Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)

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 AG881-C-004 is a phase 3, multicenter, randomized, double-blind, placebo-controlled study comparing the efficacy of vorasidenib 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 340 participants are planned to be randomized 1:1 to receive orally administered vorasidenib 40 mg QD or placebo.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Glioma; Grade 2 Glioma; Residual Glioma
• Intervention / Treatment: Drug: Vorasidenib; Drug: Matching Placebo

• Study Type: Interventional
• Enrollment (Actual): 331
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer Agency
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • McGill University Health Center
• France
  • Lille, France, 59037
    • Centre Hospitalier Universitaire De Lille
  • Lyon, France, 69394
    • Hôpital Pierre Wertheimer
  • Marseille, France, 13385
    • Hopitaux de La Timone
  • Paris, France, 75013
    • Hospitalier Pitié Salpétrière
• Germany
  • Essen, Germany, 45122
    • Universitatsklinikum Essen
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg Eppendorf
  • Heidelberg, Germany, 69120
    • UniversitatsKlinikum Heidelberg
  • Mannheim, Germany, 68135
    • Klinikum Mannheim Universitätsklinikum
• Israel
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center
  • Petah Tikva, Israel, 49100
    • Rabin Medical Center
  • Ramat-Gan, Israel, 52621
    • Chaim Sheba Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bologna, Italy, 40139
    • Ospedale Bellaria
  • Padua, Italy, 35128
    • Istituto Oncologico Veneto - I.R.C.C.S.
  • Roma, Italy, 144
    • Istituto Nazionale Tumori Regina Elena
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • Azienda Ospedaliera Città della Salute e della Scienza di Torino
• Japan
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Kyoto, Japan, 602-8566
    • University Hospital, Kyoto Prefectural University of Medicine
  • Kyoto, Japan, 606-8507
    • Kyoto University Hospital
  • Okayama, Japan, 700-8558
    • Okayama University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
      • Nagoya University Hospital
    • Toyoake, Aichi, Japan, 470-1192
      • Fujita Health University Hospital
  • Hiroshima
    • Minami-Ku, Hiroshima, Japan, 734-8551
      • Hiroshima University Hospital
  • Tokyo
    • Bunkyō-Ku, Tokyo, Japan, 113-8655
      • The University of Tokyo Hospital
    • Chuo Ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Netherlands
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medical Center
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
  • Zuid-Holland
    • Leidschendam, Zuid-Holland, Netherlands, 2262 BA
      • Haaglanden MC, Antoniushove
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• Switzerland
  • Geneva, Switzerland, 1211
    • Hôpitaux Universitaire de Genève
  • Lausanne, Switzerland, 1011
    • Centre Hospitalier Universitaire Vaudois
  • Zürich, Switzerland, 8006
    • Universitatsspital Zurich
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XY
    • Western General Hospital Edinburgh - PPDS
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • England
    • Newcastle Upon Tyne, England, United Kingdom, NE7 7DN
      • Freeman Hospital
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden NHS Foundation Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Los Angeles, California, United States, 90095
      • UCLA Oncology Center
    • Orange, California, United States, 92868
      • University of California Irvine - Hospital
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Cancer Pavilion
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University, Yale Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center - University of Miami Hospital and Clinics
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Medical Partners Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • John Hopkins Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55416
      • Metro Minnesota Community Oncology
    • Rochester, Minnesota, United States, 55905
      • Mayo Comprehensive Cancer
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Hillman Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • The University of Utah, Huntsman Cancer Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (-1 month) and not more than 5 years (+3 months) before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy and not be in need of immediate chemotherapy or radiotherapy in the opinion of the Investigator.
• 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 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, laser ablation, etc.
• Have features assessed as high-risk 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vorasidenib; Vorasidenib 40 mg, continuous daily dosing.	Drug: Vorasidenib; Vorasidenib oral film-coated tablets; Other Names: AG-881
Placebo Comparator: Matching Placebo; Matching placebo 40 mg, continuous daily dosing.	Drug: Matching Placebo; Matching Placebo oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS is defined as the time from date of randomization to date of first documented radiographic PD (as assessed by the blinded independent review committee (BIRC) per modified Response Assessment for Neuro-oncology for Low-Grade Gliomas or date of death due to any cause, whichever occurs earlier.	Up to approximately 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Next Intervention (TTNI)	TTNI is defined as the time from randomization to the initiation of the first subsequent anticancer therapy (including vorasidenib, for subjects randomized to placebo who subsequently cross over) or death due to any cause.	Up to approximately 3 years
Tumor Growth Rate (TGR)	Calculated as the mean of the percentage change in tumor volume every 6 months	every 6 months, up to 2 years and 9 months
Objective Response (OR) as Assessed by the Blinded Independent Review Committee (BIRC)	OR is defined as a best overall response (BOR) of Complete Response, Partial Rresponse, or minor Response as assessed by the BIRC per the modified Response Assessment in Neuro-oncology for Low-grade Gliomas (RANO-LGG).	approximatively 30 months
Complete Response (CR) and Partial Response (PR) by BIRC	CR and PR is defined as a BOR of CR or PR as assessed by BIRC per the modified RANO-LGG	Approximatively 30 months
Time to Response (TTR) by BIRC	TTR is defined as the time from the date of randomization to the date of first documented CR, PR, or mR by BIRC per the modified RANO-LGG	Approximatively 30 months
Time to CR+PR by BIRC	Time to CR+PR is defined as defined as the time from the date of randomization to the date of first documented CR or PR for subjects with CR or PR per the modified RANO-LGG (by BIRC)	Approximatively 30 months
Duration of Response (DoR)	DoR is defined as the time from the date of first documented CR, PR, or mR to the date of death due to any cause or date of first documented radiographic Prgressive Disease, whichever occurred earlier	Approximatively 30 months
Duration of CR+PR	Duration of CR+PR is defined as the time from the date of first documented CR or PR to the date of death due to any cause or first documented radiographic PD, whichever occurred earlier	Approximatively 30 months
Overall Survival (OS)	OS wad defined as the time from the date of randomization to the date of death due to any cause or data cutoff.	Approximatively 30 months
Progression-Free Survival (PFS) by the Investigator	PFS as assessed by the Investigator per the modified RANO-LGG	Approximatively 30 months
Health-Related Quality of Life (FACT-Br)	Health-Related Quality of Life (HRQoL) Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 50-item measure comprising the following subscales: Physical Well-Being, Functional Well-Being, Emotional Well-Being, and Social Well-Being subscales from the FACT-General (FACT-G), with the addition of a 23-item brain tumor-specific subscale. These subscales are summed to provide a total score. The total score is given at the end of treatment and total scores range from 0 to 200. Higher scores indicate a better HRQoL	Approximatively 30 months

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier

Publications and helpful links

General Publications

• Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, Mendez J, Yust-Katz S, Welsh L, Mason WP, Ducray F, Umemura Y, Nabors B, Holdhoff M, Hottinger AF, Arakawa Y, Sepulveda JM, Wick W, Soffietti R, Perry JR, Giglio P, de la Fuente M, Maher EA, Schoenfeld S, Zhao D, Pandya SS, Steelman L, Hassan I, Wen PY, Cloughesy TF; INDIGO Trial Investigators. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023 Aug 17;389(7):589-601. doi: 10.1056/NEJMoa2304194. Epub 2023 Jun 4.

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2020
• Primary Completion (Actual): September 6, 2022
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: November 11, 2019
• First Submitted That Met QC Criteria: November 14, 2019
• First Posted (Actual): November 15, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: AG-881
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Recurrence; Glioma
• Other Study ID Numbers: AG881-C-004; 2019-002481-13 (EudraCT Number); 2024-512961-15-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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 Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No