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)

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Depatuxizumab mafodotin; Drug: Temozolomide; Drug: Lomustine

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 The EMEA-001732-PIP02-15 pediatric investigation plan was withdrawn on 07 July 2019 due to the discontinuation of the depatuxizumab mafodotin research program.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Port Macquarie, New South Wales, Australia, 2444
      • Port Macquarie Base Hospital /ID# 134569
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital /ID# 153533
    • Saint Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital /ID# 147092
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle /ID# 134570
    • Wollongong, New South Wales, Australia, 2500
      • Southern Medical Day Care Ctr /ID# 134495
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital /ID# 147091
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital /ID# 135208
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital /ID# 135209
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Barwon Health University Hospital Geelong /ID# 134493
    • Melbourne, Victoria, Australia, 3052
      • Royal Children's Hospital /ID# 157624
• Austria
  • Graz, Austria, 8036
    • LKH-Univ. Klinikum Graz /ID# 139071
  • Linz, Austria, 4020
    • Kepler Universitätsklinikum GmbH - Neuromed Campus /ID# 139068
  • Niederoesterreich
    • St. Pölten, Niederoesterreich, Austria, 3100
      • University Hospital St. Polten /ID# 139070
• Belgium
  • Antwerp, Belgium, 2020
    • ZNA Middelheim /ID# 137926
  • Leuven, Belgium, 3000
    • UZ Leuven /ID# 137925
  • Bruxelles-Capitale
    • Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium, 1200
      • Cliniques Universitaires Saint Luc /ID# 139391
  • Hainaut
    • Charleroi, Hainaut, Belgium, 6000
      • Grand Hôpital de Charleroi /ID# 139342
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • UZ Gent /ID# 152944
  • West-Vlaanderen
    • Brugge, West-Vlaanderen, Belgium, 8000
      • AZ St-Jan Brugge-Oostende AV /ID# 137927
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institut /ID# 136309
• Czechia
  • Brno, Czechia, 656 53
    • Masarykuv onkologikcy ustav /ID# 139508
  • Hradec Kralove, Czechia, 500 05
    • FN Hradec Kralove /ID# 139510
  • Ostrava, Czechia, 708 52
    • Univ Hosp Ostrava-Poruba /ID# 139507
  • Praha 5
    • Prague 5, Praha 5, Czechia, 150 06
      • Fakultni Nemocnice v Motole /ID# 139509
• Finland
  • Helsinki, Finland, 00290
    • Helsinki Univ Central Hospital /ID# 140078
  • Helsinki, Finland, 00290
    • Helsinki Univ Central Hospital /ID# 153069
  • Turku, Finland, 20520
    • Turku University Hospital /ID# 140861
• France
  • Angers, France, 49055
    • Institut de Cancer de l'Ouest /ID# 137909
  • Bron, France, 69500
    • Hospices Civils de Lyon /ID# 137913
  • Paris, France, 75651
    • Hopital Pitie Salpetriere /ID# 145887
  • Hauts-de-France
    • Lille, Hauts-de-France, France, 59020
      • Centre Oscar Lambret /ID# 169619
    • Lille CEDEX, Hauts-de-France, France, 59045
      • CHRU Lille - Hôpital Claude Huriez /ID# 137916
  • Ile-de-France
    • Bobigny, Ile-de-France, France, 93000
      • CHU-Hopital Avicenne /ID# 137910
    • Villejuif, Ile-de-France, France, 94805
      • Gustave Roussy /ID# 137912
  • Loire-Atlantique
    • St Herblain CEDEX, Loire-Atlantique, France, 44805
      • Institut de Cancer de l'Ouest /ID# 137914
  • Provence-Alpes-Cote-d Azur
    • Marseille CEDEX 05, Provence-Alpes-Cote-d Azur, France, 13385
      • Hopital de la Timone /ID# 137911
    • Nice CEDEX 1, Provence-Alpes-Cote-d Azur, France, 06002
      • CHU de Nice /ID# 137917
  • Rhone
    • Lyon CEDEX 08, Rhone, France, 69373
      • Centre Leon Berard /ID# 137918
• Germany
  • Hamburg, Germany, 20246
    • Univ Klinik Eppendorf Hamburg /ID# 137921
  • Munich, Germany, 80337
    • LMU Klinikum der Universität München /ID# 137922
  • Tuebingen, Germany, 72076
    • Universitatsklinikum Tubingen /ID# 137923
  • Baden-Wuerttemberg
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Universitaetsklinik Heidelberg /ID# 137924
  • Bayern
    • Ratisbon, Bayern, Germany, 93053
      • Universitatsklinik Regensburg /ID# 137920
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem /ID# 152578
  • Budapest, Hungary, 1122
    • National Institute of Oncology /ID# 135970
  • Budapest, Hungary, 1145
    • Orszagos Klinikai Idegtudomany /ID# 135971
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Központ /ID# 135969
  • Pecs
    • Pécs, Pecs, Hungary, 7624
      • Pecsi Tudomanyegyetem /ID# 136111
• Ireland
  • Cork, Ireland, T12 E8YV
    • Cork University Hospital /ID# 136828
  • Dublin, Ireland, D09 XR63
    • Beaumont Hospital /ID# 136829
• Italy
  • Bologna, Italy, 40139
    • Ospedale Bellaria.Azienda USL IRCCS.Istituto delle Scienze Neurologiche di Bolog /ID# 138335
  • Bolzano, Italy, 39100
    • Ospedale Generale di Bolzano /ID# 138338
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta /ID# 140395
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto /ID# 138336
  • Rome, Italy, 00189
    • Azienda Ospedaliera Sant' Andrea /ID# 138337
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital /ID# 136840
  • Gyeonggido
    • Seongnam, Gyeonggido, Korea, Republic of, 13620
      • Seoul National Univ Bundang ho /ID# 136841
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06351
      • Samsung Medical Center /ID# 136842
• Mexico
  • San Pedro Garza García, Mexico, 66278
    • Hospital Zambrano Hellion /ID# 138076
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Vrije Universiteit Medisch Centrum /ID# 137221
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen /ID# 138266
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus Medisch Centrum /ID# 136981
  • The Hague, Netherlands, 2512 VA
    • Haaglanden Medisch Centrum /ID# 137222
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht /ID# 137219
  • Utrecht, Netherlands, 3584 EA
    • Prinses Maxima Centrum /ID# 204409
• Poland
  • Lodz, Poland, 93-509
    • Wojewodzkie Wielospecjalistycz /ID# 137654
  • Mazowieckie
    • Gdansk, Mazowieckie, Poland, 80-214
      • Uniwersyteckie Centrum Kliniczne /ID# 137919
• Singapore
  • Singapore, Singapore, 119074
    • National University Hospital /ID# 135951
  • Singapore, Singapore, 169610
    • National Cancer Ctr Singapore /ID# 135952
  • Singapore, Singapore, 229899
    • KK Women's & Children Hospital /ID# 153676
• Spain
  • Barcelona, Spain, 08908
    • Instituto Catalan de Oncologia (ICO) & Hosp. de Bellvitge /ID# 137688
  • Madrid, Spain, 28009
    • Hospital Universitario Nino /ID# 153800
  • Madrid, Spain, 28041
    • Hosp Univ 12 de Octubre /ID# 137908
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Instituto Catalán de Oncología (ICO) Badalona /ID# 140976
  • Navarra, Comunidad
    • Pamplona, Navarra, Comunidad, Spain, 31008
      • Clinica Universitar de Navarra - Pamplona /ID# 140047
• Switzerland
  • Lausanne, Switzerland, 1011
    • Centre Hospitalier Univ Vaudoi /ID# 137929
  • Zurich, Switzerland, 8091
    • University Hospital Zurich /ID# 137930
• Taiwan
  • Taichung City, Taiwan, 40705
    • Taichung Veterans General Hosp /ID# 136977
  • Taipei City, Taiwan, 11217
    • Taipei Veterans General Hosp /ID# 136974
  • Taoyuan City, Taiwan, 33305
    • Linkou Chang Gung Memorial Ho /ID# 136944
  • Taichung
    • Taichung City, Taichung, Taiwan, 40447
      • China Medical University Hosp /ID# 136976
  • Taipei
    • Taipei City, Taipei, Taiwan, 10002
      • National Taiwan Univ Hosp /ID# 136975
• United Kingdom
  • Birmingham, United Kingdom, B15 2TG
    • Univ Hospitals Birmingham NHS Foundation trust /ID# 136978
  • Glasgow, United Kingdom, G12 0YN
    • Gartnavel General Hospital /ID# 136979
  • Hull, United Kingdom, HU8 9HE
    • Hull and East Yorkshire NHS /ID# 136917
  • London, United Kingdom, NW1 2BU
    • University College Hospitals /ID# 136879
  • London, United Kingdom, WC1N 3JH
    • Great Ormond St Hospital NHS /ID# 153421
  • Manchester, United Kingdom, M20 4BX
    • Christie NHS Foundation Trust /ID# 140313
  • London, City Of
    • London, London, City Of, United Kingdom, SE1 9RT
      • Guy's and St Thomas' NHS Found /ID# 140312
• United States
  • California
    • Palo Alto, California, United States, 34304
      • Lucile Packard Children's Hosp /ID# 153678
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado /ID# 153677
    • Aurora, Colorado, United States, 80045
      • Univ of Colorado Cancer Center /ID# 134882
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute at HealthONE - Denver /ID# 141798
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center /ID# 137542
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 154210
  • New York
    • Lake Success, New York, United States, 11042
      • Long Island Brain Tumor Center /ID# 134496
    • New York, New York, United States, 10032-3725
      • Weill Cornell Medicine /ID# 152656
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Main Campus /ID# 137540
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh MC /ID# 134491
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC /ID# 134492
  • Texas
    • Dallas, Texas, United States, 75390-7208
      • UT Southwestern Medical Center /ID# 136718
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center /ID# 136719

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 99 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ABT-414/temozolomide; Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks in combination with temozolomide (TMZ) to adult participants	Drug: Depatuxizumab mafodotin; 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).; Other Names: ABT-414; Drug: Temozolomide; 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.; Other Names: TMZ
Experimental: ABT-414_adult; Depatuxizumab mafodotin (ABT-414) administered once every 2 weeks to adult participants	Drug: Depatuxizumab mafodotin; 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).; Other Names: ABT-414
Active Comparator: 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.	Drug: Lomustine; 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.; Other Names: Gleostine
Active Comparator: 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.	Drug: Temozolomide; 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.; Other Names: TMZ
Experimental: 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).	Drug: Depatuxizumab mafodotin; 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).; Other Names: ABT-414

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC

Publications and helpful links

General Publications

• Clement PMJ, Dirven L, Eoli M, Sepulveda-Sanchez JM, Walenkamp AME, Frenel JS, Franceschi E, Weller M, Chinot O, De Vos FYFL, Whenham N, Sanghera P, Looman J, Kundu MG, Peter de Geus J, Nuyens S, Spruyt M, Gorlia T, Coens C, Golfinopoulos V, Reijneveld JC, van den Bent MJ. Impact of depatuxizumab mafodotin on health-related quality of life and neurological functioning in the phase II EORTC 1410/INTELLANCE 2 trial for EGFR-amplified recurrent glioblastoma. Eur J Cancer. 2021 Apr;147:1-12. doi: 10.1016/j.ejca.2021.01.010. Epub 2021 Feb 15.
• Van Den Bent M, Eoli M, Sepulveda JM, Smits M, Walenkamp A, Frenel JS, Franceschi E, Clement PM, Chinot O, De Vos F, Whenham N, Sanghera P, Weller M, Dubbink HJ, French P, Looman J, Dey J, Krause S, Ansell P, Nuyens S, Spruyt M, Brilhante J, Coens C, Gorlia T, Golfinopoulos V. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro Oncol. 2020 May 15;22(5):684-693. doi: 10.1093/neuonc/noz222. Erratum In: Neuro Oncol. 2021 Aug 2;23(8):1415.
• Lassman AB, van den Bent MJ, Gan HK, Reardon DA, Kumthekar P, Butowski N, Lwin Z, Mikkelsen T, Nabors LB, Papadopoulos KP, Penas-Prado M, Simes J, Wheeler H, Walbert T, Scott AM, Gomez E, Lee HJ, Roberts-Rapp L, Xiong H, Ansell PJ, Bain E, Holen KD, Maag D, Merrell R. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial. Neuro Oncol. 2019 Jan 1;21(1):106-114. doi: 10.1093/neuonc/noy091.
• Gan HK, Reardon DA, Lassman AB, Merrell R, van den Bent M, Butowski N, Lwin Z, Wheeler H, Fichtel L, Scott AM, Gomez EJ, Fischer J, Mandich H, Xiong H, Lee HJ, Munasinghe WP, Roberts-Rapp LA, Ansell PJ, Holen KD, Kumthekar P. Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Neuro Oncol. 2018 May 18;20(6):838-847. doi: 10.1093/neuonc/nox202.
• Reardon DA, Lassman AB, van den Bent M, Kumthekar P, Merrell R, Scott AM, Fichtel L, Sulman EP, Gomez E, Fischer J, Lee HJ, Munasinghe W, Xiong H, Mandich H, Roberts-Rapp L, Ansell P, Holen KD, Gan HK. Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. Neuro Oncol. 2017 Jul 1;19(7):965-975. doi: 10.1093/neuonc/now257.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2015
• Primary Completion (Actual): June 24, 2019
• Study Completion (Actual): June 24, 2019

Study Registration Dates

• First Submitted: December 22, 2014
• First Submitted That Met QC Criteria: January 16, 2015
• First Posted (Estimate): January 22, 2015

Study Record Updates

• Last Update Posted (Actual): May 22, 2020
• Last Update Submitted That Met QC Criteria: May 8, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Children; Temozolomide; Brain Tumor; Recurrent glioblastoma; Glioblastoma; Antibody Drug Conjugate; Epithelial Growth Factor vIII mutation; Lomustine; ABT-414; European Organization for Research and Treatment of Cancer; Epithelial Growth Factor; Brain Tumor Group; EORTC; Pediatric High Grade Gliomas; Pediatric Diffuse Intrinsic Pontine Glioma; Pediatric WHO grade III glioma; Pediatric WHO grade IV glioma; EGFR amplification
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Lomustine
• Other Study ID Numbers: M14-483; 2014-004438-24 (EudraCT Number); EORTC 1410-BTG (Other Grant/Funding Number: European Organization for Research and Treatment of Cancer)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No