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
Condition: Glioblastoma
MeSH terms: Glioblastoma
Intervention: Depatuxizumab mafodotin; Temozolomide; Lomustine
Intervention description: 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).; 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.
Intervention MeSH terms: Temozolomide; Lomustine; ABT-414
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 266.0
Sex: All
Maximum age: 99 Years
Healthy volunteers: No
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

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.
    

Eligibility criteria:

        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.