Symptoms and General Pathology

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Temozolomide

Lomustine

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Factor VIII

ABT-414

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunoconjugates

Immunologic Factors

Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants

Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants

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.

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.

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).

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).

Depatuxizumab mafodotin

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.

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.

AbbVie Inc.

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.

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.

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

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

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

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).

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.

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)

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.

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.

Half-life is the calculated time it takes for half of the drug to leave the body.

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.

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.

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.

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.

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.

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.

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.

European Organisation for Research and Treatment of Cancer - EORTC

AbbVie

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 were to be collected only if they were considered by the Investigator to be causally related to required study procedures.

Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult subjects

ABT-414/Temozolomide

Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult subjects

ABT-414_adult

Adult subjects 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.

Control_lomustine

Adult subjects 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.

Control_ Temozolomide

ABT-414_ Pediatric

Total

Age, Continuous

Sex: Female, Male

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or other Pacific Islander

White

Other

Not Reported

Missing

Race/Ethnicity, Customized

Intention-to-treat population (ITT): all randomized participants

Global Medical Services

Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, \> 0), timing of relapse (\< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).

25th quartile

50th quartile

75th quartile

Adult participants relapsing during temozolomide (TMZ) treatment or within the first 16 weeks after the first day of the last TMZ cycle who 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 OR adult subjects relapsing 16 weeks or more after the first day of the last temozolomide (TMZ) cycle who 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.

Control (Temozolomide/Lomustine)

All randomized adult participants; participants in the control arms were treated based on the time of relapse and they differ in prognostic profile, therefore data were combined.

Adult Study: Overall Survival (OS)

Adult Study: Progression-Free Survival (PFS)

Pediatric participants (safety population)

Pediatric Study: Percentage of Participants With Adverse Events From the First Visit Until 49 Days After the Last Dose of Study Drug

Pediatric participants with available data

Pediatric Study: Maximum Observed Serum Concentration (Cmax) of ABT-414

Pediatric Study: Maximum Observed Plasma Concentration (Cmax) of Cys-mcMMAF

Pediatric Study: Half-life (t1/2) Observed for ABT-414

Pediatric Study: Half-life (t1/2) Observed for Cys-mcMMAF

Pediatric Study: Area Under the Concentration-time Curve (AUC) Observed for ABT-414

Pediatric Study: Area Under the Concentration-time-curve (AUC) Observed for Unconjugated Cys-mcMMAF

Comparison is based on Cochran-Mantel-Haenszel method with stratification factors. Stratified at randomization by regions of the world (North America, Europe and Australia, Asia/Other Regions), WHO performance status (0, \> 0), timing of relapse (\< 16 weeks, ≥ 16 weeks after first day of last TMZ cycle).

Participants with measurable disease at baseline; participants in the control arms were treated based on the time of relapse and they differ in prognostic profile, therefore data were combined.

Adult Study: Objective Response Rate (ORR)

Randomized adult participants with EGFRvIII-mutated tumors; participants in the control arms were treated based on the time of relapse and they differ in prognostic profile, therefore data were combined.

Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation

Pediatric efficacy data were not collected

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT02343406	Glioblastoma	Depatuxizumab m... Temozolomide Lomustine	- 99 Years	AbbVie
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	NCT02343406	Glioblastoma	Depatuxizumab m... Temozolomide Lomustine	- 99 Years	AbbVie

Spots Global Cancer Trial Database for pediatric who grade iii glioma