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

• ClinicalTrials.gov Identifier: NCT03343197
• Recruitment Status: Active, not recruiting
• First Posted: November 17, 2017
• Last Update Posted: February 26, 2024
• Sponsor: Institut de Recherches Internationales Servier
• Information provided by (Responsible Party): Servier ( Institut de Recherches Internationales Servier )

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.

Condition or disease	Intervention/treatment	Phase
Glioma	Drug: AG-120; Drug: AG881	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 20, 2018
• Actual Primary Completion Date: August 2, 2019
• Estimated Study Completion Date: May 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: AG-120; 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; 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.
Experimental: AG-881; 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; 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.
No Intervention: No Treatment Pre-Surgery; Subjects will not receive treatment prior to surgery. Following surgery, subjects will have the option to receive treatment with AG-120 or AG-881.

Outcome Measures

Primary Outcome Measures :

1. 2-HG concentration in surgically resected tumors [ Time Frame: Up to 4 weeks, on average ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Be ≥18 years of age.
2. Have histologically or cytologically confirmed recurrent Grade 2 or 3 LGG (oligodendroglioma or astrocytoma according to World Health Organization 2016 classification).
3. Have documented IDH1 R132H gene mutation by local testing and known 1p19q or ATRX mutation status by local testing.
4. 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.
5. 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).
6. Have KPS of ≥60%
7. Have expected survival of ≥12 months.

Exclusion Criteria:

1. 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.
2. Have had radiation within 6 months of the first dose of AG-120 or AG-881. (Note: Prior biopsy or surgery is allowed.)
3. Have received any prior treatment with an IDH inhibitor.
4. Have received any prior treatment with bevacizumab (Avastin).

Contacts and Locations

Locations

United States, California

United States, California

Los Angeles, California, United States, 90024

United States, California

San Francisco, California, United States, 94143

United States, Massachusetts

United States, Massachusetts

Boston, Massachusetts, United States, 02215

United States, New York

United States, New York

New York, New York, United States, 10065

United States, North Carolina

United States, North Carolina

Durham, North Carolina, United States, 27710

United States, Texas

United States, Texas

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Institut de Recherches Internationales Servier

More Information

Study Data/Documents: Individual Participant Data Set 

Study Protocol 

Statistical Analysis Plan 

Informed Consent Form 

Clinical Study Report 

Study-level clinical trial data 

• Responsible Party: Institut de Recherches Internationales Servier
• ClinicalTrials.gov Identifier: NCT03343197
• Other Study ID Numbers: AG120-881-C-001
• First Posted: November 17, 2017
• Last Update Posted: February 26, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• 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.
• URL: https://clinicaltrials.servier.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Servier ( Institut de Recherches Internationales Servier ):

Glioma; IDH1; AG-120; AG-881

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Ivosidenib; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action