Vorasidenib in Combination With Temozolomide (TMZ) in IDH-mutant Glioma

NCT06478212 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: S095032-211
• Study Type: interventional
• Target: 51
• Locations: 11 countries
• Sites: 28

Brief Summary

The objective of this study is to determine the safety and tolerability of vorasidenib in combination with temozolomide (TMZ) and to establish the recommended combination dose (RCD) of vorasidenib. The study will begin as a Phase Ib study to determine the RCD and then will transition to a Phase II study to assess the clinical efficacy of vorasidenib at the RCD in combination with TMZ. During the treatment period participants will have study visits on day 1 and 22 of each cycle, with additional visits occurring during the first cycle of the Phase 1b study. Approximately 30 days after treatment has ended, a safety follow-up visit will occur and then participants will be followed for survival every 3 months. Study visits may include questionnaires, blood tests, ECG, vital signs, and a physical examination.

Conditions

IDH1-mutant Glioma; IDH2-mutant Glioma

Keywords

IDH-mutant glioma; IDH mutation; vorasidenib; S95032; Phase 1/2; pediatric

Outcome Measures

Primary Outcomes (3)

• Phase 1b ONLY: Dose-limiting toxicities (DLTs)

  Through cycle 1 (each cycle is 28 days)

• Number and severity of adverse events (AEs), serious adverse events (SAEs), and AEs of special interest (AESIs)

  Through 30 days after the end of treatment (Approximately 3 years)

• Progression-free Survival (PFS) status at 12 months

  12 months after treatment initiation

Secondary Outcomes (14)

• PFS

  Through study completion (Approximately 3 years)

• Overall survival (OS)

  Through study completion (Approximately 3 years)

• Objective response rate (ORR)

  Through study completion (Approximately 3 years)

• Clinical benefit rate (CBR) (CR+partial response [PR]+stable disease [SD])

  Through study completion (Approximately 3 years)

• Plasma concentration of vorasidenib and its metabolite AGI-69460

  Through cycle 13 (each cycle is 28 days)

Study Arms (2)

Phase 1b: Vorasidenib and Temozolomide (TMZ)

EXPERIMENTAL

Drug: Vorasidenib; Drug: Temozolomide (TMZ)

Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)

EXPERIMENTAL

Drug: Vorasidenib; Drug: Temozolomide (TMZ)

Interventions

Vorasidenib DRUG

To be taken by mouth once daily in 28-day cycles with no break between cycles

Phase 1b: Vorasidenib and Temozolomide (TMZ); Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)

Temozolomide (TMZ) DRUG

To be taken by mouth once daily for the first 5 days of each 28-day cycle, for a maximum of 12 cycles

Phase 1b: Vorasidenib and Temozolomide (TMZ); Phase 2: Vorasidenib recommended combination dose (RCD) and Temozolomide (TMZ)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Be ≥12 years of age with a weight at screening ≥40 kg.
• Have documented IDH1 or IDH2 mutation based on local testing of tumor tissue by an accredited laboratory
• Have adequate renal function, defined as a creatinine clearance ≥40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation: (140 - Age) × (Weight in kg) × (0.85 if female) / 72 × serum creatinine (mg/dL).
• Have adequate bone marrow function as evidenced by:
• Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L
• Hemoglobin ≥9 g/dL or 90 g/L
• Platelets ≥100,000/mm3 or 100×109/L
• Have expected survival of ≥3 months.
• KPS or LPPS ≥70 at the start of study treatment.
• Participants on corticosteroids for reasons related to glioma must be on a stable or decreasing dose (≤4mg/day dexamethasone or equivalent) for ≥5 days before the start of study treatment.
• Female participants of reproductive potential must have a negative serum pregnancy test before starting study treatment.
• Phase 1b ONLY:
• Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).
• For oligodendroglioma: Have local testing at an accredited laboratory demonstrating presence of 1p19q co deletion
• For astrocytoma: Have local testing by an accredited laboratory demonstrating lack of 1p19q co-deletion and/or documented loss of nuclear ATRX expression or ATRX mutation

You may not qualify if:

• Unable to swallow oral medication.
• Are pregnant or breastfeeding.
• 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.
• Received prior therapy with an IDH inhibitor, IDH-directed vaccine, or bevacizumab.
• Have a history of another concurrent primary cancer, with the exception of:
• curatively resected non-melanoma skin cancer, or
• curatively treated carcinoma in situ. Participants with other previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening.
• Have a known diagnosis of replication repair-deficient glioma (e.g., a known diagnosis of constitutional mismatch repair deficiency or Lynch syndrome).
• Have a known hypersensitivity to any of the components or metabolites of vorasidenib or TMZ.
• Have significant active cardiac disease within 6 months before Screening, including New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
• Have heart rate corrected QT interval (using Fridericia's formula) (QTcF) ≥450 msec or have other factors that increase risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome). Right bundle branch block and prolonged QTcF interval may be permitted based on local cardiology assessment.
• 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 will be permitted. Participants with chronic HBV or HIV that is adequately suppressed per institutional practice will be permitted.
• Phase 1b ONLY:

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead

Study Sites (28)

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Medical University of Vienna - AKH

Vienna, 01090, Austria

Location

Beijing Tiantan Hospital, Capital Medical University

Beijing, 100050, China

Location

Huashan Hospital, Fudan University

Shanghai, 200040, China

Location

Hôpital Pierre Wertheimer

Lyon, 69003, France

Location

Hôpital Pitié-Salpêtrière

Paris, 75013, France

Location

IUCT-Oncopole Institut Universitaire du Cancer

Toulouse, 31059, France

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Medizinische Fakultät Mannheim, Universität Heidelberg

Mannheim, 68167, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93053, Germany

Location

The Tel Aviv Sourasky Medical Center (TASMC) (Ichilov Hospital)

Tel Aviv, 64239, Israel

Location

Instituto Clinico Humanitas IRCCS

Rozzano, Milan, 20089, Italy

Location

IOV - Ospedale Busonera

Padua, 35128, Italy

Location

Ospedale Molinette - Centro Oncologico Ematologico

Turin, 10126, Italy

Location

Kumamoto University Hospital

Kumamoto, 860-8556, Japan

Location

Kyoto University Hospital

Kyoto, 606-8507, Japan

Location

Nagoya University Hospital

Nagoya, 466-8550, Japan

Location

National Cancer Center Hospital

Tokyo, 104-0045, Japan

Location

Erasmus MC

Rotterdam, 503015, Netherlands

Location

H. Valle de Hebron

Barcelona, 08035, Spain

Location

Hospital 12 de Octubre

Madrid, 28041, Spain

Location

Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

The Royal Marsden in Sutton

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Interventions

vorasidenib; Temozolomide

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 17, 2024
• First Posted: June 27, 2024
• Study Start: January 22, 2025
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After Marketing Authorization 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

JP (4); FR (3); GB (2); CN (2); ES (2); US (6); AU (1); DE (3); IL (1); NL (1); IT (3)