Study of Vorasidenib and Pembrolizumab Combination in Recurrent or Progressive IDH-1 Mutant Glioma
- Conditions
- AstrocytomaOligodendroglioma
- Interventions
- Registration Number
- NCT05484622
- Lead Sponsor
- Institut de Recherches Internationales Servier
- Brief Summary
Vorasidenib in combination with pembrolizumab in participants with recurrent or progressive isocitrate dehydrogenase-1 (IDH-1) mutant Glioma.
- Detailed Description
The study is divided into 2 phases, a Safety Lead-In phase and a randomized perioperative phase. In the Safety Lead-In Phase, the recommended combination dose (RCD) of vorasidenib will be determined. In the Randomized Perioperative Phase, the Lymphocytes infiltration in tumors will be evaluated following pre-surgical treatment with vorasidenib and pembrolizumab combination, compared to untreated control tumors. Prior to surgery, participants will be randomized to receive vorasidenib at the RCD in combination with pembrolizumab, or vorasidenib only, or no treatment (untreated control group). Following surgery, participants will have the option to receive treatment with vorasidenib in combination with pembrolizumab in 21-day cycles.
Study treatment will be administered until participant experiences unacceptable toxicity, disease progression, or other discontinuation criteria are met.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 72
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Have Karnofsky Performance Status (KPS) of ≥ 70%.
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Have expected survival of ≥ 3 months.
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Have histologically confirmed Grade 2 or Grade 3 glioma (per the 2016 or 2021 World Health Organization [WHO] Classification of Tumors of the central nervous system)
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Have:
- Documented IDH1-R132H gene mutation; and
- For Astrocytomas: Absence of 1p19q co-deletion (i.e., exclusion of combined whole-arm deletions of 1p and 19q) and/or documented loss of nuclear ATRX expression or ATRX mutation by local testing. For Oligodendrogliomas: Presence of 1p19q co-deletion (i.e., combined whole-arm deletions of 1p and 19q) by local testing.
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Have measurable, magnetic resonance imaging (MRI)-evaluable, unequivocal contrast enhancing disease as determined by institutional radiologist/Investigator at Screening on either 2D T1 post-contrast weighted images or 3D T1 post-contrast weighted images. Per mRANO criteria, measurable lesion is defined as at least 1 enhancing lesion measuring ≥ 1 cm x ≥ 1 cm. OR (in the absence of measurable enhancing disease) measurable, MRI-evaluable, unequivocal non enhancing disease as determined by institutional radiologist/Investigator at Screening on either 2D or 3D T2-weighted image or FLAIR. Per RANO 2.0 criteria, measurable lesion is defined as at least 1 non enhancing lesion measuring ≥ 1 cm × ≥ 1 cm.
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Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both.
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Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g., for whom surgery within the next 6-9 weeks is appropriate). (NOTE: This criterion only applies to participants enrolled in the perioperative phase of the study. Participants in the Safety Lead-In should not require surgery).
- Have received prior systemic anti-cancer therapy within 1 month of the first dose of IMP, radiation within 12 months of the first dose of IMP, or an investigational agent < 14 days prior to the first dose of IMP. In addition, the first dose of IMP should not occur before a period of ≥ 5 half-lives of the investigational agent has elapsed.
- Have received 2 or more courses of radiation.
- Have received any prior treatment with an isocitrate dehydrogenase (IDH) inhibitor; anti-programmed cell death 1 (PD1), anti-programmed cell death ligand 1 (PD-L1), or anti-PD-ligand 2 (L2) agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137); any other checkpoint inhibitor; bevacizumab; or any prior vaccine therapy.
Note: Other inclusion and exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Safety Lead-In Phase: Vorasidenib + Pembrolizumab Pembrolizumab Participants will receive vorasidenib orally, once daily (QD) in combination with pembrolizumab 200 mg intravenous (IV) infusion, once every 3 weeks (Q3W) in each 21-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met. Safety Lead-In Phase: Vorasidenib + Pembrolizumab Vorasidenib Participants will receive vorasidenib orally, once daily (QD) in combination with pembrolizumab 200 mg intravenous (IV) infusion, once every 3 weeks (Q3W) in each 21-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met. Randomized Perioperative Phase: Vorasidenib Only Vorasidenib Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery. Randomized Perioperative Phase: Vorasidenib + Pembrolizumab Vorasidenib Participants will receive vorasidenib recommended combination dose (RCD) determined in the Safety Lead-in phase, orally, QD from Day 1 to 28 in combination with pembrolizumab 200 mg IV infusion, Q3W on Days 1 and 22 of a 28-day cycle prior to surgery. Randomized Perioperative Phase: Vorasidenib + Pembrolizumab Pembrolizumab Participants will receive vorasidenib recommended combination dose (RCD) determined in the Safety Lead-in phase, orally, QD from Day 1 to 28 in combination with pembrolizumab 200 mg IV infusion, Q3W on Days 1 and 22 of a 28-day cycle prior to surgery.
- Primary Outcome Measures
Name Time Method Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs) First 21 days of dosing (Cycle 1) in safety lead-in phase Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) approximately up to 19 months Percentage of Tumor-infiltrating Lymphocyte (TIL) Cells in Surgically Resected Tumors Following Treatment With Vorasidenib + Pembrolizumab Compared to Untreated Control Tumors approximately 2 months TIL is defined as the percentage of tumor-infiltrating lymphocyte cells on a logarithmic scale.
- Secondary Outcome Measures
Name Time Method AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib approximately 16 months Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors approximately 2 months Concentration of Vorasidenib in Surgically Resected Tumors approximately 2 months Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria Up to approximately 16 months Overall Survival (OS) Up to approximately 55 months Overall survival is defined as the time from the date of first dose (in Safety Lead-in) or first postoperative dose (in randomized perioperative phase) to the date of death due to any cause.
Time to response Up to approximately 55 months Defined as the time from the date of first dose (in Safety Lead-In) or the date of first postoperative dose (in randomized perioperative phase) to the date of first documented objective response as assessed by the Investigator per Modified Response Assessment in Neuro-oncology (mRANO) criteria.
Cmax: Maximum Observed Plasma Concentration of Vorasidenib approximately 16 months
Trial Locations
- Locations (16)
Northwestern University (Site: 840123)
🇺🇸Chicago, Illinois, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Mayo Clinic Florida
🇺🇸Cleveland, Ohio, United States
University of California, Los Angeles (Site: 840113)
🇺🇸Los Angeles, California, United States
University of California, San Francisco (Site: 840149)
🇺🇸San Francisco, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
University of Miami (Site: 840129)
🇺🇸Miami, Florida, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital (Site: 840104)
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute (Site: 840139)
🇺🇸Boston, Massachusetts, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Memorial Sloan Kettering Cancer Center (Site: 840117)
🇺🇸New York, New York, United States
Duke University (Site: 840110)
🇺🇸Durham, North Carolina, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
MD Anderson Cancer Center (Site: 840102)
🇺🇸Houston, Texas, United States
University of Utah, Huntsman Cancer Center
🇺🇸Salt Lake City, Utah, United States