Study of Vorasidenib and Pembrolizumab Combination in Recurrent or Progressive Enhancing IDH-1 Mutant Astrocytomas

Study Overview
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Brief Summary
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Vorasidenib in combination with pembrolizumab in participants with recurrent or progressive enhancing isocitrate dehydrogenase-1 (IDH-1) mutant astrocytomas.

Detailed Description
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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.

Official Title
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A Phase 1, Safety Lead-in and Randomized, Open-label, Perioperative Study of Vorasidenib in Combination With Pembrolizumab in Subjects With Recurrent or Progressive Enhancing IDH-1 Mutant Astrocytomas

Conditions
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Astrocytoma

Intervention / Treatment
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* Drug: Vorasidenib
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Karnofsky Performance Status (KPS) of ≥ 70%. Have expected survival of ≥ 3 months. Have histologically confirmed Grade 2 or Grade 3 astrocytoma (per the 2016 or 2021 World Health Organization [WHO] Classification of Tumors of the central nervous system) Have documented IDH1-R132H gene mutation and 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 measurable, magnetic resonance imaging (MRI)-evaluable, unequivocal contrast enhancing disease as determined by institution 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. Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both. 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: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential design for safety lead-in and randomized perioperative phases, parallel design within randomized perioperative phase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-In Phase: Vorasidenib + Pembrolizumab<br>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. | Drug: Vorasidenib<br>* Administered orally as tablets.<br>* Other names: AG-881;Drug: Pembrolizumab<br>* Administered as IV infusion.<br>* Other names: KNB39;|
| Experimental: Randomized Perioperative Phase: Vorasidenib + Pembrolizumab<br>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. | Drug: Vorasidenib<br>* Administered orally as tablets.<br>* Other names: AG-881;Drug: Pembrolizumab<br>* Administered as IV infusion.<br>* Other names: KNB39;|
| Experimental: Randomized Perioperative Phase: Vorasidenib Only<br>Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery. | Drug: Vorasidenib<br>* Administered orally as tablets.<br>* Other names: AG-881;|
| No Intervention: Randomized Perioperative Phase: Untreated Control Group<br>Participants will not receive any treatment prior to surgery. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | TIL is defined as the percentage of tumor-infiltrating lymphocyte cells on a logarithmic scale. | approximately 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | Up to approximately 55 months | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vorasidenib, AG-881, Pembrolizumab, IDH-1, Astrocytoma