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Phase III

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study of AG-881 in Subjects With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation

  • Study HIC#:2000026755
  • Last Updated:07/15/2021

Study AG881-C-004 is a phase 3, multicenter, randomized, double-blind, placebo-controlled study comparing the efficacy of AG-881 to placebo in participants with residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation who have undergone surgery as their only treatment. Participants will be required to have central confirmation of IDH mutation status prior to randomization. Approximately 366 participants are planned to be randomized 1:1 to receive orally administered AG-881 40 mg QD or placebo.

  • GenderBoth
  • Start Date08/05/2020
  • End Date10/01/2024

Trial Purpose and Description

Primary Outcome Measures  :

  1. Progression-Free Survival (PFS) [ Time Frame: Up to approximately 30 months ]

Secondary Outcome Measures  :

  1. Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 30 months ]
  2. Tumor Growth Rate as Assessed by Volume [ Time Frame: Up to approximately 30 months ]
  3. Time to Next Intervention [ Time Frame: Up to approximately 5 years ]
  4. Objective Response Rate [ Time Frame: Up to approximately 30 months ]
  5. Time to Response [ Time Frame: Up to approximately 30 months ]
  6. Duration of Response [ Time Frame: Up to approximately 30 months ]
  7. Overall Survival [ Time Frame: Up to approximately 5 years ]
  8. Health-Related Quality of Life as Measured by Functional Assessment of Cancer Therapy-Brain Questionnaire (FACT-Br) [ Time Frame: Up to approximately 30 months ]The FACT-Br is a participant-reported measure designed to assess the quality of life for participants with brain tumors. The FACT-Br is a measure comprising the following subscales: Physical Well-Being, Functional Well-Being, Emotional Well-Being, and Social Well-Being subscales from the FACT-G, with the addition of a brain tumor- specific subscale.
  9. Progression-Free Survival (PFS) as Assessed by the Investigator [ Time Frame: Up to approximately 30 months ]
  10. Maximum Observed Serum Concentration (Cmax) of AG-881 [ Time Frame: Days 1 and 15 of Cycle 1(predose and multiple timepoints up to 4 hours postdose), Day 1 of Cycle 2(predose and multiple time points up to 4 hours postdose), Predose on Day 1 of every cycle thereafter(each cycle is 28 days), and within 7 days of last dose ]
  11. Area Under Concentration Time Curve from Time 0 to Tau (AUC0-tau) of AG-881 [ Time Frame: Days 1 and 15 of Cycle 1(predose and multiple timepoints up to 4 hours postdose), Day 1 of Cycle 2(predose and multiple time points up to 4 hours postdose), Predose on Day 1 of every cycle thereafter(each cycle is 28 days), and within 7 days of last dose ]
  12. Time to Reach Maximum Serum Concentration (Tmax) of AG-881 [ Time Frame: Days 1 and 15 of Cycle 1(predose and multiple timepoints up to 4 hours postdose), Day 1 of Cycle 2(predose and multiple time points up to 4 hours postdose), Predose on Day 1 of every cycle thereafter(each cycle is 28 days), and within 7 days of last dose ]

Eligibility Criteria

Key Inclusion Criteria:

  • Be at least 12 years of age and weigh at least 40 kg.
  • Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria.
  • Have had at least 1 prior surgery for glioma (biopsy, sub-total resection, gross-total resection), with the most recent surgery having occurred at least 1 year and not more than 5 years before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy.
  • Have confirmed IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) gene mutation status disease by central laboratory testing during the Prescreening period and available 1p19q status by local testing (eg, fluorescence in situ hybridization [FISH], comparative genomic hybridization [CGH] array, sequencing) using an accredited laboratory.
  • Have MRI-evaluable, measurable, non-enhancing disease, as confirmed by the blinded independent review committee (BIRC)
  • Have a Karnofsky Performance Scale (KPS) score (for participants ≥16 years of age) or Lansky Play Performance Scale (LPPS) score (for participants <16 years of age) of ≥80%.

Key Exclusion Criteria:

  • Have had any prior anticancer therapy other than surgery (biopsy, sub-total resection, gross-total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, etc.
  • Have high-risk features as assessed by the Investigator, including brainstem involvement either as primary location or by tumor extension, clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed), or uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen).

Sub-Investigators

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