Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation

NCT02073994 | Completed Phase 1

• 1 other identifier: AG120-C-002
• Study Type: interventional
• Target: 174
• Locations: 2 countries
• Sites: 12

Brief Summary

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four arms of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or at Investigator discretion.

Conditions

Cholangiocarcinoma; Chondrosarcoma; Glioma; Other Advanced Solid Tumors

Keywords

chondrosarcoma; cholangiocarcinoma; glioma; advanced solid tumors; IDH1; AG-120

Outcome Measures

Primary Outcomes (2)

• Safety/tolerability: incidence of adverse events

  Up to 26 weeks, on average

• Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced solid tumors, including glioma

  Up to 26 weeks, on average

Secondary Outcomes (4)

• Dose Limiting Toxicities of AG-120 in subjects with advanced solid tumors, including glioma

  Up to 26 weeks, on average

• Pharmacokinetics of AG-120 in subjects with advanced solid tumors, including glioma

  Up to 26 weeks, on average

• Pharmacodynamic relationship of AG-120 and 2-HG

  Up to 26 weeks, on average

• Clinical Activity associated with AG-120 in subjects with advanced solid tumors, including glioma

  Up to 26 weeks, on average

Study Arms (1)

AG-120

EXPERIMENTAL

AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression, development of other unacceptable toxicity or Investigator discretion.

Drug: AG-120

Interventions

AG-120 DRUG

AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression or development of other unacceptable toxicity

AG-120

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose Escalation
• Subjects must have histologically or cytologically confirmed, IDH1 gene-mutated advanced solid tumors, including glioma, that have recurred or progressed following standard therapy, or that have not responded to standard therapy.
• Subjects must have evaluable disease by RECIST v1.1 for subjects without glioma or by RANO criteria for subjects with glioma.
• Dose Expansion: Cholangiocarcinoma
• Subjects must have histologically-confirmed diagnosis of IDH1 gene-mutated cholangiocarcinoma Stage II, III, or IV (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
• Cholangiocarcinoma subjects must have progressed following gemcitabine-based regimen.
• Cholangiocarcinoma subjects must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a radiologist, is acceptable.
• Dose Expansion: Chondrosarcoma
• a. Subjects must have IDH1 gene-mutated chondrosarcoma that is either locally advanced or metastatic and not amenable to complete surgical excision.
• Dose Expansion: Non-enhancing Glioma
• Subjects must have progressive glioma that is solely non-enhancing on MRI.
• Progression of glioma must have occurred over 12 months or less.
• Subject must have available at least 3 prior full sets of scans (not including screening), each separated by at least 2 months 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.
• Subjects must not have had prior surgery (biopsy allowed) or radiation therapy within 6 months of enrollment.
• Dose Expansion: Solid Tumors Not Otherwise Eligible for the Cholangiocarcinoma, Chondrosarcoma, or Non-enhancing Glioma Cohorts

You may not qualify if:

• Subjects who received systemic anticancer therapy or radiotherapy \<21 days prior to their first day of study drug administration.
• Subjects who received an investigational agent \<14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
• Subjects taking the following sensitive cytochrome P450 (CYP) 3A4 substrate medications are excluded from the study unless they can be transferred to other medications prior to enrolling: alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz.
• Subjects taking the following P-glycoprotein (P-gp) transporter-sensitive substrate medications are excluded from the study unless they can be transferred to other medications prior to enrolling: aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, fexofenadine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, and tolvaptan.
• Subjects for whom potentially curative anticancer therapy is available.
• Subjects who are pregnant or breast feeding.
• Subjects with an active severe infection that required anti-infective therapy or with an unexplained fever \>38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
• Subjects with known hypersensitivity to any of the components of AG-120.
• Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.
• Subjects with a history of myocardial infarction within the last 6 months.
• Subjects with known unstable or uncontrolled angina pectoris.
• Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
• Subjects taking medications that are known to prolong the QT interval (see Section 9.11.3).
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
• Subjects with any other medical or psychological condition, deemed by the Investigator to be likely to interfere with a subject's ability to sign informed consent, cooperate, or participate in the study.

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead

Study Sites (12)

Unknown Facility

Scottsdale, Arizona, 85258, United States

Location

Unknown Facility

Los Angeles, California, 90095, United States

Location

Unknown Facility

Aurora, Colorado, 80045, United States

Location

Unknown Facility

Miami, Florida, 33136, United States

Location

Unknown Facility

Baltimore, Maryland, 21218, United States

Location

Unknown Facility

Boston, Massachusetts, 02215, United States

Location

Unknown Facility

New York, New York, 10065, United States

Location

Unknown Facility

Nashville, Tennessee, 37203, United States

Location

Unknown Facility

Dallas, Texas, 75390, United States

Location

Unknown Facility

Houston, Texas, 77030, United States

Location

Unknown Facility

San Antonio, Texas, 78229, United States

Location

Unknown Facility

Villejuif, 94800, France

Location

Related Publications (7)

• Tap WD, Cote GM, Burris H, Gore L, Elias A, Beeram M, Conley AP, Gianolio DA, Qu Z, Pandya S, Trent JC. Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Long-term Safety and Clinical Activity in Patients with Conventional Chondrosarcoma. Clin Cancer Res. 2025 Jun 3;31(11):2108-2114. doi: 10.1158/1078-0432.CCR-24-4128.

  PMID: 40100120 BACKGROUND

• Ellingson BM, Kim GHJ, Brown M, Lee J, Salamon N, Steelman L, Hassan I, Pandya SS, Chun S, Linetsky M, Yoo B, Wen PY, Mellinghoff IK, Goldin J, Cloughesy TF. Volumetric measurements are preferred in the evaluation of mutant IDH inhibition in non-enhancing diffuse gliomas: Evidence from a phase I trial of ivosidenib. Neuro Oncol. 2022 May 4;24(5):770-778. doi: 10.1093/neuonc/noab256.

  PMID: 34751786 DERIVED

• Aguado-Fraile E, Tassinari A, Ishii Y, Sigel C, Lowery MA, Goyal L, Gliser C, Jiang L, Pandya SS, Wu B, Bardeesy N, Choe S, Deshpande V. Molecular and morphological changes induced by ivosidenib correlate with efficacy in mutant-IDH1 cholangiocarcinoma. Future Oncol. 2021 Jun;17(16):2057-2074. doi: 10.2217/fon-2020-1274. Epub 2021 Mar 12.

  PMID: 33709779 DERIVED

• Mellinghoff IK, Ellingson BM, Touat M, Maher E, De La Fuente MI, Holdhoff M, Cote GM, Burris H, Janku F, Young RJ, Huang R, Jiang L, Choe S, Fan B, Yen K, Lu M, Bowden C, Steelman L, Pandya SS, Cloughesy TF, Wen PY. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma. J Clin Oncol. 2020 Oct 10;38(29):3398-3406. doi: 10.1200/JCO.19.03327. Epub 2020 Jun 12.

  PMID: 32530764 DERIVED

• Tap WD, Villalobos VM, Cote GM, Burris H, Janku F, Mir O, Beeram M, Wagner AJ, Jiang L, Wu B, Choe S, Yen K, Gliser C, Fan B, Agresta S, Pandya SS, Trent JC. Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma. J Clin Oncol. 2020 May 20;38(15):1693-1701. doi: 10.1200/JCO.19.02492. Epub 2020 Mar 24.

  PMID: 32208957 DERIVED

• Lowery MA, Burris HA 3rd, Janku F, Shroff RT, Cleary JM, Azad NS, Goyal L, Maher EA, Gore L, Hollebecque A, Beeram M, Trent JC, Jiang L, Fan B, Aguado-Fraile E, Choe S, Wu B, Gliser C, Agresta SV, Pandya SS, Zhu AX, Abou-Alfa GK. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019 Sep;4(9):711-720. doi: 10.1016/S2468-1253(19)30189-X. Epub 2019 Jul 9.

  PMID: 31300360 DERIVED

• Fan B, Mellinghoff IK, Wen PY, Lowery MA, Goyal L, Tap WD, Pandya SS, Manyak E, Jiang L, Liu G, Nimkar T, Gliser C, Prahl Judge M, Agresta S, Yang H, Dai D. Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors. Invest New Drugs. 2020 Apr;38(2):433-444. doi: 10.1007/s10637-019-00771-x. Epub 2019 Apr 26.

  PMID: 31028664 DERIVED

MeSH Terms

Conditions

Cholangiocarcinoma; Chondrosarcoma; Glioma

Interventions

ivosidenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2014
• First Posted: February 28, 2014
• Study Start: March 1, 2014
• Primary Completion: January 4, 2024
• Study Completion: January 4, 2024
• Last Updated: February 17, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (11); FR (1)