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A Randomized, Placebo Controlled Phase 3 Study of ABT-414 With Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification (Intellance1)

Primary Objective: Phase 2b: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ prolongs Progression Free Survival (PFS) among subjects with newly diagnosed GBM harboring EGFR amplification. Phase 3: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ prolongs Overall Survival (OS) among subjects with newly diagnosed GBM harboring EGFR amplification. Secondary Objectives: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: PFS (secondary endpoint for Phase 3) OS (secondary endpoint for Phase 2b) OS for the EGFRvIII-mutated tumor subgroup PFS for EGFRvIII-mutated tumor subgroup Time to deterioration in symptom severity score M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Time to deterioration in symptom interference score (MDASI-BT) Time to deterioration in neurocognitive functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) Safety: Assessment of comparative safety Exploratory Objectives: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: OS at 1 year OS at 2 years PFS at 1 year PFS at 2 years OS for non-EGFRvIII subjects (comparison between arms) PFS for non-EGFRvIII subjects (comparison between arms) OS and PFS for Total EGFR expressions levels EGFRvIII status (as a prognostic factor independent of treatment assignment) overall and among molecular subgroups Time to deterioration in HRQoL European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30/BN20 scale scores) Change from baseline in HRQoL (EORTC QLQ-C30/BN20 scale scores) Change from baseline in symptom severity factor groupings (MDASI-BT neurologic, cognitive, and treatment) Time to deterioration in performance status Karnofsky Performance Status (KPS) Change from baseline in performance status (KPS) Median time KPS score was maintained at 70 or higher Time to deterioration in neurocognitive functioning on Controlled Oral Word Association (COWA-FAS) Change from baseline in neurocognitive functioning (HVLT-R and COWA-FAS) Change from baseline in Vision item on the MDASI-BT and EORTC BN20 Change from baseline in health status (EQ-5D-5L and EQ-5D-VAS) Changes in EGFR molecular profile during therapy among subjects who undergo additional surgery as part of routine care Pharmacokinetics of ABT-414, total ABT-806, and unconjugated cys-mcMMAF To determine the relationship of neurocognitive function (HVLT-R, COWA-FAS) and patient reported outcomes (PRO) (EORTC QLQ-C30/BN 20, MDASI-BT) with progression-free and overall survival To determine the association between tumor molecular profile and neurocognitive function (HVLT-R, COWA-FAS) and PROs (EORTC QLQ-C30/BN 20, MDASI-BT) Change from maximum corticosteroid dosing

Primary Objective: Phase 2b: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ prolongs Progression Free Survival (PFS) among subjects with newly diagnosed GBM harboring EGFR amplification. Phase 3: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ prolongs Overall Survival (OS) among subjects with newly diagnosed GBM harboring EGFR amplification. Secondary Objectives: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: PFS (secondary endpoint for Phase 3) OS (secondary endpoint for Phase 2b) OS for the EGFRvIII-mutated tumor subgroup PFS for EGFRvIII-mutated tumor subgroup Time to deterioration in symptom severity score M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Time to deterioration in symptom interference score (MDASI-BT) Time to deterioration in neurocognitive functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) Safety: Assessment of comparative safety Exploratory Objectives: To determine whether the addition of ABT-414 to concomitant radiotherapy and TMZ plus adjuvant TMZ improves outcomes among subjects with newly diagnosed GBM harboring EGFR amplification for the following endpoints: OS at 1 year OS at 2 years PFS at 1 year PFS at 2 years OS for non-EGFRvIII subjects (comparison between arms) PFS for non-EGFRvIII subjects (comparison between arms) OS and PFS for Total EGFR expressions levels EGFRvIII status (as a prognostic factor independent of treatment assignment) overall and among molecular subgroups Time to deterioration in HRQoL European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30/BN20 scale scores) Change from baseline in HRQoL (EORTC QLQ-C30/BN20 scale scores) Change from baseline in symptom severity factor groupings (MDASI-BT neurologic, cognitive, and treatment) Time to deterioration in performance status Karnofsky Performance Status (KPS) Change from baseline in performance status (KPS) Median time KPS score was maintained at 70 or higher Time to deterioration in neurocognitive functioning on Controlled Oral Word Association (COWA-FAS) Change from baseline in neurocognitive functioning (HVLT-R and COWA-FAS) Change from baseline in Vision item on the MDASI-BT and EORTC BN20 Change from baseline in health status (EQ-5D-5L and EQ-5D-VAS) Changes in EGFR molecular profile during therapy among subjects who undergo additional surgery as part of routine care Pharmacokinetics of ABT-414, total ABT-806, and unconjugated cys-mcMMAF To determine the relationship of neurocognitive function (HVLT-R, COWA-FAS) and patient reported outcomes (PRO) (EORTC QLQ-C30/BN 20, MDASI-BT) with progression-free and overall survival To determine the association between tumor molecular profile and neurocognitive function (HVLT-R, COWA-FAS) and PROs (EORTC QLQ-C30/BN 20, MDASI-BT) Change from maximum corticosteroid dosing