Study of AG-120 and AG-881 in Subjects With Low Grade Glioma

Study Overview
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Brief Summary
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Study to evaluate the suppression of 2-HG (2-hydroxyglutarate) in IDH-1 mutant gliomas in resected tumor tissue following pre-surgical treatment with AG-120 or AG-881.

Detailed Description
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A phase-1, multi-center study in recurrent non-enhancing gliomas with IDH1 R132H mutation for patients who require surgery. The purpose of this study is to evaluate the suppression of 2-HG by comparing the concentration of 2-HG in resected tumors from IDH1 mutant glioma subjects following AG-120 or AG-881 treatment with the 2-HG concentration in untreated, control tumors. The safety, tolerability, PK/PD, and anti tumor activity data from the study in subjects with recurrent non-enhancing Grade 2/3 LGG with an IDH1 R132H mutation for whom surgical resection is indicated will identify the recommended dose of AG-120 and AG-881 for future studies in glioma.

Official Title
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A Phase 1, Multicenter, Randomized, Controlled, Open-Label, Perioperative Study of AG-120 and AG-881 in Subjects With Recurrent, Non-Enhancing, IDH1 Mutant, Low Grade Glioma

Conditions
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Glioma

Intervention / Treatment
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* Drug: AG-120
* Drug: AG881


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥18 years of age. Have histologically or cytologically confirmed recurrent Grade 2 or 3 LGG (oligodendroglioma or astrocytoma according to World Health Organization 2016 classification). Have documented IDH1 R132H gene mutation by local testing and known 1p19q or ATRX mutation status by local testing. Have central confirmation of primarily non-enhancing disease by MRI with less than or equal to 5 mm slice thickness and up to 1 mm interslice gap on either 2D T2 weighted image, 3D T2 weighted image, or FLAIR, with at least 1 non-enhancing tumor measuring 1×1×1 cm. Be candidates for clinical resection but for whom surgery is not urgently indicated (eg, for whom surgery within the next 2-4 months is appropriate). Have KPS of ≥60% Have expected survival of ≥12 months. Exclusion Criteria: Have received prior systemic anti-cancer therapy within 1 month of the first dose of AG-120 or AG-881 or have received an investigational agent <14 days prior to their first dose of AG-120 or AG-881. In addition, the first dose of AG-120 or AG-881 should not occur before a period of ≥5 half-lives of the investigational agent has elapsed. Have had radiation within 6 months of the first dose of AG-120 or AG-881. (Note: Prior biopsy or surgery is allowed.) Have received any prior treatment with an IDH inhibitor. Have received any prior treatment with bevacizumab (Avastin).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-120<br>AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-120 . | Drug: AG-120<br>* Prior to surgery subjects will receive AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects without residual disease following surgery will have the option to receive treatment for up to a year, until disease progression or unacceptable toxicity, whichever occurs first. Subjects with residual disease following surgery will have the option to receive treatment, until disease progression or unacceptable toxicity.<br>|
| Experimental: AG-881<br>AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-881. | Drug: AG881<br>* Prior to surgery subjects will receive AG-881 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects without residual disease following surgery will have the option to receive treatment for up to a year, until disease progression or unacceptable toxicity, whichever occurs first. Subjects with residual disease following surgery will have the option to receive treatment, until disease progression or unacceptable toxicity.<br>|
| No Intervention: No Treatment Pre-Surgery<br>Subjects will not receive treatment prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-120 or AG-881. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-HG concentration in surgically resected tumors |  | Up to 4 weeks, on average | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: incidence of adverse events and serious adverse events |  | Up to 48 weeks, on average | 
| Pharmacodynamics of AG-120 or AG-881 measured by 2-HG concentration in plasma. |  | Up to 4 weeks, on average | 
| Peak Plasma Concentration (Cmax) of AG-120 or AG-881 |  | Up to 4 weeks, on average | 
| Time to maximum concentration (Tmax) of AG-120 or AG-881 |  | Up to 4 weeks, on average | 
| Area Under the Curve (AUC) of AG-120 or AG-881 |  | Up to 4 weeks, on average | 
| Elimination half-life of AG-120 or AG-881 |  | Up to 4 weeks, on average | 
| Clinical activity associated with AG-120 or AG-881 according to modified RANO_LGG criteria. |  | Up to 48 weeks, on average | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDH1, AG-120, AG-881, Glioma