original was distributed under the terms of the Creative 
Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which 
permits unrestricted use, distribution, and reproduction in any medium, provided that the user gives 
appropriate credit to the original author(s) and the source, provides a link to the Creative Commons 
license, and indicates if changes were made.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-534 Version 4.0
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Figure 1.
Radiographic Response Assessment Rubric for Newly Diagnosed Glioblastoma
GBM = glioblastoma; MRI = magnetic resonance imaging; PD = progressive disease; PR = partial response; PsP = pseudoprogression; RT = radiation; SD = stable disease; 
Tx = treatment; wrt = with regard to
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