Adult Study: ABT-414 Alone or ABT-414 Plus Temozolomide vs. Lomustine or Temozolomide for Recurrent Glioblastoma Pediatric Study: Evaluation of ABT-414 in Children With High Grade Gliomas

Study Overview
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Brief Summary
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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
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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 The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.

Official Title
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INTELLANCE-2: ABT-414 Alone or ABT-414 Plus Temozolomide Versus Lomustine or Temozolomide for Recurrent Glioblastoma: A Randomized Phase 2 Study of the EORTC Brain Tumor Group

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Depatuxizumab mafodotin
* Drug: Temozolomide
* Drug: Lomustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants (greater than or equal to 18 years old): Histologically confirmed de novo (primary) glioblastoma with unequivocal tumor progression or recurrence. 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 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. Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE] tumor) for central testing of Epithelial Growth Factor Receptor (EGFR) amplification Presence of EGFR amplification confirmed by central assessment; participants with undetermined EGFR status are excluded World Health Organization (WHO) Performance status 0 - 2 No more than one line of chemotherapy (concurrent and adjuvant Temozolomide 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. Post surgery MRI within 48 hours following surgery, however an MRI scan has to be done within 2 weeks prior to randomization. Surgery completed at least 2 weeks before randomization and patients should have fully recovered as assessed by investigators. Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula. Liver function: bilirubin < 1.5× upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT) < 2.5× ULN Pediatric sub-study participants (less than 18 years old): 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]). 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. The tumor tissue must have been determined to have EGFR amplification, (by local or other testing service). Availability of adequate biological material for retrospective confirmatory central testing of EGFR amplification Participant has sufficiently recovered from previous therapy. The investigator believes that 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. Renal function: calculated creatinine clearance ≥ 30 mL/min by the Cockcroft-Gault formula for pediatric patients ≥12 years of age and estimated glomerular filtration rate ≥ 30 mL/min/1.73 m^2 by modified Schwartz equation for pediatric patients < 12 years of age. Liver function: Total bilirubin ≤ 1.5× upper limit of the normal range (ULN), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) <= 3× ULN. Participants with Gilbert's syndrome documented in medical history may be enrolled if total bilirubin is < 3 times ULN. Not allowed are participants with known chronic liver disease and/or cirrhosis. Exclusion Criteria: Adult population (greater than or equal to 18 years old): Prior treatment with nitrosoureas Prior treatment with bevacizumab Previous exposure to Epithelial Growth Factor Receptor (EGFR) targeted agents, including EGFRvIII targeting agents Prior discontinuation of temozolomide chemotherapy for toxicity reasons Prior Radiation Therapy (RT) with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven 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 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. No history of wheat allergies and Coeliac disease. No EIAED, 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. Pediatric sub-study (less than 18 years old): (For recurrent disease) No prior RT with a dose over 65 Gy to the brain, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven No current or recent (within 4 weeks or 5 half-lives [whichever is shorter] before enrollment) treatment with another investigational drug Female participants 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.

Ages Eligible for Study
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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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-414/temozolomide<br>Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants | Drug: Depatuxizumab mafodotin<br>* 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).<br>* Other names: ABT-414;Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;|
| Experimental: ABT-414_adult<br>Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants | Drug: Depatuxizumab mafodotin<br>* 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).<br>* Other names: ABT-414;|
| Active Comparator: Control_lomustine<br>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. | Drug: Lomustine<br>* 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.<br>* Other names: Gleostine;|
| Active Comparator: Control_ temozolomide<br>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. | Drug: Temozolomide<br>* 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.<br>* Other names: TMZ;|
| Experimental: ABT-414_ pediatric<br>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). | Drug: Depatuxizumab mafodotin<br>* 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).<br>* Other names: ABT-414;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult Study: Overall Survival (OS) | Overall Survival (OS) was defined as time from randomization to death due to any cause, regardless of whether the event occurred on or off study drug (depatuxizumab mafodotin/temozolomide/lomustine). | From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months. | 
| Adult Study: Progression-Free Survival (PFS) | Progression-free survival was assessed per response assessment in neuro-oncology criteria (RANO) criteria and assessed by an independent review committee and was defined as the length of time during and after the treatment of a disease, that the participant lived with the disease but did not get worse. | Measured every 8 weeks from date of randomization until the date of first objective progression or subject's death, whichever occurred first, up to 2 years | 
| Pediatric Study: Percentage of Participants With Adverse Events From the First Visit Until 49 Days After the Last Dose of Study Drug | The severity of each adverse event was rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0) | From participant's first visit until 49 days after the participant's last dose of study drug, up to 63 weeks | 
| Pediatric Study: Maximum Observed Serum Concentration (Cmax) of ABT-414 | Cmax is the peak concentration that a drug achieves in a specified compartment after the drug has been administrated and before administration of a second dose. | Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose | 
| Pediatric Study: Maximum Observed Plasma Concentration (Cmax) of Cys-mcMMAF | Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose. Cys-mcMMAF is a toxic metabolite of depatuxizumab mafodotin. | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 
| Pediatric Study: Half-life (t1/2) Observed for ABT-414 | Half-life is the calculated time it takes for half of the drug to leave the body. | Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose | 
| Pediatric Study: Half-life (t1/2) Observed for Cys-mcMMAF | Half-life is the calculated time it takes for half of the drug or drug metabolite to leave the body. CysmcMMAF is a toxic metabolite of depatuxizumab mafodotin. | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 
| Pediatric Study: Area Under the Concentration-time Curve (AUC) Observed for ABT-414 | AUC is a measure of how long and how much drug is present in the body after dosing. The AUC of depatuxizumab mafodotin (ABT-414) in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population. | Samples collected Cycle 1 Days 1, 2,3,5,8,15; Cycle 2 Day 1; Cycle 3 Day 1; Cycle 5 Day 1; Day 1 of every two cycles starting with Cycle 5; and 35 days after the last dose | 
| Pediatric Study: Area Under the Concentration-time-curve (AUC) Observed for Unconjugated Cys-mcMMAF | AUC is a measure of how long and how much drug or drug metabolite is present in the body after dosing. The AUC of Cys-mcMMAF, a toxic metabolite of depatuxizumab mafodotin, in the pediatric population was measured following treatment to confirm that this was comparable to adults, and that the dosing levels are appropriate for a pediatric population. | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult Study: Objective Response Rate (ORR) | The objective response rate (ORR) included best overall responses - complete response (CR) and partial response (PR) - assessed by the independent review committee per response assessment in neurooncology criteria (RANO) criteria from the date of randomization until disease progression or death, whichever came first. All objective responses (CR and PR) must be have been confirmed by repeat MRI 4 weeks after 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 was considered a nonresponder. | Every 8 weeks at each assessment of disease, up to 28 months | 
| Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | Overall Survival (OS) was defined as time from randomization to death due to any cause, regardless of whether the event occurred on or off study drug (depatuxizumab mafodotin/temozolomide/lomustine) for all randomized participants that had the Epidermal Growth Factor Receptor (EGFRvIII) mutation. | From the date of randomization up to the date of participant's death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months | 
| Pediatric Study: Objective Response Rate (ORR) | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks | 
| Pediatric Study: Best Tumor Response Rate | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks | 
| Pediatric Study: Duration of Response | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Evaluated every 8 weeks (+/- 7 days) at each assessment of disease according to response assessment in neuro-oncology criteria (RANO), until progression or withdrawal up to approximately 52 weeks | 
| Pediatric Study: Overall Survival | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | From the date of enrollment to the date of death; participants who completed treatment were to be assessed every 12 weeks, up to 28 months | 
| Pediatric Study: Time to Progression | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/ temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, pediatric time to progression data analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant's death, whichever occurs first, up to approximately 52 weeks | 
| Pediatric Study: Progression-Free Survival | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Evaluated every 8 weeks (+/- 7 days) from the date of enrollment until the date of first objective progression or participant's death, whichever occurs first, up to approximately 52 weeks | 
| Pediatric Study: Percentage of Participants With Changes in Neurological Status and Functioning | The pediatric data collection for this study was still ongoing when INTELLANCE-1 (NCT02573324; EudraCT number 2015-001166-26) interim efficacy results overall indicated no survival benefit to adding depatuxizumab mafodotin to standard radiotherapy/temozolomide therapy in newly diagnosed glioblastoma patients. Based on the INTELLANCE-1 results, AbbVie decided to stop further enrollment of pediatric participants into the pediatric substudy and to stop the collection of efficacy data. Because of this decision not to summarize except for safety data, the pediatric substudy ORR analysis was not summarized due to the small number of pediatric participants enrolled in the study. | Baseline, Day 1 and 15 of each cycle, every 6 months for 5 years thereafter, and then annually | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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