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Temozolomide

Lomustine

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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

Pediatric Study: Objective Response Rate (ORR)

Pediatric Study: Best Tumor Response Rate

Pediatric Study: Duration of Response

Pediatric Study: Overall Survival

Pediatric Study: Time to Progression

Pediatric Study: Progression-Free Survival

Pediatric Study: Percentage of Participants With Changes in Neurological Status and Functioning

Overall Study

Pharmaceutical Solutions

Vasoconstrictor Agents

Ophthalmic Solutions

Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days

Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 - 6 times on day of infusion in total (5 - 10 minutes before infusion; at end of infusion; and 2 - 4 times during the remainder of the infusion day). Continuing 4 - 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 - 3 with each depatuxizumab mafodotin infusion. The cold compress was to be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable).

Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 - 6 times on day of infusion in total (5 - 10 minutes before infusion; at end of infusion; and 2 - 4 times during the remainder of the infusion day). Continuing 4 - 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 - 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable).

Steroid eye drops

Vasoconstrictor eye drops

Cold compress

Ophthalmic steroid ointment

During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 - 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 - 40 minute infusion for 12 cycles.

Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 - 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.

Radiation therapy treatment planning and administration was to be performed as per local institutional guidelines.

Radiation

The objective of this study was to evaluate the effect of several ophthalmologic prophylactic treatment strategies for the management of ocular side effects (OSEs) in participants with epidermal growth factor receptor (EGFR)-amplified glioblastoma (GBM) who were being treated with depatuxizumab mafodotin (ABT-414).

This Phase 3b open-label, randomized, exploratory study included 2 phases during the treatment period: chemoradiation therapy (radiation plus temozolomide \[RT/TMZ\]) and adjuvant therapy (TMZ). All participants received depatuxizumab mafodotin during both phases of the treatment period plus 1 of 3 prophylactic ophthalmologic treatments (standard steroids; standard steroids with vasoconstrictors and cold compress; and enhanced steroids with vasoconstrictors and cold compress. The study comprised a screening period of up to 7 weeks after surgery, a 6-week concomitant Chemoradiation Phase, an Adjuvant Phase beginning approximately 4 weeks after completion of chemoradiation, and a Follow-Up Phase.

UNITE Study: Understanding New Interventions With GBM ThErapy

Phase 3b Study for Management of Ocular Side Effects in Subjects With EGFR-amplified Glioblastoma Receiving Depatuxizumab Mafodotin (ABT-414)

Inadequate control of ocular side effects (OSE) was defined as either a ≥ 3-line decline from baseline (≥ +0.3 on LogMAR scale) in visual acuity (with baseline correction determined at the screening ophthalmology visit)) or ≥ Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) scale.

The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. The baseline observation is defined as the last non-missing measurement collected prior to the first dose of depatuxizumab mafodotin.

The time to initiation of bandage contact lenses for those participants who required intervention due to inadequate control of ocular side effects (OSE) was calculated.

Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs.

The cumulative dose of depatuxizumab mafodotin administered was tabulated.

The corneal epithelial adverse event (CEAE) rating scale is designed to record symptoms associated with corneal epitheliopathy caused by antibody-drug conjugates and to grade the severity of findings. The overall CEAE grade is measured on a scale of 0 to 5, with higher values being more severe, reflecting the impact of corneal abnormalities on visual activities of daily living (ADLs). Additional detailed information is collected for specific domains that are commonly affected, with the following ranges (each in order of increasing severity): ocular discomfort (0 - 4), photophobia (0 - 3), and reading (1 - 3).

The change on the LogMAR Scale from last assessment prior to BCL intervention to 2 weeks after BCL intervention was calculated. The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment.

Recovery was defined as return to \<3-line decline from baseline (≤ +0.3 LogMAR) in visual acuity after BCL intervention.

Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs after BCL intervention.

The time to restart depatuxizumab mafodotin treatment if it was interrupted due to ocular side effects after BCL Intervention was tabulated.

The time from discontinuation of depatuxizumab mafodotin to OSE symptom resolution (reversibility) was to be recorded.

The time from dose interruption until re-initiation or permanent discontinuation of depatuxizumab mafodotin was to be recorded.

TEAEs and SAEs are defined as any AE or SAE with onset or worsening reported by a participant from the time that the first dose of depatuxizumab mafodotin is administered until 49 days have elapsed following discontinuation of study drug. TEAEs were collected whether elicited or spontaneously reported by the participant.

Standard Steroids

Standard Steroids + Vasoconstrictor + Cold Compress

Enhanced Steroids + Vasoconstrictor + Cold Compress

Safety population: All randomized participants who received at least 1 dose of depatuxizumab mafodotin

Bilateral vision

Vision in worst eye

Safety population: all randomized participants who received at least 1 dose of depatuxizumab mafodotin and had at least 1 post-baseline assessment within 8 weeks after the initial dose for either LogMAR or CEAE

Percentage of Participants Who Required a Change in Ocular Side Effect (OSE) Management

Safety population: all randomized participants who received at least 1 dose of depatuxizumab mafodotin and had available data.

Maximum Change From Baseline on the Logarithm of the Minimum Angle of Resolution (LogMAR) Scale

Safety population: all randomized participants who received at least 1 dose of depatuxizumab mafodotin and had available data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
UNITE Study: Understanding New Interventions With GBM ThErapy	NCT03419403	Glioblastoma Mu...	Steroid eye dro... Vasoconstrictor... Cold compress Ophthalmic ster... Depatuxizumab m... Temozolomide Radiation	18 Years -	AbbVie
UNITE Study: Understanding New Interventions With GBM ThErapy	NCT03419403	Glioblastoma Mu...	Steroid eye dro... Vasoconstrictor... Cold compress Ophthalmic ster... Depatuxizumab m... Temozolomide Radiation	18 Years -	AbbVie

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