Overview

Condition glioblastoma multiforme
Treatments abt-414, lomustine, temozolomide
Phase phase 2
Sponsor AbbVie
Collaborator European Organisation for Research and Treatment of Cancer - EORTC
Start date February 2015
End date December 2019
Trial size 260 participants
Trial identifier NCT02343406, 2014-004438-24, EORTC 1410-BTG, M14-483

Summary

This study is to evaluate the efficacy and safety of ABT-414 alone or with temozolomide versus temozolomide or lomustine alone in participants with recurrent glioblastoma multiforme.

The study includes a Pediatric sub-study to evaluate safety, tolerability and pharmacokinetics of ABT-414 in a pediatric population.

Adult enrollment has been completed and the study is now only recruiting for pediatric participants.

Recruiting in the following locations…

United States Colorado, Illinois, New York, Ohio, Pennsylvania, and Washington
Other Countries Australia, Canada, Czech Republic, Finland, France, Germany, Hungary, Italy, Korea, Republic of, Mexico, and 6 other states

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
ABT-414 administered via intravenous infusion every two weeks in combination with Temozolomide
abt-414
ABT-414 will be administered by intravenous infusion over approximately 30-40 minutes.
temozolomide
Temozolomide (TMZ) will be administered orally.
(Experimental)
ABT-414 administered every two weeks as monotherapy
abt-414
ABT-414 will be administered by intravenous infusion over approximately 30-40 minutes.
(Active Comparator)
Lomustine: For patients relapsing during TMZ treatment, or within 16 weeks after first day of last TMZ cycle: Lomustine will be administered on day 1 of every 42 day cycle.
abt-414
ABT-414 will be administered by intravenous infusion over approximately 30-40 minutes.
lomustine
Lomustine will be administered orally.
(Active Comparator)
Temozolomide re-challenge: For patients that relapse 16 weeks or more after the first day of last dose of TMZ cycle: TMZ will be administered on day 1-5 of every 28 day cycle
abt-414
ABT-414 will be administered by intravenous infusion over approximately 30-40 minutes.
temozolomide
Temozolomide (TMZ) will be administered orally.
(Experimental)
ABT-414 at a dose of 1.0 mg/kg for participants who are 6 to 17 years old (at the date of first ABT-414 dose), or 1.3 mg/kg for participants who are 0 to 5 years old administered via intravenous infusion every other week. Prophylactic steroid eye drops (temozolomide) will be administered as described for the adult participants. Investigator discretion to use ABT-414 as monotherapy or in combination with temozolomide.
abt-414
ABT-414 will be administered by intravenous infusion over approximately 30-40 minutes.

Primary Outcomes

Measure
Adult study: Overall Survival (OS)
time frame: Measured from the date of randomization up to the date of participant's death. Participants who complete treatment will be assessed every 12 weeks, up to 28 months.
Adult study: Progression Free Survival (PFS)
time frame: PFS will be measured every 8 weeks from date of randomization until the date of first objective progression or participant's death, whichever occurs first, up to 2 years. This will be assessed at interim analysis, when 45 PFS events are observed.
Pediatric study: Percentage of participants with adverse events
time frame: From participants first visit until 35 days after the participant's last dose of study drug
Pediatric study: Maximum observed serum concentration (Cmax) for ABT-414
time frame: Samples collected at various time points from Cycle 1 Day 1 up to 35 days after the participant's last dose of study drug
Pediatric study: Half-life (t1/2) observed for ABT-414
time frame: Samples collected at various time points from Cycle 1 Day 1 up to 35 days after the participant's last dose of study drug.
Pediatric study: Area Under the Concentration-time Curve (AUC) observed for ABT-414
time frame: Samples collected at various time points from Cycle 1 Day 1 up to 35 days after the participant's last dose of study drug.
Pediatric study: Maximum observed plasma concentration (Cmax) for Cys-mcMMAF (toxin, identified as a metabolite of ABT-414)
time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Pediatric study: t1/2 for Cys-mcMMAF (toxin, identified as a metabolite of ABT-414)
time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8
Pediatric study: AUC for Cys-mcMMAF (toxin, identified as a metabolite of ABT-414)
time frame: Samples collected Cycle 1 Days 1, 2, 3, 5, 8

Secondary Outcomes

Measure
Adult study: Progression Free Survival (PFS)
time frame: Progression Free Survival will be measured every 8 weeks from date of randomization until the date of first objective progression or date of participant's death, whichever occurs first, assessed up to 28 months.
Adult study: Overall Response Rate (ORR)
time frame: The overall response rate will be evaluated every 8 weeks at each assessment of disease according to RANO criteria, up to 28 months.
Adult study: Overall Survival in the subgroup with Epithelial Growth Factor Receptor (EGFRvIII) mutation
time frame: Measured from date of randomization until death, or lost to follow up, assessed up to 28 months.
Pediatric study: Rate of tumor response using RANO criteria (progression of disease [PD], stable disease [SD], partial response [PR], or complete response [CR]).
time frame: Evaluated every 8 weeks at each assessment of disease according to RANO criteria, until progression or withdrawal up to approximately 52 weeks.

Eligibility Criteria

Male or female participants up to 99 years old.

Inclusion Criteria: - Adult participants (greater than or equal to 18 years old): - Histologically confirmed de novo (primary) Glioblastoma Multiforme 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. 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, performed either by local or central laboratory. If EGFR amplification is identified by local laboratory, the results from central confirmation of EGFR amplification are not necessary before enrollment of the patient in the study. - Participant has sufficiently recovered from previous therapy. 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, 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 65Gy 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.

Additional Information

Official title Adult Study: ABT-414 Alone or ABT-414 Plus Temozolomide vs. Lomustine or Temozolomide for Recurrent Glioblastoma: A Randomized Phase II Study of the EORTC Brain Tumor Group (EORTC Protocol 1410-BTG) Pediatric Study: Evaluation of ABT-414 in Children With High Grade Gliomas
Description The pediatric sub-study is an uncontrolled, open-label, single-arm global study. This sub-study is to evaluate the safety, tolerability, and pharmacokinetics of ABT-414 in a pediatric population less than 18 years of age as well as to assess the effect of ABT-414 on tumor response per Response Assessment in Neuro-Oncology (RANO) criteria.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by AbbVie.