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A Phase 1b/2, multicenter study of vorasidenib in combination with temozolomide (TMZ) in participants with IDH1-or IDH2-mutant glioma (Vorasidenib in combination with temozolomide (TMZ) in IDH-mutant glioma)

A Phase 1b/2, multicenter study of vorasidenib in combination with temozolomide (TMZ) in participants with IDH1- or IDH2-mutant glioma (S095032 (AG-881))

Therasse Patrick

Institut de Recherches Internationales Servier (I.R.I.S.)

22 route 128 / rue Francis Perrin 91190 Gif-sur-Yvette, FRANCE

patrick.therasse@servier.com

International center clinical operation department

Nihon Servier Company Limited

Hongo MK building, 1-28-34 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan

+81-3-5842-7111

clinicaltrials.jpn@servier.com

Not Recruiting

Mar. 24, 2025

Interventional

single arm study

open(masking not used)

dose comparison control

single assignment

treatment purpose

Males or non-pregnant and non-lactating females aged 12 years or older with a weight of 40 kg or more at screening.
Have documented IDH1 or IDH2 mutation based on local testing of tumor tissue by an accredited laboratory.
Have adequate renal, bone marrow and hepatic function.
KPS or LPPS of 70 or higher at the start of study treatment.
Additional Inclusion Criteria for Phase 1b:
Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).
Are appropriate to receive TMZ as post- RT adjuvant therapy or as treatment for first disease recurrence after prior RT and/or chemotherapy, per Investigator judgment.
Additional Inclusion Criteria for Phase 2:
Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria).
Have absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) and/or documented loss of nuclear ATRX expression or ATRX mutation by local testing.
Have received SOC RT with concurrent TMZ (RT-TMZ) before enrollment.

Unable to swallow oral medication.
Are participating in another interventional study at the same time; participation in non-interventional registries or epidemiological studies is allowed.
Have leptomeningeal disease.
Have a known coagulopathy.
Have a known diagnosis of replication repair-deficient glioma (e.g., a known diagnosis of constitutional mismatch repair deficiency or Lynch syndrome).
Have significant active cardiac disease within 6 months before Screening, including New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
Have a heart rate corrected QT interval (using Fridericia's formula) (QTcF) 450 msec or higher or have other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS)-related illness. Participants with a sustained viral response to HCV treatment or immunity to prior HBV infection, or chronic HBV or HIV that are adequately suppressed per institutional practice will be permitted.
Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band, dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).
Additional Exclusion Criteria for Phase 2:
Have received any other glioma-directed therapy other than surgery and SOC RT TMZ.
Have progressive disease during RT-TMZ or after completion of SOC RT-TMZ and before the start of study treatment.

Both

IDH1- or IDH2-mutant glioma

Oral administration of vorasidenib will occur once daily (QD) in 28-day cycles with no rest period between cycles. Temozolomide will be administered QD for the first 5 days of each cycle for 6 to 12 cycles.
Phase 1b: An initial cohort of at least 3 DLT-evaluable participants will receive a dose of vorasidenib 40 mg QD in combination with TMZ at the recommended dosage of 150 mg/m2 per day for 5 days in Cycle 1 with
escalation to 200 mg/m2 per day for 5 days in Cycles 2 to 12, provided the participant experienced no or minimal toxicity in Cycle 1.
Phase 2: Participants will receive vorasidenib at the RCD in combination with TMZ for 6 to 12 cycles. Temozolomide dosing will be 150 mg/m2 per day for 5 days in Cycle 1 with escalation to 200 mg/m2 per day for 5 days in Cycles 2 to 12 if the participant experienced no or minimal toxicity in Cycle 1.

DLTs (for Phase 1b only), incidence and severity of AEs, SAEs, and AESIs
PFS status at 12 months

PFS, OS, OR, and clinical benefit (CR+ PR+SD)
Plasma concentrations and PK parameters of vorasidenib and its metabolite AGI-69460 and TMZ

+81-3-3542-2511

Mar. 03, 2025

No

CHINA/FRANCE/GERMANY/BENELUX/ITALY/SPAIN/UK/USA