Glioblastoma
Conditions
Keywords
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
Brief summary
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
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 The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.
Interventions
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).
DRUGTemozolomide
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.
DRUGLomustine
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.
Sponsors
European Organisation for Research and Treatment of Cancer - EORTC
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pediatric Study: Area Under the Concentration-time-curve (AUC) Observed for Unconjugated Cys-mcMMAF | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 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. |
| Adult Study: Overall Survival (OS) | 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. | 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). |
| Adult Study: Progression-Free Survival (PFS) | 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 | 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. |
| Pediatric Study: Percentage of Participants With Adverse Events From the First Visit Until 49 Days After the Last Dose of Study Drug | From participant's first visit until 49 days after the participant's last dose of study drug, up to 63 weeks | 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) |
| Pediatric Study: Maximum Observed Serum Concentration (Cmax) of ABT-414 | 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 | 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. |
| Pediatric Study: Maximum Observed Plasma Concentration (Cmax) of Cys-mcMMAF | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 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. |
| Pediatric Study: Half-life (t1/2) Observed for ABT-414 | 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 | Half-life is the calculated time it takes for half of the drug to leave the body. |
| Pediatric Study: Half-life (t1/2) Observed for Cys-mcMMAF | Samples collected Cycle 1 Days 1, 2, 3, 5, 8 | 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. |
| Pediatric Study: Area Under the Concentration-time Curve (AUC) Observed for ABT-414 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adult Study: Objective Response Rate (ORR) | Every 8 weeks at each assessment of disease, up to 28 months | 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. |
| Adult Study: Overall Survival in the Subgroup With 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 | 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. |
| Pediatric Study: Objective Response Rate (ORR) | 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 | 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. |
| Pediatric Study: Best Tumor Response Rate | 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 | 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. |
| Pediatric Study: Duration of Response | 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 | 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. |
| Pediatric Study: Overall Survival | 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 | 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. |
| Pediatric Study: Time to Progression | 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 | 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. |
| Pediatric Study: Progression-Free Survival | 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 | 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. |
| Pediatric Study: Percentage of Participants With Changes in Neurological Status and Functioning | Baseline, Day 1 and 15 of each cycle, every 6 months for 5 years thereafter, and then annually | 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. |
Countries
Australia, Austria, Belgium, Canada, Czechia, Finland, France, Germany, Hungary, Ireland, Italy, Mexico, Netherlands, Poland, Singapore, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Intention-to-treat population (ITT): all randomized participants. Nine enrolled adult participants did not have a screen failure form reported and were not randomized. In the table below, Completed and Not completed refer to study drug treatment, and the reasons not completed listings refer to study drug treatment.
Participants by arm
| Arm | Count |
|---|---|
| ABT-414/Temozolomide Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants | 88 |
| ABT-414_adult Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants | 86 |
| Control_lomustine 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. | 60 |
| Control_ Temozolomide 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. | 26 |
| ABT-414_ Pediatric 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). | 6 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 8 | 6 | 3 | 0 |
| Overall Study | Death | 2 | 1 | 0 | 0 | 0 |
| Overall Study | Other, not specified | 2 | 1 | 1 | 4 | 0 |
| Overall Study | Other primary malignancy | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 72 | 70 | 43 | 15 | 5 |
| Overall Study | Start of a new anti-cancer treatment | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 4 | 8 | 3 | 0 |
Baseline characteristics
| Characteristic | ABT-414/Temozolomide | ABT-414_adult | Control_lomustine | Control_ Temozolomide | ABT-414_ Pediatric | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 8.15 | 58.1 years STANDARD_DEVIATION 9.18 | 57.8 years STANDARD_DEVIATION 10.62 | 55.9 years STANDARD_DEVIATION 11.04 | 10.5 years STANDARD_DEVIATION 5.43 | 56.7 years STANDARD_DEVIATION 11.65 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 7 Participants | 5 Participants | 2 Participants | 0 Participants | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 64 Participants | 73 Participants | 43 Participants | 19 Participants | 3 Participants | 202 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 6 Participants | 12 Participants | 4 Participants | 3 Participants | 41 Participants |
| Sex: Female, Male Female | 29 Participants | 36 Participants | 19 Participants | 9 Participants | 5 Participants | 98 Participants |
| Sex: Female, Male Male | 59 Participants | 50 Participants | 41 Participants | 17 Participants | 1 Participants | 168 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 80 / 88 | 80 / 84 | 52 / 56 | 21 / 21 | 5 / 6 |
| other Total, other adverse events | 84 / 88 | 76 / 84 | 46 / 56 | 20 / 21 | 6 / 6 |
| serious Total, serious adverse events | 39 / 88 | 30 / 84 | 19 / 56 | 5 / 21 | 3 / 6 |
Outcome results
Primary
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).
Time frame: 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.
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-414/Temozolomide | Adult Study: Overall Survival (OS) | 75th quartile | 16.9 months |
| ABT-414/Temozolomide | Adult Study: Overall Survival (OS) | 50th quartile | 9.6 months |
| ABT-414/Temozolomide | Adult Study: Overall Survival (OS) | 25th quartile | 5.7 months |
| ABT-414_adult | Adult Study: Overall Survival (OS) | 50th quartile | 7.9 months |
| ABT-414_adult | Adult Study: Overall Survival (OS) | 25th quartile | 4.6 months |
| ABT-414_adult | Adult Study: Overall Survival (OS) | 75th quartile | 15.5 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival (OS) | 25th quartile | 4.9 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival (OS) | 75th quartile | 12.6 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival (OS) | 50th quartile | 8.2 months |
Comparison: 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).p-value: =0.06295% CI: [0.5, 1.02]Log Rank
Comparison: 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).p-value: =0.83595% CI: [0.73, 1.48]Log Rank
Primary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-414/Temozolomide | Adult Study: Progression-Free Survival (PFS) | 50th quartile | 2.7 months |
| ABT-414/Temozolomide | Adult Study: Progression-Free Survival (PFS) | 25th quartile | 1.8 months |
| ABT-414/Temozolomide | Adult Study: Progression-Free Survival (PFS) | 75th quartile | 4.9 months |
| ABT-414_adult | Adult Study: Progression-Free Survival (PFS) | 50th quartile | 1.9 months |
| ABT-414_adult | Adult Study: Progression-Free Survival (PFS) | 25th quartile | 1.5 months |
| ABT-414_adult | Adult Study: Progression-Free Survival (PFS) | 75th quartile | 3.5 months |
| Control (Temozolomide/Lomustine) | Adult Study: Progression-Free Survival (PFS) | 25th quartile | 1.6 months |
| Control (Temozolomide/Lomustine) | Adult Study: Progression-Free Survival (PFS) | 75th quartile | 4.2 months |
| Control (Temozolomide/Lomustine) | Adult Study: Progression-Free Survival (PFS) | 50th quartile | 1.9 months |
p-value: =0.12395% CI: [0.55, 1.07]Log Rank
p-value: =0.11795% CI: [0.93, 1.84]Log Rank
Primary
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.
Time frame: 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
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Area Under the Concentration-time Curve (AUC) Observed for ABT-414 | 3170 µg*h/mL | Standard Deviation 1320 |
Primary
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.
Time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Area Under the Concentration-time-curve (AUC) Observed for Unconjugated Cys-mcMMAF | 14.1 ng*h/mL | Standard Deviation 6.22 |
Primary
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.
Time frame: 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
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Half-life (t1/2) Observed for ABT-414 | 9.0 days | Standard Deviation 1.5 |
Primary
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.
Time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Half-life (t1/2) Observed for Cys-mcMMAF | 11.2 days | Standard Deviation 22.9 |
Primary
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.
Time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Maximum Observed Plasma Concentration (Cmax) of Cys-mcMMAF | 0.272 ng/mL | Standard Deviation 0.0983 |
Primary
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.
Time frame: 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
Population: Pediatric participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Maximum Observed Serum Concentration (Cmax) of ABT-414 | 31.4 µg/mL | Standard Deviation 15 |
Primary
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)
Time frame: From participant's first visit until 49 days after the participant's last dose of study drug, up to 63 weeks
Population: Pediatric participants (safety population)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-414/Temozolomide | Pediatric Study: Percentage of Participants With Adverse Events From the First Visit Until 49 Days After the Last Dose of Study Drug | 100 percentage of participants |
Secondary
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.
Time frame: Every 8 weeks at each assessment of disease, up to 28 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-414/Temozolomide | Adult Study: Objective Response Rate (ORR) | 14.3 percentage of participants |
| ABT-414_adult | Adult Study: Objective Response Rate (ORR) | 7.7 percentage of participants |
| Control (Temozolomide/Lomustine) | Adult Study: Objective Response Rate (ORR) | 4.4 percentage of participants |
Comparison: 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).p-value: =0.0695% CI: [0.6, 16.16]Cochran-Mantel-Haenszel
Comparison: 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).p-value: =0.76795% CI: [0.12, 12.49]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 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
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-414/Temozolomide | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 50th quartile | 9.4 months |
| ABT-414/Temozolomide | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 25th quartile | 6.3 months |
| ABT-414/Temozolomide | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 75th quartile | 14.4 months |
| ABT-414_adult | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 50th quartile | 8.4 months |
| ABT-414_adult | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 25th quartile | 5.0 months |
| ABT-414_adult | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 75th quartile | 13.9 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 25th quartile | 4.7 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 75th quartile | 12.4 months |
| Control (Temozolomide/Lomustine) | Adult Study: Overall Survival in the Subgroup With Epidermal Growth Factor Receptor (EGFRvIII) Mutation | 50th quartile | 7.5 months |
p-value: =0.12795% CI: [0.4, 1.13]Log Rank
p-value: =0.6495% CI: [0.52, 1.49]Log Rank
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: Baseline, Day 1 and 15 of each cycle, every 6 months for 5 years thereafter, and then annually
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected
Secondary
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.
Time frame: 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
Population: Pediatric efficacy data were not collected