A Study of ABT-414 in Participants With Newly Diagnosed Glioblastoma (GBM) With Epidermal Growth Factor Receptor (EGFR) Amplification

Study Overview
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Brief Summary
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This study seeks to determine whether the addition of ABT-414 to concomitant radiotherapy and temozolomide (TMZ) followed by combination of ABT-414 with adjuvant TMZ prolongs overall survival (OS) among participants with newly diagnosed glioblastoma (GBM) with epidermal growth factor receptor (EGFR) amplification. In addition, there is a Phase 1, open-label, multicenter sub-study to assess the pharmacokinetics, safety and tolerability of ABT-414 in participants with newly diagnosed EGFR-amplified GBM who have mild or moderate hepatic impairment.

Official Title
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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)

Conditions
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Glioblastoma, Gliosarcoma

Intervention / Treatment
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* Drug: Temozolomide
* Drug: Depatuxizumab mafodotin
* Radiation: Radiation
* Drug: Placebo for ABT-414


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a clinical diagnosis of glioblastoma (GBM). Must have a confirmed epidermal growth factor receptor amplification in tumor tissue. Must have a Karnofsky Performance Status (KPS) >= 70 at assessment <= 14 days prior to randomization (N/A to the sub-study). Must have recovered from effects of surgery, postoperative infection and other complications of surgery. Must have adequate bone marrow, renal, and hepatic function (For the sub-study, the participant must have adequate bone marrow and renal function and have mild-to-moderate hepatic impairment). Exclusion Criteria: Multifocal, recurrent or metastatic GBM or gliomatosis cerebri (For the sub-study, the participant can have multifocal GBM and glimatosis cerebri but can't have recurrent or metastatic GBM). Prior chemo therapy or radiosensitizer for head and neck cancer. Prior radiotherapy to the head or neck in overlap of radiation fields. Prior therapy for glioblastoma or other invasive malignancy. Prior, concomitant or planned treatment with Novo Tumor Treatment Fields (Novo-TTF), EGFR-targeted therapy, bevacizumab, Gliadel wafers or other intratumoral or intracavity anti-neoplastic therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Depatuxizumab Mafodotin, Radiation and Temozolomide (TMZ)<br>Depatuxizumab mafodotin is given on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Depatuxizumab mafodotin is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase. | Drug: Temozolomide<br>* Oral Capsule<br>Drug: Depatuxizumab mafodotin<br>* Intravenous (IV) Infusion<br>* Other names: ABT-414;Radiation: Radiation<br> <br> |
| Placebo Comparator: Placebo, Radiation and TMZ<br>Placebo is given on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Placebo is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase. | Drug: Temozolomide<br>* Oral Capsule<br>Radiation: Radiation<br> <br> Drug: Placebo for ABT-414<br>* IV Infusion (IV)<br>|
| Experimental: Open-Label Sub-Study: Depatuxizumab Mafodotin, Radiation and TMZ<br>Depatuxizumab mafodotin is given to participants with hepatic impairment on Day 1 of Week 1, 3 and 5 along with the standard therapy of TMZ and radiation during the chemoradiation phase. Depatuxizumab mafodotin is given on Day 1 and 15 of each cycle along with TMZ (Days 1-5 of each cycle) per standard of care during the adjuvant phase. | Drug: Temozolomide<br>* Oral Capsule<br>Drug: Depatuxizumab mafodotin<br>* Intravenous (IV) Infusion<br>* Other names: ABT-414;Radiation: Radiation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS for the O6-methylguaninemethlytransferese (MGMT) Unmethylated Group | Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause. Unmethylated MGMT promoter is associated with a worse prognosis in GBM | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| OS for the MGMT Methylated Group | Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| OS for the Epidermal Growth Factor Receptor (EGFR)vIII-Mutated Tumor Subgroup | Time to OS is defined as the number of days from the date of randomization to the date of death due to any cause. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| Progression-Free Survival (PFS) | PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria (see Wen et al. J Clin Oncol. 2010 Apr 10;28(11):1963-72) or to the date of death, if disease progression does not occur. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| PFS for EGFRvIII-Mutated Tumor Subgroup | PFS will be defined as the number of days from the date of randomization to the date of earliest disease progression based on Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if disease progression does not occur. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| Deterioration Free Survival in M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score | The MDASI-BT assesses the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours. It consists of 22 symptom items and 6 interference items, each rated from 0 to 10. MDASI-BT symptom severity score is defined as average over 13 core symptom items and 9 brain tumor symptom items, with a total score of 0 to 10, with higher score indicating worse symptoms/interference. Changes in symptom severity score were classified into 3 categories: improved (≤ -1), stable (> -1 and < 1), and deteriorated (≥ 1). Deterioration is defined as satisfying the deterioration criteria (i.e., increase in symptom severity score by ≥ 1 unit) without further improvement (i.e., failing to satisfy deterioration criteria) within 8 weeks or occurrence of death. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| Deterioration Free Survival in MDASI-BT Symptom Interference Score | The MDASI-BT assesses the severity of multiple brain tumor-related symptoms and the impact of these symptoms on daily functioning in the last 24 hours. It consists of 22 symptom items and 6 interference items, each rated from 0 to 10. MDASI-BT symptom interference score is defined as an average of 6 interference items, with a total score of 0 to 10, where higher scores indicate worse interference. Changes in symptom interference score were classified into 3 categories: improved (≤ -1), stable (> -1 and < 1), and deteriorated (≥ 1). Deterioration is defined as satisfying the deterioration criteria (i.e., increase in symptom interference score by ≥ 1 unit) without further improvement (i.e., failing to satisfy deterioration criteria) within 8 weeks or occurrence of death. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 
| Deterioration Free Survival in Neurocognitive Functioning on the Hopkins Verbal Learning Test Revised (HVLT-R) Total Recall Score | The HVLT-R consists of 3 parts. Free call has a range of 0 to 36, delayed recall has a range from 0 to 12, and delayed recognition has a range of -12 to 12. Higher scores indicating better function in all 3 parts. When scoring the HVLT-R, the 3 learning trials are combined to calculate a total recall score (range -12 to 60). Deterioration is defined as satisfying the deterioration criteria (i.e., decrease in HVLT-R total recall score by 5 units) without further improvement within 8 weeks or occurrence of death. | Overall median duration of follow-up was 15.5 months (range: 0.1, 35.6). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly Diagnosed Glioblastoma, Epithelial Growth Factor Receptor (EGFR), Temozolomide, ABT-414, Radiology Therapy Oncology Group, Antibody Drug Conjugate, Brain Tumor, Brain Tumor Group, EGFRvIII, EGFR Amplified, First Line Therapy, Brain Cancer