Astrocytoma, Oligodendroglioma
Conditions
Keywords
Vorasidenib, AG-881, Pembrolizumab, IDH-1, Astrocytoma, Oligodendroglioma, Enchancing, Non-enchancing
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.
Interventions
DRUGVorasidenib
Administered orally as tablets.
DRUGPembrolizumab
Administered as IV infusion.
Sponsors
Institut de Recherches Internationales Servier
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Sequential design for safety lead-in and randomized perioperative phases, parallel design within randomized perioperative phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have Karnofsky Performance Status (KPS) of ≥ 70%. 2. Have expected survival of ≥ 3 months. 3. 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) 4. Have: 1. Documented IDH1-R132H gene mutation; and 2. 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. 5. 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. 6. Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both. 7. 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).
Exclusion criteria
1. 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. 2. Have received 2 or more courses of radiation. 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib | approximately 16 months | — |
| Cmax: Maximum Observed Plasma Concentration 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 | — |
| 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. |
Countries
United States
Outcome results
None listed