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

Primary Purpose

Glioma

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

AG-120

AG881

About this trial

This is an interventional treatment trial for Glioma focused on measuring Glioma, IDH1, AG-120, AG-881

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

United States, California
United States, California
United States, Massachusetts
United States, New York
United States, North Carolina
United States, Texas

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

No Intervention

Arm Label

AG-120

AG-881

No Treatment Pre-Surgery

Arm Description

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 .

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.

Subjects will not receive treatment prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-120 or AG-881.

Outcomes

Primary Outcome Measures

2-HG concentration in surgically resected tumors

Secondary Outcome Measures

Safety and tolerability: incidence of adverse events and serious adverse events

Pharmacodynamics of AG-120 or AG-881 measured by 2-HG concentration in plasma.

Peak Plasma Concentration (Cmax) of AG-120 or AG-881

Time to maximum concentration (Tmax) of AG-120 or AG-881

Area Under the Curve (AUC) of AG-120 or AG-881

Elimination half-life of AG-120 or AG-881

Clinical activity associated with AG-120 or AG-881 according to modified RANO_LGG criteria.

Full Information

NCT ID

NCT03343197

First Posted

November 7, 2017

Last Updated

May 16, 2022

Sponsor

Institut de Recherches Internationales Servier

1. Study Identification

Unique Protocol Identification Number

NCT03343197

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

March 20, 2018 (Actual)

Primary Completion Date

August 2, 2019 (Actual)

Study Completion Date

May 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut de Recherches Internationales Servier

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioma

Keywords

Glioma, IDH1, AG-120, AG-881

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

49 (Actual)

8. Arms, Groups, and Interventions

Arm Title

AG-120

Arm Type

Experimental

Arm Description

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 .

Arm Title

AG-881

Arm Type

Experimental

Arm Description

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.

Arm Title

No Treatment Pre-Surgery

Arm Type

No Intervention

Arm Description

Subjects will not receive treatment prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-120 or AG-881.

Intervention Type

Drug

Intervention Name(s)

AG-120

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

AG881

Intervention Description

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.

Primary Outcome Measure Information:

Title

2-HG concentration in surgically resected tumors

Time Frame

Up to 4 weeks, on average

Secondary Outcome Measure Information:

Title

Safety and tolerability: incidence of adverse events and serious adverse events

Time Frame

Up to 48 weeks, on average

Title

Pharmacodynamics of AG-120 or AG-881 measured by 2-HG concentration in plasma.

Time Frame

Up to 4 weeks, on average

Title

Peak Plasma Concentration (Cmax) of AG-120 or AG-881

Time Frame

Up to 4 weeks, on average

Title

Time to maximum concentration (Tmax) of AG-120 or AG-881

Time Frame

Up to 4 weeks, on average

Title

Area Under the Curve (AUC) of AG-120 or AG-881

Time Frame

Up to 4 weeks, on average

Title

Elimination half-life of AG-120 or AG-881

Time Frame

Up to 4 weeks, on average

Title

Clinical activity associated with AG-120 or AG-881 according to modified RANO_LGG criteria.

Time Frame

Up to 48 weeks, on average

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Facility Information:

Facility Name

United States, California

City

Los Angeles

State/Province

California

ZIP/Postal Code

90024

Country

United States

Facility Name

United States, California

City

San Francisco

State/Province

California

ZIP/Postal Code

94143

Country

United States

Facility Name

United States, Massachusetts

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

United States, New York

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

United States, North Carolina

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

United States, Texas

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data. Access can be requested for all interventional clinical studies: used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US). where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope. In addition, access can be requested for all interventional clinical studies in patients: sponsored by Servier with a first patient enrolled as of 1 January 2004 onwards for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

IPD Sharing Time Frame

After Marketing Authorisation in EEA or US if the study is used for the approval.

IPD Sharing Access Criteria

Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.

IPD Sharing URL