Conditions: Glioblastoma
Keywords: Glioblastoma Epithelial Growth Factor vIII mutation Temozolomide Lomustine ABT-414 European Organization for Research and Treatment of Cancer Recurrent glioblastoma Epithelial Growth Factor Brain Tumor Brain Tumor Group Antibody Drug Conjugate EORTC Pediatric High Grade Gliomas Pediatric Diffuse Intrinsic Pontine Glioma Pediatric WHO grade III glioma Pediatric WHO grade IV glioma EGFR amplification Children
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 266
Healthy volunteers: no

Brief summary:
This study was conducted to evaluate the efficacy and safety of depatuxizumab mafodotin (ABT-414) alone or with temozolomide versus temozolomide or lomustine alone in adult participants with recurrent glioblastoma. The study also included a substudy to evaluate safety, tolerability and pharmacokinetics of ABT-414 in a pediatric population.

Detailed description:
The study objectives were to assess whether depatuxizumab mafodotin (ABT-414) alone or in combination with temozolomide (TMZ) improved overall survival (OS), progression-free survival (PFS), tumor response, quality of life, neurological deterioration-free survival (NDFS), and steroid use compared to standard treatment with lomustine single agent or TMZ re-challenge in adult subjects ≥ 18 years of age with centrally-confirmed recurrent epidermal growth factor receptor (EGFR)-amplified glioblastoma. The safety, pharmacokinetics, and efficacy of depatuxizumab mafodotin in children \<18 years of age was evaluated in a pediatric substudy. The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.

Arms:
arm 1: Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants arm 2: Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants arm 3: Adult participants relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle received lomustine on Day 1 of every 42-day treatment period until one of the treatment withdrawal criteria was met, up to a maximum of 1 year. arm 4: Adult participants relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle received TMZ on Day 1 to Day 5 for the first 28-day cycle, with dose escalation in subsequent cycles in case of adequate tolerance and treatment continuing until one of the treatment withdrawal criteria was met. arm 5: Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to pediatric participants. Temozolomide (TMZ) was only allowed for pediatric participants if its use was in accordance with local clinical practice, and was not considered an investigational product for the study (unless this was a local requirement).

Interventions: intervention 1: Depatuxizumab mafodotin intervention 2: Temozolomide intervention 3: Lomustine
Intervention descriptions: intervention 1: Adults: intravenous administration (1.25 mg/kg or 1.0 mg/kg body weight) over 30 to 40 minutes once every 2 weeks until one of the treatment withdrawal criteria was met. The dose was 1.25 mg/kg in the original protocol (Version 1) and Version 2, Amendment 1, and was lowered to 1.0 mg/kg in protocol Version 3, Amendment 2. Pediatric participants: Intravenous administration (1.0 mg/kg body weight for those who were 6 to 17 years old at the date of first dose, or 1.3 mg/kg for those who were 0 to 5 years old) over 30 to 40 minutes or as directed by the guidelines once every 2 weeks until one of the treatment withdrawal criteria was met, for a maximum of one year. If used in combination with temozolomide, depatuxizumab mafodotin was dosed on Day 1 and Day 15 of the TMZ cycle (assuming a standard regimen of 200 mg/m\^2/day for 5 days of each 28-day cycle; for other TMZ schedules, timing of the depatuxizumab mafodotin dosing schedule were to be discussed with the medical monitor). intervention 2: Capsules administered orally, 150 mg/m\^2 on Days 1-5 for the first 28-day cycle, with dose escalation to 200 mg/m\^2 in subsequent cycles in case of adequate tolerance until one of the treatment withdrawal criteria was met. intervention 3: Capsules administered orally, 110 mg/m\^2 on Day 1 of every 42-day treatment period. Treatment continued until one of the treatment withdrawal criteria was met, for a maximum of one year.

Protocol document:
Prot_000.pdf: 
NCT02343406


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Contact addresses 
Writing Committee: 
 
Erasmus MC Cancer Institute - location 
Daniel den Hoed, Rotterdam, The Netherlands 
EORTC Headquarters Team, Brussels, Belgium. 
Study Coordinator:  
Study Co-coordinator: 
Clinical Research 
Physician: 
Project Manager: 
Data Manager: 
Statistician: 
Safety Management 
Oncology AbbVie: 
Study team: 
Study steering 
committee: 
Study coordinator 
Study co-coordinator 
Study Clinical Research Physician 
Study statistician 




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1. I have received and reviewed the Investigator's Brochure for ABT-414  
2. I have read this protocol and agree that the study is ethical. 
3. I agree to conduct the study as outlined and in accordance with all applicable regulations and 
guidelines. 
4. I agree to maintain the confidentiality of all information received or developed in connection with this 
protocol. 
5. I agree that all electronic signatures will be considered the equivalent of a handwritten signature and 
will be legally binding. 
Protocol EORTC-1410:INTELLANCE 2 : ABT-414 alone or ABT-414 plus temozolomide versus lomustine or 
temozolomide for recurrent glioblastoma: a randomized phase II study of the EORTC Brain Tumor Group 
Protocol, version 8.0, January 04, 2019. 
 
 
Investigator:  
 
 
____________________________________ __________________ __________________ 
Investigator’s full name (in capitals)  
 
(Signature) 
 
 
(Date) 
 


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Table of contents: 
Protocol summary ......................................................................................................................................... 11 
1 
Background and introduction ............................................................................................................... 22 
1.1 
Introduction ................................................................................................................................... 22 
1.2 
Chemotherapy and outcome in recurring glioblastoma ............................................................... 22 
1.3 
EGFR in glioblastoma ..................................................................................................................... 23 
1.4 
EGFR as a target in glioblastoma ................................................................................................... 24 
1.5 
ABT-414 and recurrent glioblastoma ............................................................................................ 24 
1.6 
Pharmacokinetics of ABT-414 ....................................................................................................... 25 
1.7 
Safety profile of ABT-414 .............................................................................................................. 26 
1.8 
Potential combination effect of ABT-414 with temozolomide and the choice for the control arm
 
27 
1.9 
Evaluation of ABT-414 in Children with High Grade Gliomas ....................................................... 28 
2 
Objectives of the trial ............................................................................................................................ 28 
2.1 
General objectives ......................................................................................................................... 28 
2.2 
End-points ..................................................................................................................................... 28 
2.2.1 Primary endpoint....................................................................................................................... 28 
2.2.2 Secondary endpoints ................................................................................................................. 28 
3 
Patient selection criteria ....................................................................................................................... 29 
3.1 
Registration ................................................................................................................................... 29 
3.2 
Randomization .............................................................................................................................. 29 
4 
Study Procedures .................................................................................................................................. 31 
5 
Therapeutic regimens, expected toxicity, dose modifications ............................................................. 34 
5.1 
General information ...................................................................................................................... 34 
5.1.1 ABT-414 ..................................................................................................................................... 34 
5.1.1.1 
Drug supplies 
34 
5.1.1.2 
Packaging, dispensing and storage 
34 
5.1.1.3 
Drug reconciliation procedures 
34 
5.1.2 Lomustine .................................................................................................................................. 35 
5.1.3 Temozolomide (TMZ) ................................................................................................................ 35 
5.2 
Initial dose and administration ..................................................................................................... 35 
5.2.1 ABT-414 ..................................................................................................................................... 35 
5.2.2 Lomustine .................................................................................................................................. 36 
5.2.3 Temozolomide ........................................................................................................................... 36 
5.3 
Treatment duration ....................................................................................................................... 36 


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5.4 
Withdrawal criteria ....................................................................................................................... 36 
5.5 
Dose and schedule modifications ................................................................................................. 37 
5.5.1 ABT-414 ..................................................................................................................................... 37 
5.5.1.1 
Allergic reactions 
38 
5.5.1.1.1 Severe allergic reactions (grade 3 or grade 4) 
38 
5.5.1.1.2 Moderate allergic reactions (grade 1 or grade 2) 
39 
5.5.1.2 
Dermatologic toxicities 
39 
5.5.1.3 
Ophthalmologic toxicities 
39 
5.5.1.3.1 Prophylaxis 
39 
5.5.1.3.2 Treatment once symptoms occur 
40 
5.5.1.3.3 Discussions with patients 
40 
5.5.1.3.4 Ophthalmological photography 
40 
5.5.1.4 
Hepatic Laboratory Abnormalities (ABT-414) 
41 
5.5.2 Lomustine .................................................................................................................................. 42 
5.5.2.1 
Dose levels of lomustine 
42 
5.5.2.1.1 Hematological toxicity 
42 
5.5.2.1.2 Non hematological toxicity 
42 
5.5.3 Temozolomide ........................................................................................................................... 43 
5.5.4 Concomitant treatments ........................................................................................................... 44 
5.5.4.1 
Prophylactic treatments 
44 
5.5.5 Other concomitant medication ................................................................................................. 44 
6 
Clinical evaluation, laboratory tests and follow-up .............................................................................. 44 
6.1 
Registration ................................................................................................................................... 44 
6.2 
Before randomization ................................................................................................................... 45 
6.3 
From treatment start until end of protocol treatment ................................................................. 46 
6.3.1 Day 1 of each cycle .................................................................................................................... 46 
6.3.2 Day 1 and day 5 for cycles 1 and 2; day 1 for cycle 3 and every 2 cycles thereafter (day 1 of 
C5, C7 etc.)............................................................................................................................................. 46 
6.3.3 Day 14 of each cycle - Arm 1 and 2 patients only ..................................................................... 48 
6.3.4 Day 21 of each cycle - Arm 1 and 3B patients only ................................................................... 48 
6.3.5 Day 28 of each cycle - Arm 3A patients only ............................................................................. 48 
6.3.6 Every 8 weeks (+/- 7 days) ......................................................................................................... 48 
6.3.7 At end of treatment (35 days after last administration/infusion) ............................................ 48 
6.3.8 At end of treatment (49 days after last administration/infusion) ............................................ 48 
6.3.9 At 6 months after randomization (+/- 1 month) ....................................................................... 48 
6.4 
After end of treatment .................................................................................................................. 49 


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6.4.1 From end of study treatment until progressive disease ........................................................... 49 
6.5 
Summary table .............................................................................................................................. 50 
7 
Criteria of evaluation ............................................................................................................................. 53 
7.1 
Evaluation of activity ..................................................................................................................... 53 
7.1.1 General method of response assessment ................................................................................. 53 
7.1.1.1 
Definition of target lesions 
53 
7.1.1.2 
Evaluation of patient treated after re-operation 
54 
7.1.1.3 
Schedule of disease evaluation 
54 
7.1.1.4 
Definition of response 
54 
7.1.2 Overall Survival .......................................................................................................................... 56 
7.1.3 Overall response ........................................................................................................................ 56 
7.1.3.1 
Best overall response 
56 
7.1.3.2 
Objective response 
56 
7.1.3.3 
Response duration 
56 
7.1.3.4 
Clinical /neurological progression 
56 
7.1.4 Progression Free Survival .......................................................................................................... 57 
7.1.5 Neurological deterioration-free survival ................................................................................... 57 
7.2 
Evaluation of safety ....................................................................................................................... 57 
7.2.1 Adverse events and side effects ................................................................................................ 57 
7.2.1.1 
Definitions 
58 
7.2.1.2 
Adverse Event 
58 
7.2.1.3 
Serious Adverse Events 
59 
7.2.1.4 
Deaths 
60 
7.2.1.5 
Lack of Efficacy or Worsening of Disease 
60 
7.2.1.6 
Adverse Event Severity 
60 
7.2.1.7 
Relationship to Study Drug 
61 
7.2.1.8 
Adverse Event Collection Period 
61 
7.2.1.9 
Serious Adverse Event Reporting 
61 
7.2.1.10 Pregnancy 
62 
7.2.1.11 Toxicity Management 
63 
7.3 
Evaluation of Quality of Life .......................................................................................................... 63 
8 
Statistical considerations ...................................................................................................................... 63 
8.1 
Statistical design ............................................................................................................................ 63 
8.1.1 Sample size ................................................................................................................................ 63 
8.1.2 Randomization and stratifications ............................................................................................ 64 


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8.2 
Statistical analysis plan .................................................................................................................. 64 
8.2.1 Primary and secondary endpoints ............................................................................................ 64 
8.2.1.1 
Primary endpoint 
64 
8.2.1.2 
Secondary and exploratory endpoints 
64 
8.2.1.2.1 Secondary Endpoints 
64 
8.2.1.2.2 Exploratory Endpoints 
64 
8.2.2 Analysis populations .................................................................................................................. 65 
8.2.3 Statistical methods .................................................................................................................... 65 
8.2.3.1 
Overall Survival 
65 
8.2.3.2 
Progression Free Survival 
65 
8.2.3.3 
Radiological response 
66 
8.2.3.4 
OS and PFS in patients with EGFRvIII mutation 
66 
8.2.3.5 
Neurological Deterioration Free Survival 
66 
8.2.3.6 
Global strategy to control type I error for efficacy endpoints 
66 
8.2.3.7 
Safety and tolerability 
68 
8.2.3.7.1 Hematological parameters 
68 
8.2.3.7.2 Biochemical parameters 
68 
8.2.3.7.3 All AEs 
68 
8.2.3.7.4 SAEs 
68 
8.2.3.7.5 Related AEs 
68 
8.2.4 Pre-planned sensitivity or exploratory analyses ....................................................................... 68 
8.2.5 Prognostic factor analyses ........................................................................................................ 69 
8.2.6 Data re-coding and display ........................................................................................................ 69 
8.3 
Interim futility analyses ................................................................................................................. 70 
8.4 
Re-randomization Test .................................................................................................................. 70 
8.5 
End of study ................................................................................................................................... 71 
9 
Trial Governance and Data Monitoring................................................................................................. 71 
9.1 
Study committees ......................................................................................................................... 71 
9.1.1 Study Management Group (SMG) ............................................................................................. 71 
9.1.2 Study Steering committee (SSC)................................................................................................ 71 
9.1.3 Independent data monitoring committee (IDMC) .................................................................... 71 
9.2 
Data Monitoring ............................................................................................................................ 72 
9.2.1 Monitoring during medical review meetings ............................................................................ 72 
9.2.2 Monitoring by the IDMC............................................................................................................ 72 
10 Quality of Life assessment..................................................................................................................... 72 


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10.1 
Rationale ....................................................................................................................................... 72 
10.2 
Objective ....................................................................................................................................... 73 
10.3 
HRQoL instrument ......................................................................................................................... 73 
10.4 
Study design .................................................................................................................................. 73 
10.5 
Statistical considerations .............................................................................................................. 74 
10.5.1 
Missing data .......................................................................................................................... 74 
11 Translational research ........................................................................................................................... 75 
11.1 
General principles for human biological material (HBM) collection............................................. 75 
11.2 
Pharmacokinetic Analysis of Blood Samples for ABT-414, Total ABT-806, Unconjugated Cys-
mcMMAF, and ADA (nADA) ...................................................................................................................... 76 
11.3 
Pharmacodynamic Analysis of Plasma Markers and Serum Markers ........................................... 76 
11.4 
Pharmacogenetic Analysis of Blood Samples - optional ............................................................... 77 
11.5 
Methylation status of the primary tumor ..................................................................................... 77 
11.6 
RNA expression profiling ............................................................................................................... 77 
11.7 
Targeted next-generation sequencing of relevant cancer genes ................................................. 78 
11.8 
Future translational studies - optional .......................................................................................... 78 
11.9 
Data storage, transfer and development of technical appendices ............................................... 78 
12 Investigator authorization procedure ................................................................................................... 79 
13 Patient registration and randomization procedure .............................................................................. 79 
13.1 
Registration (step 1) ...................................................................................................................... 80 
13.2 
Central lab review procedure (step 2) .......................................................................................... 80 
13.3 
Randomization procedure (step 3) ............................................................................................... 80 
13.4 
Confirmation of treatment arm and drug dispensation ............................................................... 81 
13.5 
Interactive Response Technology (IRT) ......................................................................................... 81 
14 Forms and procedures for collecting data ............................................................................................ 81 
14.1 
Case report forms and schedule for completion .......................................................................... 81 
14.2 
Data flow ....................................................................................................................................... 82 
15 Quality assurance .................................................................................................................................. 83 
15.1 
Control of data consistency ........................................................................................................... 83 
15.2 
Routine Monitoring Visits ............................................................................................................. 83 
15.3 
Audits............................................................................................................................................. 83 
15.4 
Central review of histology ........................................................................................................... 84 
15.5 
External review of responses ........................................................................................................ 84 
15.6 
Scan submission Quality Assurance and Quality Control in imaging ............................................ 85 
16 Ethical considerations ........................................................................................................................... 85 
16.1 
Patient protection ......................................................................................................................... 85 


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16.2 
Subject identification .................................................................................................................... 85 
16.3 
Informed consent .......................................................................................................................... 85 
17 Administrative responsibilities .............................................................................................................. 86 
17.1 
The study coordinator ................................................................................................................... 86 
17.2 
The EORTC Headquarters .............................................................................................................. 87 
17.3 
The EORTC group ........................................................................................................................... 87 
17.4 
AbbVie (Study Sponsor)................................................................................................................. 88 
18 Trial insurance ....................................................................................................................................... 88 
19 Publication policy .................................................................................................................................. 88 
 
Table of appendices: 
Appendix A: References 
89 
Appendix B: Abbreviations 
93 
Appendix C: WHO performance status scale 
96 
Appendix D: New York Heart Association (NYHA) classification of heart failure 
97 
Appendix E: Calculation of the glomerular filtration rate (GFR) 
98 
Appendix F: Common Terminology Criteria for Adverse Events 
99 
Appendix G: EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
100 
Appendix H: Adverse Events expected due to GBM or progression of GBM 
102 
Appendix I: Evaluation of ABT-414 in Children with High Grade Gliomas 
105 
Appendix J: Karnofsky and Lansky Performance Status 
117 
Appendix K: PedsQL Guidelines for Administration 
119 
Appendix L: Hepatic Laboratory Abnormalities (safety monitoring and observation guidelines) 
122 
Appendix M: Child-Pugh score 
125 
 


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Protocol summary 
Title of the Study 
INTELLANCE 2: ABT 414 alone or ABT 414 plus temozolomide versus 
lomustine or temozolomide for recurrent glioblastoma: a randomized 
phase II study of the EORTC Brain Tumor Group 
Objective(s) 
The objectives of the trial are to assess whether ABT-414 alone or in 
combination with TMZ improves overall survival (OS), PFS, tumor 
response, quality of life, NDFS and steroid use compared to standard 
treatment with lomustine single agent or TMZ re-challenge in patients 
with centrally confirmed recurrent EGFR-amplified glioblastoma. 
Additional exploratory objectives include analyses by stratum of EGFR 
pathway abnormalities (specifically EGFRvIII mutation), correlation of 
MGMT methylation status with clinical outcome (PFS/OS), and exploratory 
clinical and translational research program.  
The objectives will be achieved within a testing strategy, which aims to 
preserve the global type I error. The objectives will be realized according 
to the following hierarchical sequence: OS, PFS, response, OS in EGFRVIII 
mutated. Secondary objectives not included in the testing sequence will be 
realized for exploratory purpose. 
Methodology 
This is a comparative randomized open label multicenter multi-arm phase 
II trial. A 1:1:1 randomization is used. 
Number of patients  
Number planed 
(Statistical design) 
Number analyzed 
Based on literature review, a median OS of 7 months and PFS of 2.6 
months is expected in the mixed control arm (lomustine or TMZ). Based on 
a one-sided log rank test, at an overall significance level of 2.5% and a 
power of 91.7% (accounting for the global testing strategy), a total of 170 
deaths (118 per comparison, i.e. monotherapy ABT-414 versus control and 
combination ABT-414 + TMZ versus control) are needed to detect an 
increase of median OS to 12.9 months in the treatment arms 
corresponding to a Hazard Ratio (HR) equal to 0.54 (i.e. a reduction in the 
hazard of death of 46%). Assuming a monthly accrual of 10 patients during 
month 1 to 12 and 20 patients per month after 12 months, 240 patients 
can be recruited within 18 months. A duration of follow-up of 13 months 
after end of accrual is required to observe the 170 deaths. 
At interim analysis one or both of the ABT-414 arms might be discontinued 
based on lack of efficacy for PFS (Reject H1 in favor of H0) according to 
RANO criteria assessed by IRC.  
It is assumed that median PFS is 2.6 months in the control arm and 4.8 
months in the treatment arms corresponding to HR equal to 0.54. 
Assuming an accrual rate of 10 patients/month and activation phase of 
one year, at least 45 PFS events should be observed. Analyses will be 
performed when at least 31 PFS events are observed in each comparison. 
Treatment arms which did not show a minimum level of efficacy, defined 
as a computed treatment PFS HR lower than 0.91 will be dropped. The trial 
will continue with remaining treatment arm(s) and control. There will be 


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no interruption of accrual for the interim analysis.  
An alpha spending of 0.00001 will be allocated to the futility analysis. For 
the final analyses, efficacy endpoint will be tested at a nominal 1-sided 
alpha level of 0.02499 Treatment PFS HR will be presented with two-sided 
95% CI. 
For each of the two treatment arms the probability of stopping for futility 
at the interim is 7.4% if the true PFS HR is 0.54 and 60% if the true PFS HR 
is 1.0 (no benefit).  
Based on the assumed accrual rates and treatment effects stated above, 
the interim futility analysis is expected to be performed when 90 
randomized patients (30 patients per arm) have completed approximately 
4 months of follow-up. 
Diagnosis and main 
criteria for inclusion 
Registration 
x
Histologically confirmed de novo (primary) glioblastoma before or 
at the time of first progression after RT concurrent/adjuvant TMZ 
chemotherapy.  
x
In case of testing at the time of first progression: either at least 3 
months after the end of radiotherapy or have tumor progression 
that is clearly outside the radiation field or have tumor progression 
unequivocally proven by surgery/biopsy 
x
ŐĞшϭϴǇĞĂƌƐ 
x
Absence of any psychological, familial, sociological or geographical 
factors potentially hampering compliance with the study protocol 
and follow-up schedule; such conditions should be assessed with 
the patient before registration in the trial.  
x
Availability of adequate biological material (formalin-fixed paraffin 
embedded [FFPE] tumor) for central testing of EGFR amplification 
x
Written informed consent for central EGFR screening must be 
given according to ICH/GCP, and national/local regulations.  
Randomization 
x
Histologically confirmed de novo (primary) glioblastoma with 
unequivocal first progression after RT concurrent/adjuvant TMZ 
chemotherapy either at least 3 months after the end of 
radiotherapy or have tumor progression that is clearly outside the 
radiation field or have tumor progression unequivocally proven by 
surgery/biopsy 
x
Presence of EGFR amplification confirmed by central assessment; 
patients with undetermined EGFR status are excluded 
x
WHO Performance status 0 - 2 (see Appendix C) 
x
No prior treatment with nitrosoureas 
x
No prior treatment with bevacizumab 
x
No previous exposure to EGFR targeted agents, including EGFRvIII 
targeting agents and participation to placebo controlled trials on 
EGFR targeted agents 


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x
No prior discontinuation of temozolomide chemotherapy for 
toxicity reasons 
x
No more than one line of chemotherapy (concurrent and adjuvant 
TMZ based chemotherapy including in combination with another 
investigational agent is considered one line of chemotherapy). 
Chemotherapy must have been completed at least 4 weeks prior to 
randomization. 
x
No prior RT with a dose over 65 Gy to the brain, stereotactic 
radiosurgery or brachytherapy unless the recurrence is 
histologically proven 
x
No previous other malignancies, except for any previous 
malignancy which was treated with curative intent more than 5 
years prior to randomization, and except for adequately controlled 
limited basal cell carcinoma of the skin, squamous carcinoma of the 
skin or carcinoma in situ of the cervix 
x
Absence of known hypersensitivity to any part of the ABT-414 
compound, TMZ, dacarbazine or lomustine formulations, or to any 
IgG containing agent  
x
No history of Coeliac disease and wheat allergy 
x
Patient may have been operated for recurrence. If operated: 
x
Residual and measurable disease after surgery is not required but 
surgery must have confirmed the recurrence 
x
A post-surgery MRI must be available within 48 hours following 
surgery, however an MRI scan has to be done within 2 weeks prior 
to randomization 
x
Surgery completed at least 2 weeks before randomization and 
patients should have fully recovered as assessed by investigators. 
Criteria for full recovery will include absence of active post-
operative infection, recovery from medical complications and 
capacity for fluid and food intake.  
x
For non-operated patients, recurrent disease must include at least 
one bi-dimensionally measurable contrast-enhancing lesion with 
clearly defined margins by MRI scan, with minimal diameters of 10 
mm, visible on 2 or more axial slices 5 mm apart, based on an MRI 
scan done within 2 weeks prior to randomization 
x
Stable or decreasing dosage of steroids for 7 days prior to the 
baseline MRI scan 
x
No current or recent (within 4 weeks before randomization) 
treatment with another investigational drug 
x
Patients who require anti-convulsant therapy must be taking non-
enzyme inducing antiepileptic drugs (non-EIAED). Patients 
previously on EIAED must be fully switched to non-EIAED at least 2 
weeks prior to randomization 
x
No underlying or previous conditions that could interfere with 
treatment, including but not limited to: 
x
No evidence of active infection requiring hospitalization or 


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antibiotics, within 2 weeks prior to randomization 
x
No active infectious keratitis 
x
No other diseases interfering with follow up 
x
No planned vaccinations with live vaccines 
x
Adequate hematological function defined as͗ŶĞƵƚƌŽƉŚŝůƐшϭ͘ϱ × 
109 cells/L and ƉůĂƚĞůĞƚƐш 100 × 109 cells/L and 
hemoglobin ш 6.2 mmol/L (9.9 g/dl) 
x
Normal liver function: bilirubin < 1.5× upper limit of the normal 
range (ULN), alkaline phosphatase and transaminases (ASAT) < 2.5× 
ULN 
x
RĞŶĂůĨƵŶĐƚŝŽŶ͗ĐĂůĐƵůĂƚĞĚĐƌĞĂƚŝŶŝŶĞĐůĞĂƌĂŶĐĞшϯϬŵ>ͬŵŝŶďǇƚŚĞ
Cockcroft-Gault formula (see Appendix E) 
x
Absence of pregnancy. Women of childbearing potential (WOCBP) 
must be using an adequate method of contraception to avoid 
pregnancy throughout the study and for 6 months beyond the end 
of treatment in such a manner that the risk of pregnancy is 
minimized. In general, the decision for appropriate methods to 
prevent pregnancy should be determined by discussions between 
the investigator and the study subject. WOCBP include any female 
who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or is not postmenopausal. 
Females should not be breastfeeding. 
x
Post menopause is defined as: aŵĞŶŽƌƌŚĞĂшϭϮĐŽŶƐĞĐƵƚŝǀĞ
months without another cause or for women with irregular 
menstrual periods and on hormone replacement therapy (HRT), a 
documented serum follicle stimulating hormone (FSH) level > 
35 mIU/mL 
x
Women who are using oral contraceptives, other hormonal 
contraceptives (vaginal products, skin patches, or implanted or 
injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, 
spermicide) to prevent pregnancy, or are practicing abstinence or 
where their partner is sterile (e.g., vasectomy) should be 
considered to be of childbearing potential. 
x
Women of childbearing potential must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 72 hours prior to randomization. 
x
Female patients within one year of entering the menopause must 
agree to use an effective non-hormonal method of contraception 
during the treatment period and for at least 6 months after the last 
study treatment.  
x
Males must agree to use an effective method of contraception 
during the treatment period and for at least 6 months after the last 
study treatment.  
x
Before patient randomization and study related procedures (that 


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would not have been performed as part as standard care), written 
informed consent must be given according to ICH/GCP, and 
national/local regulations. Informed consent should also be given 
for biological material to be stored and used for future research on 
brain tumors. 
x
Patients with a buffer range from the normal values of +/- 5 % for 
hematology and +/- 10% for biochemistry are acceptable. A 
maximum of +/- 2 days for timelines are acceptable (with the 
exception of the pregnancy test). 
Treatment 
Test product, dose 
and mode of 
administration 
Arm 1: patients will be treated with ABT-414 1.0 mg/kg IV infusion over 30 
to 40 minutes once every 2 weeks in combination with TMZ 150 mg/m2 
day 1 to 5, for the first 28-day cycle, with dose escalation to 200 mg/m2 in 
subsequent cycles in case of good tolerance and until one of the treatment 
withdrawal criteria has been met. 
Arm 2: patients will be treated with ABT-414 monotherapy 1.0 mg/kg IV 
infusion over 30 to 40 minutes on days 1 and 15 of every 28-day cycle until 
one of the treatment withdrawal criteria has been met. 
Arm 3: Patients in the control arm will be treated according to the timing 
of relapse.  
Arm 3A: Patients relapsing during TMZ treatment or within the first 16 
weeks after the first day of the last TMZ cycle will be treated with 
lomustine 110 mg/m2 on day 1 of every 42-day treatment period. 
Treatment will continue until one of the treatment withdrawal criteria has 
been met. Lomustine will be given for a maximum of one year. 
Arm 3B: Patients relapsing 16 weeks or more after the first day of the last 
TMZ cycle will be treated with TMZ 150 mg/m2 on day 1 to 5 for the first 
28-day cycle, with dose escalation to 200 mg/m2 in subsequent cycles in 
case of adequate tolerance. Treatment will continue until one of the 
treatment withdrawal criteria has been met. 
Duration of 
treatment 
Whatever the disease status, the treatment will always be discontinued in 
case of 
x
disease progression 
x
patient refusal 
x
excessive toxicity precluding further therapy, according to the treating 
physician 
x
physician decision, according the best interest of the patient 
x
start of any other anti-cancer agent or modality; surgery at recurrence 
is allowed 
x
pregnancy 
Patients discontinuing therapy in the absence of progression should not 
receive any other cancer treatment before their disease progresses, unless 
this is clearly not in the interest of the patient. If, after treatment 
discontinuation, there is additional clinical information leading the 
investigator to conclude that the reason for discontinuation is no longer 


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valid (except for toxicity), 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 
treating physician. Any anti-cancer therapy other than the study drug will 
not be considered as part of the protocol treatment. 
Criteria for 
evaluation and 
endpoints 
The primary endpoint will be OS at final analysis and PFS according to 
RANO criteria and assessed by IRC at the interim analysis. 
Secondary endpoints will be: 
x
PFS according to RANO criteria and assessed by IRC  
x
Objective response rate (ORR) assessed by IRC 
x
OS in the subgroup with EGFRvIII mutation  
The following are exploratory endpoints: 
x
Best overall response rate (BOR), complete response rate (CRR), 
duration of response (DR) assessed by IRC will be computed in each 
arm  
x
PFS in the subgroup with EGFRvIII mutation 
x
Neurological deterioration-free survival (NDFS)  
x
Frequencies and percentages of worst Adverse Events (AEs) or 
Laboratory Event grades 
x
Quality of life 
x
Steroid use  
Efficacy/Safety 
Statistical methods 
Analysis populations 
x
Intention-to-treat population (ITT): All randomized patients will be 
analyzed in the arm they were allocated by randomization. 
x
Per protocol population (PP): All patients who are eligible and have 
received at least one dose of the study drug (i.e. one dose of lomustine 
or TMZ (arm 3), of ABT-414 (arm 2) and of TMZ and ABT-414 (arm 1)). 
Patients will be classified and analyzed in the arm they were assigned 
at the time of randomization. 
x
Safety population (SP): All randomized patients who have received at 
least one dose of the study drug i.e. one dose of lomustine or TMZ 
(arm 3), of ABT-414 (arm 2) and of TMZ and ABT-414 (arm 1)). Patients 
will be classified according to treatment received. 
Global testing strategy 
To meet global regulatory requirements, a multiple testing strategy for the 
following ordered endpoints will be implemented to control the family-
wise type I error (alpha) for comparisons of Arm 1 (ABT-414 + TMZ) versus 
Arm 3 (TMZ/lomustine) and Arm 2 (ABT-414 alone) versus Arm 3 with 
respect to overall survival (OS) and the pre-defined secondary efficacy 
endpoints, namely progression-free survival (PFS), objective response rate 


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(ORR), and OS for patients with EGFR vIII mutation. 
The following null hypotheses are considered: 
H1: Arm 1 is not superior to Arm 3 in OS. 
H2: Arm 2 is not superior to Arm 3 in OS. 
H1a: Arm 1 is not superior to Arm 3 in PFS. 
H2a: Arm 2 is not superior to Arm 3 in PFS. 
H1b: Arm 1 is not superior to Arm 3 in ORR. 
H2b: Arm 2 is not superior to Arm 3 in ORR. 
H1c: Arm 1 is not superior to Arm 3 in OS among EGFR vIII mutated 
patients. 
H2c: Arm 2 is not superior to Arm 3 in OS among EGFR vIII mutated 
patients. 
To maintain the overall type I error control for the study, the following null 
hypotheses will be tested in a fixed sequence of {H1, H2, H1a, H2a, H1b, 
H2b, H1c, H2c} in order at a 1-sided 2.5% level of significance. Hypothesis 
H1 will be tested first at a 1-sided 2.5% level. No further tests will be 
performed if H1 is not rejected. Each hypothesis will be tested in order 
specified above if H1 and all preceding hypotheses show statistically 
significant results at the 1-sided 2.5% level of significance. Otherwise 
testing in the fixed sequence will stop. 
All other endpoints, e.g., PFS in EGFRvIII mutated, global health/QoL status 
(GHQs), and neurological disease-free survival (NDFS) are considered 
exploratory and will be tested at a 2-sided 5% level of significance. 
Chapter 8 details all statistical methods. 
 
 
 


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Translational 
research 
In this study, biological material will be shipped from the study site to a 
designated CRO according to instructions provided in the study specific 
laboratory manual. Following the tissue analysis for EGFR amplification 
and EGFRvIII mutation, all biologic material will be centralized and stored 
at 
. From here, the 
biological material will be used or distributed to the other research 
laboratories involved in the translational research (TR) projects specified in 
this protocol or defined in the future. 
The following translational research projects are planned for this protocol 
x
Testing for MGMT promoter methylation status of the primary tumor 
x
Assessment of EGFR mutations 
x
Targeted next-generation sequencing of relevant cancer genes 
x
Optional future translational research studies according to questions 
that may arise during the conduct of the study 
The translational research projects are described in detail in chapter 11. 
Quality of Life 
Health-related quality of life patient reported outcomes will be collected 
using questionnaires (EORTC QLQ-C30 and BN-20). These must be 
completed at baseline; during treatment at weeks 8 and 16; and at 6 
months after randomization for all patients. The primary HRQoL endpoint 
for this study is clinically relevant (i.Ğ͘шϭϬƉŽŝŶƚƐͿ change from baseline in 
the global health/HRQoL status scale. 
PK – PD 
Serum or plasma samples for the translational research, determination of 
the concentrations of ABT-414, total ABT-806 antibody and unconjugated 
cys-mcMMAF will be collected during the study. In addition, serum 
samples for determination of antidrug antibody will be collected 
throughout the study. Population PK analyses will be performed to identify 
demographic and/or disease-specific variable(s) that affect the PK of ABT-
414, total ABT-806, and cys-mcMMAF. Dose/exposure analyses for 
relevant safety, efficacy variables will be conducted to understand the 
contribution of ABT-414, Total ABT-806 antibody and cys-mcMMAF to 
efficacy and safety. 
Pediatric Sub-Study 
(see Appendix I) 
Population: Subjects < 18 years old with histologically proven high grade 
glioma (HGG: WHO grade III glioma [e.g anaplastic astrocytoma, anaplastic 
oligodendroglioma, anaplastic oligoastrocytoma], grade IV glioma [e.g 
glioblastoma, gliosarcoma] or diffuse intrinsic pontine glioma [DIPG]). 
Objective: The primary objective will be the evaluation of safety, 
tolerability and pharmacokinetic of ABT-414 in a pediatric population < 18 
years of age. The secondary objective will be to assess the effect of ABT-
414 on tumor response per RANO criteria. 
Methodology: This is an uncontrolled, open-label, single-arm global study. 
Number of patients: There will be no maximum enrollment for children 
with HGG and EGFR amplified; however it is expected that at least 6 
subjects will be enrolled. 


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Diagnosis and main criteria for inclusion:  
Registration Criteria- 
x
Subjects must have a histologically proven high grade glioma (WHO 
grade III glioma [e.g anaplastic astrocytoma, anaplastic 
oligodendroglioma, anaplastic oligoastrocytoma], grade IV glioma [e.g 
glioblastoma, gliosarcoma] or DIPG). 
x
Subjects must be <18 years of age.  
x
The tumor tissue must have been determined to have EGFR 
amplification (by local or other testing service) 
x
Availability of adequate biological material (formalin-fixed paraffin 
embedded [FFPE] tumor) for central testing of EGFR amplification. 
There must be sufficient tissue to submit for (retrospective) 
confirmatory EGFR FISH testing at the study-designated central 
laboratory. If there are less than the requested 30 slides available, it is 
acceptable to continue the registration process, assuming sufficient 
material is available for central testing of EGFR amplification. 
x
Before patient registration or any study-related procedures that would 
not have been performed as part of standard care, written informed 
consent/assent by subjects and/or their legal guardians must be given 
according to ICH/GCP, and national/local regulations. 
Enrollment Criteria -  
x
Subject must either have recurrent/progressive tumor or, if newly 
diagnosed, have completed any planned radiation therapy at least 4 
weeks prior to first dose of ABT-414.  
x
The investigator must confirm that the subject is able to complete the 
procedures required in order to assess the primary endpoints, 
including PK blood draws and safety assessments over the first four 
weeks of therapy including Day 1 of Week 5. 
x
The investigator believes that the potential benefit of treating the 
pediatric subject with ABT-414 outweighs the expected risks and that 
this treatment is in the best interests of the pediatric subject. 
x
Subjects and/or their legal guardians must be able to understand the 
risks and potential benefits, and grant assent/consent to participate by 
signing the applicable pediatric-specific informed assent and/or 
consent forms. 
x
Subject has sufficiently recovered from previous therapy.  
x
(For recurrent disease) No prior RT with a dose over 65Gy to the brain, 
sterotactic radiosurgery or brachytherapy unless the recurrence is 
histologically proven 
x
No current or recent (within 4 weeks or 5 half-lives (whichever is 
shorter) before enrollment) treatment with another investigational 
drug 
x
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Cockcroft-Gault formula for pediaƚƌŝĐƉĂƚŝĞŶƚƐшϭϮǇĞĂƌƐŽĨĂŐĞĂŶĚ
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Schwartz equation for pediatric patients < 12 years of age 
 
x
>ŝǀĞƌĨƵŶĐƚŝŽŶ͗dŽƚĂůďŝůŝƌƵďŝŶчϭ͘ϱƚŝŵĞƐƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů;h>EͿ͕
Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) 
чϯƚŝŵĞƐh>E͘^ƵďũĞĐƚƐǁŝƚŚ'ŝůďĞƌƚΖƐƐǇŶĚƌŽŵĞĚŽĐƵŵĞŶƚĞĚŝŶ
medical history may be enrolled if total bilirubin is < 3 times ULN. 
Not allowed are subjects with known chronic liver disease and/or 
cirrhosis documented by the presence of one or more of the following 
(assessments to be performed per standard of care only if liver disease 
is suspected): 
x
Liver biopsy with histologic findings consistent with cirrhosis 
x
CT or US evidence of liver disease with or without portal 
hypertension 
x
Physical examination and clinical and laboratory evidence of 
chronic liver disease 
x
Colloid shift on a liver-spleen scan 
x
A Child-Pugh score of 6 or higher (see Appendix M) 
x
Absence of pregnancy. Female subjects of childbearing potential must 
be using an adequate method of contraception to avoid pregnancy 
from Study Day 1 throughout the study and for 6 months beyond the 
end of treatment in such a manner that the risk of pregnancy is 
minimized. In general, the decision for appropriate methods to prevent 
pregnancy should be determined by discussions between the 
investigator and the study subject. Female subject of childbearing 
potential includes any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). Female subjects of 
non-child bearing potential do not need to use birth control. 
x
Pediatric female patients are not considered to be of child bearing 
potential if meeting any of the following criteria: 
 
x
Permanently surgically sterile (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy). 
x
Females who have not experienced menarche (at least one 
menstrual period). 
x
Female subjects of childbearing potential must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 72 hours prior to enrollment. 
x
Female subjects must not be pregnant, breastfeeding, or considering 
becoming pregnant during the study or for at least 6 months after the 
last dose of study drug. 
x
Male subjects that are sexually active with female partner(s) of 
childbearing potential must agree to use an effective method of 
contraception from Study Day 1, during the treatment period and for 
at least 6 months after the last study treatment.  
 
 


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x
Male subjects must not be considering fathering a child or donating 
sperm during the study or for at least 6 months after the last dose of 
study drug. 
x
Before patient registration, enrollment and study-related procedures 
that would not have been performed as part of standard care, written 
informed consent must be given according to ICH/GCP, and 
national/local regulations. 
x
Subject must not have a history of a major immunologic reaction to 
any IgG-containing agent. 
Treatment: All subjects will receive ABT-414 administered at a starting 
dose of 1.0 mg/kg (age 6-17) or 1.3 mg/kg (age 0-5) IV every other week. 
Prophylactic steroid eye drops will be administered as described in the 
adult protocol. It is at the investigator's discretion to use ABT-414 as 
monotherapy or in combination with temozolomide. 
Duration of treatment: ABT-414 treatment will continue for up to 12 
months. 
Criteria of evaluation: Unless otherwise stated, the criteria of evaluation 
will be the same in children as in adults. QoL will be measured using the 
PedsQL Cancer module. Performance status will be measured by 
Karnofsky/Lansky (and WHO status if initially enrolled prior to 
implementation of Amendment 5 of the protocol). For the primary 
endpoint of safety, all adverse events will be coded according to MedDRA 
preferred term, reported and graded using the NCI CTCAE v4. For the 
safety assessment, a dose limiting toxicity (DLT) will be defined as any 
grade 3 or 4 adverse event that is attributed to ABT-414, or an ABT-414 
toxicity that results in a delay of the second dose of ABT-414 by more than 
14 days. 
 
Statistical Methods: For a sample size of 6 in HGG with EGFR amplification, 
the probability of observing at least 1 tumor response will be 82.2% if the 
true response rate is 25%. 
All subjects who receive at least one dose of ABT-414 will be included in 
the analysis. No interim analysis is planned. Data will be summarized 
descriptively. 
Translational research: Tumor specimens will be collected where feasible 
for the same biomarker analyses as planned for the adult population. 
Central molecular testing will include but not be limited to EGFR, H3.1, 
H3.3, BRAF, CDKN2A/B, IDH1, INI1, MGMT, PTEN. Insufficient tissue for 
Translational Research after EGFR amplification analysis will not prevent 
enrollment of the pediatric patients. 
PK: Serum and plasma samples for the determination of the 
concentrations of ABT-414 and unconjugated cys-mcMMAF will be 
collected during the study. In addition, serum samples for determination 
of antidrug antibody will be collected throughout the study.  
 
 


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1
Background and introduction 
1.1
Introduction 
Gliomas are the most frequent primary brain tumors in adults, with an annual incidence between 4 and 5 
per 100.000 inhabitants (Ref. 1, Ref. 2, Ref. 3). According to the CBTRUS registry in the USA, each year 
over 20.000 patients are diagnosed with a glioma. Low-grade diffusely infiltrating glioma and anaplastic 
glioma constitute about 30-40% of all glial tumors in adults. Glioblastoma present most of the remaining 
60-70% of glial tumors. Glioblastomas are the most aggressive primary brain tumors in adults, with a 
median survival of 9 to 15 months. Despite aggressive treatment, glioblastomas invariably relapse after 
combined chemo-irradiation with temozolomide (RT/TMZ) (Ref. 4). Major prognostic factors for survival 
are age and performance status at the time of diagnosis (Ref. 5,  
Ref. 6). No curative treatment exists. Standard treatment consists of surgical resection to the extent 
feasible followed by radiation and concomitant and adjuvant TMZ therapy. 
1.2
Chemotherapy and outcome in recurring glioblastoma 
Once a glioblastoma recurs, the treatment options are usually limited and no uniformly accepted 
standard of care exists. The most important prognostic factors in this setting are age, performance status, 
use of steroids and size/number of enhancing lesions (Ref. 7, Ref. 8). Other factors of relevance may 
include re-resection (tumor burden), promoter methylation status of O6-methyl-guanine-methyl 
transferase (MGMT). Many patients deteriorate rapidly at the time of recurrence, making further 
treatment meaningless. Some patients have recurrences that allow re-resection but most patients have 
lesions inaccessible for surgery (e.g., involvement of the corpus callosum, deeply seated lesions, or 
lesions in eloquent areas). Re-irradiation is also being used, despite the risk of cumulative neuro-toxicity 
and this approach is feasible in patients with lesions of limited size (Ref. 9). The efficacy of re-irradiation 
in glioblastoma is however debated. Chemotherapy is commonly suggested for recurrent disease. Both 
nitrosoureas (in particular lomustine) and TMZ provide options for selected patients. Studies of 
retreatment with TMZ at the time of relapse suggest that this approach may be effective in selected 
patients: especially after a treatment free interval or in the presence of MGMT promoter methylation 
(Ref. 10). The RESCUE trial, on continuous daily dosing of TMZ in patients having relapsed after RT/TMZ 
analyzed outcome in relation to the interval between the end of initial chemotherapy and salvage TMZ 
treatment (Ref. 11). In the entire group, PFS-6 was 23.9% but PFS-6 in the patients relapsing more than 
two months after the end of TMZ was 35.7%, as opposed to only 7.4% in the patients relapsing after 
more than 6 cycles of adjuvant TMZ but while still on TMZ treatment. Of note, PFS-6 was 23.9% for 
patients relapsing during the first 6 cycles of adjuvant TMZ, but here no minimum interval between the 
end of RT and study entry was specified. The outcome in this last group is quite likely explained by the 
presence of pseudo-progression and radiation necrosis early after the end of RT, with likely spontaneous 
improvement over time even in the absence of treatment  
(Ref. 12, Ref. 13). With respect to OS, only 12 month OS was reported: this was 28% for patients relapsing 
more than 3 months after the end of TMZ adjuvant treatment and 14% for the patients relapsing within 3 
months or during TMZ treatment. Historical data (EORTC 26981) suggest that 60% of randomized 
patients will relapse before 3 months after the end of adjuvant TMZ treatment, and 40% thereafter 
(relapses during RT or in the 3 months thereafter are not eligible). The data of EORTC study 26981 also 
suggest that two-thirds of patients that do not progress until more than three months after the end of 
TMZ will have a methylated MGMT promoter. There are quite some data available on the outcome of 
TMZ retreated relapsing glioblastoma patients. The important role of adequate patient selection for 
retreatment with TMZ is further supported by the initial results reported at ASCO 2014 of the German 
randomized phase II DIRECTOR trial on ‘week on-week off’ TMZ versus ‘three weeks on-one week off’ 


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TMZ (Tabatabai et al, ASCO 2014, abstract #2015, personal communication). This study did not yield a 
clinically interesting result in the entire study population. However, the presented analysis based 
on MGMT promoter methylation is most interesting and shows the same signal as a study by Han et al on 
dose intensified TMZ retreatment: PFS-6 after dose intensified TMZ was 39.7% in patients with a 
methylated MGMT promoter gene, vs. 6.9% in patients without MGMT promoter methylation (Ref. 14). 
Median OS in the MGMT promoter methylated glioblastoma was 55 weeks, and in the unmethylated 34 
weeks. This is comparable to the observed OS of 12 and 8 months respectively for the methylated and 
unmethylated glioblastoma patients in the Dutch BELOB trial; for the lomustine single agent arm the OS 
figures are 10 and 6 months. Extrapolating from this, it is reasonable to assume that median OS will be in 
the 10-12 months range for the MGMT promoter methylated and in the 6-8 months range for the 
unmethylated MGMT promoter glioblastoma and to assume that patients relapsing less than 3 months 
after completion of TMZ predominantly have a MGMT promoter unmethylated tumor and the patients 
relapsing more than 3 months after TMZ predominantly have a MGMT promoter methylated tumor. 
Nitrosoureas are widely used in relapsed glioblastoma, in particular lomustine (CCNU) but also 
fotemustine (Ref. 15). A recent randomized study on recurrent glioblastoma that used lomustine noted a 
19% PFS probability at 6 months with lomustine, similar to what has previously been observed with TMZ 
in this indication. Because of these results, lomustine is currently used as comparator in many 
randomized controlled trials (e.g., the REGAL study, the enzastaurin study, the Dutch BELOB trial, but also 
the ongoing EORTC study 26101) (Ref. 16, Ref. 17, Ref. 18). 
Although bevacizumab, an angiogenesis inhibitor, is widely used for recurrent glioblastoma, in the 
absence of well-controlled trials its role remains unclear. A first controlled phase II study revealed limited 
single agent activity of bevacizumab, and preliminary evidence of activity of the combination 
bevacizumab and lomustine but results of the confirmatory EORTC phase III study are still pending  
(Ref. 18).  
To conclude, with the currently available treatments recurrent glioblastoma remains an unmet clinical 
need, and to meet that need novel agents must be investigated. 
1.3
EGFR in glioblastoma 
Despite several negative trials of epidermal growth factor receptor (EGFR) inhibitors in glioblastoma, the 
genetic and molecular analysis of glioblastoma continues to suggest that the EGFR signaling pathway is a 
compelling target for drug therapy. Fifty to sixty percent of glioblastomas demonstrate abnormalities of 
the EGFR pathway: 60% show overexpression of the receptor, in 45-50% the EGFR receptor is amplified, 
and about half of EGFR-amplified tumors harbor a constitutively activated EGFRvIII mutation in parts of 
the tumor. The EGFRvIII mutation is an intragenic gene rearrangement generated by an in-frame deletion 
of exons 2-7 that encode part of the extracellular region. If present, this mutation is usually expressed in 
focal areas of the tumor. In addition to the EGFRvIII mutation, other EGFR mutations are frequently 
present in EGFR amplified tumors (Ref. 19). However, the exon 19-21 mutations that signify sensitivity to 
EGFR inhibitors in NSCLC are virtually absent in glioblastoma. Although these EGFR mutations appear to 
play a pivotal biological role in individual tumors, they do not have a significant prognostic implication for 
OS in glioblastomas treated with RT/TMZ (Ref. 20). Still both EGFRvIII and EGFR amplifications are key 
oncogenic events in glioblastoma, and EGFRvIII mutation enhances the tumorigenic potential of 
glioblastoma by activating and sustaining mitogenic, anti-apoptotic, and pro-invasive signaling pathways 
(Ref. 21, Ref. 22). 
Preliminary research at Erasmus MC on a series of 51 paired glioblastoma samples taken from first 
diagnosis and at the time of recurrence, shows that in the majority of cases the EGFR status 
(EGFRvIII/EGFR amplification/EGFR normal) remains the same at the time of relapse. More in detail, of 20 


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high-level EGFR amplification patients only one lost the amplification, whereas only two of the other 
cases developed high-level amplification at the time of recurrence. This implies that EGFR amplification 
status at first diagnosis is a reasonable predictor of EGFR amplification status at the time of progression.  
1.4
EGFR as a target in glioblastoma 
In view of the prominent presence of EGFR signaling abnormalities many trials have explored the activity 
of EGFR inhibitors in recurrent glioblastoma, either using monoclonal antibodies or Tyrosine Kinase 
Inhibitors (TKI) (Ref. 23, Ref. 24). Invariably, these trials were negative, including studies on the first 
generation EGFR TKIs gefitinib and erlotinib, but also studies on second generation TKI’s such as afatinib 
and lapatinib. Other studies evaluated monoclonal antibodies, in particular cetuximab and nimotuzumab 
(Ref. 25). Notably, these studies did not restrict enrollment to glioblastoma patients with EGFR 
amplification, and several of these drugs are unlikely to cross an intact blood brain barrier. Currently, 
clinical testing is underway with dacotinib, an irreversible EGFR inhibitor that has been demonstrated to 
cross the blood brain barrier in preclinical models. The failure of the anti-EGFR agents to improve 
outcome are assumed to be related to the limited drug penetration, the absence of exon 19-21 
mutations in glioblastoma, and the failure to significantly affect downstream signaling despite target 
inhibition, because of parallel signaling pathways. These assumptions question the classical targeting with 
EGFR inhibitors in glioblastoma. 
A different approach is to target the EGFR alterations present in 50-60% of glioblastoma as a means to 
deliver cytotoxic compounds. A variety of constructs has been developed, in which toxins or 
antineoplastic agents are targeted to EGFR or EGFRvIII (Ref. 26). The absence of EGFRvIII and activated 
EGFR in normal tissues makes this tumor-specific alteration a potential candidate for such approaches. 
ABT-414 is an example of this approach which uses an antibody-drug conjugate (ADC) designed for the 
treatment of tumors expressing EGFR (Ref. 27). Antibody-drug conjugates are a rapidly growing class of 
cancer drugs that combine the targeting properties of monoclonal antibodies (mAbs) with the anti-tumor 
effects of very potent cytotoxic drugs. This approach may be successful where tumor cells use redundant 
signaling pathways to avoid other targeted approaches. A similar ADC (T-DM1) using trastuzumab as the 
targeting antibody and the microtubule-inhibitory agent DM1 as the cytotoxic was very active in 
trastuzumab-resistant metastatic breast cancer (Ref. 28). Significant technical advances in linker stability 
and toxin potency are primarily responsible for the resurgence in ADC development. 
The EGFRvIII variant can also elicit an immunogenic response, and currently a vaccine against the EGFRvIII 
mutations is being investigated in a global phase III trial (Ref. 29). Its clinical significance is still unclear. 
1.5
ABT-414 and recurrent glioblastoma 
ABT-414 is a newer generation ADC consisting of: ;ϭͿĂǀĞŶĞĞƌĞĚΗŚƵŵĂŶŝǌĞĚΗƌĞĐŽŵďŝŶĂŶƚ/Ő'ϭʃ
antibody (ABT-806) that has binding properties specific to a unique epitope of human EGFR with (2) non-
cleavable maleimido-caproyl linkers each attached to (3) a potent antimicrotubule agent, 
monomethylauristatin F (MMAF). The antibody binds to the activated EGFR epitope (even in the absence 
of the EGFRvIII mutation), is internalized, and then intracellular enzymes release the toxin leading to 
inhibition of microtubule function, the disruption of critical cellular processes, and cell death. 
Importantly, ABT-414 binds to an epitope that is available predominantly on tumor cells with either the 
EGFRde2-7 (EGFRvIII) deletion mutant or on tumor cells with activated wild-type EGFR (i.e., with EGFR 
amplification). The epitope is largely inaccessible when EGFR is expressed at normal physiological levels; 
thus, ABT-414 has limited binding to non-activated, wild-type EGFR expressed on normal tissues. These 
properties, therefore, favor limited effects of the toxin on normal tissues while maintaining a high degree 
of activity on EGFR-overexpressing tumor cells. ABT-414 has shown tumor regression in EGFR wild type 
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In an ongoing phase I study in glioblastoma, ABT-414 given intravenously (IV) every other week is 
investigated with radiotherapy and daily temozolomide (RT/TMZ) (Arm A) or with TMZ day 1-5 every four 
weeks (Arm B). The latter recruited both newly diagnosed and recurrent glioblastoma subjects; in the 
newly diagnosed setting, ABT-414 was combined with monthly maintenance TMZ after completion of 
chemo-radiation, whereas in recurrent glioblastoma ABT-414 was administered with TMZ re-challenge. In 
this phase I project, responses have been observed. Preliminary efficacy results to date showed that 4 
out of 15 recurrent glioblastoma subjects in Arm B had objective responses, including 1 of 3 patients 
treated at 0.5 mg/kg, 2 of 5 subjects at 1.0 mg/kg, 0 of 3 subjects at 1.0 mg/kg and 1 of 4 subjects at 1.5 
mg/kg (ASCO abstract 2014 and personal communication from AbbVie). Three of these responses 
occurred in patients with EGFRvIII mutation or amplification. The remaining responding patient who 
relapsed one year after combined chemo-irradiation, had a methylated MGMT promoter and had low 
EGFR expression level; therefore, the response may have been due to TMZ. Of 6 tumors that were EGFR 
amplified in recurrent glioblastoma, 3 objective responses were observed. Their responses were durable, 
as these 3 patients were on study for between 5.5 to 12.5 months (personal communication AbbVie), and 
2 of the 3 patients are still receiving ABT-414 to date. Moreover, in the first-in-man-phase I study, a 
response to ABT-414 monotherapy was observed in a non-CNS metastatic tumor (triple negative breast 
cancer) with EGFR amplification. These data warrant further exploration of ABT-414 in recurrent 
glioblastoma, alone and in combination with TMZ. Both the current data on responding patients and the 
mechanism of action of the compound warrant conducting the trial in an enriched recurrent glioblastoma 
population characterized by EGFR amplification.  
1.6
Pharmacokinetics of ABT-414 
In preclinical studies, ABT-414 pharmacokinetics was characterized following a single bolus intravenous 
(IV) dose in CD-1 mice, Sprague-Dawley rats, and cynomolgus monkeys. Additional studies characterized 
ABT-414 pharmacokinetics following once-weekly dosing in CD-1 mice and cynomolgus monkeys (4 
doses). In all studies, the ABT-414 pharmacokinetic profiles were characteristic of a monoclonal antibody, 
with low serum clearance (0.27 to 0.34 mL/hr/kg), small volumes of distribution (79.0 to 85.7 mL/kg) and 
a terminal half-life (t1/2) of 8.0 to 9.5 days. The area under the concentration-time curve (AUC) values for 
ABT-414 were approximately 40% to 50% lower than those of total ABT-806 (unconjugated ABT-806 and 
ABT-806-mcMMAF combined). Plasma concentrations of unconjugated cys-mcMMAF were very low 
following dosing with ABT-414, with both maximum observed plasma concentration (Cmax) and AUC 
values more than 3 to 5 orders of magnitude lower than Cmax and AUC of ABT-414. Following repeated 
once-weekly dosing in mice and monkeys, ABT-414 pharmacokinetics were characterized by dose 
proportional increases in AUC, with values after the third dose being approximately 1.2- to 2.4-fold 
higher than those obtained after the first dose. 
Cys-mcMMAF, identified as a metabolite of ABT-414, is eliminated through the hepatic-biliary pathway 
and is a substrate of human P-glycoprotein (P-gp, MDR-1). At concentration up to 1 μM, cys-mcMMAF 
was not a direct, time-or metabolism-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, or CYP3A4/5, nor an inducer of CYP1A2, 2B6, or 3A/4/5 enzyme activity or gene expression and 
thus, is unlikely to have drug-drug interaction in combination studies. 
The human pharmacokinetics of ABT-414 are under investigation in two ongoing clinical studies. Study 
M12-356 is a Phase 1 study of ABT-414 in combination with RT plus TMZ, with TMZ, or as single-agent 
ABT-414 in subjects with glioblastoma multiforme. Study M13-379 is a first-in-human (FIH) Phase 1/2 
study in subjects with advanced solid tumors likely to overexpress EGFR. The dose range studied was 0.5 
to 3.2 mg/kg in M12-356 and 1 to 4 mg/kg in M13-379 study. The pharmacokinetic data from both 
studies indicate that the systemic exposures (AUC and Cmax) of ABT-414, total ABT-806, and cys-
mcMMAF achieved after administration of ABT-414 via IV infusion were approximately dose-


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proportional. ABT-414 serum exposure was moderately lower than that of total ABT-806. In M13-379, for 
dose-normalized Cmax, cys-mcMMAF was approximately 400 -fold lower than that of ABT-414 in molar 
concentration. The observed harmonic mean terminal phase elimination half-life ranged approximately 
from 7.5 to 12 days and 9 to 15 days for ABT-414 and total ABT-806, respectively. The observed mean 
clearance of ABT-414 ranged approximately from 0.19 to 0.37 mL/h/kg. The observed harmonic mean 
terminal phase elimination half-life of cys-mcMMAF was approximately 4 days. 
1.7
Safety profile of ABT-414 
Subjects in ABT-414 ongoing studies have reported frequent ophthalmologic toxicities, more commonly 
at the 1.0 mg/kg dose level and above. ABT-414 is composed of an EGFR targeted antibody bound to a 
microtubule toxin, MMAF. MMAF has been described to cause a unique and specific toxicity to the 
cornea; the formation of corneal epithelial microcysts. These microcysts are thought to be in reaction to 
damage caused by MMAF to the rapidly dividing transient amplifying cells that give rise to the cornea. 
When this damage occurs, these cells become necrotic and produce very small microcysts that become 
lodged in the early corneal layer. As the cornea regenerates, the microcysts traverse across the cornea, 
causing a variety of symptoms, and ultimately are sloughed off when a completely new cornea re-
generates. It should be noted that this process can take 3-4 weeks and thus symptoms that arise may 
take at least a month or more before they start to improve. These adverse events have included dry eyes, 
blurry vision, eye pain, photophobia and watery eyes. Similar ophthalmologic toxicities have been 
previously reported with another MMAF compound, SGN-75 (Ref. 30). The ophthalmology examination 
findings with SGN-75 as well as with ABT-414 are similar to the findings noted with high dose cytarabine 
administration. Dexamethasone eye drops are commonly used with high dose cytarabine administration 
to prevent the formation of epithelial microcysts. The steroid ophthalmic solution is thought to reduce 
the cellular turnover in the epithelium and thus make the cells more resistant to the effects of 
chemotherapy damage. Dexamethasone, or an equivalent steroid ophthalmologic solution, will be 
recommended around the time of each ABT-414 infusion for all ABT-414 trials. 
At the current recommended phase II dose of 1.25 mg/kg via IV infusion every 2 weeks for ABT-414 in 
combination with TMZ in Arm B, 1 of 10 subjects had a severe adverse event of the eye attributable to 
ABT-414. In Arm C, which tested ABT-414 at 1.25 mg/kg as monotherapy in recurrent GBM, 2 of the 8 
patients enrolled had adverse eye events attributable to ABT-414. 
In the ongoing phase I study, as of April 29 2015, 40 subjects have been treated in Arm B and 42 in Arm C. 
Common treatment emergent AEs in at least 30% of subjects in Arm B included photophobia (15/37.5%), 
blurred vision (23/57.5%), nausea (19/47.5%), fatigue (17/42.5%) and headache (12/30%); in Arm C, they 
were blurred vision (25/59.5%) and fatigue (24/57.1%). Grade 3/4 AEs found in > 10% of subjects in Arm 
B included keratitis (5/12.5%), gamma GT elevation (4/10%) and decreased platelet (4/10%); in Arm C, 
the only grade 3/4 AEs of > 10% was keratitis (6/14.3%). Overall, in the 1.25 mg/kg dose cohort the grade 
3/4 ocular toxicity rate was 27%. ABT-414 administration was suspended in those who developed grade 
3/4 eye toxicity until symptoms recovered to grade 1, which took a median of 40 days.  
Because of the high rate of significant eye toxicity and the need for drug interruption, the starting dose of 
ABT-414 for the present study for both Arm 1 and 2 will be 1.00 mg/kg.  
Additional Safety Information: 
Preliminary safety data were available for 488 subjects who received at least 1 dose of ABT-414 in 4 
open-label studies at the most recent IB update (version 7.0). This Phase 2 Study M14-483 (INTELLANCE-
2) in recurrent GBM is the only trial for which safety data from a control arm (TMZ or lomustine 
monotherapy) is available. Adverse events reported for more than 20% of subjects receiving ABT-414 


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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 ABT-414 (77.3%) 
experienced at least 1 Treatment Emergent Adverse Event coded to the Standard Organ Class of Eye 
Disorders. In addition to ocular side effects related to corneal epitheliopathy, treatment-emergent 
adverse events reported by ш 10% of subjects in the ABT-414 treatment groups and ш 5% more frequently 
than the lomustine/TMZ control group included headache, fatigue, constipation, and liver transaminase 
elevations (alanine aminotransferase and aspartate aminotransferase). The rate of constipation was 
mainly accounted for by the ABT-414/TMZ combination arm, for which the rate was similar to that of 
subjects receiving TMZ monotherapy. 
In an ongoing blinded study in newly diagnosed GBM (M13-813 (RTOG 3508)), one subject receiving ABT-
414 (unblinded) with radiation and TMZ in the chemoradiation phase and with TMZ in the adjuvant phase 
experienced Grade 5 (fatal) events of acute liver injury and cerebral edema after approximately 5 months 
of treatment. The subject had grade 4 GGT (>33x ULN) and grade 1 fatty liver at Screening. The 
investigator considered the event of fatal acute liver injury to be reasonably possibly related to ABT-414. 
The sponsor also assessed that there was a reasonable possibility that ABT-414 caused or contributed to 
the liver injury and subsequent death. The above-described case is the only event of fatal liver injury that 
has been reported in ABT-414 open-label or blinded studies, in which approximately 809 people have 
received ABT-414 to date.  
Taken together, the efficacy and safety data available to date demonstrate an acceptable benefit/risk 
profile of ABT-414 in patients with EGFR-amplified GBM and support continued clinical research of this 
investigational agent in the current trial. 
1.8
Potential combination effect of ABT-414 with temozolomide and 
the choice for the control arm 
In a U87 model expressing EGFRvIII, the activity of RT/TMZ was significantly increased when ABT-414 was 
co-administered, whereas ABT-414 plus TMZ was more effective compared to ABT-414 with RT. The 
responses observed in the ongoing phase I study were on patients receiving both TMZ and ABT-414. This 
leaves the possibility open that TMZ may add to the activity of ABT-414. In case of favorable results in the 
combination arm ABT-414/TMZ it will be possible that this is in part caused by activity of TMZ. This brings 
the need to design phase II studies in a way this can be addressed. It is however not justifiable to have a 
control arm with TMZ in a phase II study on recurrent glioblastoma, as many glioblastoma patients are 
relapsing during or shortly after TMZ chemotherapy. In these patients, retreatment with temozolomide is 
not rational, and another comparator is needed. Still, having TMZ treated patients in the control arm will 
allow some further analysis of a potential TMZ contribution to the outcome. As illustrated above, for 
selected glioblastoma patients (in particular those relapsing more than three months after the end of 
adjuvant TMZ adjuvant chemotherapy) TMZ re-treatment is an option. Therefore, the treatment in the 
control arm will depend on the timing of relapse in relation to the end of adjuvant TMZ treatment (as 
part of the initial treatment with chemo-irradiation). Thus, this study will be developed as a three-arm 
study with the control arm being treated by either lomustine or TMZ depending on the timing of the 
relapse: (A) patients relapsing within 3 months from the end of adjuvant TMZ cycles (16 weeks from the 
first day of the last TMZ cycle) will receive lomustine; (B) patients relapsing three months or more after 
the end of TMZ chemotherapy (16 weeks from the first day of the last TMZ cycle) will receive TMZ 
standard dosing day 1-5 every 4 weeks.  


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1.9
Evaluation of ABT-414 in Children with High Grade Gliomas 
Appendix I provides information related to the evaluation of ABT-414 in children (M14-483 pediatric sub-
study). Unless specifically addressed in Appendix I, all of the adult protocol elements will apply to the 
pediatric population. 
Background: Pediatric high grade gliomas [HGG] (WHO grade III and IV glioma and diffuse intrinsic 
pontine glioma [DIPG]) have no adequate therapy and are almost universally fatal. Unlike in adult GBM, 
EGFR amplification is rare (3% or lower) in pediatric HGG and screening for EGFR amplification is not 
routinely part of standard care for pediatric tumors, which makes it profoundly difficult to identify 
children with EGFR amplified HGG. Consequently, it is not feasible to conduct a stand-alone study in this 
population. It is most important that a pediatric study in EGFR-amplified HGG addresses whether a 
proposed dose of ABT-414 can be used safely in the pediatric population, with recognition that 
assessment of efficacy beyond a description of outcomes in a very small number of subjects is likely 
infeasible.  
2
Objectives of the trial 
2.1
General objectives 
The objectives of the trial are to assess whether ABT-414 alone or in combination with TMZ improves 
overall survival (OS), PFS, tumor response, quality of life, NDFS and steroid use compared to standard 
treatment with lomustine single agent or TMZ re-challenge in patients with centrally confirmed recurrent 
EGFR-amplified glioblastoma. 
Additional exploratory objectives include analyses by stratum of EGFR pathway abnormalities (specifically 
EGFRvIII mutation), correlation of MGMT methylation status with clinical outcome (PFS/OS), and 
exploratory clinical and translational research program.  
The objectives will be achieved within a testing strategy, which aims to preserve the global type I error. 
The objectives will be realized according to the following hierarchical sequence: OS, PFS, response, OS in 
EGFRVIII mutated. Secondary objectives not included in the testing sequence will be realized for 
exploratory purpose. 
2.2
End-points 
2.2.1
Primary endpoint  
The primary endpoint will be OS at final analysis and Progression Free Survival (PFS) according to RANO 
criteria and assessed by IRC at the interim analysis. 
2.2.2
Secondary endpoints 
Secondary endpoints will be: 
x
PFS according to RANO criteria and assessed by IRC  
x
Objective response rate (ORR) assessed by IRC 
x
OS in the subgroup with EGFRvIII mutation 
The following are exploratory endpoints: 
x
Best overall response rate (BOR), complete response rate (CRR), duration of response (DR) assessed 
by IRC will be computed in each arm  
x
PFS in the subgroup with EGFRvIII mutation 
x
Neurological deterioration-free survival (NDFS)  


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x
Steroid use  
x
Frequencies and percentages of worst Adverse Events (AEs) or Laboratory Event grades 
x
Quality of life 
3
Patient selection criteria 
Patients with histologically confirmed de novo (primary) glioblastoma may register and have their tumor 
tissue screened after diagnose and before tumor progression. Eligibility at the time of tumor progression 
will depend on the confirmation of EGFR amplification during the screening, the fulfillment of all other 
patient selection criteria and the trial status (whether the study is still open for accrual). 
For patients < 18 years old, please refer to the inclusion criteria listed in Appendix I 
3.1
Registration 
x
Histologically confirmed de novo (primary) glioblastoma before or at the time of first progression 
after RT concurrent/adjuvant TMZ chemotherapy.  
x
In case of testing at the time of first progression: either at least 3 months after the end of 
radiotherapy or have tumor progression that is clearly outside the radiation field or have tumor 
progression unequivocally proven by surgery/biopsy 
x
ŐĞшϭϴǇĞĂƌƐ 
x
Absence of any psychological, familial, sociological or geographical factors potentially hampering 
compliance with the study protocol and follow-up schedule; such conditions should be assessed with 
the patient before registration in the trial.  
x
Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE] tumor) for 
central testing of EGFR amplification 
x
Written informed consent for central EGFR screening must be given according to ICH/GCP, and 
national/local regulations.  
3.2
Randomization 
The following criteria should be assessed within 2 weeks prior to randomization. 
x
Histologically confirmed de novo (primary) glioblastoma with unequivocal first progression after RT 
concurrent/adjuvant TMZ chemotherapy either at least 3 months after the end of radiotherapy or 
have tumor progression that is clearly outside the radiation field or have tumor progression 
unequivocally proven by surgery/biopsy 
x
Presence of EGFR amplification confirmed by central assessment; patients with undetermined EGFR 
status are excluded 
x
WHO Performance status 0 - 2 (see Appendix C) 
x
No prior treatment with nitrosoureas 
x
No prior treatment with bevacizumab 
x
No previous exposure to EGFR targeted agents, including EGFRvIII targeting agents and participation 
to placebo controlled trials on EGFR targeted agents 
x
No prior discontinuation of temozolomide chemotherapy for toxicity reasons 
x
No more than one line of chemotherapy for GBM (concurrent and adjuvant TMZ based chemotherapy 
including in combination with another investigational agent is considered one line of chemotherapy). 
Chemotherapy must have been completed at least 4 weeks prior to randomization. 
x
No prior RT with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the 
recurrence is histologically proven 


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x
No previous other malignancies, except for any previous malignancy which was treated with curative 
intent more than 5 years prior to randomization, and except for adequately controlled limited basal 
cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix 
x
Absence of known hypersensitivity 
x
to any part of the ABT-414 compound, TMZ, dacarbazine or lomustine formulations 
x
to any IgG containing agent  
x
No history of Coeliac disease and wheat allergy 
x
Patient may have been operated for recurrence. If operated: 
x
residual and measurable disease after surgery is not required but surgery must have confirmed 
the recurrence 
x
a post-surgery MRI must be available within 48 hours following surgery, however an MRI scan has 
to be done within 2 weeks prior to randomization 
x
surgery completed at least 2 weeks before randomization and patients should have fully 
recovered as assessed by investigators. Criteria for full recovery will include absence of active 
post-operative infection, recovery from medical complications and capacity for fluid and food 
intake.  
x
For non-operated patients, recurrent disease must include at least one bi-dimensionally measurable 
contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 
mm, visible on 2 or more axial slices 5 mm apart, based on an MRI scan done within 2 weeks prior to 
randomization 
x
Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan 
x
No current or recent (within 4 weeks before randomization) treatment with another investigational 
drug 
x
Patients who require anti-convulsant therapy must be taking non-enzyme inducing antiepileptic drugs 
(non-EIAED). Patients previously on EIAED must be fully switched to non-EIAED at least 2 weeks prior 
to randomization 
x
No underlying or previous conditions that could interfere with treatment, including but not limited to: 
x
no evidence of active infection requiring hospitalization or antibiotics, within 2 weeks prior to 
randomization 
x
no active infectious keratitis 
x
no other diseases interfering with follow up 
x
No planned vaccinations with live vaccines 
x
Adequate hematological function defined as͗ŶĞƵƚƌŽƉŚŝůƐшϭ͘ϱ × 109 cells/L and ƉůĂƚĞůĞƚƐш 100 × 
109 cells/L and hemoglobin ш 6.2 mmol/L (9.9 g/dl) 
x
Normal liver function: bilirubin < 1.5× upper limit of the normal range (ULN), alkaline phosphatase 
and transaminases (ASAT) < 2.5× ULN 
x
Renal function: calculated creatinine ĐůĞĂƌĂŶĐĞшϯϬŵ>ͬŵŝŶďǇ the Cockcroft-Gault formula (see 
Appendix E) 
x
Absence of pregnancy. Women of childbearing potential (WOCBP) must be using an adequate 
method of contraception to avoid pregnancy throughout the study and for 6 months beyond the end 
of treatment in such a manner that the risk of pregnancy is minimized. In general, the decision for 
appropriate methods to prevent pregnancy should be determined by discussions between the 
investigator and the study subject. WOCBP include any female who has experienced menarche and 


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who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Females should not be breastfeeding. 
x
Post menopause is defined as: aŵĞŶŽƌƌŚĞĂшϭϮĐŽŶƐĞĐƵƚŝǀĞŵŽŶƚŚƐǁŝƚŚŽƵƚĂnother cause or for 
women with irregular menstrual periods and on hormone replacement therapy (HRT), a 
documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL 
x
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin 
patches, or implanted or injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicide) to prevent pregnancy, or are 
practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to 
be of childbearing potential. 
x
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or  equivalent units of HCG) within 72 hours prior to randomization. 
x
Female patients within one year of entering the menopause must agree to use an effective non-
hormonal method of contraception during the treatment period and for at least 6 months after 
the last study treatment.  
x
Males must agree to use an effective method of contraception during the treatment period and for at 
least 6 months after the last study treatment.  
x
Before patient randomization and study related procedures (that would not have been performed as 
part as standard care), written informed consent must be given according to ICH/GCP, and 
national/local regulations. 
x
Patients with a buffer range from the normal values of +/- 5 % for hematology and +/- 10% for 
biochemistry are acceptable. A maximum of +/- 2 days for timelines are acceptable (with the 
exception of the pregnancy test). 
Important note: All eligibility criteria must be adhered to, in case of deviation discussion with 
Headquarters and study coordinator is mandatory. 
4
Study Procedures 
This is a randomized open label multicenter phase II trial (see objectives in chapter 2). 
For detailed statistical considerations, see chapter 8. 
Patients will be randomized at the EORTC headquarters after verification of the eligibility criteria (see 
chapter3) to receive one of the following: 
Arm 1: patients will be treated with ABT-414 1.0 mg/kg IV infusion over 30 to 40 minutes once every 2 
weeks in combination with TMZ 150 mg/m2 day 1 to 5, for the first 28-day cycle, with dose escalation to 
200 mg/m2 in subsequent cycles in case of adequate tolerance and until one of the treatment withdrawal 
criteria has been met. In this Arm 1 the schedule of clinical and lab assessments follows the cycle of TMZ 
(a delay of TMZ delays the assessment schedule, withholding ABT-414 does not affect the assessment 
schedule). 
Arm 2: patients will be treated with ABT-414 monotherapy 1.0 mg/kg IV infusion over 30 to 40 minutes 
once every 2 weeks until one of the treatment withdrawal criteria has been met. 
Arm 3: Patients in the control arm will be treated according to the timing of relapse.  
Arm 3A: Patients relapsing during TMZ treatment or within the first 16 weeks after the first day of the 
last TMZ cycle will be treated with lomustine 110 mg/m2 on day 1 of every 42-day treatment period. 


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Treatment will continue until one of the treatment withdrawal criteria has been met. Lomustine will be 
given for a maximum of one year. 
Arm 3B: Patients relapsing 16 weeks or more after the first day of the last TMZ cycle will be treated with 
TMZ 150 mg/m2 on day 1 to 5 for the first 28-day cycle, with dose escalation to 200 mg/m2 in subsequent 
cycles in case of adequate tolerance. Treatment will continue until one of the treatment withdrawal 
criteria has been met. 
Treatment should start within 96 hours from randomization. 
Treatment at further progression will be according to investigators discretion. Day 1 of the first cycle will 
be the first day when the study medication is taken.  
There will be an interim futility analysis organized. At interim analysis one or both of the ABT-414 arms 
might be discontinued based on lack of efficacy for PFS (Reject H1 in favor of H0) according to RANO 
criteria assessed by IRC (see section 8.3).  
Disease will be assessed by study-specific MRI according to the study specific imaging protocol every 8 
weeks. Response and progression will be assessed by the RANO criteria (see section 7.1). 
The safety profile will be assessed separately for each cycle of therapy with CTCAE v4 (see section 7.2). 




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5
Therapeutic regimens, expected toxicity, dose 
modifications 
5.1
General information 
5.1.1
ABT-414 
Guidelines for ABT-414 dose preparation, volume, and rate of infusion will be supplied by AbbVie to the 
site staff, within the study manual.  
5.1.1.1
Drug supplies 
Drug supplies and re-supplies will be provided free of charge by AbbVie as long as patients are on 
protocol treatment (for procedures: see study manual that will be provided at the time of activation). 
The investigator should ensure that the investigational product is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by AbbVie. If concerns 
regarding the quality or appearance of the investigational product arise, do not dispense the 
investigational product and contact AbbVie immediately. Pharmacy and clinic personnel should wear 
disposable chemotherapy gloves. Pregnant personnel should avoid exposure to the medication. 
5.1.1.2
Packaging, dispensing and storage 
Medication labels will comply with the legal requirements as applicable and will be printed in the local 
language. The storage conditions for study drug will be described on the medication label. 
5.1.1.3
Drug reconciliation procedures 
Accountability of the investigational study drug(s) is under the responsibility of the investigator and can 
be delegated to an appropriately qualified person. 
The Investigator or representative will verify that study drug supplies are received intact, at the 
appropriate temperature and in the correct amounts. This will be documented by signing and dating the 
Proof of Receipt or similar document or via direct recording in the Interactive response technology (IRT) 
An overall accountability of the study drug will be performed and verified by the AbbVie monitor 
throughout the study and at the study site closeout visit. An accurate running inventory of study drug will 
be maintained utilizing the IRT drug accountability module and, if required, according to your institutional 
policy, which should include the lot number, POR number(s), the bottle/kit numbers, and the date study 
drug was dispensed for each subject.  
In the event that the IRT is not operable, the above information will be documented on forms provided 
by the Sponsor.  
After verification of drug accountability, used/empty vials may be destroyed at the site according to local 
regulations governing biohazardous waste. Destruction of used study supplies must be documented. All 
unused study drug unit doses must be inventoried, accounted for, and returned to AbbVie or destroyed 
per instructions from AbbVie and according to local regulations. A copy of the Return Shipment Form, in 
accordance with instructions provided by the AbbVie monitor, will also be included in the shipment. 
Labels must remain attached to the containers. If pre-arranged between AbbVie and the site, destruction 
of the study drug may be performed at the site. 
In addition to internal accountability documentation on site, EORTC/AbbVie study-specific accountability 
and drug destruction forms will be supplied for this purpose, if site-specific forms are deemed not 


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sufficiently detailed or do not provide enough information, according to EORTC Quality Assurance 
criteria. 
The medication provided for this trial is to be used only as indicated in this protocol and only for the 
patients entered in this study. 
5.1.2
Lomustine 
Lomustine is considered as a standard treatment in many countries for this indication and commercial 
sources will be used. The exception will be in countries where Lomustine is not available commercially or 
in countries which mandate sponsor to supply drugs within the context of clinical trials. For those 
countries, AbbVie may provide or reimburse for Lomustine to participating sites as required based upon 
availability or local regulations. 
5.1.3
Temozolomide (TMZ) 
TMZ is considered as a standard treatment for this indication and commercial sources will be used, 
except in countries which mandate Temozolomide be supplied by the sponsor in the context of clinical 
trials. For those countries, AbbVie may provide or reimburse for TMZ to participating sites as required 
based upon availability or local regulations. 
5.2
Initial dose and administration 
5.2.1
ABT-414 
ABT-414 will be given at dose level of 1.0 mg/kg by IV infusion over 30 to 40 minutes once every 2 weeks. 
The dose of ABT-414 does not have to be adjusted unless there has been at least a 10% change in body 
weight; recalculation of ABT-414 dose for < 10% weight changes is allowed at the discretion of the 
Investigator. Each configuration of ABT-414 drug product (Type A and/or Type L) that a subject receives 
during the study will be recorded. 
Subjects will be closely monitored for treatment-related adverse events, especially allergic reactions, 
during the infusion. For the initial ABT-414 infusion, pre-infusion vital signs should be taken, direct 
observation is required for the first 15 minutes of the infusion, and subjects should be monitored for 1 
hour post-infusion. For subsequent infusions, direct observation and monitoring post-infusion are not 
required; however, pre-infusion vital signs should still be taken. 
Due to the risk of eye toxicity, each administration of ABT-414 should be given with steroid ophthalmic 
solution. The recommended type, dose, and schedule of eye drops is as follows: dexamethasone 0.1% 
solution (or equivalent corticosteroid solution), 2 drops (GTTS) in each eye (OU) every 8 hours to start 48 
hours prior to ABT-414 dosing and continue for a total of 7 days (or 21 doses total). The type of 
ophthalmic solution used may vary depending on the availability of the solution at each location. A 
modification to the eye drop dosing or schedule based on ongoing clinical experience may be suggested. 
Allergic reactions of any grade require interruption of ABT-414 treatment and management as described 
in section 5.5.1.1.  
Subjects will not be treated at doses less than 0.5 mg/kg. If a subject requires a dose modification below 
0.5 mg/kg, the subject will be discontinued from the study treatment. 
 
 


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5.2.2
Lomustine 
Arm 3A: Patients relapsing during TMZ treatment or within the first 16 weeks after the first day of the 
last TMZ cycle will be treated with lomustine 110 mg/m2 on day 1 of every 42-day treatment period. 
However, similar to subjects who are randomized to ABT-414 plus TMZ (Arm 1), ABT-414 (Arm 2) or TMZ 
control (Arm 3B), scans (MRI) should be performed as per the schedule outlined for all other arms (see 
section 6.3.5). Treatment will continue until one of the treatment withdrawal criteria has been met. 
Lomustine will be given for a maximum of one year. 
The doses may be rounded to the nearest 40 mg to accommodate tablet strengths. The dose of 
lomustine does not have to be adjusted unless there has been at least a 10% change in body weight; 
recalculation of lomustine dose for < 10% weight changes is allowed at the discretion of the Investigator. 
5.2.3
Temozolomide 
Arm 1: patients will be treated with ABT-414 1.0 mg/kg IV infusion over 30 to 40 minutes once every 2 
weeks in combination with TMZ 150 mg/m2 day 1 to 5, for the first 28-day cycle, with dose escalation to 
200 mg/m2 in subsequent cycles in case of adequate tolerance (CTCAE v.4 toxicity grade less than 2) and 
until one of the treatment withdrawal criteria has been met.  
Arm 3B: Patients relapsing 16 weeks or more after the first day of the last TMZ cycle will be treated with 
TMZ 150 mg/m2 on day 1 to 5 for the first 28-day cycle, with dose escalation to 200 mg/m2 in subsequent 
cycles in case of adequate tolerance (CTCAE v.4 toxicity grade less than 2). Treatment will continue until 
one of the treatment withdrawal criteria has been met. 
The dose of TMZ does not have to be adjusted unless there has been at least a 10% change in body 
weight; recalculation of TMZ dose for < 10% weight changes is allowed at the discretion of the 
Investigator. 
5.3
Treatment duration  
Treatment will be administered until one of the withdrawal criteria (section 5.4) has been met. Lomustine 
will be given for a maximum of one year. Administration of TMZ with ABT-414 will continue if tolerated, 
and patients receiving treatment for more than 12 months will be evaluated and assess the risk of 
prolonged treatment. 
5.4
Withdrawal criteria 
Whatever the disease status, study treatment will be discontinued in case of: 
i disease progression 
i patient refusal 
i intolerable toxicity precluding further protocol therapy 
i patient's best interest 
i start of any other anti-cancer agent/modality (surgery at recurrence is allowed) 
i pregnancy 
Patients discontinuing therapy in the absence of progression should not receive other cancer treatment 
before their disease progresses, unless this is clearly not in the interest of the patient. If, after treatment 
discontinuation, there is additional clinical information leading the investigator to conclude that the 
reason for discontinuation is no longer valid (except for toxicity), 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. In case of toxicity in the combination arm that is 


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clearly attributable to either TMZ or ABT-414, that drug can be discontinued and the other can be 
continued. Patients that discontinue study treatment for toxicity, patient refusal and other reasons 
remain 'on study' and must be followed according to the follow-up schedule for progression, survival etc 
unless patient specifically withdraws consent from all further data collection for the study (this decision 
should be clearly documented e.g in the medical notes). 
5.5
Dose and schedule modifications 
In the combination arm, dose reductions or delays should be made for the likely causative agent. If in the 
combination arm one of the agents should be stopped for any reason other than PD, the patient can 
continue on the other single agent alone.  
5.5.1
ABT-414 
ABT-414 will be given by IV infusion over 30 to 40 minutes, on Days 1 (±2 days) and 15 (±2 days) of every 
28-day cycle. Information about the ABT-414 formulation to be used in this study are presented below: 
 
ABT-414a 
Dosage Form 
Lyophilized powder for reconstitution and 
intravenous admixture 
Formulation 
Vial 
Strength (mg) 
20 or 100 
a. 
Information applicable to both ABT-414 and ABT-414 manufactured under two separate 
manufacturing processes (A and L). 
Based upon results from the first clinical and preclinical safety pharmacology evaluation of ABT-414, 
experience with other inhibitors of EGFR, and experience with MMAF ADCs, potential toxicities may 
include fatigue, vomiting, thrombocytopenia, allergic reactions, rash, eye complaints, and liver function 
test abnormalities. 
For all observed toxicities, except those listed below, subjects should be assessed for inter-current illness 
or other causes and treated as appropriate. For severe toxicities (Grade 3 or higher), dosing should be 
withheld until toxicity resolves to Grade 1 or less (unless otherwise indicated). Dose reduction of ABT-414 
for Grade 3 toxicity will be at the discretion of the investigator and the study team. Re-initiation of 
ABT-414 may be considered at a reduced dose (to 1.0 mg/kg, 0.75 mg/kg, or 0.5 mg/kg) for grade 4 
toxicities provided full recovery to grade 1 or less has occurred (unless otherwise indicated).  
All dose reductions are permanent, except as listed below (hepatic laboratory abnormalities, 
section 5.5.1.4). 
 
 


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ABT-414 Dose Modification Table 
Toxicity 
Starting Dose 
First Occurrence 
Second 
Occurrence 
Third 
Occurrence 
Grade 1 or 2 
1.0 mg/kg 
No requirement 
for dose 
reduction 
No requirement 
for dose 
reduction 
No 
requirement 
for ABT-414 
discontinuation 
Grade 3 
1.0 mg/kg 
Can continue at 
1.0 mg/kg or 
reduce to 0.75 
mg/kg once the 
toxicity has 
resolved to grade 
1 or baseline 
Can continue at 
0.75 mg/kg or 
reduce to 0.5 
mg/kg once the 
toxicity has 
resolved to 
grade 1 or 
baseline 
Can continue 
at 0.5 mg/kg 
once the 
toxicity has 
resolved to 
grade 1 or 
baseline or 
permanently 
stop ABT-414 
Grade 4 
1.0 mg/kg 
Reinitiate 
treatment at 
0.75 mg/kg once 
the toxicity has 
resolved to grade 
1 or baseline 
Reinitiate 
treatment at 
0.5 mg/kg, once 
the toxicity has 
resolved to 
grade 1 or 
baseline 
Permanently 
stop ABT-414 
 
More aggressive dose reductions are always allowed if the investigator believes that it is in the best 
interests of the subject. While investigator discretion should be used for subject management with 
regards to toxicities, some suggested guidelines are included in the following sections.  
5.5.1.1
Allergic reactions 
Subjects will be closely monitored for treatment-related adverse events, especially allergic reactions 
during all infusions. For the initial ABT-414 infusion, pre infusion vital signs should be taken and direct 
observation is required for the first 15 minutes of the infusion. Also for the initial ABT-414 infusion, 
subjects must remain at the site for monitoring for 60 minutes post infusion. For subsequent infusions, 
post-infusion monitoring is not required; however, pre-infusion vital signs should still be taken. Longer 
observation periods and more frequent vital sign checks may be required in subjects who experience 
infusion reactions. 
Institutional standards should be used to treat all allergic reactions. 
5.5.1.1.1
Severe allergic reactions (grade 3 or grade 4) 
These require the immediate interruption of ABT-414 treatment and discontinuation from the study. 
Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions. Subjects 
should be carefully observed until the complete resolution of all signs and symptoms. 
 
 


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5.5.1.1.2
Moderate allergic reactions (grade 1 or grade 2) 
These will also require the immediate interruption of ABT-414 treatment. 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. 
5.5.1.2
Dermatologic toxicities 
Subjects developing dermatologic toxicities while receiving ABT-414 should be monitored for the 
development of inflammatory or infectious sequelae, and appropriate treatment of these symptoms 
initiated. In subjects with mild and moderate (grade 1 or grade 2) skin toxicity, treatment should continue 
without dose delay or modification. Treatment with topical and/or oral antibiotics should be considered. 
If a subject experiences severe (grade 3 or grade 4) acneiform rash, ABT-414 treatment adjustments 
should be made based on a discussion between the investigator, the AbbVie medical monitor and the 
EORTC HQ team. 
Subjects who experience a grade 3 or higher dermatological toxicity will be treated as following: The 
subject will require a dose interruption and ABT-414 may be reintroduced at a reduced dose (per the 
ŐƵŝĚĂŶĐĞƉƌĞǀŝŽƵƐůǇƐƚĂƚĞĚĂďŽǀĞͿŝĨƚŚĞƚŽǆŝĐŝƚǇƌĞƚƵƌŶƐƚŽч grade 1 within 4 weeks. 
5.5.1.3
Ophthalmologic toxicities 
All subjects should receive prophylactic administration of steroid ophthalmic solution for each 
administration of ABT-414. The recommended type, dose, and schedule of eye drops is as follows: 
dexamethasone 0.1% solution, 2 drops (GTTS) in each eye (OU) every 8 (q8) hours to start 48 hours prior 
to ABT-414 dosing and continue for a total of 7 days (or 21 doses total). Subjects developing 
ophthalmologic toxicities despite the use of prophylactic steroids must have an examination by an 
ophthalmologist, including a thorough slit-lamp exam, to evaluate for the presence of epithelial 
microcysts. If ocular toxicity is grade 1 or 2, subjects may continue on ABT-414 without dose delay, 
reduction or suspension, but they must receive treatment from an ophthalmologist and will need to have 
repeated eye examinations. For grade 3 or 4 toxicity, ABT-414 must be suspended until resolution of 
ocular symptoms to grade 1. Afterward, patient may re-initiate treatment at a lower dose upon 
discussion with the medical monitor. No dose modification below a total dose of 0.5 mg/kg is allowed. 
Re-treatment at a lower dose of ABT-414 has generally resulted in no reported eye event or less severe 
toxicities. 
5.5.1.3.1
Prophylaxis 
In efforts to prevent the formation of some of these microcysts, dexamethasone and other steroids may 
be used to slow down the turn-over of the transient amplifying cells, thereby protecting them from the 
damage caused by a toxin that targets cells in rapid division. Although early use has shown that steroid 
eye drops may help reduce the severity of symptoms by preventing the formation of microcysts, they 
generally do not get rid of them completely. Given that the steroid eye drops are to be used to protect 
the transient amplifying cells during exposure to MMAF, the best time to administer them is around the 
time of infusion when the levels of MMAF are at their peak. The prolonged use of steroid eye drops 
outside of the time when there is MMAF exposure is not recommended as they may cause other side 
effects and prevent the healing process.  
Intra-ocular pressure (IOP) should be monitored as appropriate during ophthalmologic examination. If 
increase in IOP occurs, it should be controlled with IOP-lowering medication according to the investigator 
discretion. 


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5.5.1.3.2
Treatment once symptoms occur 
Once corneal microcysts have formed, there are no known therapies that can remove them from the 
cornea. Thus, only therapies that can control symptoms and promote healing are indicated. Thus, steroid 
eye drops may not be the best strategy as they may inhibit the healing process. Rather, lubricating drops 
and gels, corneal bandages, and antibiotic drops (if an infectious process is evident) are the best strategy 
for the promotion of healing and control of symptoms. Frequent monitoring by an ophthalmologist is also 
recommended at this time to make sure that the appropriate bandaging and antibiotics are prescribed 
for the promotion of healing and adequate alleviation of symptoms. 
5.5.1.3.3
Discussions with patients  
It is important that patients understand this toxicity and the importance of following the 
recommendations for the eye drops as well as the rapid reporting of their symptoms. It is also important 
to let them know that at this time, in all of the patients, symptoms have improved over time and there is 
no evidence to suggest that there is any permanent damage done to the cornea. It does take some time, 
however, for symptoms to resolve and thus an immediate reversible of symptoms should not be 
promised. At least 3-4 weeks must take place for the regeneration of the cornea; this is an approximate 
timeline for when symptoms should improve and corneal healing should take place. 
5.5.1.3.4
Ophthalmological photography 
Sites that agree will be asked to provide ophthalmologic photography (e.g slit lamp, confocal microscopy, 
Heidelberg Retinal Tomography [HRT3] etc.) of corneal abnormalities. 
Patients treated with ABT-414 and experiencing ocular side effects may be presented with an approved 
optional consent form asking them for the release of these photographs of their eyes. If patients agree 
and sign and date the form, copies of new or already taken photographs will be sent to AbbVie. Included 
are the trial number, patient number and the date the photograph was taken (either written on the 
photograph or within the file name) and the date of patient consent confirmed by the (sub)-investigator 
or delegate. Consent forms and photographs should be filed in patient notes and site file. No other 
patient identifiers should be present on the data provided to AbbVie. Photographs collected during 
scheduled visits should be of the eye or part of the eye only and not including the full face, nose, ear, or 
mouth. If two eyes are affected these should be submitted as two separate photographs. 
 
 


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5.5.1.4
Hepatic Laboratory Abnormalities (ABT-414) 
ABT-414 Dose Modification Guidelines for Hepatic Laboratory Abnormalities: 
Hepatic Laboratory Abnormality 
ABT-414 
ALT or AST >5x ULN* but чϮϬǆh>E
;ĂŶĚd>чϮǆh>EͿ 
ALT or AST > 20x ULN  
 
or  
 
ALT or AST >3x ULN and TBL >2x ULN  
* If elevated at baseline, either 5x the baseline value or 8x ULN, whichever is lower  
For guidelines for pediatric patients, see Appendix I. 


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5.5.2
Lomustine 
Patients requiring more than two consecutive lomustine dose reduction (i.e. only two dose reductions 
are allowed based on product labeling) will discontinue lomustine treatment. Study efficacy evaluations 
will not be modified because of dose delays. Dose modifications are based on toxicity during the prior 
treatment cycle. If multiple toxicities are seen, the dose administered should be based on the dose 
reduction required for the most severe grade of any single toxicity. 
5.5.2.1
Dose levels of lomustine 
The lomustine dose will be rounded to the closest multiple available; the dosage is calculated based on 
BSA but a maximum dose (cap) is used. Two dose levels of lomustine will be used. 
Dose 
Dose mg/m² q6 weeks 
0 
110 mg/m2 (cap 200 mg) 
-1 
90 mg/m2 (cap 160 mg) 
-2 
70 mg/m2 (cap 120 mg) 
5.5.2.1.1
Hematological toxicity 
In general, the nadirs for hematological toxicity with lomustine are expected between days 28 and 35. In 
case of hematological toxicity grade 3 or 4 (according to CTCAE v. 4.0), the dosage of the next cycle will 
be reduced with one level. If the hematological toxicity does not recover within 4 weeks or if after 
recovery the hematological toxicity recurs at a subsequent cycle to grade шϮ, lomustine treatment 
should be discontinued. No more than two dose reductions are allowed. 
Administration of next cycle: If blood examination on day 42 or 43 (which may have been obtained in the 
prior 48 hours) show recovery of platelets above 100×109 and granulocytes counts above 1.5×109, the 
next dose may be administered on day 43. If this is not possible, hematologic parameters will be 
repeated weekly and the next cycle will be given upon recovery of granulocytes and platelets. If after 4 
weeks the patient has still not recovered, they should discontinue study treatment and stay on study 
until progression.  
5.5.2.1.2
Non hematological toxicity 
x
Liver toxicity grade >2: the dose of the next cycles will be reduced by 1 dose level 
x
In case of pulmonary toxicity grade 1-2, or appearance of symptoms, DLCO will be performed. 
x
/Ĩ>KшϲϬйŽĨƚŚĞƉƌĞĚŝĐƚĞĚǀĂůƵĞ͗ƉĂƚŝĞŶƚǁŝůůƌĞĐĞŝǀĞƚŚĞŶĞǆƚĐǇĐůĞĂƚƚŚĞ same dose 
x
If DLCO < 60% of the predicted value: patient should discontinue study treatment and stay on 
study until progression 
x
In case of pulmonary toxicity grade 3 or higher, patient should discontinue study treatment and stay 
on study until progression 
x
Any grade 4 non hematological toxicity: the patient should discontinue study treatment and stay on 
study until progression 
x
If the non-hematological toxicity does not recover within two weeks or if non hematological toxicity 
recurs at the next cycle to a grade шϮƚŚĞƉĂƚŝĞŶƚƐŚŽƵůĚdiscontinue study treatment and stay on 
study until progression 


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5.5.3
Temozolomide  
The following dose levels of TMZ will be used: 1000 mg/m2 per cycle (5 days 200 mg/m2); 750 mg/m2 per 
cycle (5 days 150 mg/m2); 500 mg/m2 per cycle (5 days 100 mg/m2). 
 
Dose 
Dose mg/m² q4 weeks 
+1 
200 mg/m2 
0 
150 mg/m2  
-1 
100 mg/m2 
 
i The starting dose in cycle 1 is 150 mg/m2 temozolomide on day 1-5, to be taken at least 2 hours after 
a meal, on empty stomach. 
i Patients with no or only grade 1 toxicities in cycle 1 are allowed to dose escalate in any subsequent 
cycles to 200 mg/m2 day 1-5.  
i In case of nadir (usually r day 21) CTCAE hematological toxicity grade 3 or 4, the dosage of the next 
cycles will be reduced by one dose level.  
i In case of CTCAE grade 3 non-hematological toxicity, the dosage of TMZ of the next cycles will be 
reduced by one dose level.  
i In case of CTCAE grade 4 non-hematological toxicity, the patient should discontinue treatment.  
i In case of grade 3 cardiac toxicity, the patient should discontinue treatment. 
i In case of toxicity requiring dose reductions in patients treated at the 100 mg/m2 daily level 
(500 mg/m2 per cycle) the patient goes off treatment. 
i In case of dose reductions, dose re-escalation is not allowed. 
i In case of hepatic laboratory abnormalities, see Appendix L for guidelines on repeat testing and 
evaluation (regardless of the assessed relationship to study treatments). 
 
Nadir granulocytes 
Nadir thrombocytes 
Temozolomide modification 
t 1.0×109 
t 50×109 
Dose unchanged 
< 1.0×109 
<50×109 
Decrease dose by 1 dose level 
 
Administration of next cycle: If blood examination on day 28 or 29 (which may have been obtained in the 
prior 48 hours) show recovery of platelets above 100×109 and granulocytes counts above 1.5×109, the 
next dose may be administered on day 29. If this is not possible, hematologic parameters will be 
repeated weekly and the next cycle will be given upon recovery of granulocytes and platelets. If after 2 
weeks the patient has still not recovered, they should discontinue study treatment and stay on study 
until progression.  
 
 


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5.5.4
Concomitant treatments 
5.5.4.1
Prophylactic treatments 
Anti-emetic prophylaxis should be given to lomustine treated patients on day 1 and to TMZ treated 
patients on day 1-3 or day 1-5 of every treatment cycle per local practice, and thereafter as clinically 
necessary. The use of 5HT-3 antagonists is recommended, and it is recognized they may cause 
constipation. 
Hematopoietic growth factors: The prophylactic use of growth factors is not permitted during the 
screening period as a low hematologic lab value could be masked. Patients may receive red cell 
transfusions or erythropoietin to maintain hemoglobin > 9.9 mg/dL or 6.2 mmol/L. 
5.5.5
Other concomitant medication 
Corticosteroids should be used in the smallest dose possible to control symptoms of cerebral edema and 
mass effect, and should be reduced and/or discontinued if possible.  
No other anticancer agents or investigational drugs are allowed during the study or within 28 days before 
the inclusion into the trial, nor the participation into another study on investigational agents. 
The use of live attenuated vaccines is prohibited during the study and for a period of 49 days after the 
end of ABT-414 administration. 
The uses of concomitant medications that are contraindicated per the national prescribing information 
are prohibited during the conduct of the study 
All concomitant medication will be collected on the CRFs. 
6
Clinical evaluation, laboratory tests and follow-up 
Patients with histologically confirmed glioblastoma may register and have their tumor tissue screened 
after diagnose and before tumor progression. Eligibility at the time of tumor progression will depend on 
the confirmation of EGFR amplification during the screening, the fulfillment of all other in- and exclusion 
criteria and the trial status (whether the study is still open for accrual). 
Tumor tissue for EGFR assessment should be prepared and sent to central lab as described in the study 
specific study manual. 
6.1
Registration 
i Histologically confirmed de novo (primary) glioblastoma before or at the time of first progression 
after RT concurrent/adjuvant TMZ chemotherapy 
x
In case of testing at the time of first progression: either at least 3 months after the end of 
radiotherapy or have tumor progression that is clearly outside the radiation field or have tumor 
progression unequivocally proven by surgery/biopsy 
i Confirmation that biological material (at least from initial diagnosis and if further resection had been 
performed at recurrence) to determine diagnosis is available for central review 
x
Written informed consent for central EGFR screening must be given according to ICH/GCP, and 
national/local regulations 
 
 


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6.2
Before randomization 
All pretreatment evaluations should be performed within 2 weeks before randomization. 
The baseline evaluations include:  
x
Histologically confirmed de novo (primary) glioblastoma with unequivocal first progression after RT 
concurrent/adjuvant TMZ chemotherapy either at least 3 months after the end of radiotherapy or 
have tumor progression that is clearly outside the radiation field or have tumor progression 
unequivocally proven by surgery/biopsy 
x
Informed consent and consent for future studies 
x
Demographics (height, weight, race, ethnicity) 
x
Complete medical history, including documentation of any clinically significant medical condition  
x
Prior anti-cancer therapy (including start and end dates for prior TMZ chemotherapy and RT) 
x
Physical examination including, but not limited to, WHO performance status and neurological 
evaluation 
x
Ocular examination by an ophthalmologist 
x
Vital signs (blood pressure, pulse rate and body temperature)  
x
Quality of life assessment, including EORTC QLQ-C30 and EORTC-BN20 (see section 10.1) 
x
12-lead ECG 
i Concomitant medications 
i Steroid intake 
x
Assessment of all adverse events according to CTCAE 4.0  
x
Hematology (WBC, absolute neutrophil count, lymphocytes, hematocrit, hemoglobin and platelet 
count)  
x
Biochemistry (serum creatinine, total bilirubin, ASAT, ALAT, alkaline phosphatase, phosphate, total 
protein, albumin, sodium, potassium, calcium and chloride) 
x
Serum or urine pregnancy test for WOCBP within 72 hours prior to randomization. 
x
Gadolinium-enhanced MRI of the brain within 2 weeks prior to randomization. For operated patients, 
the post-surgery MRI within 48 hours is mandatory and can be used as baseline. However, if a subject 
is not randomized within 2 weeks from the post-surgery MRI, then a new MRI scan is required and 
will be used as baseline.  
x
Demonstrated EGFR gene amplification by centralized testing using EGFR FISH developed by Abbott 
Molecular.  
x
Although not considered necessary activities prior to randomization, the following samples are 
optional and all subjects randomized may consent to participate in future translational research: 
x
Tumor tissue remaining following EGFR amplification testing for future TR projects (optional 
samples, see section 11.8) 
x
Whole blood for germline DNA and TR projects (optional samples, see section 11.8) 
 
 


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6.3
From treatment start until end of protocol treatment  
6.3.1
Day 1 of each cycle 
All day 1 evaluations should be performed and laboratory results reviewed within 3 days before or at day 
1 of the cycle, and prior to dosing. For day 1 of cycle 1, if the evaluations listed below have been already 
performed during the screening phase and within 2 weeks prior to this day 1, the same results can be 
used for cycle 1 and tests do not need to be repeated. 
x
Physical examination including, but not limited to, WHO performance status and neurological 
evaluation 
x
Ocular examination if clinically indicated (Arms 1 and 2 only) 
x
Hematology and biochemistry (as section 6.2)  
x
Vital signs (as section 6.2) 
x
Weight 
x
12-lead ECG immediately after ABT-414 dosing on day 1 of cycle 1 and cycle 3, for subjects assigned 
to ABT-414 (Arm 1 or 2) 
x
Assessment of all adverse events according to CTCAE 4.0 
x
Concomitant medications, including steroid intake (maximal intake (mg per day)). 
For patients in Arm 3A, lomustine, the above physical examination, hematology, vital signs and adverse 
event assessments need to be repeated at day 28 (+/- 3 days). 
6.3.2
Day 1 and day 5 for cycles 1 and 2; day 1 for cycle 3 and every 2 cycles 
thereafter (day 1 of C5, C7 etc.) 
x
Pharmacogenetic (PG) sample: optional sample collection for all subjects that consent. If the PG 
sample is not collected at the Day 1 visit, it may be collected anytime during the study.  
x
For subjects assigned to ABT-414 (Arm 2) or ABT-414 in combination with TMZ (Arm 1): 
Pharmacokinetic (PK) and pharmacodynamic (PD) sample collection according to the following 
schedule. Refer to the study specific laboratory manual for detailed instructions on sample collection, 
volumes, processing and shipment. 
 
 


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Cycle 1 
Day 1 of 
ABT-414 
 
 
Cycle 1 
Day 5 (Day 
4 up to day 
7 is 
acceptable) 
of ABT-414 
Cycle 2 
Day 1 of 
ABT-414 
 
 
 
Cycle 2 
Day 5 (Day 4 
up to day 7 is 
acceptable) 
of ABT-414 
 
Cycle 3 
Day 1 of 
ABT-414 
 
 
 
Cycle 5, 
Cycle 7 
etc. Every 
two cycles 
starting 
from ABT-
414 cycle 
5 
35 Day 
Safety 
Follow-
up 
 
 
 
PK – ABT-414, 
and Total ABT-
806 Assays 
Xa 
Xe 
Xa 
Xe 
Xa 
Xb 
Xc 
PK - Cys-
mcMMAF 
assay 
Xa 
Xe 
Xa 
Xe 
Xa 
Xb 
 
PK Antidrug 
Antibody 
Assay 
(ADA/nADA) 
Xb 
 
Xb 
 
Xb 
Xb 
Xc 
PD Plasma 
Markers 
Xb 
 
Xb 
 
Xb 
 
 
PD serum 
markers 
Xb 
 
Xb 
 
Xb 
 
 
PG Sample 
(Optional) 
Xd 
 
 
 
 
 
 
 
a. Samples will be collected before infusion (0 hour, pre-dose) and immediately after ABT-414 infusion 
b. Samples will be collected before infusion (0 hour, pre-dose).  
c. Samples will be collected 35 days (within a two-day window) after last ABT-414 infusion for subjects 
able to return to the clinic for the follow-up visit. 
d. If the pharmacogenetic sample is not collect at this visit, it may be collected anytime during the study. 
e. Samples will be collected 96 hrs post ABT-414 infusion, but may be collected from 4 up to 7 days post 
infusion.  
The date/time of collection of each PK/ADA/PD/PG sample will be recorded. The date, start and end time 
of each ABT-414 infusion will be recorded on the appropriate eCRF. 
Dose administration information will be collected for subjects receiving TMZ and lomustine and will be 
recorded on the appropriate eCRF. 
 
 


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6.3.3
Day 14 of each cycle - Arm 1 and 2 patients only 
All day 14 evaluations should be performed and laboratory results reviewed within 3 days before or at 
day of dosing of ABT-414. 
x
Physical examination including, but not limited to, WHO performance status and neurological 
evaluation 
x
Ocular examination if clinically indicated 
x
Vital signs (as section 6.2) 
x
Hematology (as section 6.2)  
x
Assessment of all adverse events according to CTCAE 4.  
6.3.4
Day 21 of each cycle - Arm 1 and 3B patients only 
All day 21 evaluations should be performed within 3 days before or 3 days after day 21 of the cycle. 
x
Hematology (as 6.2 - this can be omitted once treatment at the present dose level was shown to 
cause only grade 1 or less hematological toxicity at day 21 and only grade 2 or less at day 28). 
6.3.5
Day 28 of each cycle - Arm 3A patients only 
All day 28 evaluations should be performed within 3 days before or 3 days after day 28 of the cycle. 
x
Physical examination including, but not limited to, WHO performance status and neurological 
evaluation 
x
Hematology (see section 6.2) 
x
Vital signs (see section 6.2) 
x
Assessment of all adverse events according to CTCAE 4.0 
6.3.6
Every 8 weeks (+/- 7 days) 
x
Gadolinium-enhanced MRI. If PR, CR, an additional scan after 4 weeks should be done to confirm the 
response (as per chapter 4) 
x
Quality of life assessment, including EORTC QLQ-C30 and EORTC-BN20 at week 8 (+/- 7 days) and 16 
(+/- 7 days) only (see section 10.1) 
6.3.7
At end of treatment (35 days after last administration/infusion) 
x
Concomitant medications 
x
Assessment of all adverse events according to CTCAE 4.0 
x
For subjects assigned to ABT-414: Pharmacokinetic sample collection 35 days (± 2 day window) after 
last infusion for subjects able to return to the clinic (see table in section 6.3.2) 
x
Steroid intake 
6.3.8
At end of treatment (49 days after last administration/infusion) 
x
Concomitant medications 
x
Assessment of all adverse events according to CTCAE 4.0 
x
Steroid intake 
6.3.9
At 6 months after randomization (+/- 1 month) 
x
Quality of life assessment, including EORTC QLQ-C30 and EORTC-BN20 (see section 10.1) 
 
 


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6.4
After end of treatment 
Every 12 weeks (+/- 14 days) since last protocol treatment administration until death or loss to follow up: 
x
Survival follow up 
x
Further anti-cancer treatments/modalities 
x
Physical examination including WHO performance status and neurological examination  
x
Ocular examination if clinically indicated 
x
Vital signs if clinically relevant 
x
Steroid intake 
x
Concomitant medication collection if clinically relevant 
x
Assessment of all adverse events according to CTCAE 4.0 (i.e. for events not resolved after the end of 
treatment and new events related to study treatment) 
If a subject is unable to return to the clinic for this visit, survival follow up and other assessments as 
appropriate may be completed via phone. 
6.4.1
From end of study treatment until progressive disease 
Every 8 weeks (+/- 7 days) 
x
Gadolinium-enhanced MRI. If PR, CR, an additional scan after 4 weeks should be done to confirm the 
response (as per chapter 4) 
 
 




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Before 
registration 
Registration 
Baseline 2 wks 
prior to 
randomization 
Randomization 
During protocol 
treatment, each cycle 
 
Every 8 
weeks 
EoT9 
6 months after 
randomization 
Follow-
up 
Day 
10 
Day 14 
Arm 1 
& 2 
Day 21 
Arm 1 
and 3B 
Day 28 
Arm 
3A14 
every 12 
weeks 
Quality of life 
assessment 
 
x 
 
 
 
 
x8 
 
x 
 
ECG 
 
x 
x5 
 
 
 
 
 
 
 
Concomitant 
medication collection 
 
x 
x 
 
 
 
 
x 
 
x10 
Steroid intake 
 
x 
x 
 
 
 
 
x 
 
x 
Prophylactic eye 
drops15 
 
 
x 
x 
 
 
 
 
 
 
Adverse events 
(CTCAE v.4.0) 
 
x 
x 
x 
 
x 
 
x 
 
x11 
Hematology2 
 
x 
x 
x 
x7 
x 
 
 
 
 
Biochemistry3 
 
x 
x 
 
 
 
 
 
 
 
Serum/urine 
pregnancy test 
 
x4 
 
 
 
 
 
 
 
 
Pk samples 
 
 
x6 
 
 
 
 
x9 
 
 
PD samples 
 
 
x12 
 
 
 
 
 
 
 
PG samples (optional) 
 
 
x13 
 
 
 
 
 
 
 
Gd-MRI 
 
x 
 
 
 
 
x 
 
 
 
Survival and further 
anti-cancer 
treatments 
 
 
 
 
 
 
 
 
 
x 
0 
For day 1 of cycle 1, if the evaluations listed here have been already performed during the screening phase and within 2 weeks prior to this day 1, the same results can be 
used for cycle 1 and tests do not need to be repeated: physical examination including, but not limited to, WHO performance status and neurological evaluation; ocular examination if 
clinically indicated; hematology and biochemistry; vital signs; weight. 


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1 
Physical examination including neurological evaluation, and ocular examination at baseline and if clinically indicated 
2 
Including WBC, absolute neutrophil count, lymphocytes, hematocrit, hemoglobin and platelet count 
3 
Including serum creatinine, total bilirubin, ASAT, ALAT, alkaline phosphatase, phosphate, total protein, albumin, sodium, potassium, calcium and chloride 
4 
Pregnancy test must be done within 72 hours prior to randomization 
5 
ECG only day 1 of cycle 1 and 3, immediately after the ABT-414 infusion and only for patient treated with ABT-414 (Arm 1 or 2) 
6 
PK samples to be collected at day 1 of ABT-414 cycles 1, 2, 3 and then every 2 ABT-414 cycles (Day 5 samples will only be collected during cycles 1 and 2) 
7 
Hematology at day 21 can be omitted once treatment at the present dose level caused only grade 1 or less hem. toxicity at day 21 and only grade 2 or less at day 28 
8 
QoL only at week 8 and week 16 while on treatment 
9 
End of Treatment visits 35 days and 49 days after last protocol drug administration. PK samples to be drawn at 35 days after last protocol drug administration only. 
10 
If clinically indicated / if clinically relevant 
11 
Assessment of AEs not resolved after EOT or AEs related to study treatment 
12 
PD samples to be collected at day 1 of cycles 1, 2 and 3 and only for patient in an ABT-414 arm (Arm 1 or 2) 
13 
PG sample optional, to be collected at day 1 of cycle 1or it may be collected anytime during the study 
14 
Repeat physical examination including WHO performance status and neurological evaluation, hematology, vital signs and adverse event assessments at day 28 for patients in 
the lomustine arm (Arm 3A) 
15 
Prophylactic steroid ophthalmic solution prior to each infusion of ABT-414; 2 drops in each eye every 8 hours to start 48 hours prior to ABT-414 dosing and continue for a 
total of 7 days 


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7
Criteria of evaluation 
7.1
Evaluation of activity 
7.1.1
General method of response assessment 
Response to treatment is assessed on the basis of a set of target lesion(s) chosen before the first 
treatment administration (the complete list of target lesions must be reported on the initial 
measurement form before the start of treatment). These lesions must initially be measured in their two 
perpendicular dimensions, and these measurements must be repeated at each evaluation of the disease 
by the same method. Response evaluation is based on neuro-radiological imaging (MRI). For this protocol 
objective response (complete, partial response) and progression will be assessed by MRI (see 
section 7.1.1.4). Objective response will only be assessed in patients not having undergone second 
surgery with complete removal of contrast enhancing lesions prior to study entry. For these patients 
measurable disease is required, which is defined as a clearly enhancing tumor with at two perpendicular 
diameters at entry equal or superior to 1 cm.  
The contrast enhancing area will be considered as the basis for the tumor size assessment. Tumor size is 
defined as the product of the two largest perpendicular diameters. For evaluating partial and complete 
response, the baseline scan must be used for initial comparison. In initially responding ;шϱϬйƌĞĚƵĐƚŝŽŶƐ
in cross-sectional areas) or stabilized (< 50% reduction and < 25% increase in cross-sectional areas) 
patients, new scans must be compared to the nadir, this is the scan showing the maximum response (i.e. 
minimum tumor size) during or after treatment. In assessing response, changes on T2 weighted images 
must be taken into consideration. 
7.1.1.1
Definition of target lesions 
Only the following lesions are eligible as target lesions: 
x
MRI contrast enhancing lesions with two perpendicular diameters of 10 mm or more visible on 2 or 
more axial slices which are 5 mm apart. 
x
Target lesion(s) must be measurable in two perpendicular diameters 
In most patients, only one lesion will be present. In case of multifocal disease, a minimum of 2 lesions 
and maximum of 3 largest enlarging lesions will be chosen as target lesions and the sum of the products 
of the perpendicular diameters will be determined. All other lesions than target lesions, if applicable, are 
assessed according to the same schedule. They are only taken into account in two situations: 
x
if one of them clearly progresses, the overall response to therapy will be evaluated as "progression", 
independent of the response of target lesions 
x
all lesions must have completely disappeared to report a "complete response".  
Adequate investigations must be carried out at each evaluation of the disease to detect eventual new 
lesions. If any new lesion is found, the response will be evaluated as "progression". Regardless of the 
status of enhancing lesions, if progressive lesions are observed on T2 weighted images or FLAIR images, 
the patient will be considered radiologically progressive, but treatment may continue if this is considered 
to be in the best interest of the patient and there are no signs or symptoms of clinical progression.  
By definition, non-target lesions are those that do not meet the criteria for target lesion.  
 
 


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7.1.1.2
Evaluation of patient treated after re-operation 
Postoperative changes on contrast enhanced neuro-imaging may interfere with disease evaluation. 
Within the first three days after surgery on MR imaging a thin linear enhancement may develop around 
the resection cavity, thereafter this enhancement may become thick and nodular. Enhancement of dura 
and meninges may be more pronounced, even within the first days. The postoperative linear 
enhancement may persist for up to 3-6 months, dural and meningeal enhancement may last much 
longer. If MRI made within 48 hours after surgery shows enhancing lesions with a nodular or mass like 
appearance in areas showing tumor on the pre-operative scans this is highly suggestive of residual tumor. 
The use of diffusion-weighted MR imaging in the immediate postoperative MRI may help with the 
identification of ischemic areas around the surgical cavity that may show enhancement with further 
follow-up. 
7.1.1.3
Schedule of disease evaluation 
The initial assessment of disease (including measurement of all target lesions) must be performed in the 
two weeks preceding randomization. Follow-up assessments will be performed every 8 weeks (or earlier 
if clinically indicated) until disease progression. 
7.1.1.4
Definition of response  
For this trial, the primary measure of response and progression will be determined by central review 
according to the RANO criteria. All treatment decisions should be based on the RANO criteria as assessed 
by the local investigator. However, local investigators assessments will be confirmed by central 
radiographic review. The independent central radiologist will give feedback on investigator reads shortly 
after MRI submissions for the first 15 PFS events. In addition, top recruiting sites will receive more 
frequent feedback from the independent central radiologist. Otherwise, local MRIs will be assessed by 
central review in batches.  
Although ORR, PFS endpoints will be mainly based upon central radiographic review, these endpoints 
based on investigator reviews will also be presented for comparisons.  
Target lesions are measured in their two largest perpendicular diameters. Their area is conventionally 
calculated as the product of these diameters. In case of multifocal disease with more than one target 
lesion, the total tumor size is calculated as the sum of the area of all target lesions. 
Response is defined as follows according to the RANO criteria, which also consider T2 weighted and FLAIR 
images: 
x
Complete response (CR) requires all of the following: 1) Complete disappearance of all enhancing 
measurable and non-measurable disease; 2) No new lesions; 3) Stable or improved non-enhancing 
abnormalities on FLAIR/T2 images as compared to baseline; 4) Patients must be off corticosteroids (or 
on physiologic replacement doses only) and stable or improved clinically. 
x
Partial response (PR) requires all of the following: 1) Only reductions of cross-sectional areas of 50% 
or more in the sum of product of perpendicular diameters of target lesions will be considered a 
response; when calculating the response, the baseline MRI must be used for comparison ; 2) No 
progression of non-target lesions; 3) No new lesions; 4) Stable or improved non-enhancing 
abnormalities on FLAIR/T2 images as compared to baseline; 5) Patients should be on a corticosteroid 
dose that should not be greater than the dose at time of baseline scan, and should be stable or 
improved clinically. 
 
 


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x
Progressive disease (PD): 
x
Progression is defined by any of the following: 1) 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable 
or increasing doses of corticosteroids; 2) a significant increase in T2/FLAIR non-enhancing lesions 
on stable or increasing doses of corticosteroids compared with baseline scan or best response 
after initiation of therapy, not due to comorbid events; 3) the appearance of any new lesions; 4) 
clear progression of non-measurable lesions; or 5) definite clinical deterioration not attributable 
to other causes apart from the tumor, or to decrease in corticosteroid dose. Failure to return for 
evaluation as a result of death or deteriorating condition should also be considered as 
progression.  
x
If the evidence of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if PD is confirmed at the next follow-up, the earlier date must be used as the date 
of progression 
x
For patients operated at recurrence and without measurable or non-measurable disease after 
surgery, any new appearance of tumor will qualify for PD. In case non measurable tumor is left 
after surgery i.e. tumor less than 10 mm, unequivocal progression of non-target disease may be 
accepted as evidence of disease progression, where the overall tumor burden has increased 
sufficiently to merit discontinuation of treatment. Modest increase in the size of a non-target 
lesion is not considered unequivocal progression. If the evidence of PD is equivocal (target or non-
target), treatment may continue until the next assessment, but if confirmed, the earlier date must 
be used as the date of progression. This implies that in case of gross total resection of the 
enhancing lesion, if at follow up minimal enhancement of unclear significance arises, treatment 
may continue until further follow-up gives unequivocal evidence of tumor progression. 
x
Stable Disease: This occurs if the patients did not qualify for complete response, partial response, or 
progression (see below) and requires: 1) No meaningful change in the appearance of the FLAIR/T2 
images compared to baseline or to the nadir (point with the smallest FLAIR/T2 abnormalities) if a 
decrease occurred. 2) The patient should be stable clinically. In the event the steroid dosage has been 
increased for new signs and symptoms without confirmation of disease progression on imaging, and 
further follow-up imaging shows that with hindsight this increase in steroids was indeed 
unequivocally needed due to disease progression, the date of progression will be the date steroids 
were increased. 
x
In this protocol, although the primary endpoint is OS, in view of the relevance of objective responses, 
PR, CR, and equivocal PD need to be confirmed with an extra MRI made 4 weeks later.  
 
 


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Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
шϱϬйp 
<50% p but 
<25% n 
шϮϱйn 
T2/FLAIR 
Stable or p 
Stable or p 
Stable or p 
n 
New lesion 
None 
None 
None 
Present 
Corticosteroids 
None 
Stable or p 
Stable or p 
Not 
applicable* 
Clinical status 
Stable or n 
Stable or n 
Stable or n 
p 
Requirements for response 
All 
All 
All 
Any 
*increase in steroids alone does not qualify for PD 
7.1.2
Overall Survival 
Overall Survival (OS) is calculated from the date of randomization up to the date of death (any cause). For 
patients still alive or lost to follow-up at the time of analysis, survival will be censored at last follow-up 
visit date. 
7.1.3
Overall response 
The overall response is evaluated at each assessment of the disease according to RANO criteria.  
7.1.3.1
Best overall response 
Best overall response is the best response designation recorded from the date of randomization until 
disease progression.  
7.1.3.2
Objective response 
Objective response includes best overall responses CR and PR. All responses must be confirmed by repeat 
MRI 4 weeks later. 
7.1.3.3
Response duration 
For responders, duration of objective response (CR/PR) and complete response (CR) will be measured 
similarly to PFS (see section 7.1.4) but starting from the time measurement criteria for CR/PR or CR 
(whichever is recorded first) is met. 
7.1.3.4
Clinical /neurological progression 
Clinical/neurological progression is defined as the presence of the following conditions: 
x
decrease in WHO performance status: 
x
for patients with baseline WHO performance status 0 or 1: deterioration to WHO performance 
status 2 or worse for which no other explanation is present 
x
for patients with baseline WHO performance status 2: deterioration to WHO performance status 
3 or worse for which no other explanation is present 
x
deterioration of neurological functions  
x
appearance of signs/symptoms of increased intracranial pressure (headache, nausea and vomiting 
without other explanations) 


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x
and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological 
signs and symptoms, unless the increase is of short duration to control for transient clinical 
deterioration, lasting one week or less. 
7.1.4
Progression Free Survival 
Progression Free Survival (PFS) will be measured from the date of randomization until the date of first 
objective progression or the date of patient's death whichever occurs first. Patients without evidence of 
progression will be censored at the last date of adequate imaging assessment. A patient receiving a 
second anti-tumoral therapy without prior documentation of disease progression, the patient will not be 
censored at the date of starting new anti-tumoral therapy. 
7.1.5
Neurological deterioration-free survival 
This study will assess neurological deterioration-free survival (NDFS) as a secondary endpoint to correlate 
with MRI and clinical findings. Neurological deterioration (ND) is defined as a decrease in WHO 
performance status:  
x
for patients with baseline WHO performance status 0 or 1: deterioration to WHO performance status 
2 or worse for which no other explanation is present, and which is maintained for at least 3 weeks 
x
for patients with baseline WHO performance status 2: deterioration to WHO performance status 3 or 
worse for which no other explanation is present and which is maintained for at least 3 weeks 
NDFS will be measured from the date of randomization until the date of first neurological deterioration 
or the date of patient's death whichever occurs first, regardless of whether radiological progression has 
occurred or not. Patients without evidence of ND will be censored at the last WHO performance status 
assessment. If a patient received a second anti-tumoral therapy without prior documentation of disease 
progression, the patient will not be censored at the date of starting new anti-tumoral therapy. The 
assessment of neurological deterioration requires continuation of WHO performance status assessment 
after discontinuation of therapy. 
7.2
Evaluation of safety 
Safety information will be collected for all randomized subjects and reported in the safety population 
(see chapter 8).  
7.2.1
Adverse events and side effects 
The Investigator will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study. Any laboratory value outside the reference range that is considered 
clinically significant by the Investigator will be followed as appropriate. Clinically significant laboratory 
values will be recorded as adverse events if they meet the criteria specified below. The Investigator will 
assess and record any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the adverse event 
to study drug, and any action(s) taken. For serious adverse events considered as having "no reasonable 
possibility" of being associated with study drug, the Investigator will provide an Other cause of the event. 
For adverse events to be considered intermittent, the events must be of similar nature and severity. 
Adverse events, whether in response to a query, observed by site personnel, or reported spontaneously 
by the subject will be recorded. 
All adverse events will be followed to a satisfactory conclusion. 


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7.2.1.1
Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements apply in 
addition (see following chapters). 
AE: An Adverse Event (please refer to section 7.2.1.2) 
AR: An Adverse Reaction of an investigational medicinal product is defined as “any noxious and 
unintended response to a medicinal product related to any dose administered”. 
hZ: An hŶĞǆƉĞĐƚĞĚĚǀĞƌƐĞZĞĂĐƚŝŽŶ is “any adverse reaction, the nature, or severity of which is not 
consistent with the applicable product information" (e.g. investigator's brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected. 
SAE: A Serious Adverse Event (please refer to section 7.2.1.3) 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the protocol 
treatment.  
Second primary malignancy is one unrelated to the treatment of a previous malignancy (and is NOT a 
metastasis from the previous malignancy). 
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the previous malignancy. 
Any secondary malignancy should also be reported in expedited way on a SAE form with the 
appropriate seriousness criteria. 
7.2.1.2
Adverse Event 
An adverse event is defined as any untoward medical occurrence or clinical investigation in a subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product. 
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of pre-existing 
condition or illness is considered an adverse event. Worsening in severity of a reported adverse event 
should be reported as a new adverse event. Laboratory abnormalities and changes in vital signs are 
considered to be adverse events only if they result in discontinuation from the study, necessitate 
therapeutic medical intervention, meet protocol specific criteria (regarding toxicity management, refer to 
section 5.5) and/or if the Investigator considers them to be adverse events. 
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse event 
if the surgery/procedure has been pre-planned prior to study entry. However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then 
the deterioration of the condition for which the elective surgery/procedure is being done will be 
considered an adverse event. 
 
 


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The following situations do not need to be reported as SAEs: 
x
Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment. 
x
Hospitalization which was planned before the patient consented for study participation and where 
admission did not take longer than anticipated and no worsening of condition for which the 
hospitalization was planned. 
x
Hospitalization planned for protocol related treatment or protocol related procedure as per 
institutional standard timelines. 
x
Social and/or convenience admission to a hospital 
x
A medical or surgical procedure (e.g. endoscopy, appendectomy) is not a correct event term for an 
(S)AE; instead the condition that leads to the procedure should be reported as an (S)AE 
x
Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, 
overdose without occurrence of an adverse event). 
x
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
7.2.1.3
Serious Adverse Events 
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a serious adverse 
event (SAE) within 24 hours of the site being made aware of the serious adverse event: 
x
Death of Subject: An event that results in the death of a subject. 
x
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. 
x
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 or hospitalization for respite care, or 
hospitalization due solely to progression of the underlying cancer. 
x
Congenital Anomaly: An anomaly detected at or after birth, or any anomaly that results in fetal loss. 
x
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). 
x
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious Outcome: An 
important medical event that may not be immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may jeopardize the subject and may require medical 
or surgical intervention to prevent any of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity). Additionally, any elective or spontaneous abortion or stillbirth is 
considered an important medical event. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
For serious adverse events with the outcome of death, the date and cause of death will be recorded on 
the appropriate case report form. 
 
 


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7.2.1.4
Deaths 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the protocol specified 
adverse event collection period (section 7.2.1.8) that are more likely related to disease progression will 
therefore be an expected adverse event and will not be an expedited report to the regulatory agencies or 
IRB/EC. 
Death should be considered an outcome and not a distinct event. The event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the adverse event 
eCRF/Paper 500AE CRF. Generally, only one such event should be reported. The term "sudden death" 
should only be used for the occurrence of an abrupt and unexpected death due to presumed cardiac 
causes in a patient with or without pre-existing heart disease, within 1 hour of the onset of acute 
symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the adverse event eCRF/Paper 500AE CRF. If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced by the 
established cause of death. 
7.2.1.5
Lack of Efficacy or Worsening of Disease 
Events that are clearly consistent with the expected pattern the disease or of progression of the 
underlying disease are considered an expected outcome for this study and will not be subject to 
expedited reporting. These data will be captured as efficacy assessment data only. Appendix H contains a 
list of expected adverse events related to GBM or progression of GBM. These events may occur alone or 
in various combinations and are considered expected for reporting purposes for this protocol. If there is 
any uncertainty as to whether an event is due to disease progression, it should be reported as an adverse 
event. 
Although exempted from expedited reporting to Health Authorities and ethics committees as individual 
cases, if an event commonly associated with GBM or progression of GBM meets seriousness criteria (as 
defined in Section 7.2.1.3), it must be reported to AbbVie within 24 hours of the site being made aware 
of the serious adverse event. 
7.2.1.6
Adverse Event Severity 
The Investigator will rate the severity of each adverse event according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0). A copy of the CTCAE can be 
accessed from the CTEP home page (Error! Hyperlink reference not valid.https://ctep.cancer.gov/). 
NYHA criteria will be used for reporting congestive heart failure. 
If a reported adverse event increases in severity, the initial adverse event should be given an outcome 
date and a new adverse event should be reported to reflect the change in severity. 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate or severe, or as described in CTC grades); the event itself, however, may be of relative minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to patient’s life 
or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
 
 


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7.2.1.7
Relationship to Study Drug 
The Investigator will use the following definitions to assess the relationship of the adverse event to the 
use of study drug (ABT-414, Temozolomide or Lomustine): 
Reasonable Possibility: An adverse event where there is evidence to suggest a causal relationship 
between the study drug and the adverse event. 
No Reasonable Possibility: An adverse event where there is no evidence to suggest a causal relationship 
between the study drug and the adverse event. 
For causality assessments, events assessed as having a reasonable possibility of being related to the study 
drug will be considered "associated". Events assessed as having no reasonable possibility of being related 
to study drug will be considered "not associated". In addition, when the Investigator has not reported a 
causality or deemed it not assessable, AbbVie will consider the event associated. 
If an Investigator's opinion of no reasonable possibility of being related to study drug is given, an Other 
cause of event must be provided by the Investigator for the serious adverse event. 
7.2.1.8
Adverse Event Collection Period 
All adverse events reported from the time of study drug administration until 49 days following 
discontinuation of study drug administration have elapsed will be collected, whether solicited or 
spontaneously reported by the subject. 
In addition, serious and non-serious adverse events occurring after the subject signed the study-specific 
informed consent and prior to the initial dose of study drug will be collected only if they are considered 
by the Investigator to be causally related to required study procedures. 
Adverse event information will be collected as shown below. 
Adverse Event Collection 
 
Protocol Related SAEs 
and Nonserious 
Adverse Events* 
 
Serious and Nonserious Adverse Events 
Elicited and/or Spontaneously Reported 
_ 
 
 _ 
 
_ 
 
_ 
Consent 
Signed 
 
Study 
Drug 
Start 
 
Study 
Drug 
Stopped 
 
49 Days 
After Study 
Drug 
Stopped** 
* Only if considered by the Investigator to be casually related to study-required procedures. 
**If an AE/SAE occurs more than 49 days after study drug was stopped, it only needs to be reported it is 
considered to have a reasonable possibility to be related to the protocol treatment or study participation. 
7.2.1.9
Serious Adverse Event Reporting 
In the event of a serious adverse event, whether associated with study drug or not, the Investigator will 
notify the AbbVie Oncology Clinical Safety Management Team within 24 hours of the site being made 
aware of the serious adverse event. Notification to AbbVie will be done by submitting the paper SAE 
forms to the email or fax specified below. 
FAX to: 
 
Email:
 


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In order to be compliant with regulatory reporting requirements, all initial SAE reports should always 
include the following minimal information: 
x
Name of person sending the report (i.e., name, address of Investigator)  
x
Patient identification (screening/randomization number, NOT patient name or initials)  
x
Protocol number  
x
Description of SAE  
x
Causality assessment  
All applicable forms need to be dated and signed by the principal investigator (PI) or designated sub-
investigator (Sub-I).  
For serious adverse event concerns, contact the Oncology Safety Team at:  
Safety Management Oncology 
AbbVie 
1 North Waukegan Road 
North Chicago, IL 60064 
Contact Information: 
 
 
EORTC Clinical Research Physician:  
For any subject safety concerns, please contact the listed below: 
In case of subject safety concerns or medical emergencies the individuals noted above are unavailable, 
please call the following central back-up number: 
Phone: 
 
The Sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting 
for the Investigational Medicinal Products (IMP) ABT-414, Lomustine and Temozolomide in accordance 
with Directive 2001/20/EC. The reference documents used for SUSAR reporting in the EU countries will 
be the most current version of the Investigator's Brochure for ABT-414 and Summary of Product 
Characteristics (SmPC) for Lomustine and Temozolomide. 
7.2.1.10
Pregnancy 
Pregnancy in a study must be reported to AbbVie within 1 working day of the site becoming aware of the 
pregnancy. This applies to subjects who become pregnant during the study while on study drug or within 
49 days post study drug discontinuation. 
Subjects who become pregnant during the study must be discontinued (section 5.4). 
Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will 
be collected. 


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Male subjects should be informed that contraceptive measures should be taken by their female partners. 
If the subject's partner should become pregnant during the study, this should also be reported and data 
may be collected. In the event of pregnancy occurring in the partner of an enrolled subject, written 
informed consent for release of medical information from the partner must be obtained prior to the 
collection of any pregnancy-specific information and the pregnancy will be followed to outcome. 
Pregnancy in a study is not considered an adverse event. However, the medical outcome of an elective or 
spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse event and must be 
reported to AbbVie within 24 hours of the site becoming aware of the event. 
7.2.1.11
Toxicity Management 
For the purpose of medical management, all adverse events and laboratory abnormalities that occur 
during the study must be evaluated by the Investigator. The table of clinical toxicity grades modified from 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 is 
to be used in the grading of adverse events and laboratory abnormalities that are reported as adverse 
events, each of which will be followed to satisfactory clinical resolution. 
7.3
Evaluation of Quality of Life 
Quality of life assessment is described in detail in chapter 10.  
8
Statistical considerations 
8.1
Statistical design 
8.1.1
Sample size 
This is a comparative randomized open label multicenter/multiarm phase II trial. Overall Survival (OS) is 
the primary endpoint. 
Based on literature review, a median OS of 7 months is expected in the mixed control arm (lomustine or 
TMZ). Based on a one-sided logrank test, at an overall significance level of 2.5% and a power of 91.7% 
(accounting for the global testing strategy), a total of 170 deaths (118 per comparison, i.e. monotherapy 
ABT-414 versus control and combination ABT-414 + TMZ versus control) are needed to detect an increase 
of median OS to 12.9 months in the treatment arms corresponding to a Hazard Ratio (HR) equal to 0.54 
(i.e. a reduction in the hazard of death of 46%). Assuming a monthly accrual of 10 patients during month 
1 to 12 and 20 patients per month after 12 months, 240 patients can be recruited within 18 months. A 
follow-up duration of 13 months after end of accrual is required to observe the 170 deaths. 
There will be an interim futility analysis organized after observation of 45 PFS events (see section 8.3).  
Provided that PFS and OS effects are independent, the overall power of the study is estimated to be 
approximately 85%. However, treatment effect on PFS and on OS may reasonably be assumed to be 
positively correlated, and hence the overall power of the study accounting for the interim analysis is 
expected to exceed 85%. 
 
 


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8.1.2
Randomization and stratifications 
All patients entered in this trial will be centrally randomized at the EORTC Headquarters (for practical 
details, see section 13.3 on randomization procedure). The minimization technique (Ref. 37) used by the 
EORTC for random treatment allocation is based on the variance method with semi-random assignment 
dependent on a preset threshold as implemented by Freedman and White (Ref. 38). However, per 
suggestion of the ICH E9 statistical guidelines, the algorithm has been modified to incorporate a random 
allocation component in order to ensure an additional 15% of completely random assignments.  
In this trial, the threshold is set to 3, the total number of stratification factors.  
Stratification factors are: 
x
Regions of the world (North America (USA, Puerto Rico & Canada) vs Europe and Australia vs 
Asia/other regions) 
x
WHO Performance Status (0 vs >0) 
x
Timing of relapse (< 16 weeks vs ш 16 weeks after the first day of the last TMZ cycle) 
8.2
Statistical analysis plan 
8.2.1
Primary and secondary endpoints 
8.2.1.1
Primary endpoint 
The primary endpoint is OS at the final analysis and Progression Free Survival (PFS) according to RANO 
criteria and assessed by IRC at the interim analysis. In addition to the OS Hazard Ratio, the following 
parameters will be assessed: median OS, probability of survival at 1 year (OS12), probability of survival at 
2 years (OS24). See chapter 1 for the definition of endpoints. 
8.2.1.2
Secondary and exploratory endpoints 
8.2.1.2.1
Secondary Endpoints 
x
PFS assessed according to RANO criteria and assessed by IRC. In addition to the Hazard Ratio, the 
following parameters will be computed in each arm: median PFS, probability of progression or death 
at 6 months (PFS6), probability of progression or death at 1 year (PFS12). 
x
The OS analysis will be performed in the subgroup with EGFRvIII mutation. 
x
Objective response rate (ORR) assessed by IRC will be computed in each arm. 
8.2.1.2.2
Exploratory Endpoints 
x
The PFS analysis will be performed in the subgroup with EGFRvIII mutation. 
x
Best overall response rate (BOR), complete response rate (CRR), duration of response (DR) assessed 
by IRC will be computed in each arm. 
x
Neurological Deterioration Free Survival (NDFS), in addition to the Hazard Ratio, the following 
parameters will be computed in each arm: median NDFS, probability of NDFS at 6 months (NDFS6), 
probability of survival at 1 year (NDFS12). 
x
Frequencies and percentages of worst Adverse Event (AEs) or Laboratory Event grades and grade 3/4 
per AE term and category as measured by CTCAEs Version 4.0 criteria. 
x
Quality of Life will be assessed and analyzed according to the methodology described in chapter 10. 
x
Use of steroids will be analyzed (but not exclusively) with the methodology developed by 
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8.2.2
Analysis populations 
i Intention-to-treat population (ITT): All randomized patients will be analyzed in the arm they were 
allocated by randomization. 
i Per protocol population (PP): All patients who are eligible and have received at least one dose of the 
study drug (i.e. one dose of lomustine or TMZ (arm 3), of ABT-414 (arm 2) and of TMZ and ABT-414 
(arm 1)). Patients will be classified and analyzed in the arm they were assigned at the time of 
randomization. 
i Safety population (SP): All randomized patients who have received at least one dose of the study drug 
(i.e. one dose of lomustine or TMZ (arm 3), of ABT-414 (arm 2) and of TMZ and ABT-414 (arm 1)). 
Patients will be classified according to treatment received.  
A patient will be considered to be eligible if he/she did not have any deviation from the patient entry 
criteria listed in chapter 3 of the protocol. Potential eligibility problems will be assessed by the Clinical 
Research Physician at time of medical review. 
8.2.3
Statistical methods 
8.2.3.1
Overall Survival 
In the ITT: 
OS will be compared between arm 1 versus arm 3 and/or arm 2 versus arm 3 when 170 deaths (118 per 
comparison) are observed.  
Differences between the treatment groups in OS will be assessed by a Logrank test stratified by the 
randomization stratification factors, testing the null hypotheses (H1: Arm 1 is not superior to Arm 3 in OS; 
H2: Arm 2 is not superior to Arm 3 in OS, respectively). The hazard ratios of the two treatment arms over 
the control arm will be calculated by Cox's proportional hazards model (score test) stratified by 
randomization stratification factors. 
The OS probability at 12 months (OS12), at 2 years (OS24) and the median OS (mOS) will be estimated 
from the Kaplan-Meyer OS curve. Two-sided 95% CI will be computed based on the Greenwood's 
formula. For the median the Reflected Method will provide two-sided 95% CI. 
8.2.3.2
Progression Free Survival 
In the ITT (RANO criteria assessed by IRC): 
Differences between the treatment groups in PFS will be assessed by a Logrank test stratified by the 
randomization stratification factors, testing the null hypotheses (H1a: Arm 1 is not superior to Arm 3 in 
PFS; H2a: Arm 2 is not superior to Arm 3 in PFS, respectively). The hazard ratios of the two treatment 
arms over the control arm will be calculated by Cox's proportional hazards model (score test) stratified by 
randomization stratification factors. 
The PFS probability at 6 months (PFS6), at 12 months (PFS12) and the median PFS (mPFS) will be 
estimated from the Kaplan-Meyer PFS curves. Two-sided 95% CI will be computed based on the 
Greenwood's formula. For the median the Reflected Method will provide two-sided 95% CI. 
 
 


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8.2.3.3
Radiological response 
In the ITT (RANO criteria assessed by IRC): 
The best overall response will be presented in contingency table with frequencies and percentages. The 
objective response (ORR: CR/PR) and complete response rates will be reported with exact (binomial) two-
sided 95% CI. The medians of objective (PR/CR) and complete (CR) response duration will be estimated 
from the Kaplan-Meier curves. The Reflected Method will provide two-sided 95% CI. 
8.2.3.4
OS and PFS in patients with EGFRvIII mutation 
In the ITT (for PFS, RANO criteria assessed by IRC): 
OS and PFS analyses will be performed in the subgroup of patients with EGFRvIII mutation at final 
analysis. The same methodology as for analyses in the whole cohort will be applied (see sections 8.2.3.1, 
8.2.3.2). 
8.2.3.5
Neurological Deterioration Free Survival 
In the ITT: 
Differences between the treatment groups in NDFS will be assessed by a Logrank test stratified by the 
randomization stratification factors, testing the null hypotheses (H0: NDFS of the 2 treatment arms equal 
to that of control arm; Arm 1 vs. Arm 3 and Arm 2 vs. Arm 3, respectively). The hazard ratios of the two 
treatment arms over the control arm will be calculated by Cox's proportional hazards model (score test) 
stratified by randomization stratification factors. 
The NDFS probability at 6 months (NDFS6), at 12 months (NDFS12) and the median NDFS (mNDFS) will be 
estimated from the Kaplan-Meyer NDFS curve. Two-sided 95% CI will be computed based on the 
Greenwood's formula. For the median the Reflected Method will provide two-sided 95% CI. 
8.2.3.6
Global strategy to control type I error for efficacy endpoints  
To meet global regulatory requirements, a multiple testing strategy for the following ordered endpoints 
will be implemented to control the family-wise type I error (alpha) for comparisons of Arm 1 (ABT-414 + 
TMZ) versus Arm 3 (TMZ/lomustine) and Arm 2 (ABT-414 alone) versus Arm 3 with respect to overall 
survival (OS) and the pre-defined secondary efficacy endpoints, namely progression-free survival (PFS), 
objective response rate (ORR), and OS for patients with EGFR vIII mutation. 
The following null hypotheses are considered: 
H1: Arm 1 is not superior to Arm 3 in OS. 
H2: Arm 2 is not superior to Arm 3 in OS. 
H1a: Arm 1 is not superior to Arm 3 in PFS. 
H2a: Arm 2 is not superior to Arm 3 in PFS. 
H1b: Arm 1 is not superior to Arm 3 in ORR. 
H2b: Arm 2 is not superior to Arm 3 in ORR. 
H1c: Arm 1 is not superior to Arm 3 in OS among EGFR vIII mutated patients. 
H2c: Arm 2 is not superior to Arm 3 in OS among EGFR vIII mutated patients. 
To maintain the overall type I error control for the study, the following null hypotheses will be tested in a 
fixed sequence of {H1, H2, H1a, H2a, H1b, H2b, H1c, H2c} in order at a 1-sided 2.5% level of significance. 
Hypothesis H1 will be tested first at a 1-sided 2.5% level. No further tests will be performed if H1 is not 


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rejected. Each hypothesis will be tested in order specified above if H1 and all preceding hypotheses show 
statistically significant results at the 1-sided 2.5% level of significance. Otherwise testing in the fixed 
sequence will stop. 
All other endpoints, e.g., PFS in EGFRvIII mutated, global health/QoL status (GHQs), and neurological 
disease-free survival (NDFS) are considered exploratory and will be tested at a 2-sided 5% level of 
significance. 
 
 
 
 


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8.2.3.7
Safety and tolerability 
In the SP: 
The safety and tolerability analyses will be presented for the whole study duration. Severe grades (3/4) 
which did not resolve after treatment discontinuation or emerged during follow-up will be identified and 
listed. All forms up to the last safety assessment before progression or start of further anti-tumoral 
therapy will be used. There will be no formal comparison of safety endpoints. No p-value and confidence 
intervals will be carried out. Baseline laboratory and AE grades will not be accounted for in whole study 
duration safety analyses.  
Laboratory and AE events occurring in patients who did not start their allocated treatment (ie excluded 
from SP) will be reported separately. 
8.2.3.7.1
Hematological parameters 
The worst value of each hematological category will be identified and graded for each patient. 
Frequencies and percentages of each category will be tabulated per arm. A table with grade 3/4 
frequencies and percentages will be provided. 
8.2.3.7.2
Biochemical parameters 
The worst value of each biochemical category will be identified and graded for each patient. Frequencies 
and percentages of each category will be tabulated. A table with grade 3/4 frequencies and percentages 
will be provided. 
8.2.3.7.3
All AEs 
The worst grade of each AE item will be identified for each patient. Frequencies and percentages of each 
CTCAE term will be tabulated grouped by System Organ Class (SOC). Tables with all grades and grade 3/4 
frequencies and percentages will be provided. 
8.2.3.7.4
SAEs 
After reconciliation with the SAEs listing extracted from the pharmacovigilance database, the worst grade 
of each SAE item will be identified for each patient and will be considered for the analysis. Frequencies 
and percentages of each CTCAE term will be tabulated grouped by SOC. Tables with all grades and grade 
3/4 frequencies and percentages will be provided. 
8.2.3.7.5
Related AEs 
The worst grade of each related AE item will be identified for each patient. Frequencies and percentages 
of each CTCAE term will be tabulated grouped by SOC. Tables with all grades and grade 3/4 frequencies 
and percentages will be provided. 
8.2.4
Pre-planned sensitivity or exploratory analyses 
In case more than 10% are excluded from the PP, OS analysis (both comparisons) will be performed in the 
PP population at two-sided alpha 5%. 
In the ITT, for OS, PFS, tumor response, NDFS treatment effect will be assessed in the following 
subgroups: 
x
Timing of relapse: < 16 weeks and ш 16 weeks after the first day of the last TMZ cycle;  
x
MGMT promoter methylation status: methylated and unmethylated;  
x
EGFR pathway abnormalities: abnormal and normal.  


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To assess the predictive value of the above three factors for OS, PFS, NDFS, the score interaction test will 
be computed by fitting a Cox regression model including treatment, factor and interaction term 
(treatment X factor). Forest plots will be displayed. KM curves comparing treatments will be presented in 
each subgroup. 
To assess factor univariate prognostic value, the score test will be computed by fitting a Cox model 
including the factor in each arm (control and treatments). KM curves by factor stratum will be displayed. 
For treatment comparison and prognostic value assessment, an exploratory two-sided significance of 5% 
will apply. For each interaction test, a significance of 10% will apply. 
Treatment comparisons in the ITT population and above mentioned other sensitivity analyses will also be 
performed with PFS assessed by local investigators with the same calculation methods than for PFS 
assessed by IRC. Other exploratory analyses may be performed based on other subsets of patients. The 
results of these exploratory analyses may not serve as a basis for drawing conclusions concerning 
protocol efficacy, but rather as hypothesis generating and the rationale for additional subset analyses 
should be clearly documented. 
8.2.5
Prognostic factor analyses 
Data of this trial will be added to the EORTC Recurrent GBM data warehouse for further pooled analyses 
of prognostic factors and other research objectives. 
8.2.6
Data re-coding and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical variables by the 
levels of the variables as they appear on the CRF (with %). Categories with a text field specification will be 
tabulated as categories and then supplemented by a listing with the following information for the 
patients fulfilling the condition for the specification (patient id, institution, treatment group, value of the 
item and text field contents). 
Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) 
between the past event and the date of entry (date of randomization – date of past event + 1) and 
presented using the median and range. For example, on the randomization checklist, the date of last 
administration of prior treatment (or the date of first diagnosis of the cancer) will be presented as the 
time elapsed (in days, weeks, months or years, as appropriate) since the day of the last administration 
and the date of entry on study (date of randomization – last administration/diagnosis +1). 
Other delays (eg. re-treatment delays) are presented as continuous variables using the median and 
range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into 
categories (for adverse events, the grading scale specified in the protocol will be used). Whenever no 
specific scale exists, lab data will be categorized based on the normal range: for example, below the 
lower normal limit (when appropriate), within the normal range, above the upper normal limit (ULN) and 
the degree to which it is above the ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory 
data, the nadir is generally displayed. The nadir in a given cycle is the lowest laboratory value in that 
cycle; the overall nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) are presented using the median and range 
(minimum, maximum).  
If appropriate, continuous data may also be presented in categories (for example, age may also be 
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8.3
Interim futility analyses 
At interim analysis one or both of the ABT-414 arms might be discontinued based on lack of efficacy for 
PFS (Reject H1 in favor of H0) according to RANO criteria assessed by IRC.  
It is assumed that median PFS is 2.6 months in the control arm and 4.8 months in the treatment arms 
corresponding to HR equal to 0.54. Assuming an accrual rate of 10 patients/month and activation phase 
of one year, at least 45 PFS events should be observed. Analyses will be performed when at least 31 PFS 
events are observed in each comparison. Treatment arms which did not show a minimum level of 
efficacy, defined as a computed treatment PFS HR lower than 0.91 will be discontinued. The trial will 
continue with remaining treatment arm(s) and control. There will be no interruption of accrual for the 
interim analysis.  
Treatment PFS HR will be presented with two-sided 95% CI. However, since efficacy data will be analyzed 
for futility purpose, an alpha spending of 0.00001will be allocated to the futility analysis. For the final 
analyses, efficacy endpoint will be tested at a nominal 1-sided alpha level of 0.02499. 
For each of the two treatment arms the probability of stopping for futility at the interim is 7.4% if the 
true PFS HR is 0.54 and 60% if the true PFS HR is 1.0 (no benefit).  
Based on the assumed accrual rates and treatment effects stated above, the interim futility analysis is 
expected to be performed when 90 randomized patients (30 patients per arm) have completed 
approximately 4 months of follow-up. 
8.4
Re-randomization Test 
The robustness of the results to the use of the minimization randomization algorithm will be evaluated by 
performing a re-randomization test on the primary efficacy analysis, the stratified log-rank test and Cox's 
proportional hazards model (score test) stratified by randomization stratification factors, to compare the 
duration of overall survival between the treatment arm(s) and the control. 
The re-randomization test will be performed as follows: 
x
The procedure will use 50,000 replications of the ITT population (all randomized patients).  
x
Based on the value of their randomization stratification factors, for each replicate, patients will be 
(virtually) re-assigned to treatments using the original minimization randomization algorithm in the 
order in which they were randomized into the trial.  
x
For each replicate the stratified log-rank test statistic and Cox's proportional hazards model (score 
test) stratified by randomization stratification factors comparing the duration of overall survival will 
be computed.  
x
The re-randomization test p-values will be the fraction of replications where the log-rank and Cox’ 
model-based p-values from the replicates are less than or equal to the corresponding p-values from 
the original analysis. 
Robustness of the results will be established if the re-randomization test p-values are then found to be 
comparable to the corresponding p-values from the original analysis.  
 
 


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8.5
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. The trial is mature for the analysis of the primary endpoint as defined in the protocol (i.e. at least 
when 170 deaths will be observed for two comparisons and 118 deaths for one comparison). 
2. 
The database has been fully cleaned and frozen for this analysis. 
3. 
Forty nine days after all patients have stopped protocol treatment. 
9
Trial Governance and Data Monitoring  
9.1
Study committees  
9.1.1
Study Management Group (SMG) 
The Study Management Group is set up for this study. It consists of the EORTC Headquarters team in 
charge of running the study (clinical research physician, statistician, clinical scientist, clinical operations 
manager and data managers) and the principal study coordinator.  
The EORTC Headquarter team, in collaboration with AbbVie, is responsible for the day -to-day conduct of 
the trial. The Study Coordinator will assist the team in case of problems with patient evaluation 
(eligibility, treatment compliance, safety).  
The Study management Group also performs the medical review as indicated below.  
9.1.2
Study Steering committee (SSC)  
The Study Steering Committee for this study is composed of the study coordinators, the representatives 
of Academic Groups collaborating to the study, at least one representative of the EORTC Headquarters 
(Study Clinical Research Physician or Clinical Scientist) and one representative of the Sponsor, if the 
sponsor is not the EORTC.  
This committee provides the general oversight of the study and has the executive power. The SSC 
monitors study progress and conduct and advises on its scientific credibility. The SSC will consider and 
act, as appropriate, upon the recommendations of the independent data monitoring committee.  
9.1.3
Independent data monitoring committee (IDMC)  
The independent data monitoring committee for EORTC studies (IDMC) is in charge of the independent 
oversight of this study. The composition of the IDMC is described in EORTC Policy "Independent Data 
Monitoring Committees for EORTC studies" (ref. EORTC POL004) and its functioning is ruled by the 
charter annexed to the Policy.  
The study-specific experts on the IDMC performing this review will be selected for their relevant 
expertise with the disease and/or treatments assessed in the study.  
The IDMC reports its recommendations in writing to the Study Management Group through the clinical 
operations manager to the Study Steering Committee and other relevant parties (supporting bodies, 
collaborative groups…).  


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9.2
Data Monitoring  
9.2.1
Monitoring during medical review meetings  
The medical review will be performed on a regular basis by the clinical research physician assisted as 
needed by the study management group. The main study coordinator will, in particular, support the 
Study Clinical Research Physician during the medical review process and will assist the team in case of 
problems with patient evaluation (safety, eligibility, treatment compliance). The main study coordinator 
is also responsible for the review and approval of the medical review plan and medical review reports.  
For blinded trials, the medical review is conducted blinded to treatment allocation. 
If at any time during the course of the study, the medical review identifies safety signals or other 
elements that could affect the potential risks and benefits to the study participants. These will be 
reported to the Study Steering Committee and may trigger a review by the EORTC Independent Data 
Monitoring Committee (IDMC) as well as the collaborative partner (AbbVie). 
9.2.2
Monitoring by the IDMC  
The IDMC will be asked to give advice on whether the accumulating data from the trial justifies 
continuing recruitment of further patients or further follow-up. 
The IDMC will review the trial whenever safety problems or other elements are identified during the 
medical review or by the SMG and/or SSC that could affect the potential risks and benefits for study 
participants.  
The IDMC will also review the intermediate reports of accumulating data according to the study interim 
monitoring plan described in the statistical section of this protocol. If a decision is made to continue 
without change, the IDMC may advise on the frequency of future reviews of the data on the basis of 
accrual and event rates. 
While the trial is ongoing the accumulating data will generally remain confidential, unless the SSC and 
IDMC agree that the data should be made public. 
10 Quality of Life assessment 
10.1 Rationale 
Health related quality of life (HRQoL) is a multidimensional construct, which can be defined as a state of 
general wellbeing reflecting physical, psychological, and social wellbeing and the impact of the disease 
and/or treatment related symptoms on daily-life functioning. The patient’s subjective perspective is an 
inherent component of HRQoL and is therefore best assessed via self-administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical research. 
Nevertheless, issues such as reducing side effects, symptom relief and improving patients’ satisfaction 
have also become relevant parameters in the evaluation of medical strategies. Cancer treatments may 
produce adverse effects and diminish a patient’s quality of life even when survival is extended. Progress 
in the acceptance of new cancer therapies is sometimes critically dependent on their HRQoL 
consequences. 
 
 


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10.2 Objective 
The current experience with angiogenesis inhibiting agents in recurrent GBM has demonstrated 
considerable difficulties with assessing response and progression in previously treated patients. So, we 
hypothesize that measures of clinical functioning will yield information (HRQoL, need for steroids, 
cognitive functioning) that is critical for the patient perception of clinical benefit. 
The study hypothesis is that ABT-414 alone or in combination with TMZ improves overall survival 
compared to lomustine or TMZ single agent. In the present study, HRQOL is an exploratory endpoint. The 
main objective of HRQOL assessment within this trial is to determine the impact of ABT-414 on overall 
global health and HRQoL. A secondary objective is to evaluate the effect of the treatment on the 
remaining symptoms and functioning scales as treatment-related side effects may have a (temporary) 
negative influence on the health related domains of HRQOL of these patients.  
10.3 HRQoL instrument 
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. This is 
composed of multi-item and single scales. These include five functional scales (physical, role, emotional, 
social, and cognitive), three symptoms (fatigue, nausea and vomiting and pain) and a global health 
status/HRQoL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and 
financial difficulties). All scales and single items meet the standards for reliability. The reliability and 
validity of the questionnaire is highly consistent across different language-cultural groups (Ref. 32). While 
this standard is used in EORTC studies, it lacks some dimensions that pertain to the QL issues in certain 
brain cancer. Therefore, we will use the EORTC Brain Cancer module (QLQ-BN20), designed for use in 
patients undergoing protocol treatment or radiotherapy. It includes 20 items assessing visual disorders, 
motor dysfunction, communication deficit, future uncertainty, as well as other specific symptoms, such 
as headaches, seizures or drowsiness. A retrospective validation study has been performed confirming 
the psychometric validity of this questionnaire (Ref. 33). 
10.4 Study design 
Patients are eligible for the quality of life assessment in this study if they fulfill the eligibility criteria 
(Chapter3). Should the HRQoL forms not be available in the required language or should the patient 
refuse to fill out the form, then this should not exclude the patient from further participation in the 
study. Patients will be informed in the patient informed consent form that they will have their quality of 
life assessed regularly while involved in this trial. In this phase II trial, HRQoL will be an exploratory 
outcome and evaluated in a longitudinal design in all patients entered in this study. 
HRQoL questionnaires must be filled out at the hospital when patients come for a scheduled visit 
according to the EORTC “Guidelines for administration of questionnaires” (see Appendix G). The pre-
treatment questionnaires must be filled within 2 weeks before randomization. Subsequent 
questionnaires are administered at week 8 and 16 on-treatment, coinciding with the imaging visits. All 
patients are requested to complete a HRQoL assessment 6 months after randomization. 
Master copies of the HRQoL questionnaires will be sent to the institutions. Additional copies or 
translations can be provided upon request via the EORTC contact person. The clinical report forms will 
include a question whether the HRQoL forms have been filled in, and if not, the reason why. The 
questionnaire will be handed out to the patients by the investigator or a study nurse prior to seeing the 
doctor for clinical evaluations. The patient should complete the questionnaires by her/himself in her/his 
own language during the visit as completely and accurately as possible. It is recommended that a key 
person (e.g. research nurse) at each center should be responsible for questionnaire data collection in 
order to optimize the compliance of the patient and to ensure the completeness of the data. 


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The time windows for eligible HRQoL assessments will be as follows: 
Assessment 
Time window  
Baseline 
For all patients. 
Can be completed before or on the day of randomization 
itself but no earlier than 2 weeks before. 
Week 8 
(on-treatment) 
To be completed at the week 8 MRI visit while on protocol 
treatment. 
Week 16 
(on-treatment) 
To be completed at the week 16 MRI visit while on protocol 
treatment. 
At 6 months 
For all patients. 
Can be completed at any time during the sixth and seventh 
month after date of randomization regardless of treatment 
or progression status. 
10.5 Statistical considerations 
The primary HRQoL endpoint that is considered relevant for this study is the Global health/QoL status 
(GHQs) scale of the QLQ-C30 instrument. Other scales will be analyzed on an exploratory basis as 
secondary HRQoL endpoints, such as fatigue, communication deficit etc. The financial difficulties scale 
will not be analyzed. 
The GHQs scale will be used as primary outcome of interest for this study. A change of 10 points on the 
100-point QLQ-C30 scale will be considered as clinically relevant. The standard deviation of this scale is 
approximately 20 points. With the 2-sided alpha set at 5% and a power of 80% to detect a difference of 
10 points (effect size of 0.5), a minimum of 128 patients (64 per treatment arm) is required. For an effect 
size of 0.75 (difference of 15 points), 56 patients (28 per treatment arm) are required. Therefore, this 
study is sufficiently powered to detect differences in HRQoL, although the emphasis is on establishing the 
magnitude and relevance of HRQoL differences rather than comparative tests. 
Data will be scored according to the algorithm described in the EORTC scoring manual. All scales and 
single items are scored on categorical scales and linearly converted to 0-100 scales. 
Changes in HRQoL scores per time point will be evaluated by classifying them according to the 10 point 
change threshold into 3 categories: improved, stable and deteriorated. Patients without a valid HRQoL 
outcome will be considered as having deteriorated. In case of discrete numbers (N<10), categories may 
be combined. The subsequent proportions will be compared between treatment arms using a chi-square 
test in the intent-to-treat population. In order to assess the robustness of the results, the following 
sensitivity analyses will be performed: a clinical relevant threshold of 5 and 15 points will be used and 
patients without a valid HRQoL score will be classified according to the reported reason for non-
compliance. 
10.5.1
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
In order to check the potential impact in the study, the compliance mechanism will be investigated prior 
to initiating the HRQoL analysis. Characteristics of patients with and without valid HRQoL data will be 
compared and trends over time per dropout pattern will be investigated. Model building will be used in 
order to investigate whether the compliance mechanism is linked to selected prognostic variables. 


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Once the main analysis is completed, sensitivity analyses will be undertaken to verify the robustness of 
the results vis-à-vis the missing data.  
In case overall compliance is deemed too low (<50%), only an exploratory analysis will be performed in 
lieu of the main analysis. 
11 Translational research 
11.1 General principles for human biological material (HBM) 
collection 
In this study, biological material (tumor tissue) will be shipped from the study site to a designated CRO 
according to instructions provided in the study specific laboratory manual. Following the tissue analysis 
for EGFR amplification and EGFRvIII mutation, all biologic material will be centralized and stored at 
. From here, the biological material will be used or 
distributed to the other research laboratories involved in the translational research (TR) projects 
specified in this protocol or defined in the future.  
To allow confirmatory studies for EGFR and other mutations in glioblastoma DNA will be collected as part 
of the study protocol for confirmatory studies. In addition, the biobank will distribute HBM to the other 
research laboratories involved in the translational research (TR) projects specified in this protocol or 
defined in the future.  
The following principles apply to storage of HBM: 
x
The biobank will have a designated manager responsible for collection and will act as a 
communication point with the EORTC 
x
The collected HBM should be documented, i.e. the amount remaining and its location. 
x
The 1410-BTG study steering committee (SSC) will be responsible for TR project review and 
prioritization, including the consideration of newly proposed TR projects not specified in the protocol. 
In the absence of a SSC, responsibilities of the SSC are transferred to the Group and/ or EORTC HQ as 
applicable. 
Final decisions on the use of HBM will be determined by a majority vote of the SSC/BTG committee. 
Additional expertise may be sought through advisory non-SSC/BTG committee members. 
Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another purpose for which 
it was originally collected, subject to meeting ethical principles/and is covered by informed 
consent/ethics approval. In the case of secondary use of HBM, (i.e. for new TR projects that are not 
specified in the clinical study protocol and that were not foreseen at the time of protocol writing) 
interested parties may apply for the use of HBM and will follow the next steps:  
A short description of the new TR projects will be written and submitted to EORTC HQ for coordination 
with the SSC/BTG committee. 
x
The SSC/BTG committee will prioritize the TR projects. Access procedures defined by the SSC/BTG 
committee will build on the following key points:  
x
Project prioritization  
x
should be strongly based on scientific merit,  
x
should consider the contribution of the different investigators to the trial and TR project,  


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x
will take into consideration if the applicant is an EORTC member or not (whilst maintaining the 
principle of access to the wider scientific community and commitments owed to study 
participants and ethical committees). 
x
Protection of confidentiality must be respected. 
x
An EORTC HQ feasibility check, including recommendations for regulatory and ethical matters and 
other restrictions on the use of the HBM, will take place. If in the event the HBM collections are still 
retained at individual clinical sites, the TR project leader and the involved EORTC Group are 
responsible for collecting and providing information on availability of HBM for the feasibility 
assessment. 
x
Prioritized TR projects will then be reviewed by the Translational Research Advisory Committee 
(TRAC). 
Once SSC/BTG committee prioritization, the EORTC HQ feasibility assessment, and TRAC review are 
complete and when all applicable competent Ethics Committees approvals are in place and ethical 
principles are met, the TR project can be activated and HBM release and analysis can commence. 
The EORTC Board will mediate any disagreements of opinion between TRAC, the EORTC HQ feasibility 
assessment, the SSC/BTG committee and the TR project leader(s), as needed. 
11.2 Pharmacokinetic Analysis of Blood Samples for ABT-414, Total 
ABT-806, Unconjugated Cys-mcMMAF, and ADA (nADA) 
In this study, pharmacokinectic blood and/or serum samples collected from subjects in Arms 1 and 2 will 
be shipped from the study site to a designated CRO according to instructions provided in the study 
specific laboratory manual. Serum or plasma concentrations of ABT-414, Total ABT-806, ADA/nADA, and 
unconjugated cyc-mcMMAF will be determined using validated methods under the supervision of the 
Drug Analysis Department at AbbVie. 
Peak and trough concentrations (Cmax and Ctrough) of ABT-414 and total ABT-806 antibody will be 
summarized from the observed concentration data. A nonlinear mixed effect modeling analysis will be 
conducted to estimate the population pharmacokinetic parameters of ABT-414, total ABT-806 and cys-
mcMMAF such as clearance and volume of distribution. Effect of demographic and/or disease-specific 
variable(s) on the PK parameters of ABT-414, total ABT-806, and cys-mcMMAF will be examined. 
Exposure-response analyses for relevant safety and/or efficacy variables may be conducted to 
understand the contribution of ABT-414, total ABT-806 antibody, and cys-mcMMAF to efficacy and 
safety. 
11.3 Pharmacodynamic Analysis of Plasma Markers and Serum 
Markers 
Pharmacodynamic plasma and serum samples collected from subjects randomized to Arm 1 and 2 will be 
shipped from the study site to a designated CRO according to instructions provided in the study specific 
laboratory manual and will be analyzed by AbbVie. Examination of the plasma and serum components of 
blood in subjects may reveal patterns of metabolites, cell-free nucleic acids or protein/peptide 
concentrations that may be further evaluated in future clinical studies to determine any prognostic value 
and any correlation with clinical response. Serum and plasma samples may be analyzed for predictive or 
drug-responsive proteomic or nucleic acid markers 


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11.4 Pharmacogenetic Analysis of Blood Samples - optional 
All subjects enrolled in the study may consent to provide samples for the optional pharmacogenetic 
analysis. These samples will be shipped from the study site to a designated CRO according to instructions 
provided in the study specific laboratory manual. The PG samples may be analyzed by Abbvie or 
companies working with AbbVie. DNA samples may be sequenced and data analyzed for genetic factors 
contributing to the disease or subject's response to ABT-414, or other study treatment, in terms of 
pharmacokinetics, efficacy, tolerability and safety. Such genetic factors may include genes for drug 
metabolizing enzymes, drug transport proteins, genes within the target pathway, or other genes believed 
to be related to drug response or disease. Some genes currently insufficiently characterized or unknown 
may be understood to be important at the time of analysis. The samples may be analyzed as part of a 
multi-study assessment of genetic factors involved in the response to ABT-414, drugs of this class, or the 
disease state. The samples may also be used for the development of diagnostic tests related to the 
disease or ABT-414 (or drugs of this class). The results of pharmacogenetic analyses may not be reported 
with the study summary. 
11.5 Methylation status of the primary tumor 
It is increasingly clear that the methylation status of the MGMT promoter gene plays a primary role in the 
resistance of glioma against alkylating agents. In newly diagnosed GBM, MGMT promoter gene 
methylation was correlated with clinical benefit from combined chemo-irradiation with temozolomide 
(Ref. 34). Several studies have now given evidence of the impact of MGMT promoter methylation at the 
time of primary diagnosis for the outcome of treatment at the time of recurrence, with an impact on 
both PFS and OS in lomustine and TMZ treated patients (Ref. 14, Ref. 18). It is however unclear if MGMT 
status is only predictive for response to alkylating agents or whether it is also prognostic in recurrent 
GBM. In view of the improved outcome of MGMT promoter methylated patients after combined chemo-
irradiation with TMZ, it is anticipated that with longer time to first progression the percentage of patients 
with a MGMT promoter methylated tumor will increase. For exploratory analysis of the correlation 
between outcome and MGMT promoter methylation MGMT promoter status will therefore be assessed, 
using methylation specific PCR (MS-PCR). Analysis will explore whether MGMT status is balanced 
between the groups, and will correlate OS and PFS with MGMT status in each of the treatment arms (see 
section 8.2.4). 
Although IDH mutations have prognostic significance in glioblastoma and are associated with MGMT 
promoter methylation, the presence of IDH mutations is mutually exclusive with the presence of EGFR 
amplification and IDH mutational status assessment in this study is not required. 
Tissue samples submitted for EGFR amplification from subjects that have been enrolled in the study will 
be analyzed for methylation status.  
11.6 RNA expression profiling 
Due to the pivotal relevance of EGFRvIII mutations for this study, EGFRvIII status will also be determined 
retrospectively by PCR on tumor tissue samples.  
ABT-414 is an ADC composed of the anti-EGFR antibody ABT-806 conjugated to the potent tubulin 
inhibitor monomethylauristatin F (MMAF). ABT-806 is a humanized gamma 1 antibody with kappa light 
ĐŚĂŝŶ;/Ő'ϭʃͿƐƉĞĐŝĨŝĐĨŽƌĂƵŶŝƋƵĞĞƉŝƚŽƉĞŽĨƚŚĞEGFR which is largely inaccessible when EGFR is 
expressed at physiological levels. The targeted epitope is however accessible in tumors that express EGFR 
with deletion of exons 2 through 7 (EGFRde2-7, also referred to as EGFRvIII) and in tumors with wild-type 
amplified EGFR or excessive EGFR activation. Although one of the inclusion criteria in this trial is EGFR 
amplification (which results in receptor activation), many other mutations in the EGFR receptor gene are 


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often present in EGFR amplified tumors and often 3-4 different mutations are detected within a single 
tumor. For example, a single EGFR-amplified GBM may harbor several different intrachromosomal 
deletions (EGFRvIII ex12-13, ex14-15), point mutations (A289V, G598V) and/or 3’deletions (Ref. 19,  
Ref. 35). When different mutations also show differential sensitivity to EGFR inhibitors, this may impact 
the efficacy of treatments targeting the activated EGF receptor (Ref. 36). Therefore, any treatment that 
specifically targets EGFR should determine which genetic alterations are present and at what frequency 
in the EGFR locus. As most mutations are present only in a minority of alleles, the sensitivity of targeted 
re-sequencing on the DNA level will be insufficient. RNA-sequencing can identify such changes and at 
present this technique appears the most sensitive and cost effective method to detect somatic 
alterations of the EGFR locus. RNA sequencing may also allow exploratory analysis of mechanisms of 
resistance of the tumor involved in resistance to the active portion of ABT414, MMAC.  
See section 8.2.4 for statistical considerations. 
Tissue samples submitted for EGFR amplification from subjects that have been enrolled in the study will 
be further assessed for additional EGFR mutations.  
11.7 Targeted next-generation sequencing of relevant cancer genes 
Samples submitted for EGFR amplification testing from subjects that have been randomized will also be 
assessed for other DNA mutations, including but not limited to, mutations in the EGFR signaling pathway, 
such as PTEN, TP53, Rb, CDKN2A, and PI3K. All analysis of outcome related to these mutations will be 
exploratory. 
11.8  Future translational studies - optional 
During the conduct of the study and thereafter new questions may arise regarding the biological behavior 
of glioblastoma and/or treatment of glioblastoma with ABT-414, TMZ, lomustine or other agents. For 
these new research questions, analysis of tumor samples collected within the present studies may prove 
useful. Therefore, all patients will be asked for consent for future translational research on remaining 
tumor and all other remaining material from patients treated within this study, including the optional 
translational research blood sample. Details on handling and shipment of the human biological material 
can be found in the study manual. 
Translational research projects will be coordinated by:  
 
Erasmus MC Hospital 
Dept. of Neurology - Erasmus MC Hospital 
Postbus 2040 ('s-Gravendijkwal 230) 
3000 CA Rotterdam 
Netherlands 
11.9 Data storage, transfer and development of technical appendices 
The translational projects will be the result of the work of collaborating institutions and EORTC HQ. 
Bioinformatics and statistical analysis plan will be jointly developed for each project. These documents 
will be developed and approved before starting any analysis. They will specify the analytical and 
methodological details. Clinical data will be stored in the EORTC clinical database and biological 
investigational data will be stored in respective collaborating institutions. Transfer of data will be 
performed according to applicable policies in each organization (e.g. EORTC POL008) or according to 
jointly approved data transfer charters. 


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12 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize/enroll patients in this trial only once they 
have returned the following documents to AbbVie: 
i The updated signed and dated curriculum vitae of the Principal Investigator in English with a GCP 
training proof. 
i The Study Agreement between Abbvie and investigator’s institution. 
i A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee 
mentioning the documents that were reviewed (including the version numbers and version dates of 
all documents). A list of all members of the ethics committee is also requested. 
i A copy of the translated and adapted (according to all national requirements) Patient Information / 
Informed Consent sheet. Version numbers and dates must be clearly stated on each page.  
i The full name, address, phone numbers and e-mail address of the local pharmacist who will be 
responsible for the trial medication (for any trial where the drug will be provided). 
Also should be provided prior to use of local labs: 
x
The current list of normal ranges for the investigator’s institution to include all lab tests required by 
the protocol.  
x
An accreditation, a certification, an established quality control / external quality assessment or 
another validation should be provided for the own laboratory. 
The new investigator will be added to the “authorization list”, and will be allowed to 
register/randomize/enroll patients in the trial as soon as 
i Investigational Product release approval received from AbbVie. 
i All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list will not be 
accepted. 
Additional documents may be requested by AbbVie to initiate release of study drug and activation of the 
centers in the IRT system. 
13 Patient registration and randomization procedure 
Patient registration will only be accepted from authorized investigators (see chapter on “investigator 
authorization procedure”). 
Patients should be registered immediately after signing the informed consent for registration, directly on 
the EORTC online randomization system (ORTA = online randomized trials access), accessible 24 hours a 
day, 7 days a week, through the internet. To access the interactive randomization program, the 
investigator needs a username and a password (which can be requested at http://orta.eortc.be/). 
In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00 pm (Belgian 
local time) from Monday through Friday in order to randomize patients via the EORTC call center. 
Randomization via the phone is not available on Belgian holidays. A list of these holidays is available on 
the EORTC web site (http://orta.eortc.be/) and it is updated annually. 
Through internet: 
 
http://orta.eortc.be/ 
In case of problems randomization by phone:  
 
 


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A patient can only be registered/randomized after verification of eligibility. Both the eligibility check 
and randomization must be done before the start of the protocol treatment. 
13.1 Registration (step 1) 
A list of questions to be answered during the registration procedure is included in the registration 
checklist, which is part of the case report forms. 
STANDARD INFORMATION REQUESTED: 
i institution number  
i protocol number (1410) 
i step number: (1 - New patient) 
i name of the responsible investigator  
i patient's code (maximum 4 alphanumerics)  
x
patient's birth date (year only) in the day/month/year format, to be captured as 01/01/year; for 
pediatric patients the month and year of birth (01/month/year) will be captured. 
i PROTOCOL SPECIFIC QUESTIONS: 
i all registration criteria will be checked one by one 
i date of written informed consent for registration (day/month/year) 
Once registration criteria have been verified, a sequential patient identification number (“seqID”) will be 
allocated. This number will allow the identification of the patients in the VISTA/Remote Data Capture 
system (VISTA/RDC) that will be used to complete the Case Report Forms. 
All SAMPLE SHIPMENTS and REPORTS must be identified with the EORTC Id (seqID) attributed at 
registration 
13.2 Central lab review procedure (step 2) 
After registration and shipment of the sample, the central laboratories will assess the patient’s EGFR 
status. Details of the testing procedure are specified in the laboratory manual. The assessment results of 
the central lab will be entered in the ORTA system (step 2). 
A patient who has not been registered before the EGFR assessment will not be accepted for the study at 
a later date and cannot be entered for the second step of the study. Patients who have tissue screening 
prior to tumor progression will have their information registered and EGFR assessment recorded in the 
ORTA system but will not proceed further until tumor progression. At the time of tumor progression, all 
eligibility criteria must be met before proceeding to step 3 (below). 
At the end of step 2, once the test results have been verified, the site will be informed by a notification 
email if, following the EGFR assessment, the patient is eligible to start the randomization procedure 
(step 3). 
The central lab review procedure is not applicable for the pediatric sub-study. 
13.3 Randomization procedure (step 3) 
A patient who has not been registered and had the EGFR assessment done by the central lab will not be 
accepted for the study at a later date and cannot be checked for eligibility by the third step of the study. 
An exhaustive list of questions to be answered during the randomization procedure is included in the 
eligibility checklist, which is part of the case report forms. 
 
 


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STANDARD INFORMATION REQUESTED: 
x
institution number 
x
protocol number (1410) 
x
step number: (3 – Existing patient) 
x
name of the responsible investigator 
The patient will have to be selected in the list of patients that have already been registered in the first 
step. Once the patient has been identified in the list, select the corresponding patient’s code. The 
patient’s code and date of birth will automatically be inserted in the identification screen. 
PROTOCOL SPECIFIC QUESTIONS: 
x
all eligibility criteria will be checked one by one 
x
actual values of the eligibility parameters will be requested when applicable 
x
stratification factors 
x
date of written informed consent for the main study (day/month/year) 
Once eligibility and stratification factors have been checked, the treatment will be randomly allocated to 
the patient (minimization technique) and the site will be informed of it by an automatic notification email 
if the patient is eligible. 
Pediatric patients will have Enrollment in ORTA as Step 2. There is no requirement to wait for central lab 
EGFR amplification result. Enrollment in ORTA follows a similar procedure although patients will not be 
randomized.  
13.4 Confirmation of treatment arm and drug dispensation 
Once a subject's eligibility has been confirmed and randomization has been completed, sites will access 
the Interactive response technology (IRT) system and confirm the treatment arm the subject was 
randomized to. This will initiate drug dispensation and allocation of the proper study drug (ABT-414 and 
TMZ and lomustine for the countries where these will be provided by the sponsor). 
STANDARD INFORMATION REQUESTED: 
x
patient's SeqID 
x
treatment arm 
13.5 Interactive Response Technology (IRT) 
Before the study is initiated, the telephone log-in/call-in directions for the IRT will be provided to each 
site. Study drug will be dispensed at the study visits summarized in chapter 6. Unused study drug should 
not be redispensed to the subject. 
14 Forms and procedures for collecting data 
14.1 Case report forms and schedule for completion 
Data will be reported on the forms specifically designed by the EORTC Headquarters for this study. Forms 
should be electronically sent to the EORTC Headquarters through the VISTA/RDC (Remote Data Capture) 
system, with the exception of the Quality of Life form, the SAE form and the Pregnancy notification form 
which are paper CRFs. 
 
 


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Copies of the Quality of Life forms should be sent directly to the EORTC Headquarters by one of the 
following means: 
x
By fax, to the attention of BTG Data manager: + 
 
x
By scanning and e-mailing the forms (see Guidelines for completion of Case Report Forms) to 
 
x
By post to the EORTC Headquarters: 
(BTG Data Manager) 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
^Z/Kh^sZ^sEd^AND PREGNANCY NOTIFICATION FORMS ^,Kh>/DD/d>z
ZWKZdKZ/E'dKd,WZKhZd/>/Ed,/^WZKdKK> (see chapter on Reporting 
Serious Adverse Events). 
A. Before the treatment starts: 
i The patient must be registered/randomized in the trial by INTERNET or in case of problems by phone. 
The electronic CRFs to be completed for a patient are available on the VISTA/RDC website one day after 
the registration on http://rdc.eortc.be/ or on http://www.eortc.org in the section for "Research Tools". 
The paper CRF(s) will be made available to the institution at the time the institution is authorized. 
B. During/after treatment 
The list of forms to be completed for this study and their submission schedule are available on the 
VISTA/RDC website and are also described in the "guidelines for completion of case report forms" that 
are provided to each participating investigator.  
ALL Forms must be electronically approved and sent by the responsible investigator or one of his/ her 
authorized staff members with the exception of the paper Quality of Life form (no signature needed). 
14.2 Data flow 
The case report forms must be completed electronically, with the exception of the paper forms (SAE 
form, Pregnancy Notification form if applicable, and the Quality of Life forms), dated and signed by the 
investigator or one of his/her authorized staff members as soon as the requested information is 
available. 
The list of staff members authorized to sign case report forms (with a sample of their signature) must be 
sent to the EORTC Headquarters by the responsible investigator before the start of the study. To enter 
the RDC system, the investigator or authorized staff member needs to use the same username and 
password that are used to access the interactive randomization program (ORTA). 
In all cases, it remains the responsibility of the principal investigator to check that data are entered as 
soon as possible and that the (electronic) forms are filled out completely and correctly. The EORTC data 
manager will subsequently apply the corrections into the database. 
The EORTC Headquarters will perform extensive consistency checks on the CRFs and issue queries in case 
of inconsistent data. The queries for the electronic forms will appear in the VISTA/RDC system and must 
be answered there directly. 


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If an investigator (or an authorized staff member) or monitor needs to modify a CRF after the form has 
been electronically sent to the EORTC Headquarters, he/she should create a request for data correction 
in the VISTA/RDC system. 
The data corrections will appear in the VISTA/RDC system and the EORTC data manager will subsequently 
apply the corrections into the database. 
When satellite institutions are involved all contacts are done exclusively with the primary institution, for 
purposes of data collection and all other study related issues. 
More details on the data flow and related monitoring activities can be found in the Guidelines for 
completion of Case Report Forms. 
15 Quality assurance 
15.1 Control of data consistency 
Data forms will be electronically sent to the EORTC Headquarters database by the VISTA/RDC (Remote 
Data Capture) system. Computerized and manual consistency checks will be performed on newly 
received forms; queries will be issued in case of inconsistencies. Consistent forms will be validated by the 
data manager. Inconsistent forms will be kept "pending" until resolution of inconsistencies. 
15.2 Routine Monitoring Visits 
AbbVie will perform on-site monitoring visits, as follows: 
The initial site monitoring visit will be conducted within approximately 2-6 weeks following first subject 
enrolled. The frequency of the routine monitoring visits will be approximately every 10-14 weeks, but 
may be adjusted as appropriate based on enrollment, visit schedule or subject status at the investigative 
site. 
The aim of these site visits will be: 
x
to verify that the site facilities remain adequate for performing the trial 
x
to verify that the principal investigator and site staff involved in the trial are working in compliance 
with GCP and protocol requirements  
x
to assess the consistency of data reported on the case report forms with the source data 
x
to check that Serious Adverse Events have been properly reported and that follow-up information or 
queries are correctly fulfilled 
x
to assist the site in resolving any outstanding queries 
x
to control the drug accountability process 
15.3 Audits 
AbbVie, any third party (e.g. a CRO) acting on behalf of the EORTC, or any domestic or foreign regulatory 
agency, may come at any time to audit or inspect their site and all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of documentation 
and practices, review of facilities, equipment and source data verification. 
The investigator will grant direct access to paper and/or electronic documentation pertaining to the 
clinical study (e.g. CRFs, source documents such as hospital patient charts and investigator study files) to 
these authorized individuals. All site facilities related to the study conduct could be visited during an 
audit (e.g. pharmacy, laboratory, archives …). The investigator agrees to co-operate and provide 
assistance at reasonable times and places with respect to any auditing activity. 


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If applicable, the company(ies) supplying the study drug(s), if different from the sponsor, may have 
access to anonymized data but will not have access to source documents. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters 
QA&C Unit immediately (contact at: 
 
In this way EORTC can provide support in preparing and/or facilitating the inspection. EORTC 
representatives/delegates may also attend the inspection. 
15.4 Central review of histology 
Central pathology review will be performed retrospectively at the end of the study for all patients 
included.  
Human biological material needed for the review is:  
x
A paraffin embedded tumor sample (tumor material at initial diagnosis and/or recurrence if available) 
(preferably a tumor block, otherwise 30 unstained slides)  
x
The anonymized local pathology report  
For further operational procedure refer to the study manual. 
The review will be done by: 
 
Josephine Nefkens Institute - Dept of Pathology 
Doctor Molewaterplein 50-60 
3000DR Rotterdam 
The Netherlands  
E-mail: 
  
Phone:  
 
Fax: 
 
 
15.5 External review of responses 
All MRI scans of all patients will be centrally reviewed using the RANO criteria during the conduct of the 
study. The radiology reviewer will be kept blinded to the study treatment. Centers will be requested to 
submit anonymized imaging data of all patients meeting this criterion, for external independent review 
(IRC) of responses (as described in the study manual). Reviews will be done independently without 
knowledge of the local assessment, with emphasis on T2 weighted and T2-FLAIR MR images. Central 
radiologist will give feedback on investigator reads shortly after MRI submissions for the first 15 PFS 
events. In additional, top recruiting sites will receive more frequent feedback from the central radiologist. 
Otherwise, local MRIs will be assessed by central review in batches.  
The outcome of the review and the local response evaluation will be captured in the database. Central 
radiographic review will be used for all endpoints and reporting to regulatory agencies. Details on MRI 
shipment/uploading are provided in the study manual. 
 
 


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15.6 Scan submission Quality Assurance and Quality Control in 
imaging 
The designated central imaging vendor will track all scans of all patients received from the sites and will 
request/query missing/incomplete scans. Furthermore, if the scans arrive in unacceptable quality or in a 
non-acceptable format, the site will be informed to provide substitute scans.  
Scans will be uploaded by the participating centers via a central imaging platform. Please refer to the 
imaging guidelines/manual for more details regarding submission of images, qualification of sites, and 
imaging QA/QC level description.  
16 Ethical considerations 
16.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) 
and/or the laws and regulations of the country, whichever provides the greatest protection of the 
patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized 
Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-
practice_en.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the applicable 
national legislation. 
16.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential 
identification number will be automatically allocated to each patient registered in the trial. This number 
will identify the patient and will be included on all case report forms. In order to avoid identification 
errors, the patient’s code (maximum of 4 alphanumerics) and date of birth (year only) will also be 
reported on the case report forms (for pediatric patients the month and year of birth). 
16.3 Informed consent 
All patients will be informed about 
x
the aims of the study 
x
the possible adverse events 
x
the procedures and possible hazards to which the patient will be exposed 
x
the mechanism of treatment allocation 
x
strict confidentiality of any patient data 
x
medical records possibly being reviewed for trial purposes by authorized individuals other than their 
treating physician 
The template of the patient’s informed consent statement is given as a separate document dated and 
version controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the responsibility 
of the Coordinating investigators for this trial (sometimes called National Coordinators) to adapt it to 
national/local requirements where necessary. 


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The translated informed consent documents are to be submitted to ethics committees for approval. The 
competent ethics committee for each institution must approve the informed consent documents before 
the center can join the study. It is the responsibility of the competent ethics committee to ensure that 
the translated informed documents comply with ICH-GCP guidelines and all applicable national 
legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the patient is 
free to refuse further participation in the protocol whenever he/she wants to. This will not have any 
impact on the patient’s subsequent care. Documented informed consent must be obtained for all 
patients included in the study before they are registered and/or randomized at the EORTC Headquarters. 
The written informed consent form must be signed and personally dated by the patient or by the 
patient’s legally acceptable representative. 
All of the above must be done in accordance with the applicable national legislation and local regulatory 
requirements. 
17 Administrative responsibilities 
17.1 The study coordinator 
The Study Coordinator works closely with the study team to develop the outline and full protocol and 
discusses the contents of the reports with the study team. The Study coordinator is responsible for 
publishing the study results. He/she will assist the Clinical Research Physician for answering some clinical 
questions concerning eligibility, treatment, and contributes to the medical review of the patients. 
Study coordinator: 
 
Erasmus MC - Daniel den Hoed Cancer Center 
(Postbus 5201) Groene Hilledijk 301, 
3075 EA Rotterdam 
The Netherlands 
Phone:  
 
Fax: 
 
 
E-mail: 
 
Study co-coordinator: 
 
Ospedale Bellaria 
Via Altura, 3 
Bologna 
Italy 
Phone:  
 
Fax: 
 
 
E-mail:
  
 
 


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17.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing the protocol, 
setting up the trial, collecting case report forms, controlling the quality of the reported data, organizing 
the medical review and generating reports and analyses in cooperation with the Study Coordinator. All 
methodological questions should be addressed to the EORTC Headquarters. 
KZd,YhZdZ^ 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
Fax: 
 
17.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the chairman and/or 
secretary of the group. 
For new membership contact Membership Committee at 
 
EORTC Brain Tumor group 
Chairman: 
 
UniversitaetsSpital Zurich 
Raemistrasse 100 
8091 Zurich 
Switzerland 
Phone:  
 
Fax: 
 
 
E-mail:
 
Secretary: 
 
Vrije Universiteit Medisch Centrum  
P.O. Box 7057 - (De Boelelaan 1117) 
1007MB Amsterdam 
Netherlands  
Phone:  
 
Fax: 
 
E-mail:
  
 
 


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17.4 AbbVie (Study Sponsor) 
AbbVie Study Designated Physician: 
 
Senior Medical Director AbbVie B.V. 
Oncology Development, Global Pharmaceutical R & D 
Wegalaan 9 
2132 JD Hoofddorp 
NETHERLANDS 
OFFICE: 
 
CELL:  
 
E-MAIL: 
 
18 Trial insurance 
Clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. An insurance certificate will be made available to the participating sites at the time of study 
initiation, as required per local requirements.  
19 Publication policy 
All publications must comply with the terms specified in the EORTC Policy 009 “Release of Results and 
Publication Policy” version 4.02 dated 19/03/2012.  
The final publication of the main trial results will be written by the EORTC Study Coordinator on the basis 
of the final analysis performed at the EORTC Headquarters and published in a major scientific journal.  
The final publication of associated translational research studies will be written by the Coordinator of the 
corresponding translational research study. 
Authors of the manuscript(s) will include the Study Coordinators, the investigators who have included 
more than 5% of the eligible patients in the trial (by order of inclusion), the central review pathologist, 
neuro-radiologists, the statistician and clinical research physician in charge of the trial at the EORTC 
Headquarters. For publication of translational research results, co-authors will also include scientific 
collaborators who made substantial contribution to the research. 
The title of all manuscripts will include “EORTC”, and all manuscripts will include an appropriate 
acknowledgment section, mentioning all investigators who have contributed to the trial, the EORTC 
Headquarters staff involved in the study, as well as AbbVie. 
Prior to submission, all publications (papers, abstracts, presentations, etc.) including data pertaining to 
patients from the present trial will be submitted for review to the EORTC Headquarters, to all co-authors, 
and to AbbVie. 
The above rules are applicable to publications involving any individual patient registered/randomized in 
the trial.  
The data collected during this study are confidential. Any publications or abstracts arising from this study 
require approval by EORTC and AbbVie prior to publication or presentation and must adhere to EORTC's 
publication requirements as set forth in the approved clinical trial agreement (CTA). All draft publications, 
or detailed summaries of any proposed presentations, must be submitted to the EORTC and AbbVie at 
the earliest practicable time for review, not less than 30 days (14 days for abstracts) before submission or 
presentation unless otherwise set forth in the CTA. 


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Ref. 5 
Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach J, Chang CH, Rotman M, Asbell 
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Ref. 6 
Simpsom JR, Horton J, Scott C, Curran W, Rubin P, Fischbach J, Isaacson S, Rotman M, Asbell SO, 
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Gorlia T, Stupp R, Brandes AA, Rampling RR, Fumoleau P, Dittrich C, Campone MM, Twelves CC, 
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der Maazen RWM. Reirradiation of primary brain tumors: survival, clinical response and 
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monotherapy, and in combination with lomustine, versus lomustine alone in patients with 
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Ref. 20 Weller M, Kaulich K, Hentschel B, Felsberg J, Gramatzki D, Pietsch T, Simon M, Westphal M, 
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Ref. 21 Prigent SA, Nagane M, Lin H, Huvar I, Boss GR, Feramisco JR, Cavenee WK, Huang HS. Enhanced 
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Herndon JE, Kunwar S, et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent 
malignant brain tumors. Neuro.Oncol. 2008 Jun;10(3):320-9 


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Ref. 33 Taphoorn MJ, Claassens L, Aaronson NK, Coens C, Mauer M, Osoba D, Stupp R, Mirimanoff RO, 
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Ref. 40 Korshunov A1, Ryzhova M, Hovestadt V, Bender S, Sturm D, Capper D, Meyer J, Schrimpf D, Kool 
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Appendix B: Abbreviations 
Abbreviations 
ADA 
Antidrug Antibody 
ADC 
Antibody-Drug Conjugate 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BOR 
Best Overall Response 
CNS 
Central Nervous System 
CR 
Complete Response 
CRR 
Complete Response Rate 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
Drug Induced Liver Injury 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DNA 
Deoxyribonucleic acid 
DR 
Duration of Response 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
EGFR 
Epidermal Growth Factor Receptor 
EGFRde2-7 (EGFRvIII) EGFR variant III containing deletion of exons 2-7 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
US Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FIH 
First in Human 
GBM 
Glioblastoma Multiforme 
GCP 
Good Clinical Practice 
GGT 
Gamma–Glutamyl Transferase 
GLP 
Good Laboratory Practice 


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Gtts 
Drops 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee  
IV 
Intravenous 
mAbs 
monoclonal Antibodies  
MMAF 
Monomethyl auristatin F 
MRI 
Magnetic Resonance Imaging 
NASH 
Non-Alcoholic Steatohepatitis 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NDFS 
Neurological Deterioration Free Survival 
OE 
Each Eye 
ORR 
Objective Response Rate 
OS  
Overall Survival 
PD 
Progressive Disease 
PE 
Physical Exam 
PG 
Pharmacogenetic 
PK 
Pharmacokinetic 
PR 
Partial Response 
RANO 
Response Assessment in Neuro-Oncology 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SMG 
Study Management Group 


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SmPC 
Summary of Product Characteristics 
TBL 
Total Bilirubin 
TMZ 
Temozolomide 
TRAC 
Translational Research Advisory Committee 
TTP 
Time to Progression 
ULN 
Upper limit of normal range 
WBC 
White Blood Cell 
 
Pharmacokinetic and Statistical Abbreviations 
AUC 
Area under the plasma concentration-time curve 
AUCt 
Area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
AUCь 
Area under the plasma concentration-time curve from time zero to infinity 
CL/F 
Apparent oral clearance 
Cmax 
Maximum observed plasma concentration 
t1/2 
Terminal phase elimination half-life 
Tmax 
Time to maximum observed plasma concentration 


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Appendix C: WHO performance status scale 
Grade 
Performance scale 
0 
Able to carry out all normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out light work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work; up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 


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Appendix D: New York Heart Association (NYHA) 
classification of heart failure 
 
Class I 
Patients with cardiac disease but without resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal 
pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or 
anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, 
dyspnoea or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased. 
 
(The Criteria Committee of the New York Heart Association: Diseases of the Heart and Blood Vessels; 
Nomenclature and Criteria for Diagnosis, 6th ed Boston, Little, Brown 1964). 


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Appendix E: Calculation of the glomerular filtration rate 
(GFR) 
 
COCKCROFT AND GAULT FORMULA 
 
For the calculation of GFR age is measured in years and weight is measured in kilograms. 
 
 
 
If serum creatinine is measured in μmol/l, the following formula applies: 
 
In males:     GFR[ml/min]   =  1.23 x (140 - age) x weight 
 
 
 
 
 
 
serum creatinine 
 
In females:  GFR[ml/min]   = 1.05 x (140 - age) x weight 
 
 
 
 
 
 
serum creatinine 
 
 
If serum creatinine is measured in mg/dl, the following formula applies: 
 
In males:     GFR[ml/min]   =  (140 - age) x weight 
 
 
 
 
 
  72 x serum creatinine 
 
In females:  GFR[ml/min]   = 0.85 x (140 - age) x weight 
 
 
 
 
 
 72 x serum creatinine 
 


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Appendix F: Common Terminology Criteria for Adverse 
Events 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the  
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the 
following address: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40 
. 
The EORTC Headquarters web site   https://www.eortc.be/services/doc/ctc/     provides a link to the 
appropriate CTC web site. This link will be updated if the CTC address is changed. 


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Appendix G: EORTC Quality of Life evaluation: 
guidelines for administration of questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
The instructions given below are intended to provide some general guidelines for collecting quality of life 
(QOL) data in EORTC studies. These instructions apply for all types of questionnaires. 
1. Who is the responsible person (RP) for QOL data collection? 
In each institution, the principal investigator is the responsible for the local organization of QoL data 
collection. This can be delegated to a physician, data manager, (research) nurse or a psychologist. Such a 
person should have the full protocol at his/her disposal as well as the questionnaire(s). This person would 
also be the intermediate contact point in case of any necessary clarification asked by the EORTC 
Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient who has to complete the QOL forms and preferably without help from others. 
In the case where a patient is too sick to fill out the questionnaire by him/herself or if the patient is not 
able to complete the questionnaire for such reasons as forgetting his/her glasses, another person could 
read the questions without making any suggestions and report the answers on the forms. It is not 
allowed for another person to fill in the questionnaire as if (s)he was the patient (proxy assessment) 
unless specifically allowed by the protocol. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the study and 
instructions for completing the questionnaires. 
The patient should be informed that participation in the QOL protocol is voluntary and that the 
information provided is confidential (identification is only for administrative purposes and includes date 
of birth and today’s date (completion date)). 
The following issues should be explained to the patient: 
x
The schedule of assessments. 
x
The questionnaire is a self administered questionnaire that should be completed by the patient 
him(her)self. The patient can ask for aid in reading or writing but should not let another person 
provide the answers. 
x
The patient should   circle   the choice that best corresponds to his/her situation. 
x
There is no right or wrong answer to any of these questions. The answers will not influence any 
 
medical decision making. 
x
All questions should be answered.  
x
The patient will be given a questionnaire in the default language(s) of the hospital. If desired, the 
 
patient may request another language. The RP will then contact the EORTC Headquarters for the 
 
appropriate translation. 


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The RP should make sure that the patient understands the instructions. 
At each subsequent assessment as defined by the protocol, the patient should receive the questionnaire 
from the RP or from other appropriate staff if the RP is unavailable. 
4. Where should the patient complete the questionnaire? 
The patient should complete the questionnaire at the clinic, and, ideally in a quiet, private room. If this is 
not possible, the waiting room is an acceptable alternative. In general it does not take long to complete 
the questionnaire, but patients should be given the time they need to answer all questions. 
ϱ͘tŚĞŶƐŚŽƵůĚƚŚĞǇĐŽŵƉůĞƚĞƚŚĞƋƵĞƐƚŝŽŶŶĂŝƌĞ͍ 
The timing of the planned QoL assessments is detailed in the protocol. When a QOL assessment is 
planned, the questionnaire should be given to the patient preferably before the meeting with the 
physician, ensuring that the patient has enough time to complete the questionnaire. If the patient is to 
receive a therapy, the questionnaire should be filled out before administration of the treatment (unless 
indicated otherwise in the protocol). The questionnaire should not be taken home and/or mailed (unless 
indicated otherwise in the protocol). 
6. Review of the completed questionnaire 
After the patient has completed the questionnaire, the person handling the questionnaire should: 
x
Complete the “Hospital Staff” specific data box. 
x
Check that the completion date is correctly filled in by the patient. 
x
Screen the questionnaire for omissions. 
If this is the case: 
x
Please ask the patient the reason for omissions. It may be that patient forgot to flip a page or did not 
understand a question. The patient should not be forced to provide an answer if (s)he does not wish 
to do so. 
x
Additional explanation may be provided, but the questions should not be rephrased. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life questionnaire the 
reason and the date of visit should be documented on the corresponding CRF (case report form).  
8. Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the 
original source document should be kept on site. As it is impossible to retrospectively collect missing 
quality of life data, please make sure the patient completes the questionnaire at the time-point when 
he/she is supposed to complete it. 
Thank you very much for your cooperation.  
E-mail: 
 


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Appendix H: Adverse Events expected due to GBM or 
progression of GBM 
x
Tinnitus 
x
Diplopia 
x
Dysphagia 
x
Hypoaesthesia oral 
x
Paraesthesia oral 
x
Facial pain 
x
Disease progression 
x
Pyrexia 
x
Subdural haematoma 
x
Subdural haemorrhage 
x
Abnormal loss of weight 
x
Decreased appetite 
x
Dehydration 
x
Anaplastic astrocytoma 
x
Glioblastoma 
x
Glioblastoma multiforme 
x
Malignant glioma 
x
Malignant neoplasm progression 
x
Neoplasm progression 
x
VIIth nerve paralysis 
x
Oculofacial paralysis 
x
Facial nerve disorder 
x
Facial paresis 
x
Facial neuralgia 
x
Hypoaesthesia 
x
Burning sensation 
x
Paralysis 
x
Dementia 
x
Dysarthria 
x
Agnosia 
x
Prosopagnosia 
x
Apraxia 
x
Hemiapraxia 
x
Gait apraxia 
x
Dyspraxia 
x
Agraphia 
x
Alexia 
x
Cerebral haemorrhage 
x
Cerebral haematoma 
x
Hyperaesthesia 
x
Ataxia 
x
Cerebellar ataxia 


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x
Cerebral ataxia 
x
Myoclonus 
x
Post-anoxic myoclonus 
x
Amnesia 
x
Ataxia 
x
Atonic seizures 
x
Balance disorder 
x
Brain compression 
x
Brain oedema 
x
Cerebrospinal fluid retention 
x
Cerebrospinal thrombotic tamponade 
x
Cervicogenic headache 
x
Clonic convulsion 
x
Clumsiness 
x
Cluster headache 
x
Convulsion 
x
Convulsions local 
x
Coordination abnormal 
x
Cranial nerve disorder 
x
Cranial nerve palsies multiple 
x
Cranial nerve paralysis 
x
Epilepsy 
x
Epileptic aura 
x
Exertional headache 
x
Fumbling 
x
Headache 
x
Hemianopia 
x
Hemiparesis 
x
Hemiplegia 
x
IIIrd nerve paralysis 
x
IIIrd nerve paresis 
x
Incoherent 
x
Intracranial pressure increased 
x
IVth nerve paresis 
x
Language disorder 
x
Lethargy 
x
Loss of consciousness 
x
Memory impairment 
x
Movement disorder 
x
Myoclonic epilepsy 
x
Paraesthesia 
x
Paresis cranial nerve 
x
Partial seizures 
x
Partial seizures with secondary generalisation 
x
Postictal headache 


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


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Appendix I: Evaluation of ABT-414 in Children with 
High Grade Gliomas 
This appendix provides information related to the evaluation of ABT-414 in children (M14-483 pediatric 
sub-study). Unless specifically addressed below, all of the adult protocol elements will apply to the 
pediatric population. 
Background  
Pediatric high grade gliomas [HGG] (WHO grade III and IV glioma and diffuse intrinsic pontine glioma 
[DIPG]) have no adequate therapy and are almost universally fatal. Unlike in adult GBM, EGFR 
amplification is rare (3% or lower) in pediatric HGG and screening for EGFR amplification is not routinely 
part of standard care for pediatric tumors, which makes it profoundly difficult to identify children with 
EGFR amplified HGG. Consequently, it is not feasible to conduct a stand-alone study in this population. It 
is most important that a pediatric study in EGFR-amplified HGG address whether a proposed dose of ABT-
414 can be used safely in the pediatric population, with recognition that assessment of efficacy beyond a 
description of outcomes in a very small number of subjects is likely infeasible. 
Molecular marker panels for subjects with HGG are increasingly including EGFR amplification assessment. 
Potentially eligible subjects for the pediatric sub-study may be identified by investigators from the results 
of locally arranged diagnostic testing. EGFR amplification will then be confirmed retrospectively by 
central FISH (Fluorescent In-Situ Hybridization) assay once subjects are enrolled on the study. 
To ensure that enough subjects can be enrolled to address pharmacokinetic and safety objectives, both 
eligibility criteria and subject treatment options need to be as flexible as possible. Data from adults 
receiving ABT-414 as monotherapy or in combination with temozolomide suggest that the toxicities of 
ABT-414 and temozolomide (predominantly ocular and hematologic, respectively) are independent of 
each other, with no evidence that one agent exacerbates the toxicity of the other, and there is no 
evidence of pharmacokinetic interactions between the two agents.  
To assess if there would be any additional toxicity of ABT-414 on patients aged under 3 years (compared 
to what is already known from the adult toxicity profile), Juvenile Crl:CD1(ICR) mice were administered 5, 
25, or 50 mg/kg/dose ABT-414 once every two weeks from Postnatal Day (PND) 7 to 70, followed by a 98 
day non-dosing recovery phase. ABT-414 administered to juvenile mice once every 2 weeks from Post 
Natal Day (PND) 7 to 70 was associated with adverse histological effects in the testes, lung, ovaries and 
ŚĞĂƌƚĂƚшϱŵŐͬŬŐ͘dŚĞƌĞĨŽƌĞ͕ĂŶŽ-observed-adverse-effect-level (NOAEL) for ABT-414 in juvenile mice 
was not established, and was determined to be <5 mg/kg (PND 63 Conjugated Antibody AUC of 15400 
μg*hr/mL). In addition, the overall systemic exposure to ABT-414 and its toxicity profile in this repeat 
dose juvenile mouse toxicity study was comparable to the toxicity profile observed in repeat dose adult 
mouse toxicity studies, and no new or unexpected toxicities were observed. Therefore, following the 
completion of the mouse study, the pediatric sub-study was opened to include patients aged under 3 
years. 
Allowing investigator discretion to use ABT-414 as monotherapy or in combination with temozolomide 
(informed by factors such as patient preference and prior exposure to temozolomide) minimizes barriers 
to subject inclusion, and it is reasonable to extrapolate from adult data that variable temozolomide use in 
children receiving ABT-414 will not affect the ability to assess pharmacokinetic or safety objectives of this 
sub-study. The use of TMZ in combination with ABT-414 for a pediatric patient must be reviewed by the 
EORTC/AbbVie medical monitor prior to the initiation of therapy. The safety profile of ABT-414 in 
combination with other anti-neoplastic agents has not been assessed to date. 


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This appendix will describe the evaluation of pharmacokinetics, safety and efficacy of ABT-414 in the 
pediatric HGG population, allowing access to a novel therapy for those who are in great need of better 
treatment options. Subjects < 18 years of age with pediatric HGG whose tumors demonstrate EGFR 
amplification will be assigned to this pediatric sub-study. Pediatric subjects will receive open-label ABT-
414 at a dose of 1.0 mg/kg for subjects who are 6 to 17 years old (at the date of first ABT-414 dose), or 
1.3 mg/kg for subjects who are 0 to 5 years old. These dosages are expected to produce pharmacokinetic 
drug exposures comparable to a 1.0 mg/kg dose in adults, the recommended starting dose for the adult 
portion of the study. 
Objectives of the sub-study 
The primary objectives will be the evaluation of safety, tolerability and pharmacokinetics of ABT-414 in a 
pediatric population < 18 years of age. The secondary objective will be to assess the effect of ABT-414 on 
tumor response per RANO (Response Assessment in Neuro-Oncology) criteria. 
 
Primary Endpoints of the pediatric sub-study:  
Safety including toxicities according to CTCAE criteria (Percentage of subjects with adverse events from 
subject's first visit until 49 days after the subject's last dose of study drug) 
Pharmacokinetic parameters for ABT-414 and cys-mcMMAF (Maximum observed serum concentration 
(Cmax) for ABT-414 and Cys-mcMMAF (toxin), half-life for ABT-414 and Cys-mcMMAF (toxin), and total 
drug exposure over time (AUC: Area Under the Curve) for ABT-414 and Cys-mcMMAF (toxin) 
 
Secondary Endpoints of the pediatric sub-study: 
Objective response rate, best response rate, and duration of response based on RANO criteria 
Overall survival, Time to Progression, and Time to progression-free survival 
Changes in neurological status and functioning (including PedsQL cancer module) 
 
Exploratory Endpoints of the pediatric sub-study: 
Assessment for tumor aberrations of H3.1, H3.3, BRAF, CDKN2A/B, IDH1, INI1, MGMT, PTEN. 
Anti-drug antibodies 
 
Methodology:  
This is an uncontrolled, open-label, single-arm global study. 
Patient selection criteria: Registration and enrollment of pediatric subjects is projected to take up to 3 
years and the study will remain open after the adult portion of the study has completed. Given the rarity 
of the eligible population, the pediatric registration and enrollment criteria are written to be as inclusive 
as possible. Registration and Enrollment criteria for pediatric subjects are noted below. 
 
 
 


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Registration criteria 
x
Subjects must have a histologically proven high grade glioma (WHO grade III glioma [e.g anaplastic 
astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma], grade IV glioma [e.g 
glioblastoma, gliosarcoma] or DIPG). 
x
Subjects must be <18 years of age 
x
The tumor tissue must have been determined to have EGFR amplification, (by local or other testing 
service).  
x
Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE] tumor) for 
central testing of EGFR amplification. There must be sufficient tissue to submit for (retrospective) 
confirmatory EGFR FISH testing at the study-designated central laboratory. If there are less than the 
requested 30 slides available, it is acceptable to continue the registration process, assuming sufficient 
material is available for central testing of EGFR amplification. 
x
Before patient registration and study-related procedures that would not have been performed as part 
as standard care, written informed consent/assent by subjects and/or their legal guardians must be 
given according to ICH/GCP, and national/local regulations. 
Enrollment criteria 
x
Subject must either have recurrent/progressive tumor or, if newly diagnosed, have completed 
radiation therapy at least 4 weeks prior to first dose of ABT-414.  
x
The investigator must confirm that the subject is able to complete the procedures required in order 
to assess the primary endpoints, including PK blood draws and safety assessments over the first four 
weeks of therapy including Day 1 of Week 5. 
x
The investigator believes that the potential benefit of treating the pediatric subject with ABT-414 
outweighs the expected risks and that this treatment is in the best interests of the pediatric subject. 
x
Subjects and/or their legal guardians must be able to understand the risks and potential benefits, and 
grant assent/consent to participate by signing the applicable pediatric-specific informed assent 
and/or consent forms. 
x
Subject has sufficiently recovered from previous therapy.  
x
(For recurrent disease) No prior RT with a dose over 65Gy to the brain, stereotactic radiosurgery or 
brachytherapy unless the recurrence is histologically proven 
x
No current or recent (within 4 weeks or 5 half-lives (whichever is shorter) before enrollment) 
treatment with another investigational drug 
x
ZĞŶĂůĨƵŶĐƚŝŽŶ͗ĐĂůĐƵůĂƚĞĚĐƌĞĂƚŝŶŝŶĞĐůĞĂƌĂŶĐĞшϯϬŵ>ͬŵŝŶďǇƚŚĞŽĐŬĐƌŽĨƚ-Gault formula 
(Appendix E) ĨŽƌƉĞĚŝĂƚƌŝĐƉĂƚŝĞŶƚƐшϭϮǇĞĂƌƐŽĨĂŐĞĂŶĚĞƐƚŝŵĂƚĞĚŐůŽŵĞƌƵůĂƌĨŝůƚƌĂƚŝŽŶƌĂƚĞшϯϬ
mL/min/1.73 m2 by modified Schwartz equation for pediatric patients < 12 years of age  
 
 
 


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Modified Schwartz equation (pediatric patients < 12 years of age)a: 
 
CrCl (ml/min/1.73 m2) = (K * Ht) / Scr 
 
height (Ht) in cm; serum creatinine (Scr) in mg/dl 
K (proportionality constant): 
 
Female Child (< 12 years): K=0.55 
Male Child (< 12 years): K=0.70 
 
a. From FDA guidance on “General Clinical Pharmacology Considerations for Pediatric Studies for Drugs 
and Biological Products”, December 2014 
 
x
>ŝǀĞƌĨƵŶĐƚŝŽŶ͗dŽƚĂůďŝůŝƌƵďŝŶчϭ͘ϱƚŝŵĞƐƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů;h>EͿ͕ƐƉĂƌƚĂƚĞŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ
;^dͿ͕ĂŶĚůĂŶŝŶĞŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;>dͿчϯƚŝŵĞƐh>E͘^ƵďũĞĐƚƐǁŝƚŚ'ŝůďĞƌƚΖƐƐǇŶĚƌŽŵĞ
documented in medical history may be enrolled if total bilirubin is < 3 times ULN. 
Not allowed are subjects with known chronic liver disease and/or cirrhosis documented by the 
presence of one or more of the following (assessments to be performed per standard of care only 
if liver disease is suspected): 
x
Liver biopsy with histologic findings consistent with cirrhosis 
x
CT or US evidence of liver disease with or without portal hypertension 
x
Physical examination and clinical and laboratory evidence of chronic liver disease 
x
Colloid shift on a liver-spleen scan 
x
A Child-Pugh score of 6 or higher (see Appendix M) 
x
Absence of pregnancy. Female subjects of childbearing potential must be using an adequate method 
of contraception to avoid pregnancy from Study Day 1 throughout the study and for 6 months beyond 
the end of treatment in such a manner that the risk of pregnancy is minimized. In general, the 
decision for appropriate methods to prevent pregnancy should be determined by discussions 
between the investigator and the study subject. Female subject of childbearing potential includes any 
female who has experienced menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Female 
subjects of non-childbearing potential do not need to use birth control.  
Pediatric female patients are not considered to be of child bearing potential if meeting any of the 
following criteria: 
x
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 
x
Females who have not experienced menarche (at least one menstrual period). 
x
Female subjects of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to enrollment. 
x
Female subjects must not be pregnant, breastfeeding, or considering becoming pregnant during the 
study or for at least 6 months(5 × the half-life of AbbVie product or 30 days, whichever is longer, plus 
an additional 30 days to the 5 half-lives, if genotoxic) after the last dose of study drug. 


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x
Male subjects that are sexually active with female partner(s) of childbearing potential must agree to 
use an effective method of contraception from Study Day 1, during the treatment period and for at 
least 6 months after the last study treatment.  
x
Male subjects must not be considering fathering a child or donating sperm during the study or for at 
least 6 months after the last dose of study drug. 
x
Before patient registration, enrollment and study-related procedures that would not have been 
performed as part as standard care, written informed consent must be given according to ICH/GCP, 
and national/local regulations. 
x
Subject must not have a history of a major immunologic reaction to any IgG-containing agent. 
Important note: All eligibility criteria must be adhered to, in case of deviation discussion with the study 
coordinator is mandatory. 
 
Pre-Enrollment Recommendations to Support Efficacy Evaluation:  
Although not required for study eligibility, the following guidelines should be followed whenever possible 
to maximize the likelihood that tumor assessments yield data interpretable for tumor response 
assessment: 
If the subject has been operated upon for recurrence: 
Residual and measurable disease after surgery is not required, but surgery must have confirmed 
recurrence 
A post-surgery MRI should be available following surgery and an additional MRI scan (baseline scan) has 
to be done within 2 weeks prior to the first dose of ABT-414. 
Surgery completed at least 2 weeks before the first dose of ABT-414 and subjects should have fully 
recovered as assessed by investigators. Criteria for full recovery will include absence of active post-
operative infection, recovery from medical complications and capacity for fluid and food intake. 
Dosage of steroids is stable or decreasing for 7 days prior to the baseline MRI scan. 
Randomization: Subjects will not be randomized. All subjects will receive ABT-414 at a starting dose of 1.0 
mg/kg (age 6-17) or 1.3 mg/kg (age 0 - 5). Treatment should start within 96 hours from enrollment. No 
stratification will be used. 
 
Study Procedures:  
The subjects will follow the same study procedure table as described in the adult protocol (refer to 
Chapter 6), with the exception of research blood samples, ocular assessments, and long term follow up as 
described in this appendix. 
 
 


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The PK schedule for 3 to 17 year olds will be as follows:  
 
Cycle 1 
Day 1  
Cycl
e 1 
Day 
2 
Cycle 
1 Day 
3 
Cycle 
1 Day 
5 
Cycle 
1 Day 
8 
Cycle 
1 Day 
15 
Cycle 
2 
Day1 
Cycle 
3 Day 
1 
Cycle 5, 
Cycle 7 etc. 
Every two 
cycles 
starting 
from Cycle 5 
35 Day 
Safety 
Follow-
up 
PK – ABT-414 
Assay 
Xa 
Xb 
Xc 
Xd 
Xe 
Xf 
Xf 
Xf 
Xg 
Xh 
PK – Cys-mc 
MMAF Assay 
Xa 
Xb 
Xc 
Xd 
Xe 
 
 
 
 
 
PK Antidrug 
Antibody Assay 
(ADA/nADA) 
Xg 
 
 
 
 
 
Xg 
Xg 
Xg 
Xh 
 
The PK schedule for < 3year old will be as follows:  
 
Cycle 1 
Day 1  
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Day1 
Cycle 3 
Day 1 
Every four 
cycles 
starting 
from Cycle 
5 
35 Day 
Safety 
Follow-up 
PK – ABT-414 Assay 
Xi 
Xe 
Xf 
Xg 
Xg 
Xg 
Xh 
PK Antidrug 
Antibody Assay 
(ADA/nADA) 
Xg 
 
 
Xg 
Xg 
Xg 
Xh 
 
a. Samples will be collected before infusion (0 hour, pre-dose), immediately after ABT-414 infusion, and 
4 hr after the start of infusion. 
b. One sample at the 24-hour time point only 
c. One sample at the 48-hour time point only (within ± 4 hours) 
d. One sample at the 96-hour time point only (within ± 24 hours) 
e. One sample at the 168-hour time point only (within ± 4 hours) 
f. Samples will be collected before infusion (0 hour, pre-dose) and immediately after ABT-414 infusion 
g. Samples will be collected before infusion (0 hour, pre-dose) 
h. Samples will be collected 35 days (within a two-day window) after last ABT-414 infusion for subjects 
able to return to the clinic for the follow-up visit. 
i. Samples will be collected immediately after ABT-414 infusion 
 
 


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NOTE:  
For 0 - 5 year-old population 1mL of blood for each analyte (ABT-414, cys-mcMMAF) will be collected. For 
ABT-414, the resulting serum of ~0.5mL will be put into one split and labeled accordingly. For cys-
mcMMAF, the resulting ~0.45mL plasma will be equally distributed into two splits. For ADA and nADA 
1ml of blood will be drawn and the resulting serum volume of approximately 0.5mL will be split into two 
tubes and labeled accordingly.  
For 6 – 17 year-old population 2 mL of blood will be collected for ABT-414 and the resulting ~1 mL serum 
will be split into two tubes and labeled accordingly.  
1 mL of blood will be collected for cys-mcMMAF and the resulting ~0.45mL plasma will be equally 
distributed into two splits. For ADA and nADA, 1ml of blood will be drawn and the resulting serum 
volume of approximately 0.5mL will be split into two tubes and labeled accordingly. 
Pharmacogenetic (PG) sample: optional 3mL blood sample collection for all pediatric subjects that 
consent. If the PG sample is not collected at the Day 1 visit, it may be collected anytime during the study.  
MRI scanning frequency will be as described in the adult protocol, but may be less frequent if deemed to 
be appropriate by the investigator (e.g. subject is unable to tolerate the scanning frequency). 
 
Therapeutic regimens, expected toxicity, dose modifications:  
ABT-414 will be administered at a starting dose of 1.0 mg/kg or 1.3 mg/kg IV (depending on the age) over 
30 – 40 minutes or as directed by the administration guidelines every 2 weeks. ABT-414 treatment will 
continue for up to 12 months. Prophylactic steroid eye drops will be administered as described in the 
adult protocol. Each subject enrolled will have PK sampling to assess the exposure of ABT-414 in the 
pediatric population. Pediatric PK data will be assessed on an ongoing basis throughout the study, and 
the ABT-414 dosage or frequency of dosing may be adjusted for individual pediatric subjects or for all 
pediatric subjects subsequently enrolled if exposures are substantially outside the range predicted from 
the adult experience. If the dose is revised for all newly enrolling pediatric subjects, the Sponsor will 
notify the sites of this new dose as a written communication, and the change in dose will be described in 
a later amendment to the protocol. ABT-414 has not been studied in children; therefore the expected 
toxicities are unknown but expected to be similar to the adult experience. Dose modifications from 
toxicities will follow the recommendations in the adult protocol, with successive dose reductions from 
1.0 mg/kg to 0.75 mg/kg to 0.5 mg/kg in 6 – 17 year-olds, and from 1.3 mg/kg to 1.0 mg/kg to 0.67 mg/kg 
in 0 - 5 year-olds. More aggressive dose reductions are allowed if the investigator believes that it is in the 
best interest of the subject. 
If ABT-414 is used in combination with temozolomide, ABT-414 will be dosed on Day 1 and Day 15 of the 
temozolomide cycle (assuming a standard regimen of 200 mg/m2/day for 5 days of each 28-day cycle; for 
other temozolomide schedules, timing of the ABT-414 dosing schedule should be discussed with the 
medical monitor). Temozolomide will be allowed only if its use is in accordance with local clinical 
practice. Temozolomide will not be considered an investigational product for the study (unless this is a 
local requirement). Anti-neoplastic agents other than temozolomide are specifically prohibited during 
study treatment unless allowed after discussion with the EORTC study chair. Live attenuated vaccines are 
not allowed during the study treatment period and for a period of 49 days after last ABT-414 
administration. 
 
 


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Clinical evaluation, laboratory tests, and follow-up:  
The clinical evaluation, laboratory tests and follow up will follow the adult protocol, except as noted 
below. 
Pediatric subjects will have an ophthalmology examination during screening (baseline); prior to dosing 
(within 7 days) on Day 1 of cycles 2, 3, 4 and all even-numbered cycles thereafter while ABT-414 
treatment is being received; at the 49-Day Safety Follow-Up visit; and at any other time as clinically 
indicated. The schedule of eye examinations may be altered as appropriate to synchronize with ABT-414 
dosing if the frequency of ABT-414 dosing is altered as described above.  
Physical exams will include regular height assessment (at a minimum height should be collected once 
every 3 months whilst on treatment). The performance status collected will be KĂƌŶŽĨƐŬǇ;ĂŐĞшϭϲǇĞĂƌƐͿ 
or Lansky (age < 16 years), and WHO status if initially enrolled prior to implementation of Amendment 5 
of the protocol. See Appendix J. 
The PedsQL Cancer Module will be administered as a QoL measure, in place of the EORTC QLQ C30 and 
BN20. See Appendix K. 
Long-term follow up: All subjects will be followed up every 6 months for 5 years following the study and 
annually thereafter until death or loss to follow up. Subjects will be evaluated in long-term follow-up care 
clinics for:  
x
visual functioning  
x
neurocognitive adverse events 
x
possible treatment related AEs (see section 7.2.1.8) 
x
serious AEs (see section 7.2.1.8) 
x
growth and developmental delays 
x
progression/relapse and survival 
Accurate information on the age (years and months) at the time of the adverse reaction, weight, height, 
dose (including individual and total daily dose of study drugs), relevant medical history, other drugs, and 
onset of reaction will be collected. 
In case hepatic laboratory abnormalities are observed, follow guidance below in place of section 5.5.1.4; 
Appendix L should also be followed.  
 
 


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ABT-414 Dose Modification Guidelines for Hepatic Laboratory Abnormalities in Pediatric patients: 
Hepatic Laboratory Abnormality 
ABT-414 
ALT or AST > ϯǆďƵƚчϱǆh>EΎ 
(and TBL чϮǆh>EͿ 
May proceed with dosing. 
Perform testing (ALT, AST, ALP, TBL) within 3 days prior to 
next dose. 
ALT or AST >5x ULEΎďƵƚчϮϬǆ
h>E;ĂŶĚd>чϮǆh>EͿ 
Hold drug regardless of assessed relationship to drug. See 
Appendix L for guidelines on repeat testing (ALT, AST, ALP, 
TBL) and evaluation. 
Dosing may not be resumed until ALT and AST have 
ƌĞĐŽǀĞƌĞĚƚŽчϱǆh>EΎ 
Dosing may be resumed at the same dose if ALT or AST was 
elevated >5x 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 section 
5.5.1 ABT-414 Dose Modification Table) if ALT or AST was 
elevated >5x ULN* for more than 2 weeks and no other 
likely cause has been identified. 
 
Following dose reduction, iĨ>dĂŶĚ^dƌĞŵĂŝŶчϱǆh>EΎ
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. 


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Hepatic Laboratory Abnormality 
ABT-414 
ALT or AST > 20x ULN  
 
or  
 
ALT or AST >3x ULN and TBL >2x 
ULN  
Hold drug regardless of assessed relationship to drug. See 
Appendix L 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 чϱǆh>EĂŶĚd>чϮǆh>E 
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 the following are met: 
x
the subject has shown important benefit from the 
drug and other options are not available, 
x
>dĂŶĚ^dŚĂǀĞƌĞĐŽǀĞƌĞĚƚŽчϱǆh>EĂŶĚd>
ŚĂƐƌĞĐŽǀĞƌĞĚƚŽчϮǆh>E͕ 
x
the subject and/or subjects legal guardians have 
been informed of the potential risk and have 
assented/consented to the rechallenge (as 
appropriate) 
x
close follow-up of the subject is feasible. 
* If elevated at baseline, either 5x the baseline value or 8x ULN, whichever is lower 
 
Criteria of evaluation:  
Unless otherwise stated, the criteria of evaluation will be the same in children as in adults. QoL will be 
reported descriptively. For the primary endpoint of safety, all adverse events will be coded according to 
MedDRA preferred term and reported and graded using the NCI CTCAE v4. For the safety assessment, a 
dose limiting toxicity (DLT) will be defined as any grade 3 or 4 adverse event that is attributed to ABT-414, 
or an ABT-414 toxicity that results in a delay of the second dose of ABT-414 by more than 14 days. 
 
 


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Statistical considerations:  
There will be no maximum enrollment for children with HGG and EGFR amplification; however it is 
expected that at least 6 subjects will be enrolled. A dose in children where there are 1 or fewer dose 
limiting toxicities (DLTs) is expected to be determined. Given the small expected sample size, the 
pharmacokinetic profile, safety assessments, and efficacy evaluations, including neurological status and 
PedsQL™ Cancer Module Questionnaires will be summarized descriptively. 
Kaplan-Meier survival curve will be estimated for overall survival. Joint Kaplan-Meier survival plots with 
matched historical patients at least from Korshunov (2015) (Ref. 40) will also be presented. 
Pharmacokinetic parameters of ABT-414 and Cys-mcMMAF will be determined by noncompartmental 
methods. Individual pharmacokinetic parameters will be listed and summarized. The pediatric 
pharmacokinetic data may be analysed with adult pharmacokinetic data from other studies in a non-
linear mixed effects modelling to estimate population pharmacokinetic parameters of ABT-414 and csy-
mcMMAF, such as clearance and volume of distribution. The effect of demographic and/or disease-
specific variable(s) on the pharmacokinetic parameters of ABT-414 and csy-mcMMAF will also be 
examined. 
Assuming tŚĞƐĂŵĞW<ǀĂƌŝĂďŝůŝƚǇĂƐŝŶĂĚƵůƚƐ͕шϲƉĞĚŝĂƚƌŝĐƐƵďũĞĐƚƐǁŝůůǇŝĞůĚĂƚǁŽ-sided 95% confidence 
interval within 60% and 140% of the geometric mean estimate for the area under the concentration-time 
curve (AUC) with greater than 90% probability. This criteria follows FDA draft guidance on the General 
Clinical Pharmacology Considerations for Pediatric Studies (released Dec 2014). 
For a sample size of 6 in HGG with EGFR amplification, the probability of observing at least 1 tumor 
response will be 82.2% if the true response rate is 25%.  
Response rate 
Probability of observing 1 or more tumor responses 
Sample size N = 6 
Sample size N = 9 
Sample size N = 12 
15% 
62.3% 
76.8% 
85.8% 
20% 
73.8% 
86.6% 
93.1% 
25% 
82.2% 
92.5% 
96.8% 
 
All subjects who receive at least one dose of ABT-414 will be included in analyses. No interim analysis is 
planned.  
 
Data Monitoring:  
The EORTC and sponsor study teams will have open access to pediatric data throughout the study to 
inform the ongoing conduct of this open-label sub-study. EORTC will identify at least three individuals (a 
statistician, the PI, and a clinician from headquarters) that will review the safety events from the 
pediatric patients at the following timepoints: 4 weeks after each subject is enrolled and again at q4-6 
month intervals while there are subjects that remain on therapy. If there are no subjects on active 
therapy, then the EORTC will not hold pediatric safety reviews. 
Otherwise, data monitoring will be the same as specified for the adult population (refer to Chapter 9). 
Pediatric data will be analyzed separately from the adult study, but findings will be compared to those 
from the adult study. Pediatric data will not be included in the efficacy and safety analyses of the adult 
main study.  
 


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Translational research:  
Tumor specimens will be collected where feasible for the same biomarker analyses that are planned for 
the adult population. Central molecular testing will include but not be limited to EGFR, H3.1, H3.3, BRAF, 
CDKN2A/B, IDH1, INI1, MGMT, PTEN. Insufficient tissue for Translational Research after EGFR 
amplification analysis will not prevent enrollment of the pediatric patients. 
 
Forms and procedures for collecting data:  
Data will be reported on the forms specifically designed by the EORTC Headquarters for this pediatric 
sub-study. Forms will be sent electronically to the EORTC Headquarters through the VISTA/RDC (Remote 
Data Capture System) as outlined in Chapter 14 of the adult protocol.  
 
Informed consent:  
Subjects and/or their legal guardians must be able to understand the risks and potential benefits and 
grant assent/consent to participate by signing a pediatric-specific informed assent/consent form(s) as per 
local and country specific laws and regulations. 
 


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Appendix J: Karnofsky and Lansky Performance Status 
Karnofsky Performance status, for assessment in Pediatric patients aged 16 or older.  
Performance 
status %  
Comments  
100  
Normal. No complaints. No evidence of disease.  
90  
Able to carry on normal activity. Minor signs or symptoms of disease.  
80  
Normal activity with effort. Some signs or symptoms of disease.  
70  
Cares for self. Unable to carry on normal activity or to do active work.  
60  
Requires occasional assistance, but is able to care for most of personal needs.  
50  
Requires considerable assistance and frequent medical care.  
40  
Disabled. Requires special care and assistance.  
30  
Severely disabled. Hospital admission is indicated although death is not imminent.  
20  
Hospitalization necessary. Very sick, active supportive treatment necessary.  
10  
Moribund; fatal processes progressing rapidly.  
0  
Dead.  
 
(Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutics in cancer. In: MacLoed CM, ed. 
Evaluation of Chemotherapeutic Agents. New York: Columbia University Press, 1949; page 196.) 
 
 
 


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Lansky Performance status for patients aged under 16 years.  
Performance 
status %  
Comments  
100  
Fully active, normal 
90  
Minor restrictions in physically strenuous activity 
80  
Active, but tires more quickly 
70  
Both greater restriction of, and less time spent in, active play 
60  
Up and around, but minimal active play; keeps busy with quieter activities 
50  
Gets dressed, but lies around much of the day; no active play; able to participate in all 
quiet play and activities 
40  
Mostly in bed; participates in quiet activities 
30  
In bed; needs assistance even for quiet play 
20  
Often sleeping; play entirely limited to very passive activities 
10  
No play: does not get out of bed 
0  
Unresponsive 
 
 (Lansky SB, List MA, Lansky LL, et al. The measurement of performance in childhood cancer patients. 
Cancer 1987; 60:1651–1656) 
 
 


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Appendix K: PedsQL Guidelines for Administration 
The following guidelines are intended for use by individuals trained in the administration of standardized 
questionnaires. The PedsQL™ administrator is crucial in developing rapport with the respondents, 
emphasizing the importance of the questionnaire, addressing concerns, and ensuring that the PedsQL™ is 
completed accurately and confidentially. 
General Protocol 
If feasible, the PedsQL™ should be completed before the respondents complete any other health data 
forms and before they see their physician or healthcare provider. 
PedsQL™ Cancer Module Questionnaires should be completed at the visit as below: 
Age 0-1 
No questionnaire  
Age 2-4 
Parent questionnaire (2-4) 
Age 5-7 
Interview administered young child (5-7) AND parent 
questionnaire (5-7) 
Age 8-12 
Child self-report (8-12) AND parent questionnaire (8-12) 
Age 13-18 
Adolescent self-report (13-18) AND parent questionnaire (13-18) 
 
Parents, Children (8-12 years) and Teens (13-18 years) may self-administer the PedsQL™ after 
introductory instructions from the administrator. If the administrator determines that the child or teen is 
unable to self-administer the PedsQL (e.g., due to illness, fatigue, reading difficulties), the PedsQL 
should be read aloud to the child or teen. For the Young Child (5-7 years), the PedsQL™ should be 
administered by reading the instructions and each item to the young child word for word. At the 
beginning of each subscale repeat the recall interval instructions (one month) to remind the young child 
to respond only for that specific recall interval. Use the separate page with the three faces response 
choices to help the young child understand how to answer. When reading items aloud to a child, 
intonation should be kept neutral to avoid suggesting an answer. 
If a child has difficulty understanding the age-appropriate PedsQL, the preceding age group version 
may be administered to the child (e.g., administering the Young Child (5-7 years) Self-Report version with 
the three faces response choices to an 8 year old). However, if a child presents with severe cognitive 
impairments (as determined by the administrator), the PedsQL may not be appropriate for that child. 
In such cases, only the Parent-Proxy Report should be administered to the child’s parent. 
The parent and child must complete the questionnaires independently of one another. Discourage the 
parent, child, or other family members from consulting with one another during the completion of the 
questionnaire. Let them know that they can feel free to discuss their answers following completion of the 
questionnaires, but that it is important to get both the parent’s and the child’s individual perspectives. If 
you are administering the questionnaire to the child, the child should be facing away from the parent. 
If the child or parent has a question about what an item means or how they should answer it, do not 
interpret the question for them. Repeat the item to them verbatim. Ask them to answer the item 
according to what they think the question means. If they have trouble deciding on an answer, ask them 
to choose the response that comes closest to how they feel. The child and/or the parent has the option 
of not answering a question if they truly do not understand the question.  


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If a parent/child asks you to interpret the responses, tell her/him that you are not trained to interpret or 
provide a score for the answers given. If the PedsQL™ is being used for a clinical study, let the 
parent/child know that their answers will be combined with other participants’ answers and analyzed as 
a group rather than as individual respondents. 
Document all reasons for refusals and non-completions of the PedsQL™. 
 
Administering the PedsQL™ 
 
The following scripts have been developed as a guide to introduce the PedsQL™ to the child and his/her 
parent(s). Modify the language to a style that is most appropriate for you and the respondent. 
 
For the child: 
"The PedsQL™ asks you questions about how you feel and what you think about your health. It is not a 
test, and there are no right or wrong answers. It takes about 5 minutes to complete. If you have any 
questions, please let me know." 
 
For the parent: 
"The PedsQL™ is a questionnaire that assesses health-related quality of life in children and adolescents. It 
contains questions about your child’s physical, emotional, social, and school functioning in the past one 
month. 
The PedsQL™ is brief and typically takes less than 5 minutes to complete. It is not a test, and there are no 
right or wrong answers. Please be sure to read the instructions carefully and choose the response that is 
the closest to how you truly feel. Please do not compare your answers with your child's responses. We 
are interested in your and your child’s individual perspectives. However, feel free to discuss the 
questionnaire with your child after you have both completed it and returned it to me. If you have any 
questions, please let me know." 
 
Provide the respondent with a pen or pencil and a solid writing surface. If a table is not available, the 
participant should be provided with an item such as a clipboard. Remain nearby should questions or 
concerns arise. 
When the parent/child returns the PedsQL™, look it over and check to see that all answers have been 
completed. Verify that no item has more than one response. If any responses are incomplete, illegible, or 
there are multiple responses for an item, please ask the parent or child to indicate their response. 
Ask the participants if they had any difficulties completing the questionnaire or if they have any other 
comments regarding the questionnaire. Document any important feedback. 
Thank the parent and child for taking the time to complete the questionnaire. If the study design involves 
following up with these respondents, let them know that they may be asked to complete the PedsQL™ 
again at another time. Indicate when they can expect to be contacted again if known. 
 
 
 


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Review of the completed questionnaire 
After the patient or parent has completed the questionnaire, the person handling the questionnaire 
should: 
x
Complete the “Hospital Staff” specific data box. 
x
Check that the completion date is correctly filled in by the patient. 
x
Screen the questionnaire for omissions. 
If this is the case: 
x
Please ask the patient or parent the reason for omissions. It may be that patient forgot to flip a page 
or did not understand a question. The patient or parent should not be forced to provide an answer if 
(s)he does not wish to do so. 
x
Additional explanation may be provided, but the questions should not be rephrased. 
Missing forms 
If for some reason the patient or parent is unable or does not wish to complete a quality of life 
questionnaire the reason and the date of visit should be documented on the corresponding CRF (case 
report form).  
Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the 
original source document should be kept on site. As it is impossible to retrospectively collect missing 
quality of life data, please make sure the patient or parent completes the questionnaire at the time-point 
when he/she is supposed to complete it. 
Thank you very much for your cooperation. If you have any remarks about this leaflet or if you need 
further information, please contact: 
Quality of Life Department - EORTC Headquarters: 
Phone: 
 
&Ăǆ͗
 
E-mail: 
 
 
 


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Appendix L: Hepatic Laboratory Abnormalities (safety 
monitoring and observation guidelines) 
 
This section provides information on safety monitoring, evaluation of potential causes, and appropriate 
documentation for subjects with hepatic laboratory abnormalities suggesting potential drug-induced liver 
injury (DILI). It was adapted with modifications from the FDA Guidance for Industry, Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM17
4090.pdf) in consultation with a hepatologist with expertise in DILI. 
 
Information derived from the scientific literature and public databases on liver injury attributable to 
prescription and nonprescription medications, herbals and dietary supplements can be found at the 
LiverTox database (https://livertox.nlm.nih.gov). 
 
If a subject develops one of the following laboratory abnormalities, hepatic laboratory abnormalities 
should be confirmed by repeat testing, and the subject should be monitored and evaluated as described 
in this section, regardless of the assessed relationship to the study treatments: 
 
x
ALT or AST > 3× ULN and TBL > 2× ULN, or 
x
ALT or AST > 5x ULN (or >5x the baseline value if elevated or >8x ULN, whichever is lower) 
 
Confirmation of Liver Test Abnormalities 
For subjects meeting either of the criteria above, confirmation of hepatic laboratory abnormalities should 
be done as follows:  
x
Repeat testing of all four of the usual measures (ALT, AST, alkaline phosphatase, and TBL) 
should be performed within 3 days of the initial abnormality to confirm the abnormalities and to 
determine if they are increasing or decreasing. 
x
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.  
x
The need for prompt repeat testing is especially great if AST or ALT is >3x ULN and TBL > 2x 
ULN.  
x
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.  
x
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. 
 
 


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Close Observation 
It is appropriate to initiate close observation 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 (as described above) persist or if repeat testing shows: 
x
ALT or AST > 5x ULN (or 5x baseline if elevated or >8x ULN, whichever is lower) or  
x
ALT/AST > 3x ULN and total bilirubin > 2x ULN. 
It is critical to initiate this close observation immediately upon detection and confirmation of early signals 
of possible DILI, 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 (international normalized ratio), 
which represent substantial liver injury. 
Close observation includes: 
x
Repeating liver enzyme (AST, ALT, ALP) 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.  
x
Obtaining additional tests, as appropriate, to evaluate liver function, (e.g. INR); diagnostic 
measures (e.g. ultrasound of the liver), serum ammonia, etc. 
x
Obtaining a more detailed history of symptoms and prior or concurrent diseases. Update the 
appropriate eCRFs (if applicable). 
x
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). 
x
Ruling out other immediately apparent possible causes of aminotransferase (ALT or AST) elevation 
and hyperbilirubinemia, as described below. 
x
Obtaining a history of exposure to environmental chemical agents. 
x
Considering gastroenterology or hepatology consultations. 
Relevant supplemental information must be collected and entered in the appropriate eCRF(s) for 
instances observed after the implementation of protocol version 7.  
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: 
x
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. 


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Version 8.0 
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January 04, 2019 
Adolescent and young adult patients with possible DILI should be tested for Epstein-Barr virus. 
Hepatitis is common among transplant patients with cytomegalovirus disease. 
x
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).  
x
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.  
x
NASH (non-alcoholic steatohepatitis). 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.  
x
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.  
x
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-hƉƚŽZĞƐŽůƵƚŝŽŶ 
For all subjects showing hepatic laboratory abnormalities suggestive of possible DILI, an attempt should 
be made to follow the subject 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 (protocol section 5.5). 
 
 


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Version 8.0 
125 / 125 
January 04, 2019 
Appendix M: Child-Pugh score 
 
Parameter 
Points Assigned for Observed Findings 
1 
2 
3 
Total bilirubin, μmol/L (mg/dL) 
< 34.2 
(< 2) 
34.2 – 51.3 
(2 – 3) 
> 51.3 
(> 3) 
Serum albumin, g/L (g/dL) 
> 35 
(> 3.5) 
28 – 35 
(2.8 – 3.5) 
< 28 
(< 2.8) 
INR 
< 1.7 
1.7 – 2.3 
> 2.3 
Ascites 
None 
Slight 
Moderate to severe 
Hepatic encephalopathy* 
None 
Grade 1 or 2 
(or suppressed with 
medication) 
Grade 3 or 4 
(or refractory) 
* 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram. 
 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves. 
 
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic 
waves. 
 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves. 
 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2 to 3 cps delta activity. 
The Child-Pugh classification is defined in terms of the sum of the scores for the five parameters. 
x
A score of 5 or 6 indicates Child-Pugh Category A (mild hepatic impairment). 
x
A score of 7, 8, or 9 indicates Child-Pugh Category B (moderate hepatic impairment). 
 

SAP_001.pdf: 
ABT-414
M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
1
1.0
Title Page
Statistical Analysis Plan
EORTC PROTOCOL 1410-BTG/
ABBVIE PROTOCOL M14-483
INTELLANCE 2:  ABT-414 Alone or ABT-414 Plus 
Temozolomide Versus Lomustine or Temozolomide 
for Recurrent Glioblastoma:  a Randomized Phase II 
Study of the EORTC Brain Tumor Group
Date:  30 May 2017
Version 2.0
Prepared in collaboration by
, PhD, AbbVie
And
, PhD, EORTC
SAP Version
Date of Approval/Finalized
1.0
August 15, 2016
2.0
May 24, 2017
NCT02343406


ABT-414
M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................5
4.1
Objectives .............................................................................................. 5
4.2
Design Diagram ..................................................................................... 5
4.3
Randomization and Stratification.......................................................... 11
4.4
Sample Size.......................................................................................... 11
4.5
Interim Futility Analysis....................................................................... 12
4.6
Type I Error Adjustment Procedures for Multiple Testing .................... 14
5.0
Analysis Sets ........................................................................ 16
6.0
Analysis Conventions .......................................................... 17
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies................................................... 20
7.1
Demographic and Baseline Characteristics ........................................... 20
7.2
Medical History.................................................................................... 21
7.3
Prior and Concomitant Medications...................................................... 21
7.4
Prior Anti-Cancer Treatment and Surgery............................................. 21
8.0
Subject Disposition..............................................................22
9.0
Study Drug Exposure and Compliance.............................. 23
9.1
Dosage ................................................................................................. 23
9.2
Study Drug Exposure ........................................................................... 24
9.3
Compliance .......................................................................................... 25
9.4
Protocol Deviations .............................................................................. 25
10.0
Efficacy Analysis .................................................................25
10.1
General Considerations......................................................................... 25
10.2
Efficacy Endpoints ............................................................................... 26
10.3
Efficacy Analyses................................................................................. 29
10.4
Re-Randomization Test ........................................................................ 39
10.5
Sensitivity Analyses ............................................................................. 39


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10.6
Subgroup Analyses............................................................................... 41
11.0
Safety Analysis.....................................................................42
11.1
General Considerations......................................................................... 42
11.2
Analysis of Adverse Events.................................................................. 42
11.2.1
Adverse Events of Special Interest (AESI)............................................ 44
11.2.1.1
Adverse Event of Special Interest......................................................... 45
11.2.1.2
Time to Onset of Adverse Event of Special Interest.............................. 45
11.3
Deaths.................................................................................................. 46
11.4
Analysis of Laboratory, Vital Signs, and ECG Data.............................. 46
11.4.1
Assessment of Potentially Clinically Significant Laboratory 
Values .................................................................................................. 48
11.4.2
Assessment of Hepatotoxicity............................................................... 49
11.5
Analysis of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values................................................................ 50
12.0
Summary of Differences Between EORTC and 
AbbVie Analyses..................................................................51
13.0
References............................................................................54
14.0
Summary of Major Changes...............................................55
List of Tables
Table 1.
Study Activities...................................................................................... 8
Table 2.
Visit Window....................................................................................... 18
Table 3.
Conversion Factor to Dexamethasone Equivalent Dose ........................ 31
Table 4.
Scoring the QLQ-C30........................................................................... 34
Table 5.
Scoring the QLQ-BN20........................................................................ 35
Table 6.
Visit Window for QoL.......................................................................... 37
Table 7.
Adverse Events of Special Interest........................................................ 45
Table 8.
Criteria for Potentially Clinically Significant Laboratory Values –
Hematology Variables .......................................................................... 49
Table 9.
Criteria for Potentially Clinically Significant Laboratory Values –
Chemistry Variables ............................................................................. 49
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Values............ 50


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M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
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List of Figures
Figure 1.
Study Schematic..................................................................................... 7
Figure 2.
Testing Procedure................................................................................. 15


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M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
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3.0
Introduction
This statistical analysis plan (SAP), prepared jointly by AbbVie and EORTC, will provide 
details to elaborate statistical methods for efficacy and safety data in adult subjects 
collected as outlined in the protocol version 6 for Study M14-483 dated January 18, 2017 
and will describe analysis conventions to guide the statistical programming work.  For 
pediatric sub-study, a separate SAP will provide details for statistical methodologies and 
data conventions. 
Efficacy and safety analyses will be performed using SAS Version 9.2 or higher (SAS 
Institute, Inc., Cary, NC 27513) under the UNIX operating system.  The SAP will be 
signed off before the study database is locked.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objectives of the trial are to assess whether ABT-414 alone or in combination with 
temozolomide (TMZ) improves overall survival (OS), progression free survival (PFS), 
tumor response, quality of life, neurological deterioration-free survival (NDFS), and 
steroid use compared to standard treatment with lomustine single agent or TMZ 
re-challenge in subjects with centrally confirmed recurrent EGFR-amplified glioblastoma. 
Additional exploratory objectives include analyses by stratum of EGFR pathway 
abnormalities (specifically EGFRvIII mutation), correlation of MGMT methylation status 
with clinical outcome (PFS/OS).
4.2
Design Diagram
This is a comparative randomized, open label, multicenter, multi-arm, Phase II study.  The 
study will consist of three treatment arms; Arm 1 (ABT-414 plus TMZ), Arm 2 (ABT-414 
monotherapy), and Arm 3 (mixed control arm of lomustine or TMZ).  Subjects will be 
randomized in a 1:1:1 ratio at the EORTC headquarters after verification of the eligibility 
criteria discussed in Section 3 of the study protocol.  


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Arm 1:  Subjects will be treated with ABT-414 1.0 mg/kg IV infusion over 30 to 
40 minutes once every 2 weeks in combination with TMZ 150 mg/m2 Day 1 to 5, for the 
first 28-day cycle, with dose escalation to 200 mg/m2 in subsequent cycles in case of 
adequate tolerance and until one of the treatment withdrawal criteria has been met.  In this 
Arm 1 the schedule of clinical and lab assessments follows the cycle of TMZ (a delay of 
TMZ delays the assessment schedule, withholding ABT-414 does not affect the 
assessment schedule).
Arm 2:  Subjects will be treated with ABT-414 monotherapy 1.0 mg/kg IV infusion over 
30 to 40 minutes once every 2 weeks until one of the treatment withdrawal criteria has 
been met.
Subjects in the control arm (Arm 3) will be treated according to the timing of relapse.
Arm 3A:  Subjects relapsing during TMZ treatment or within the first 16 weeks after the 
first day of the last TMZ cycle will be treated with lomustine 110 mg/m2 on Day 1 of 
every 42-day treatment period.  Treatment will continue until one of the treatment 
withdrawal criteria has been met.  Lomustine will be given for a maximum of 1 year.
Arm 3B:  Subjects relapsing 16 weeks or more after the first day of the last TMZ cycle 
will be treated with TMZ 150 mg/m2 on Day 1 to 5 for the first 28-day cycle, with dose 
escalation to 200 mg/m2 in subsequent cycles in case of adequate tolerance.  Treatment 
will continue until one of the treatment withdrawal criteria has been met.
Treatment should start within 96 hours from randomization.  Treatment will be 
administered until one of the withdrawal criteria described in Section 5.4 of the study 
protocol has been met.  Treatment at further progression will be according to investigators 
discretion. 
Day 1 of the first cycle will be the first day when the study medication is taken.
A schematic of the study design is shown in Figure 1.  The study procedures for each visit 
are outlined in Table 1.


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M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
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Figure 1.
Study Schematic






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Table 1.
Study Activities (Continued)
0
For Day 1 of Cycle 1, if the evaluations listed here have been already performed during the screening phase and within 2 weeks prior to this Day 1, the same results can be 
used for Cycle 1 and tests do not need to be repeated:  physical examination including, but not limited to, WHO performance status and neurological evaluation; ocular 
examination if clinically indicated; hematology and biochemistry; vital signs; weight.
1
Physical examination including neurological evaluation, and ocular examination at baseline and if clinically indicated.
2
Including WBC, absolute neutrophil count, lymphocytes, hematocrit, hemoglobin and platelet count.
3
Including serum creatinine, total bilirubin, ASAT, ALAT, alkaline phosphatase, phosphate, total protein, albumin, sodium, potassium, calcium and chloride.
4
Pregnancy test must be done within 72 hours prior to randomization.
5
ECG only Day 1 of Cycle 1 and 3, immediately after the ABT-414 infusion and only for subject treated with ABT-414 (Arm 1 or 2).
6
PK samples to be collected at Day 1 of ABT-414 Cycles 1, 2, 3 and then every 2 ABT-414 cycles (Day 5 samples will only be collected during Cycles 1 and 2).
7
Hematology at Day 21 can be omitted once treatment at the present dose level caused only grade 1 or less hem. toxicity at Day 21 and only grade 2 or less at Day 28.
8
QoL only at Week 8 and Week 16 while on treatment.
9
End of Treatment Visit 35 days after last protocol drug administration.
10
If clinically indicated/if clinically relevant.
11
Assessment of AEs not resolved after EOT or AEs related to study treatment.
12
PD samples to be collected at Day 1 of Cycles 1, 2 and 3 and only for subject in an ABT-414 arm (Arm 1 or 2).
13
PG sample optional, to be collected at Day 1 of Cycle 1 or it may be collected anytime during the study.
14
Repeat physical examination including WHO performance status and neurological evaluation, hematology, vital signs and adverse event assessments at Day 28 for subjects in 
the lomustine arm (Arm 3A).
15
Prophylactic steroid ophthalmic solution prior to each infusion of ABT-414; 2 drops in each eye every 8 hours to start 48 hours prior to ABT-414 dosing and continue for a 
total of 7 days.


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4.3
Randomization and Stratification
All subjects entered in the study will be centrally randomized at the EORTC Headquarters 
as described in Section 13.3 of the study protocol.  The minimization technique used by 
the EORTC for random treatment allocation is based on the variance method with semi-
random assignment dependent on a preset threshold as implemented by Freedman and 
White.1  However, per suggestion of the ICH E9 statistical guidelines, the algorithm has 
been modified to incorporate a random allocation component in order to ensure an 
additional 15% of completely random assignments.
In this study, the threshold is set to 3, the total number of stratification factors.
Stratification factors are:
●
Regions of the world (North America (USA, Puerto Rico & Canada) vs. 
Europe and Australia vs. Asia/other regions)
●
WHO Performance Status (0 vs. > 0)
●
Timing of relapse (< 16 weeks vs. ≥ 16 weeks after the first day of the last 
TMZ cycle)
4.4
Sample Size
This is a comparative randomized, open label, multicenter, multi-arm, Phase II study.  
Overall Survival (OS) is the primary endpoint.
Based on a one-sided logrank test, at an overall significance level of 2.5% and a power of 
91.7% (accounting for the global testing strategy), a total of 118 deaths per comparison 
(i.e., monotherapy ABT-414 versus control and combination ABT-414 + TMZ versus 
control) are needed to detect a Hazard Ratio (HR) equal to 0.54 (i.e., a reduction in the 
hazard of death of 46%).  A median OS of 7 months is expected on the control arm 
(Arm 3) based on literature review.  The target treatment effect is assumed to be the same 
for both treatment arms (Arm 1 and Arm 2) and corresponds to an increase of median OS 


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12
to 12.9 months under proportional hazards.  It is assumed that median PFS is 2.6 months 
on the control arm and 4.8 months on the treatment arms corresponding to an HR of 0.54.  
The treatment effect on OS and PFS is generally expected to be positive correlated 
following historical trends.2  Since the interim futility criterion (see Section 4.5 below) is 
primarily based on a PFS effect, the power of the study increases with the strength of 
association between PFS and OS.  If PFS and OS effects are independent, the overall 
power of the study is estimated to be approximately 85%.  The study is therefore expected 
to have at least 85% power overall as long as OS and PFS are not negatively correlated.
4.5
Interim Futility Analysis
An interim futility analysis is planned when at least 45 PFS events (at least 31 PFS events 
are observed in each comparison) are observed.  At interim analysis one or both of the 
ABT-414 arms might be discontinued based on lack of efficacy for PFS according to 
RANO criteria assessed by IRC. 
Treatment arms which did not show a minimum level of efficacy, defined as a computed 
treatment PFS HR lower than 0.91 at the interim, will be discontinued.  The trial will 
continue with remaining treatment arm(s) and control.  The decision to discontinue a 
treatment arm not showing a minimum level of efficacy will be based on a review of the 
totality of interim data and recommendations made by the IDMC.  The interim analysis 
will be carried out according to the Statistical Considerations section in the study protocol 
and EORTC Policy 004 on Independent Data Monitoring Committees and Interim 
Analyses.
On April 28, 2016, AbbVie and EORTC contacted the IDMC chair to request a revision 
of the interim analysis plan.  Taking into account the time that was necessary to collect all 
MRI scans performed, to perform their central review, to code the resulting data in the 
EORTC database, and to submit the interim analysis report 4 weeks before the IDMC 
meeting scheduled on May 23, 2016, both AbbVie and EORTC agreed that it was difficult 
to present the results concerning the centrally reviewed PFS endpoint at the coming 


ABT-414
M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
13
IDMC meeting.  On May 20, 2016, the IDMC Chair considered this request and agreed to 
a postponement of the report. 
In May 2016, both AbbVie and EORTC agreed to maintain the same PFS HR futility 
boundary of 0.91 as initially planned based on the availability of 45 PFS events.  The 
clinical cut-off date for the revised interim analysis was set as July 01, 2016.  All scans 
from subjects randomized before May 07, 2016 with at least one baseline and one 
follow-up scan were to be reviewed.  The interim futility reports were presented to the 
IDMC on September 21, 2016 based on an interim database locked on August 16, 2016.
While there was no intent to stop the study for superior efficacy observed based on PFS 
during the interim analysis, an alpha spending of 0.00001 was allotted to the futility 
analysis per the recommendation of the US Food and Drug Administration (FDA).  
Given that a total of 47 deaths had occurred across Arms 1-3 at the time of the PFS futility 
analysis, when a fixed Haybittle Peto alpha spending (as implemented in EAST 6.3) of 
0.00001 is applied to the adjusted nominal significance levels for the final analysis for a 
range of possible values of the observed information fraction are provided in table below.
No. of OS for 2 Arms at Interim
Nominal Adjusted 1-Sided Alpha at Final OS
26 to 30
0.024996
31 to 37
0.024997
For the purposes of review by the FDA, the final adjusted significance level for each 
comparison (Arm 1 vs Arm3, and Arm2 vs Arm 3) will be determined at the end of the 
trial using the same Haybittle Peto spending approach as a function of the actual observed 
information (ratio of observed deaths at the time of the futility look and final analysis on 
the treatment and control arms).  Furthermore, since the primary efficacy endpoint (OS) 
was never analyzed during the interim analysis and an alpha penalty is technically 
unnecessary for a futility interim assessment, no adjustment to the final alpha level will be 
made for other global regulatory purposes and final analyses will be performed at a full 
overall 1-sided significance level of 0.025.


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4.6
Type I Error Adjustment Procedures for Multiple Testing
Although Section 8.2.3.6 of the study protocol dated November 25, 2015, describes a 
different testing order, the multiple testing strategy was revised per diagram (Figure 2) in 
version 1.0 of the SAP finalized prior to the interim analysis of efficacy data.  Given the 
clinical importance of an overall survival (OS) benefit in recurrent GBM subjects, 
comparing first OS of combination arm (ABT-414 + TMZ) vs. control and next OS of 
ABT-414 monotherapy vs. control, followed by comparison of other secondary efficacy 
endpoints in a similar sequence, is considered a simple and more clinically relevant 
approach to test the various study hypotheses.  At the final analysis, the treatment effects 
will be tested at the adjusted significance level mentioned in the previous section.  The 
proposed multiple testing strategy based on the above fixed hierarchical sequence 
preserves the family-wise type-I error at 1-sided 2.5% level.  This change was made by 
consensus agreement among the study sponsors (EORTC and AbbVie Inc.) without any 
knowledge of unblinded efficacy data from the trial and prior to interim futility analysis. 
To describe the multiplicity adjustment procedure fully, consider the following null 
hypotheses:
H1:  Arm 1 is not superior to Arm 3 in OS.
H2:  Arm 2 is not superior to Arm 3 in OS.
H1a:  Arm 1 is not superior to Arm 3 in PFS.
H2a:  Arm 2 is not superior to Arm 3 in PFS.
H1b:  Arm 1 is not superior to Arm 3 in ORR.
H2b:  Arm 2 is not superior to Arm 3 in ORR.
H1c:  Arm 1 is not superior to Arm 3 in OS among EGFR vIII mutated subjects.
H2c:  Arm 2 is not superior to Arm 3 in OS among EGFR vIII mutated subjects.




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All other endpoints, e.g., PFS in EGFRvIII mutated, global health/QoL status (GHQs), 
and neurological disease-free survival (NDFS) are considered exploratory and will be 
tested at a 2-sided 5% level of significance.
5.0
Analysis Sets
The following analysis sets will be used for analysis of safety and efficacy endpoints of 
the study.
●
Intention-to-treat (ITT) population will comprise all randomized subjects 
regardless of whether they received study treatment 
(ABT-414/TMZ/lomustine).  Subjects will be classified and analyzed in the 
arm they were assigned at the time of randomization.  The ITT will be the 
primary analysis set for efficacy endpoints.
●
EGFRvIII-Mutated (Ev3M) population will comprise of a subset of subjects 
who have EGFRvIII mutated tumors in the ITT.  The Ev3M will be used to 
address the objectives of improvement in OS and PFS among subjects with 
EGFRvIII mutation.
●
Safety population will comprise all randomized subjects who have received at 
least one dose of study treatment [i.e., one dose of lomustine or TMZ (Arm 3), 
of ABT-414 (Arm 2), and of TMZ and ABT-414 (Arm 1)].  Subjects will be 
classified according to treatment received.  Thus, a subject randomized to 
Arm 1 who received TMZ but did not receive ABT-414 will be considered in 
Arm 3.  Subjects allocated to Arm 3 who received at least one dose of 
ABT-414 and those allocated to Arm 2 who received at least one dose of TMZ 
will be considered in Arm 1.  The safety population will be the primary 
analysis set for analysis of safety endpoints.
●
Per-protocol population will comprise all subjects who are eligible and have 
received at least one dose of study treatment [i.e., one dose of lomustine or 
TMZ (Arm 3), of ABT-414 (Arm 2), and of TMZ and ABT-414 (Arm 1)].  A 
subject will be considered to be eligible if he/she did not have any deviation 
from the subject entry criteria listed in Section 3 of the protocol.  Subjects will 
be classified and analyzed in the arm they were assigned at the time of 


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17
randomization.  Reason for ineligibility, treatment, and safety profile of 
excluded subjects will be reported separately.
6.0
Analysis Conventions
This section provides general considerations for data handling, summary, and analysis.  
This also includes general definitions of certain kinds of endpoints.  More details about 
specific endpoints and additional analysis methods, as needed, will be specified within the 
description of analysis of data in this SAP. 
Continuous variables will be summarized by sample size (N), mean, standard deviation 
(St. Dev.), median, minimum, and maximum.  Frequency and percentage will be provided 
for categorical variables and 95% confidence intervals (CIs) will be generated for 
parameter estimates of interest.
Dealing with Multiple Values on the Same Day for Lab and Vital Signs Parameters
In cases where multiple values for the same variable are collected on the same day 
(including baseline visit and post-baseline visits), the arithmetic average will be calculated 
and used as the value for that day for mean changes in laboratory and vital signs 
parameters. 
Definition of Baseline Observation
Unless otherwise specified, the baseline observation is defined as the last non-missing 
measurement collected prior to or on randomization.  If no measurement collected prior to 
or on randomization, then the last non-missing observation prior to or on the first dose 
date of study drug (ABT-414/TMZ/lomustine) is considered. 
Definition of Final Observation
For lab and vital sign parameters, the final observation is defined as the last non-missing 
post-baseline measurement collected during the study. 


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Definition of Study Rx Days (Days Relative to the First Dose of Study Drug)
Study Rx Days are calculated for each time point relative to the first dose date of study 
drug (ABT-414/TMZ/lomustine).  They are defined as the number of days between the 
day of the first dose of study drug (ABT-414/TMZ/lomustine) and the specific time point.  
Rx days are negative values when the time point of interest is prior to the first study drug 
dose day.  Rx days are positive values when the time point of interest is after the 
first study drug dose day.  The day of the first dose of study drug 
(ABT-414/TMZ/lomustine) is defined as Study Rx Day 1, while the day prior to the first 
study drug dose is defined as Study Rx Day –1 (there is no Study Rx Day 0).
Definition of Analysis Windows
During the treatment period, all time points and corresponding time windows are based on 
Study Rx Days, unless specified otherwise.  For longitudinal analyses, especially for the 
laboratory data, the time windows in Table 2 describe how data collected at protocol 
specified visits will be assigned.  If more than one observation is included in a time 
window, the observation closest to the nominal day should be used.  If there are 
two observations equally distant to the nominal day, the later one will be used in analyses.
Table 2.
Visit Window
Study Visit (Week)*
Nominal Study Rx Day
Time Window (Study Rx Days Range)
Baseline
-
By baseline definition
2
15
2 to ≤ 18
3
22
19 to ≤ 25
4
29
26 to ≤ 32
…
…
…
X
7•X + 1
7•X – 2 to ≤ 7•X + 4
*
ECG at baseline and only Day 1 of Cycle 1 and 3, immediately after ABT-414 infusion and only subjects treated 
with ABT-414 (Arms 1 or 2).


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Time-to-Event Endpoints
All time to event (TTE) endpoints are defined using a time variable and an event 
indicator.  The time variable represents the time from a pre-defined time origin to the 
onset of a predefined event of interest or the last time when adequate assessments have 
been made to rule out the onset of the event.  The latter case indicates that the endpoint 
has been right-censored.  The event indicator is set to 1 if the event has been observed 
during the course of the study and 0 if it is censored.  When multiple assessments are 
needed to ascertain the occurrence of an event, the earliest date among all of these 
assessments is taken to be date of the event or censoring.  The time variable will be 
computed in days and converted into months (1 month = 30.4375 days) for analysis of 
TTE endpoints.  When no post-randomization observations are available for a subject for 
any given endpoint, then the endpoint is taken to be censored on the date of 
randomization.
All TTE endpoints defined in this study are concerned with only the first incidence of an 
event of interest, and recurrence of the same event is not considered.  An event, however, 
may be defined in a composite fashion, i.e., as the occurrence of one among several 
different outcomes.  An example of such an endpoint is PFS where the event is either 
disease progression or death.  The composite event is observed when at least one of the 
component events occurs, and the time to the earliest among the occurring component 
events is considered to be the TTE for the composite event.
Prior and Concomitant Medications
A prior medication is defined as any medication with an end date prior to the date of 
randomization and collected on the electronic case report forms (eCRFs).  A concomitant 
medication is defined as any drug that started on the day of or after randomization, but not 
35 days after the last protocol drug administration.  Medications with a start date prior to 
the date of randomization and continuing after randomization are also classified as 
concomitant medications.  A medication will also be considered a concomitant medication 
if one of the following three cases occur:  (1) the start date is missing and the end date is 


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either after or on the day of randomization; (2) the start date is not missing but not 35 days 
after the last protocol drug administration and the end date is missing; (3) both the start 
date and the end date are missing.
End of Study
End of study occurs when all of the following criteria have been satisfied:
●
At least 118 deaths have been observed for each treatment arm comparison 
versus control,
●
Thirty five days have passed since all subjects have stopped protocol 
treatment, and
●
The database has been fully cleaned and frozen for analyses.
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies
Data for demographic, baseline characteristics, medical history, previous/concomitant 
medications, and prior oncology therapies will be summarized for each treatment arm and 
overall on the ITT population.
7.1
Demographic and Baseline Characteristics
Continuous demographic data (e.g., age, height, and weight) will be summarized with N, 
mean, standard deviation (St. Dev.), median, minimum, and maximum.  Frequencies and 
percentages will be computed for the following parameters (but not limited to):  sex, race, 
ethnicity, age group (< 40; 40 to < 60; ≥ 60 years old), weight, height, body mass index 
(BMI), WHO performance status, MGMT methylation status, EGFR vIII status, regions 
of the world, tobacco and alcohol use, timing of relapse (< 16 weeks; ≥ 16 weeks), 
chemotherapy (≤ 1; > 1), and surgery for glioblastoma recurrence (yes; no).
There will be no statistical comparison of demographic and baseline measurements 
between treatment arms.


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7.2
Medical History
Medical history data will be summarized and presented using conditions/diagnoses as 
captured on the eCRF.  The conditions/diagnoses will be presented in alphabetical order.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized for each treatment arm.  Subjects reporting more than 
one condition/diagnosis will be counted only once for that condition/diagnosis.  There 
will be no statistical comparison of medical history between treatment arms.
7.3
Prior and Concomitant Medications 
The frequency and percentage of subjects who took at least one dose of medication other 
than study drug (ABT-414/TMZ/lomustine) during the course of the trial will be 
summarized by the generic name coded by the World Health Organization (WHO) 
dictionary.  Prior and concomitant medications will be summarized separately.  
For each concomitant medication, a listing with subject ID numbers will be provided. 
Subjects reporting the same medication generic name two or more times will be counted 
only once for that generic name.  Subjects reporting more than one medication will be 
counted only once in the total number of subjects taking a concomitant medication.  
A similar summary will be prepared for prior medications.  In addition, the frequency and 
percentage of subjects taking 0, 1, 2, 3 and > 3 prior medications will be presented for 
each treatment arm and overall.
There will be no statistical comparison for the prior and concomitant medications between 
treatment arms.
7.4
Prior Anti-Cancer Treatment and Surgery
The frequency and percentage of subjects who had prior anti-cancer treatments, including 
prior radiation therapy and prior cancer medications, will be summarized by treatment 
name.  Radiation therapy will be counted as one anti-cancer treatment.  Prior anti-cancer 


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medications will be summarized using the WHO generic drug name dictionary.  A subject 
who reported two or more uses of the same medication will be counted only once in the 
total for the associated WHO generic drug name.  Subjects will be summarized by the 
number of prior anti-cancer treatments received (0, 1, 2, 3, and > 3).  In addition, reason 
to stop and the best response to each treatment prior to study drug administration will be 
summarized. 
The frequency and percentage of subjects who had prior brain cancer surgeries will be 
summarized by the number of prior brain cancer surgeries (0, 1, 2, 3, and 4).  In addition, 
for each of initial, second, third, and fourth brain cancer surgery, extent of procedure will 
also be summarized.
There will be no statistical comparison for prior anti-cancer treatment/surgery between 
treatment arms.
8.0
Subject Disposition
Subject disposition summary (number and percentage of subjects) will be presented on all 
subjects who are registered, as described in Section 13.1 of the study protocol.  The 
number of subjects will be summarized by investigator site and overall.
●
Subjects who were registered
●
Subjects who screen failed
●
Subjects who were randomized
●
Subjects who took at least 1 dose of study drug (ABT-414/TMZ/lomustine)
●
Subjects who discontinued the study drug 
Listing for screen failure reasons/ineligibility will be provided.
In addition, a subject disposition summary will be presented on the ITT population by 
treatment arm assigned at randomization – the numbers and percentages of subjects who 
were randomized, took at least 1 dose of study drug, and discontinued the study drug.  


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Major reason for study drug discontinuation will be summarized by each of ABT-414, 
TMZ, and lomustine within treatment arm.
No statistical tests will be performed.
9.0
Study Drug Exposure and Compliance
9.1
Dosage
Analyses for the study drug (ABT-414/TMZ/lomustine) treatment will be performed on 
the Safety population.  Longitudinal summary statistics for average dose administered 
during the study will be presented.  The number and percentage of subjects at each treated 
dose will be presented longitudinally.
An overview of dose modification will be presented by treatment arm, consisting of the 
number and percentage of subjects who had at least one dose modification for each of 
ABT-414/TMZ/lomustine throughout the study. 
Dose modification of ABT-414/TMZ/lomustine will be summarized for each 
course/cycle.  The frequency and percentage of subjects will be summarized by treatment 
arm, and reasons for dose modification will also be summarized. 
For dose intensity and relative dose intensity of ABT-414 (Arms 1 and 2 only), the 
following calculation rules are applied: 
●
The dose intensity of ABT-414 is calculated on actual treatment duration (in 
weeks) and actual treatment dose received (total dose received in mg/kg).  
Whenever the treatment is given in cycles and the last planned day of 
treatment is not the last day of the cycle, the total duration of the treatment 
must account for this by adding the appropriate number of days to complete 
the last cycle.  That is, if ABT-414 stopped on Day X of a 28-day cycle, the 
total treatment duration in days is [date of last injection] – [date of 
first injection] + 1 + (28-X). 


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●
The dose intensity (mg/kg/week) of ABT-414 is the ratio of the total dose 
received (mg/kg, adjusted by weight) to the total treatment duration (weeks).
)
(
)
/
(
)
/
/
(
weeks
duration
treatment
total
Actual
kg
mg
dose
Total
week
kg
mg
DI observed
!
●
The relative dose intensity is calculated as the ratio of the dose intensity as 
calculated above to the dose intensity indicated in the protocol, expressed in 
percent (%).  To obtain a correct ratio, the theoretical dose intensity will be 
expressed in the same units of dose and treatment duration as those used for 
the actual dose intensity. 
)
(
)
/
(
)
/
/
(
weeks
cycle
one
of
duration
l
Theoretica
kg
mg
cycle
per
Dose
week
kg
mg
DI protocol
!
●
The relative dose intensity is usually presented using median and ranges, and 
by a distribution into categories (relative dose intensity ≤ 70%, > 70 – 90%, 
> 90 – 110%, > 110 – 120%, > 120%).
9.2
Study Drug Exposure
Analyses for the study drug (ABT-414/TMZ/lomustine) exposure will be performed on 
the Safety population. 
Duration of ABT-414 exposure is defined as total number of weeks a subject received 
ABT-414, i.e., (last dose date – first dose date + 1)/7.  The same calculation applies to 
TMZ and lomustine.
Descriptive statistics will be presented for the duration of exposure of 
ABT-414/TMZ/lomustine by treatment arm.  The distribution of subjects within the 
following categories will be summarized:  ≤ 4 weeks, > 4 to ≤ 8 weeks, > 8 to ≤ 12 weeks, 
etc. of ABT-414/TMZ/lomustine, respectively. 
An overview of dosing schedule change will be presented by treatment arm, consisting of 
the number and percentage of subjects who had at least one change in dosing schedule for 
each of ABT-414/TMZ/lomustine throughout the study.  The number and percentage of 


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subjects at each study drug dose in each treatment course (ABT-414 every 2 weeks; TMZ 
every 4 weeks; lomustine every 6 weeks) will also be presented.
Dosing schedule change (shortening or delay) of 3 or more days for any of the study drugs 
(ABT-414/TMZ/lomustine) will be summarized for each course.  The frequency and 
percentage of subjects with no change, delayed, and earlier than per protocol will be 
summarized respectively, by treatment arm, and reasons for schedule change per course 
will also be summarized. 
9.3
Compliance
Analyses for compliance will be performed on subjects who received at least one dose of 
TMZ. 
The frequency and percentage of subjects will be summarized by treatment arm for (1) at 
least 80% compliant of TMZ at every cycle in the investigator's opinion, (2) at least 80% 
compliant of TMZ at all but one cycle in the investigator's opinion, (3) less than 80% 
compliant of TMZ at more than one cycle in the investigator's opinion.  
9.4
Protocol Deviations
The number and percentage of subjects with protocol specified eligibility deviations will 
be summarized by treatment arm assigned at the time of randomization, and split by type 
of deviation.
10.0
Efficacy Analysis
10.1
General Considerations
Unless otherwise specified, all efficacy analyses described below will be performed on the 
ITT population according to stratification factors based on the EORTC online 
randomization system (ORTA). 
Time-to-event endpoints (TTE), such as overall survival and progression-free survival, are 
defined as the time from randomization to the first occurrence of the event.  For subjects 


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who do not experience the event, TTE will be right-censored on the date of last adequate 
post-baseline assessment for that event.  If a subject has no post-baseline assessment 
performed for the event (e.g., no imaging assessments for disease progression), then the 
data will be censored at the date of randomization.  For each TTE endpoint, the 
corresponding event and the date of censoring are described in individual sections below. 
All TTE will be computed in days and converted into months (1 month = 30.4375 days) 
for analysis, as follows:
TTE = (date of event or censoring) – date of randomization + 1)/30.4375.
For the purposes of analysis, an event indicator will also be derived for each TTE for each 
subject, taking the value 1 if the subject is reported to have experienced the event or 
0 otherwise. 
Primary analysis of efficacy endpoints related to tumor assessments (e.g., ORR and PFS) 
will be based on assessments by a blinded, independent, central imaging review 
committee (IRC).  For sensitivity analyses, these efficacy endpoints will also be analyzed 
based on assessments by local site investigators.
Tumor assessments will be based on the Response Assessment in Neuro-Oncology 
(RANO) criteria.  Subjects for whom a complete response (CR) or partial response (PR) is 
observed, an additional MRI scan should be performed at least 4 weeks later to confirm 
the response.  Any equivocal assessment of PD by the local investigator will need to be 
confirmed with an extra MRI performed at least 4 weeks later.  If these subsequent 
evaluations suggest that the subject is in fact experiencing a CR, PR or PD, then the date 
of CR, PR or PD will be taken to be the date of the first such evaluation.  
10.2
Efficacy Endpoints
The primary endpoint of this study is Overall Survival (OS), and the secondary endpoints 
are:
●
PFS according to RANO criteria and assessed by IRC 


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●
Objective response rate (ORR) assessed by IRC
●
OS in the subgroup with EGFRvIII mutation
The following are exploratory endpoints:
●
Best overall response rate (BRR), complete response rate (CRR), duration of 
response (DOR), and time to tumor response (TTR) assessed by IRC
●
PFS in the subgroup with EGFRvIII mutation
●
Neurological deterioration-free survival (NDFS) 
●
Quality of life
●
Steroid use 
Overall Survival (OS)
Overall survival (OS), or time to all-cause mortality, is defined as time from 
randomization to death due to any cause, regardless of whether the event occurred on or 
off study drug (ABT-414/TMZ/lomustine).  For a subject who is not reported to have died 
at the time of data analysis, OS will be censored on the last documented date the subject is 
known to be alive.  
Progression-Free Survival (PFS)
All disease progression assessed by IRC per RANO criteria will be included, regardless of 
whether the event occurred on or off study drug.  Progression-free survival for a given 
subject will be defined as the time from the date of randomization till the date of 
first progression or the date of subject's death, whichever occurs first.  If a subject neither 
experiences disease progression nor dies, then the subjects PFS will be censored at the last 
date of an adequate post-baseline tumor assessment. 
Neurological Deterioration-Free Survival (NDFS)
Neurological deterioration (ND) is defined as a decrease in WHO performance status: 


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●
for subjects with baseline WHO performance status 0 or 1:  deterioration to 
WHO performance status 2 or worse for which no other explanation is present, 
and which is maintained for at least 3 weeks
●
for subjects with baseline WHO performance status 2:  deterioration to WHO 
performance status 3 or worse for which no other explanation is present and 
which is maintained for at least 3 weeks
NDFS will be measured as the time from randomization until first neurological 
deterioration or death whichever occurs first, regardless of whether radiological 
progression has occurred or not.  If a subject neither experiences ND nor dies, then the 
subject's NDFS will be censored at the last date of post-baseline WHO performance status 
assessment.    
Duration of Response (DOR)
The duration of overall response (DOR) will be analyzed only for the subset of subjects 
who experience a complete or partial response (CR or PR).  For a given subject, DOR will 
be defined as the number of months from the day the criteria are met for CR or PR by IRC 
(whichever is recorded first) to the date of progressive disease or death, whichever comes 
first.  If a subject is still responding (i.e., has not progressed nor died after CR or PR), 
then the subject's data will be censored at date of the last radiological assessment.  
Time to Tumor Response (TTR)
Time to tumor response is defined as the time from the date of randomization to the 
observation of objective response (CR or PR). 
For a subject who neither respond nor progress, TTR will be censored at the subject's last 
tumor assessment date.  For subjects who progress and never respond, TTR will be set by 
convention as the longest time from randomization to the last tumor assessment observed 
across all subjects; i.e., max (last tumor assessment date – randomization date + 1) for all 
subjects.  The distinction in censoring rule is made here since, at the time of censoring, the 


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former set of subjects would still have a possibility of experiencing a response (the event 
of interest), while the latter set of subjects never will.
Best Overall Response Rate (BRR)
Best overall response is the best response assessed by IRC from the date of randomization 
until disease progression or death, whichever comes first.  Subjects who did not have 
post-baseline assessments will be considered "not-assessed."  Subjects who had only 
one response that required a confirmatory MRI scan, which was not performed, will also 
be considered not-assessed.
Objective Response Rate (ORR)
Objective response includes best overall responses – complete response (CR) and partial 
response (PR) – assessed by IRC per RANO criteria from the date of randomization until 
disease progression or death, whichever comes first.  All objective responses (CR and PR) 
must be confirmed by repeat MRI 4 weeks later than the first time when CR or PR is 
identified.  Any subject who did not meet CR or PR including those who did not have 
post-baseline radiological assessments will be considered as non-responder.
10.3
Efficacy Analyses
Statistical analyses will be performed to compare the primary and secondary endpoints 
described in Section 10.2 between each treatment arm (Arm 1 or Arm 2) and control 
(Arm 3) following the fixed sequence described in Section 4.6.
Analysis Methods for TTE Endpoints
For all TTE endpoints, differences between the treatment arms and the control arm will be 
assessed by a log-rank test stratified by the randomization stratification factors described 
in Section 4.3.  The p-value obtained from the stratified log-rank test will be considered as 
the primary basis for determination of statistical significance for the TTE endpoints. 


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Kaplan-Meier (KM) estimates of the survival distribution of each TTE endpoint in 
Arms 1 – 3 will be estimated and plotted.  Two-sided 95% CIs for the KM curves will be 
computed using Greenwood's formula and plotted.  The median for the TTE and the 
probability of being event-free at 6 months, 1 year (12 months) and 2 years (24 months), 
and their 95% CIs will be estimated from the KM curve and its 95% CI for each treatment 
arm.  
The hazard ratios of the two treatment arms over the control arm, adjusting for the main 
effects of randomization stratification factors as covariates, and their 95% CIs will be 
estimated using a Cox's proportional hazards model (score test).
The above-mentioned methods will be referred to as primary survival analysis methods
for the remainder of this SAP.  Analysis of the following endpoints will be performed 
using these primary survival analysis methods:
●
Overall Survival (OS)
●
Progression-Free Survival (PFS) assessed by IRC
●
OS and PFS in subjects with EGFRvIII Mutation (in the Ev3M population)
●
Neurological Deterioration-Free Survival (NDFS)
●
OS and PFS in the subgroup of subjects with timing of relapse (< 16 weeks vs. 
≥ 16 weeks after the first day of the last TMZ cycle)
●
Time to Tumor Response (TTR)
●
Duration of Response among treatment responders (CR or PR).  The time 
origin for calculating DOR is not the date of randomization.
Objective Response Rate (ORR)
The number and percentage of subjects with objective response will be presented by 
treatment arm.  The objective response (CR and PR) rate will be reported with exact 
(binomial) two-sided 95% CI for each treatment arm. 


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The ORR will be compared between the treatment arms over the control arm using a 
one sided Cochran-Mantel-Haenszel (CMH) test, stratified by randomization stratification 
factors.  Odds ratios will be presented with 95% CIs.
Best Overall Response Rate (BRR)
The number and percentage of subjects will be presented for each response category by 
treatment arm.
Complete Response Rate (CRR)
The same methodology as for analysis of objective response will be applied to complete 
response rate. 
Corticosteroid Use
Systemic corticosteroids that were given orally or by injection, reported either in 
prior/concomitant medication form until 35 days after the last study drug 
(ABT-414/TMZ/lomustine) or tumor assessment form will be summarized.  Baseline 
steroid use is defined as any use of systemic steroid prior to and within 14 days of 
randomization.  Post-baseline steroid use is defined as any use of systemic steroid on or 
after randomization.  Steroid dose will be converted to a dexamethasone equivalent dose.3
Table 3.
Conversion Factor to Dexamethasone Equivalent Dose
Corticosteroids (mg)
Conversion Factor*
Cortisone
0.75/25
Hydrocortisone
0.75/20
Prednisone, Prednisolone
0.75/5
Methylprednisolone, Triamcinolone
0.75/4
Betamethasone
0.75/0.6
*
Dexamethasone equivalent dose (mg) = Conversion factor x Corticosteroid dose (mg).


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Baseline steroid dose is defined as the average dose prior to and within 14 days of 
randomization, i.e., sum of daily doses divided by the number of days treated with 
steroids.  The following summary will be presented for each treatment arm:
●
The number and percentage of subjects who are treated with steroids at 
baseline (yes; no; missing) and post-baseline (yes; no; missing) in a two-way 
table.
●
For subjects with no steroids at baseline and at least one steroid at post-
baseline, simple summary statistics for time (in weeks) to steroid use during 
the study since randomization. 
●
The number and percentage of subjects who are treated with average steroid 
dose group (mg/day) at baseline (≤ 2; > 2 to ≤ 4; > 4 to ≤ 6; > 6 to ≤ 8; > 8 to 
≤20; > 20 mg/day).
●
The number and percentage of subjects with objective response (CR and PR 
assessed by IRC per RANO criteria) and Kaplan-Meier estimates of PFS, by 
baseline steroid use status (yes; no; missing), respectively.
In addition, steroid dose change (sustained reduction and complete reduction) relative to 
baseline will be summarized.  Sustained reduction of steroid dose is defined as 50% or 
more steroid dose reduction, relative to baseline, for 50% or more of the time on study 
drug (ABT-414/TMZ/lomustine).  Complete reduction is defined as discontinuation of 
steroid use for ≥ 25% of the time on study drug (ABT-414/TMZ/lomustine). 
●
The number and percentage of subjects with objective response status 
(responders; non-responders) and Kaplan-Meier estimates of PFS for subjects 
who have sustained steroid reduction and for subjects who have complete 
steroid reduction, respectively.
Quality of Life
Subject self-reported health related quality of life (HRQoL) outcomes are assessed at the 
baseline, Week 8 MRI visit (while on-treatment), Week 16 MRI visit (while 
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randomization regardless of treatment or progression status) by using the QLQ-C30 
version 3 (Table 4) and QLQ-BN20 (Table 5). 
The main objective of HRQoL assessment is to determine the impact of ABT-414 on 
overall global health and HRQoL.  A secondary objective is to evaluate the effect of the 
treatment on the remaining symptoms and functioning scales as treatment-related side 
effects may have a (temporary) negative influence on the health related domains of 
HRQoL of these subjects.  The QLQ (quality of life questionnaire) comprises distinct 
scales, each of which represents a different aspect of QoL, and the individual questions on 
the QLQ are called items. 
The QLQ-C30 is composed of global health status/QoL scale; five functional scales 
(physical, role, emotional, cognitive, and social); three symptom scales (fatigue, nausea 
and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties). 


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


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Table 5.
Scoring the QLQ-BN20
QLQ-BN20
Item (Question) Numbers
Item Range
Symptom scales
Future uncertainty (FU)
1, 2, 3, 5
3
Visual disorder (VD)
6, 7, 8
3
Motor dysfunction (MD)
10, 15, 19
3
Communication deficit (CD)
11, 12, 13
3
Headaches (H)
4
3
Seizures (S)
9
3
Drowsiness (Dr)
14
3
Hair loss (HL)
16
3
Itchy skin (IS)
17
3
Weakness of legs (WL)
18
3
Bladder control (BC)
20
3
The brain cancer module (QLQ-BN20) is meant for use among brain cancer subjects 
varying in disease stage and treatment modality (i.e., surgery, chemotherapy, 
radiotherapy, etc.).  It is meant to be complemented by the QLQ-C30.  It is composed of 
20 items forming 11 symptom scales (7 single item scales and 4 multi-item scales).
All scales and single items are reported on categorical responses, and will be linearly 
converted to numeric values 0 through 100.  Given a scale, the raw score (RS) is 
computed as the mean of component items over the number of items answered for that 
scale.  Then the scale score (SS) will be computed as following. 
For global health status/QoL, and symptom scales/items,
SS = {(RS – 1) / range} × 100.
For Functional scales,
SS = {1 – (RS – 1) / range} × 100.


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If 50% or more of the items are answered for a given scale, the scale score will be 
computed as described above.  If not, the scale score will not be computed.  For example,
physical functioning contains 5 items (questions 1 through 5), and the scale score is 
calculated if at least 3 of the items are answered.  For single-item measures (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties), none of the 
single-item measures can be computed if not answered.  If a scale score cannot be 
computed, the outcome for that score is left blank.   
Global health status/QoL is the primary HRQoL endpoint.  The other scales from the 
QLQ-C30 and QLQ-BN20 will be analyzed on an exploratory basis as secondary HRQoL 
endpoints.  The financial difficulties scale (QLQ-C30) will not be analyzed.
All QoL analyses will be performed for the subset of the ITT population for whom at least 
one valid post-baseline QoL form has been collected.  A subject will not be included in a 
change from baseline analysis unless a corresponding valid QoL form at baseline has also 
been collected. 
Compliance for a group of subjects at a certain time point T is defined as:
Compliance (T) = Valid QoL form within [L, U]
QoL form expected at T
Where L and U are the lower and upper bound of the time windows associated with T.  
The protocol schedule as specified in the protocol can be applied to this definition.  The 
resulting values for T, L and U are summarized in Table 6.


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Table 6.
Visit Window for QoL
T
L
U
Window Length
Baseline
Date of 
randomization = D0
D0 – 1 week
D0
1 week
Week 8
(on-treatment)
Week 8 MRI visit 
date = D1
D1 – 1week
D1 + 1 week
2 weeks
Week 16
(on-treatment)
Week 16 MRI visit 
date = D2
D2 – 1 week
D2 + 1 week
2 weeks
At 6 months
D0 + 6 months = D3
D3 – 30 days
D3 + 30 days
2 months
QoL forms are considered as invalid if either:
●
All questions on the form are blank.
●
The completion date is unknown or it cannot be assigned to a single 
assessment time point.
●
The completion date falls outside all time windows.
●
Multiple forms are received during the same time window.  In the latter case, 
the form closest to the intended assessment time will be kept.  In case of 
equidistance, the earlier form will be kept.
Forms are expected at T for each subject that was within the assessment window.  A 
subject is considered to be within the assessment time window if at least one of the 
following conditions is met:
●
At least one valid QoL form received within L and U
●
Time on study > time from randomization till T
For the baseline assessment, all subjects are expected to have a completed QoL form. 
The compliance rate between the arms will be compared at each post-baseline time point 
using a chi-square test.  The following analyses will be presented per time-point:
●
Compliance rate with QoL assessment by treatment group and overall
●
Percentage of questions answered by treatment group (summary statistics)


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●
Comparison of compliance rates (chi-square test or fisher exact test (if 
expected cell frequencies are < 10)
In case significant differences are found, explanation of these differences should be 
sought and the analysis strategy adapted accordingly.
For each scale, the treatment group differences will be evaluated by analyzing the change 
from baseline to each of the three post-baseline time-points and to the final measurement 
(last QoL assessment per subject) using a one-way analysis of variance (ANOVA) model.  
Simple summary statistics for QoL assessments at each timepoint will also be presented.  
No adjustment for multiplicity is made since it is exploratory.  For QoL assessment data, 
AbbVie will only perform and present simple summary statistics at each timepoint and 
change from baseline analysis.  Other QoL data will be modeled and analyzed by 
EORTC.
Changes in HRQoL scores per time point will be evaluated by classifying them according 
to the 10 point change threshold into 3 categories:
●
Improved:  defined as a 10 point or more improvement (i.e., increase for 
functional scales and decrease for symptom scales) from baseline.
●
Stable:  defined as a less than 10 point change from baseline.
●
Deteriorated:  defined as a 10 point or more deterioration (i.e., decrease for 
functional scales and increase for symptom scales) from baseline.  Subjects 
without a valid HRQoL outcome will be considered as having deteriorated. 
In case of discrete numbers (N < 10), categories may be combined.  The subsequent 
proportions will be compared between treatment arms using a chi-square test in the intent-
to-treat population.


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10.4
Re-Randomization Test
The robustness of the results to the use of the minimization randomization algorithm will 
be evaluated by performing a re-randomization test to compare overall survival between 
the treatment arm(s) and the control.
The re-randomization test will be performed as follows:
●
The procedure will use 50,000 replications of the ITT population (all 
randomized subjects). 
●
For each replicate, a virtual sequence of treatment assignments (a virtual 
re-randomization schedule) will be created using the original minimization 
randomization algorithm based on the order in which the subjects were 
originally randomized into the trial and the value of their randomization 
stratification factors.
●
For each replicate, primary survival analysis will be performed for OS. 
●
The re-randomization test p-values will be the fraction of replications where 
the log-rank p-values from the replicates are less than or equal to the 
corresponding p-values from the original analysis of overall survival.
●
The empirical distribution function of the chi-square statistics obtained from 
the replicates will be plotted against the theoretical asymptotic Chi-square(1) 
distribution of the log-rank statistic for visual comparison to assess validity of 
the test procedure. 
Robustness of the results will be established if the re-randomization test p-values are then 
found to be comparable to the corresponding p-values from the original analyses of OS, 
PFS assessed by IRC, and ORR assessed by IRC.
10.5
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PFS, ORR, BRR, duration of response will be analyzed based on assessment by local 
investigator per RANO criteria, as supportive of the efficacy analyses with central 
imaging center evaluations. 
An analysis of OS will be performed by fitting a Cox regression model with treatment 
arm and covariates identified in the references;4,5 i.e., performance status, tumor location, 
patient age, baseline steroids, tumor size and load.  Treatment will be forced in the model 
and covariates will be selected using a stepwise procedure.  Bootstrap technique will be 
used to estimate the posterior probability of inclusion in the Cox model.  EORTC will 
perform the analysis with various model section approaches. 
Modified PFS is defined as the number of months from the date of randomization until the 
date of first progression assessed by IRC or death without receiving post anti-cancer 
therapy, whichever occurs first.  Subjects for whom neither death nor progression have 
been documented will be censored on the date of the last radiological assessment if they 
have no post anti-cancer therapy.  If a subject has other post anti-cancer therapy prior to 
progression or death, the data will be censored at the date of last radiological assessment 
prior to or on the start date of post anti-cancer therapy. 
Accounting for subjects who died or progressed immediately after 2 or more consecutive 
missed assessments, modified efficacy endpoint of PFS to consider the date of the earliest 
missed radiological assessment prior to a subject's progression or death, as a date of 
progression, will be analyzed using the same statistical methodology as that for the 
secondary PFS endpoint.
For subjects with at least one measureable disease at baseline (defined as an enhancing 
tumor with two perpendicular diameters ≥ 10 mm), the number and percentage of subjects 
with objective responses will be presented using the same statistical methodology as that 
for the secondary ORR endpoint. 


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In case more than 10% are excluded from the per-protocol population, the primary 
efficacy analyses (both comparisons) will be performed in the per-protocol population at 
two-sided alpha 5%.
10.6
Subgroup Analyses
Efficacy endpoints (OS, PFS, ORR, BRR, CRR, and NDFS) will be assessed in the 
following subgroups on an as-stratified basis according to stratification data collected at 
randomization;
●
Timing of relapse (< 16 weeks or ≥ 16 weeks after the first day of the last 
TMZ cycle)
●
Region of the world (North America or Europe and Australia or Asia/other 
regions)
●
WHO Performance status (0 or > 0)
●
MGMT promoter methylation (status  methylated or unmethylated)
●
EGFR pathway abnormalities (abnormal or normal)
Differences between the treatment arms and the control arm (Arm 1 vs. Arm 3; Arm 2 vs. 
Arm 3) in time-to-event endpoints (OS, PFS, and NDFS) will be assessed by unstratified 
log-rank test.  Kaplan-Meier curves comparing treatments will be presented in each 
subgroup. 
For ORR, BRR, and CRR, the number and percentage of subjects with response will be 
reported with exact (binomial) two-sided 95% CI (CI for ORR and CRR only) in each 
subgroup by treatment arm.  The ORR and CRR will be compared between the treatment 
arms over the control arm using a chi-square (Fisher's exact) test.  
The hazard ratios (HRs) of the two treatment arms over the control arm and their 95% CIs 
will be calculated by a Cox's model with only treatment as covariate.  Odds ratios (ORs) 
will be presented with 95% CIs.  Forest plots will be presented to display these HRs and 
ORs.  The forest plot will also contain the HR and OR for the ITT population for the 
purposes of visual comparing and contrasting.  


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11.0
Safety Analysis
11.1
General Considerations
Unless otherwise specified, safety analyses will be performed on the Safety population.  
No statistical comparisons will be performed between treatment arms.  No p-values and 
CIs will be provided.
Unless specified, all summaries/analyses involving AEs will only include treatment-
emergent adverse events (TEAEs).  TEAEs are defined as any adverse event with onset or 
increase severity after the first dose of study drug (ABT-414/TMZ/lomustine) and no 
more than 35 days after the last dose of study drug (ABT-414/TMZ/lomustine).  
AEs where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the AE start time are collected 
and the AE start time is prior to the study drug start time.  If an incomplete onset date was 
collected for an AE, the AE will be assumed to be treatment-emergent unless there is 
evidence that confirms that the AE was not treatment-emergent (e.g., the AE end date was 
prior to the date of the first dose of study drug, a partial AE start date is available for 
which the month or year is prior to the first dose date of study drug).
Adverse events will be coded and summarized by system organ class and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or 
higher.  The table of clinical toxicity grades modified from the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 will be 
used in the grading of adverse events and laboratory abnormalities that are reported as 
adverse events.
11.2
Analysis of Adverse Events
The number and percentage of subjects having treatment-emergent adverse events will be 
tabulated by MedDRA system organ class and preferred term.  The tabulations will also 
be provided with further breakdowns by NCI CTCAE toxicity grade and relationship to 


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study drug (ABT-414/TMZ/lomustine).  Serious adverse events, adverse events leading to 
discontinuation of treatment, and adverse events leading to death will be summarized. 
An overview of AEs will be presented, by treatment arm and overall, consisting of the 
number and percentage of subjects experiencing the following adverse event categories.
●
Any treatment-emergent adverse event
●
Any treatment-emergent adverse event by NCI CTCAE grade
●
Any treatment-emergent adverse event with NCI CTCAE grade 3, 4 or 5
●
Any treatment-emergent adverse event NCI CTCAE grade 3 or 4 
●
Any treatment-emergent adverse event that is rated as a reasonable possibility 
of being related to ABT-414
●
Any treatment-emergent adverse event that is rated as a reasonable possibility 
of being related to TMZ
●
Any treatment-emergent adverse event that is rated as a reasonable possibility 
of being related to lomustine
●
Any treatment-emergent adverse event NCI toxicity grade 3 or 4 that is rated 
as a reasonable possibility of being related to ABT-414
●
Any treatment-emergent adverse event NCI toxicity grade 3 or 4 that is rated 
as a reasonable possibility of being related to TMZ
●
Any treatment-emergent adverse event NCI toxicity grade 3 or 4 that is rated 
as a reasonable possibility of being related to lomustine
●
Any treatment-emergent serious adverse event 
●
Any treatment-emergent serious adverse event NCI toxicity grade 3 or 4 
●
Any treatment-emergent serious adverse event that is rated as a reasonable 
possibility of being related to ABT-414
●
Any treatment-emergent serious adverse event that is rated as a reasonable 
possibility of being related to TMZ
●
Any treatment-emergent serious adverse event that is rated as a reasonable 
possibility of being related to lomustine
●
Any treatment-emergent adverse event leading to discontinuation of ABT-414 


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●
Any treatment-emergent adverse event leading to discontinuation of TMZ 
●
Any treatment-emergent adverse event leading to discontinuation of lomustine
●
Any treatment-emergent adverse event leading to dose reduction of ABT-414 
●
Any treatment-emergent adverse event leading to dose reduction of TMZ 
●
Any treatment-emergent adverse event leading to dose reduction of lomustine
●
Any treatment-emergent adverse event leading to interruption of ABT-414 
●
Any treatment-emergent adverse event leading to interruption of TMZ 
●
Any treatment-emergent adverse event leading to interruption of lomustine
●
Any treatment-emergent adverse event of special interest
●
Any treatment-emergent adverse event leading to death
The treatment-emergent adverse events of special interest will be based on microcystic 
keratopathy CMQ 80000152 (Section 11.2.1).
Additionally, selected analyses of adverse events will be performed for the subset of 
subjects with EGFRvIII mutation (on an as-treated basis in the Ev3M population) for the 
following categories.
●
Any treatment-emergent adverse event (descending frequency)
●
Any treatment-emergent serious adverse event 
●
Any treatment-emergent adverse event of special interest
11.2.1
Adverse Events of Special Interest (AESI)
The number and percentage of subjects having AESI will be tabulated by MedDRA 
system organ class and preferred term.  Specific AESI will be identified by the following 
search criteria in Table 7.


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Table 7.
Adverse Events of Special Interest
Adverse 
Event of 
Special 
Interest
Search Criteria
Event Definition/ 
Medical Concept
Microcystic 
Keratopathy
CMQ "80000152";
Preferred Terms:  Acquired corneal dystrophy, Ciliary 
hyperaemia, Corneal abrasion, Corneal cyst, Corneal 
decompensation, Corneal defect, Corneal degeneration, 
Corneal deposits, Corneal disorder, Corneal dystrophy, Corneal 
epithelial microcysts, Corneal epithelium defect, Corneal 
erosion, Corneal irritation, Corneal lesion, Corneal oedema, 
Corneal opacity, Deposit eye, Dry eye, Eye pain, Foreign body 
sensation in eyes, Keratitis, Keratopathy, Lacrimation 
increased, Limbal swelling, Ocular toxicity, Photophobia, Slit-
lamp tests abnormal, Topography corneal abnormal, Vision 
blurred
Any adverse event 
report identified by 
search criterion
11.2.1.1
Adverse Event of Special Interest
The number and percentage of subjects experiencing at least one AESI for each of the 
following events will be summarized:
●
Any AESI 
●
Any AESI by NCI CTCAE grade
●
Any AESI with NCI CTCAE grade 3 or 4
●
Any serious AESI
●
Any AESI leading to discontinuation of ABT-414 
●
Any AESI leading to dose interruption of ABT-414 
●
Any AESI leading to dose reduction of ABT-414
11.2.1.2
Time to Onset of Adverse Event of Special Interest
For specified AESIs, time to the first occurrence (onset) the event will be assessed using 
survival analysis methodology (Kaplan-Meier estimates) separately for all AESIs, for all 
AESIs with NCI CTCAE grade ≥ 2, and for all AESIs with NCI CTCAE grade ≥ 3. 


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Time to onset will be measured in days relative to the day of a subject's first dose of study 
drug (ABT-414/TMZ/lomustine) to the start date of the first occurrence of AESI.  If a 
subject has not experienced an AESI, the subject will be censored on the day of the 
subject's last assessment (i.e., the day of the subject's last known laboratory assessment, 
last known vital sign assessment, last known physical exam, last known ocular exam, last 
known tumor assessment, or last known follow-up visit, whichever is the latest) or 
35 days from the subject's last ABT-414 treatment, whichever is earliest; if the subject has 
not experienced an AESI and had no post-baseline assessment (i.e., none of laboratory 
assessment, vital sign assessment, physical exam, ocular exam, or tumor assessment), the 
subject will be censored on the day of the subject's first study drug 
(ABT-414/TMZ/lomustine).
Median onset time will be estimated using a Kaplan-Meier method with corresponding 
95% CI for the median for each treatment arm.
11.3
Deaths
The number and percentage of subject deaths will be summarized 1) for deaths occurring 
while the subject was still receiving study drug (ABT-414/TMZ/lomustine) in this study; 
2) for deaths occurring off-treatment within 35 days after the last dose of study drug 
(ABT-414/TMZ/lomustine); and 3) for all deaths in this study regardless of the number of 
days after the last dose of study drug (ABT-414/TMZ/lomustine).
Similarly, the number and percentage of subject deaths will be summarized for deaths 
occurring while the subject was still receiving 1) ABT-414; 2) within 35 days after the last 
dose of ABT-414; and 3) for all deaths regardless of the number of days after the last dose 
of ABT-414.
11.4
Analysis of Laboratory, Vital Signs, and ECG Data
Biochemical parameters (serum creatinine, total bilirubin, AST, ALT, alkaline 
phosphatase, phosphate, total protein, albumin, sodium, potassium, calcium, and chloride) 
will be collected at baseline (all Arms), and Day 1 of each cycle (all Arms).  


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Hematological parameters (WBC, absolute neutrophil count, lymphocytes, hematocrit, 
hemoglobin, and platelet count) will be collected at baseline (all Arms), Day 1 of each 
cycle (all Arms), Day 14 of each cycle (Arms 1 and 2 only), Day 21 of each cycle 
(Arms 1 and 3B only), and Day 28 of each cycle (Arm 3A only).
Vital sign parameters (diastolic/systolic blood pressure, pulse rate, and body temperature 
(°C)) will be collected at baseline (all Arms), Day 1 of each cycle (all Arms), Day 14 of 
each cycle (Arms 1 and 2 only), and Day 28 of each cycle (Arm 3A only), and follow-up 
visit if clinically indicated/relevant.
Twelve-lead ECG data will be collected at baseline, immediately after ABT-414 dosing 
on Day 1 of Cycle 1 and Cycle 3 (Arms 1 or 2 only).
For hematological, biochemical, and vital sign parameters, changes from baseline are 
analyzed for each post-baseline visit (as specified in Section 6.0 Analysis of Conventions) 
and the final visit.  If more than one measurement exists for a subject on a particular day, 
an arithmetic average will be calculated.  The average will be considered to be the 
subject's measurement of that day.  Descriptive statistics will be presented for baseline, 
each post-baseline, and the final visit by each treatment arm.  Mean change from baseline 
to each post-baseline visit and the final visit within each treatment arm will also be 
presented.  The highest and lowest values of each hematological parameter will be 
identified for each subject, and descriptive statistics for mean change from baseline within 
each treatment arm will be presented.
Biochemistry and hematology determinations will be categorized according to 
NCI CTCAE version 4.0 grades, and shifts from baseline grades to maximum and final 
post-baseline grades will be assessed.  The baseline and final grades will be defined 
respectively as the grade of the last measurement collected prior to or on randomization, 
or if missing, then prior to or on the first dose of study drug (ABT-414/TMZ/lomustine), 
and as the grade of the last post-baseline measurement collected no more than 35 days 
after the last dose of study drug (ABT-414/TMZ/lomustine).  If multiple values are 
available for a post-baseline measurement, then the value with the highest NCI CTCAE 


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grade will be used in the assessment of shift.  Frequency and percentage of subjects will 
be presented by treatment arm:  1) baseline grade vs. maximum post-baseline grades, and 
2) baseline grade vs. final post-baseline grade.  Frequency and percentage of subjects 
experiencing a shift from baseline grades of 0 to 2 to maximum post-baseline grades of 3 
to 4, and from baseline grades of 0 to 2 to final post-baseline grades of 3 to 4 will be 
presented by treatment arm.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 biochemistry 
and hematology values will be provided.  All measurements collected, regardless of the 
number of days after the last dose of study drug, will be included in these listings.
Descriptive summary statistics for categorical ECG data will be presented for baseline and 
Day 1 of Cycle 1 and Cycle 3 (Arms 1 or 2 only).  Visit window in Table 2 will not be 
applied to the ECG data.  Shift tables will also be provided. 
11.4.1
Assessment of Potentially Clinically Significant Laboratory 
Values
For selected laboratory variables, the number and percentage of subjects who had at least 
one post-baseline observation meeting the pre-defined criteria for potentially clinically 
significant values will be provided for each variable.  If a subject did not have the 
laboratory measurement at baseline but had a post-baseline measurement which met the 
pre-defined criteria, this subject is considered as meeting the criteria for potentially 
clinically significant laboratory values for the measurement.
Pre-defined criteria for potentially clinically significant laboratory values are given in 
Table 8 and Table 9 below based on NCI CTCAE criteria:


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Table 8.
Criteria for Potentially Clinically Significant Laboratory Values –
Hematology Variables
Hematology Variables
Units
Definition of Potentially Clinically 
Significant Values (NCI CTCAE Grade ≥ 3)
Hemoglobin
g/L
< 80
White blood cell count
109/L
< 2
Neutrophil count 
109/L
< 1
Lymphocyte count 
109/L
< 0.5
Platelet count 
109/L
< 50
Table 9.
Criteria for Potentially Clinically Significant Laboratory Values –
Chemistry Variables
Chemistry Variables
Units
Definition of Potentially Clinically Significant Values 
(NCI CTCAE Grade ≥ 3)
Low
High
Total bilirubin
> 3.0 × ULN
Albumin
g/L
< 20
Aspartate aminotransferase 
(AST/SGOT)
> 5.0 × ULN
Alanine aminotransferase 
(ALT/SGPT)
> 5.0 × ULN
Alkaline phosphatase
> 5.0 × ULN
Creatinine
> 3.0 × ULN
Sodium
mmol/L
< 130
> 155
Potassium
mmol/L
< 3.0
> 6.0
Total calcium
mmol/L
< 1.75
> 3.1
11.4.2
Assessment of Hepatotoxicity 
The number and percentage of subjects with maximum treatment-emergent laboratory 
values meeting the following criteria were summarized to assess potential hepatotoxicity.
Potential hepatotoxicity criteria defined in Hy's law:
●
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●
AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
●
ALT and AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN
The maximum ratio relative to the ULN will be used to determine if subjects met the 
criteria listed above.  The ALT, AST, and total bilirubin values do not need to be 
concurrent in order to meet the defined criteria as long as collected up to 35 days 
following the last dose date of study drug (ABT-414/TMZ/lomustine).  For ALT, AST, 
and total bilirubin, a subject will be counted if the post-baseline laboratory value up to 
35 days following the last dose date of study drug (ABT-414/TMZ/lomustine) met the 
above criteria regardless of the baseline laboratory value (i.e., the post-baseline laboratory 
value does not need to be worse than the baseline laboratory value).
A listing of all ALT, AST, total bilirubin, and alkaline phosphatase values will be 
provided for all subjects who meet any of the criteria defined above.
11.5
Analysis of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed by the sponsor as detailed in Table 10.
Table 10.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Significant Values
Systolic blood pressure
High
Value ≥ 160 mmHg
Diastolic blood pressure
High
Value ≥ 100 mmHg
Heart rate
Low
Value ≤50 bpm
High
Value ≥ 120 bpm
Temperature
Low
Value ≤ 32°C
High
Value > 40°C
The number and percentage of subjects with post baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  The baseline 
will be defined as the last non-missing measurement collected prior to or on the first dose 


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of study drug (ABT-414/TMZ/lomustine).  A separate listing will be provided that 
presents all of the subjects and values that meeting the criteria.  No comparisons of the 
rates of subjects met the above criteria between the treatment arms will be performed.
12.0
Summary of Differences Between EORTC and 
AbbVie Analyses 
EORTC and AbbVie Inc. may follow slightly different approaches for the analyses of 
certain types of study data.  EORTC will perform analyses primarily for the purposes of 
certain clinical publications.  Such analyses, unless also performed by AbbVie (perhaps 
using different approach), may be included in AbbVie's Clinical Study Report of this 
study. 
While there may be other differences, the following is a summary of differences in 
EORTC planned analysis from the pre-specified analysis methods described above that 
AbbVie and EORTC have been able to identify at the time of drafting this SAP 
(paragraph numbering refers to sections of the present document):
3.0
Introduction
EORTC will perform efficacy and safety analyses using SAS Version 9.4 or higher (SAS 
Institute, Inc., Cary, NC 27513) under the Windows operating system.
5.0
Analysis Sets
Safety population:  For EORTC analysis, subjects are classified and analyzed in the arm 
they were assigned at the time of randomization if they started the corresponding 
treatment.  The safety profile of subjects who did not receive the allocated treatment is 
reported separately instead of being reported in the arm actually received, as done by 
AbbVie.  The safety population for EORTC is thus strictly included in that of AbbVie and 
the approaches become identical if no subject switches between protocol treatment arms.


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7.3
Prior and Concomitant Medications
EORTC does not perform this analysis.  
9.1
Study Drug Treatment
EORTC does not perform longitudinal analysis of drug dose administered.  
9.4
Protocol Deviations
EORTC will present the trial compliance per treatment arm as evaluated during the 
medical review.  Frequencies and percentages of protocol deviations as described in the 
medical review plan will be tabulated overall and split by type of deviation and severity. 
10.3
Efficacy Analyses
For QoL assessment data, Abbvie will only perform and present simple summary 
statistics at each timepoint and change from baseline analysis.
EORTC will not perform Time to Tumor Response (TTR) analysis.
10.4
Re-Randomization Test
EORTC will not perform the analysis for PFS assessed by IRC or ORR assessed by IRC.
10.5
Sensitivity Analyses
EORTC will only present PFS, ORR, BRR, duration of response analyzed based on 
assessment by local investigator per RANO criteria. 
EORTC will perform OS analysis by fitting a Cox regression model with treatment arm 
and potential prognostic covariates using a stepwise procedure.
In case more than 10% are excluded from the per-protocol population, the primary 
efficacy analysis (both comparisons) will be performed in the per-protocol population at 
two-sided alpha 5%.


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11.2
Analysis of Adverse Events
EORTC will not present frequencies and percentages for
●
Any treatment-emergent adverse event leading to discontinuation of ABT-414 
●
Any treatment-emergent adverse event leading to discontinuation of TMZ 
●
Any treatment-emergent adverse event leading to discontinuation of lomustine
●
Any treatment-emergent adverse event leading to dose reduction of ABT-414 
●
Any treatment-emergent adverse event leading to dose reduction of TMZ 
●
Any treatment-emergent adverse event leading to dose reduction of lomustine
●
Any treatment-emergent adverse event leading to interruption of ABT-414
●
Any treatment-emergent adverse event leading to interruption of TMZ 
●
Any treatment-emergent adverse event leading to interruption of lomustine
●
Any treatment-emergent adverse event of special interest
EORTC will not perform the analyses of adverse events for the subset of subjects with 
EGFRvIII mutation
11.2.1
Adverse Events of Special Interest (AESI)
EORTC will not perform this analysis.
11.2.1.1
Analysis of Adverse Events of Special Interest (AESI)
EORTC will not perform this analysis.
11.2.1.2
Time to Onset of Adverse Event of Special Interest
EORTC will not perform this analysis.
11.4.2
Assessment of Hepatotoxicity
EORTC will not perform this analysis.


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11.5
Analysis of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
EORTC will not perform this analysis.
13.0
References
1.
Freedman LS, White SJ.  On the use of Pocock and Simon's method for balancing 
treatment numbers over prognostic factors in the controlled clinical trial.  
Biometrics.  1976;32(3):691-4.
2.
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ABT-414
M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
55
14.0
Summary of Major Changes
●
Modify Section 5.0, Interim Futility Analysis to adjust observed information 
fraction.
Rationale:  Clarification and details regarding the nominal significance level 
for the final OS analysis.
●
Modify Section 5.0, Analysis Sets to add EGFRvIII-Mutated Population.
Rationale:  To specify EGFRvIII-Mutated (Ev3M) Population is a subset of 
subjects who have EGFRvIII mutated tumors.
●
Modify Section 6.0 Analysis Conventions to clarify baseline definition. 
Rationale:  Clarification and details regarding missing measurement collected 
prior to randomization.
●
Modify Section 9.0 Dosage to include dose intensity and relative dose 
intensity. 
Rationale:  Additional assessment to summarize dose intensity and relative 
dose intensity of ABT-414, adjusting actual treatment duration.
●
Modify Section 10.1 General Considerations to provide clarification of 
stratification factors.  
Rationale:  Clarify that stratification factors based on ORTA are to be used.
●
Modify Section 10.1 General Considerations to provide overall descriptions of 
analysis method and censoring rule for TTE.  
Rationale:  Details were added for clarification.
●
Modify Section 10.2 Efficacy Endpoints to add time to tumor response (TTR).  
Rationale:  TTR was added as an exploratory endpoint to assess time to 
response.
●
Modify Section 10.3 Efficacy Analyses to revise analysis of corticosteroid use.  
Rationale:  Kaplan-Meier estimates of PFS by baseline steroid use status were 
added, taking PFS-censored subjects into account.
●
Modify Section 10.3 Efficacy Analyses to clarify analysis of QoL.  


ABT-414
M14-483 – Statistical Analysis Plan
Version 2.0 – 30 May 2017
56
Rationale:  To clarify that Abbvie only performs and presents simple 
summary statistics and change from baseline analysis.  Various QoL data 
modelings and compliance analysis will be performed by EORTC.
●
Modify Section 10.4 Re-Randomization Test to include PFS and ORR 
assessed by IRC
Rationale:  PFS and ORR re-randomization analyses were added to support 
robustness of the efficacy results.
●
Remove Section 10.7 Exploratory Analyses.  
Rationale:  Removed the analyses from SAP, as they are to be performed in a 
data dependent manner.
●
Added selected AE summaries to Section 11.2 Analyses of Adverse Events.
Rationale:  Details were added for selected AE summaries in Ev3M 
population.
●
Added AESI to Section 11.2.1 Adverse Events of Special Interest (AESI).
Rationale:  Details were added for clarification.
Removed Time to Resolution Analysis from Section 11.2.1.2 (Section 11.3
previously) Time to Onset of Adverse Event of Special Interest.
Rationale:  Analysis plan and methodological details will be available to 
integrated safety summary SAP.
●
Added Sections 11.4.1 and 11.4.2 Assessment of Potentially Clinically 
Significant Laboratory Values and Assessment of Hepatotoxicity.
Rationale:  Details were added for clarification.
●
Modified Section 11.5 Analysis for Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values. 
Rationale:  Table 10 was revised for clarification.
●
Removed Section 12.0 Pediatric Sub-Study.
Rationale:  A separate SAP for the pediatric sub-study will be provided.