ACTIVE_NOT_RECRUITING

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

Conditions

IDH1-mutant Glioma IDH2-mutant Glioma IDH-mutant glioma IDH mutation vorasidenib S95032 Phase 1/2 pediatric

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

A Phase 1b/2, Multicenter Study of Vorasidenib in Combination With Temozolomide (TMZ) in Participants With IDH1- or IDH2-mutant Glioma

Quick Facts

Study Start:2025-01-22

Study Completion:2028-06

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:ACTIVE_NOT_RECRUITING

Study ID

NCT06478212

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:12 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* 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: 1. Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L 2. Hemoglobin ≥9 g/dL or 90 g/L 3. 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. * Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma). 1. For oligodendroglioma: Have local testing at an accredited laboratory demonstrating presence of 1p19q co deletion 2. 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 * Are appropriate to receive TMZ as post-radiotherapy (RT) adjuvant therapy or as treatment for first disease recurrence after prior RT and/or chemotherapy, per Investigator judgement. For those receiving TMZ in the post-RT adjuvant setting, study treatment must begin no more than 6 weeks after completion of RT. * Have adequate hepatic function as evidenced by: 1. Serum total bilirubin ≤1.5×upper limit of normal (ULN); if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN, 2. AST and ALT ≤ULN, and 3. Alkaline phosphatase ≤2.5×ULN. * Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria). Those who meet the Grade 4 designation via homozygous deletion of CDKN2A/B are eligible. * 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. Study treatment must begin no more than 6 weeks after completion of RT-TMZ. * Have adequate hepatic function as evidenced by: 1. Serum total bilirubin ≤1.5×ULN; if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN, 2. AST and ALT at or below the upper limit of normal. An elevation ≤1.5×ULN and considered not clinically significant by the Investigator may be allowed after Medical Monitor (Sponsor) approval, and 3. Alkaline phosphatase ≤2.5×ULN.	* 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: 1. curatively resected non-melanoma skin cancer, or 2. 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. * For those receiving TMZ in the frontline post-RT adjuvant setting: Have progressive disease during RT or after completion of SOC RT and before the start of study treatment. * For those receiving TMZ in the recurrent disease setting: 1. Have received prior systemic anti-cancer therapy (other than surgery) within 1 month (or 6 weeks for nitrosoureas and 6 months for TMZ) of the start of study treatment. In addition, the first dose of study treatment should not occur before a period of 28 days or ≥5 half-lives of any prior investigational agent have elapsed, whichever is longer. 2. Have received more than one prior line of therapy for glioma (Note: prior RT + chemotherapy is considered one line of therapy). * Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during prior systemic chemotherapy * Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during a prior course of TMZ * 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. * Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during concurrent RT-TMZ * Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during concurrent RT-TMZ

Inclusion Criteria

Exclusion Criteria

* 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:
1. Absolute neutrophil count ≥1,500/mm3 or 1.5×109/L
2. Hemoglobin ≥9 g/dL or 90 g/L
3. 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.
* Have histologically confirmed Grade 2, 3 or 4 IDHm (as per WHO 2021) glioma (astrocytoma or oligodendroglioma).
1. For oligodendroglioma: Have local testing at an accredited laboratory demonstrating presence of 1p19q co deletion
2. 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
* Are appropriate to receive TMZ as post-radiotherapy (RT) adjuvant therapy or as treatment for first disease recurrence after prior RT and/or chemotherapy, per Investigator judgement. For those receiving TMZ in the post-RT adjuvant setting, study treatment must begin no more than 6 weeks after completion of RT.
* Have adequate hepatic function as evidenced by:
1. Serum total bilirubin ≤1.5×upper limit of normal (ULN); if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,
2. AST and ALT ≤ULN, and
3. Alkaline phosphatase ≤2.5×ULN.
* Have histologically confirmed Grade 4 astrocytoma, IDHm (per 2021 WHO criteria). Those who meet the Grade 4 designation via homozygous deletion of CDKN2A/B are eligible.
* 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. Study treatment must begin no more than 6 weeks after completion of RT-TMZ.
* Have adequate hepatic function as evidenced by:
1. Serum total bilirubin ≤1.5×ULN; if ≥1.5×ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN,
2. AST and ALT at or below the upper limit of normal. An elevation ≤1.5×ULN and considered not clinically significant by the Investigator may be allowed after Medical Monitor (Sponsor) approval, and
3. Alkaline phosphatase ≤2.5×ULN.

* 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:
1. curatively resected non-melanoma skin cancer, or
2. 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.
* For those receiving TMZ in the frontline post-RT adjuvant setting: Have progressive disease during RT or after completion of SOC RT and before the start of study treatment.
* For those receiving TMZ in the recurrent disease setting:
1. Have received prior systemic anti-cancer therapy (other than surgery) within 1 month (or 6 weeks for nitrosoureas and 6 months for TMZ) of the start of study treatment. In addition, the first dose of study treatment should not occur before a period of 28 days or ≥5 half-lives of any prior investigational agent have elapsed, whichever is longer.
2. Have received more than one prior line of therapy for glioma (Note: prior RT + chemotherapy is considered one line of therapy).
* Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during prior systemic chemotherapy
* Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during a prior course of TMZ
* 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.
* Had Grade 4 hematologic toxicity (excluding lymphopenia) that did not recover within 7 days during concurrent RT-TMZ
* Had Grade ≥2 hepatic-related toxicity (AST, ALT, and/or bilirubin elevations) during concurrent RT-TMZ

Contacts and Locations

Study Locations (Sites)

University of California Los Angeles

Los Angeles, California, 90095

United States

University of Miami

Miami, Florida, 33136

United States

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

United States

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

United States

Duke University Medical Center

Durham, North Carolina, 27710

United States

MD Anderson Cancer Center

Houston, Texas, 77030

United States

Collaborators and Investigators

Sponsor: Institut de Recherches Internationales Servier

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2025-01-22

Study Completion Date2028-06

Study Record Updates

Study Start Date2025-01-22

Study Completion Date2028-06

Terms related to this study

Keywords Provided by Researchers

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

Additional Relevant MeSH Terms

IDH1-mutant Glioma
IDH2-mutant Glioma