E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation |
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E.1.1.1 | Medical condition in easily understood language |
Residual or Recurrent Grade 2 Glioma (a type of brain cancer) With an IDH1 or IDH2 Mutation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018338 |
E.1.2 | Term | Glioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the efficacy of AG-881 based on radiographic progression-free survival (PFS) per blinded independent review committee (BIRC) compared with placebo in subjects with residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate safety and tolerability of AG-881 compared with placebo.
• To evaluate the efficacy of AG-881 based on tumor growth rate (TGR) as assessed by volume per the BIRC compared with placebo.
• To evaluate time to next intervention.
• To compare the efficacy of AG-881 with placebo based on objective response rate (ORR), time to response, and duration of response, with response assessed per the BIRC and the Investigator.
• To evaluate overall survival (OS).
• To evaluate health-related quality of life (HRQoL) with AG-881 compared with placebo as assessed by the Functional Assessment of Cancer Therapy – Brain questionnaire.
• To investigate PFS per the Investigator assessment.
• To evaluate the pharmacokinetics (PK) of AG-881 in plasma. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 subjects ≥16 years of age) or Lansky Play Performance Scale (LPPS) score (for subjects >16 years of age) of ≥80%. |
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E.4 | Principal 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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Radiographic PFS as assessed by the BIRC per modified Response Assessment for Neuro-oncology for Low-Grade Gliomas [RANO-LGG] |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of PFS is defined as the time from randomization to the first occurrence of radiographic PD by modified RANO-LGG assessed by the BIRC or death from any cause, whichever occurs earlier. |
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E.5.2 | Secondary end point(s) |
Efficacy:
• TGR as assessed by volume
• Time to next intervention
• ORR
• Time to response
• Duration of response
• Overall survival (OS)
• HRQoL as Assessed by the Functional Assessment of Cancer Therapy-Brain Questionnaire (FACT-Br)
• Progression-free survival as assessed by the Investigator.
Safety/PK:
• Adverse events, serious adverse events (SAEs), and AEs leading to discontinuation or death, and severity of AEs
• Safety laboratory parameters, vital signs, 12-lead electrocardiograms (ECGs), evaluation of left ventricular ejection fraction (LVEF), Karnofsky Performance Scale (KPS)/Lansky Play-Performance Scale (LPPS), and concomitant medications.
• Serial or sparse blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters of AG-881. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• TGR as assessed by volume: percentage increase in tumor volume every 6 months as assessed per BIRC and using a linear mixed effects model
• Time to next intervention: time from randomization to start of next anticancer therapy or surgery, including type of intervention
• OS: time from the date of randomization to the date of death
The following as assessed by the Investigator and by the BIRC per modified RANO-LGG:
• ORR: proportion of subjects with a best overall response being CR, PR, or MR
• Time to response: time from date of randomization to date of first documented CR, PR, or MR for responders
• Duration of response: time from date of first documented CR, PR, or MR (for responders) to date of death due to any cause or first documented radiographic PD |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
Israel |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is defined as the time at which all subjects have discontinued study treatment and completed the OS Follow-up period, died, withdrawn consent from overall study participation, or been lost to follow-up. Final analysis for OS will be conducted at the end of the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |