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

Purpose

Vorasidenib in combination with pembrolizumab in participants with recurrent or progressive enhancing isocitrate dehydrogenase-1 (IDH-1) mutant Glioma.

Condition

  • Astrocytoma

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts 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 astrocytoma (per the 2016 or 2021 World Health Organization [WHO] Classification of Tumors of the central nervous system) 4. 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. 5. 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. 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 exclusion criteria may apply.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Intervention Model Description
Sequential design for safety lead-in and randomized perioperative phases, parallel design within randomized perioperative phase.
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Safety Lead-In Phase: Vorasidenib + 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.
  • Drug: Vorasidenib
    Administered orally as tablets.
    Other names:
    • S095032
    • AG-881
  • Drug: Pembrolizumab
    Administered as IV infusion.
    Other names:
    • MK-3475
    • KEYTRUDA®
    • KEYNOTE-B39
    • MK-3475-B39
Experimental
Randomized Perioperative Phase: Vorasidenib + 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.
  • Drug: Vorasidenib
    Administered orally as tablets.
    Other names:
    • S095032
    • AG-881
  • Drug: Pembrolizumab
    Administered as IV infusion.
    Other names:
    • MK-3475
    • KEYTRUDA®
    • KEYNOTE-B39
    • MK-3475-B39
Experimental
Randomized Perioperative Phase: Vorasidenib Only 		Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery.
  • Drug: Vorasidenib
    Administered orally as tablets.
    Other names:
    • S095032
    • AG-881
No Intervention
Randomized Perioperative Phase: Untreated Control Group 		Participants will not receive any treatment prior to surgery.

Recruiting Locations

Massachusetts General Hospital (Site: 840104)
Boston, Massachusetts 02114
Contact:
lmhibyan@mgb.org

More Details

Status
Recruiting
Sponsor
Institut de Recherches Internationales Servier

Study Contact

Institut de Recherches Internationales Servier Clinical Studies Department
+33 1 55 72 43 66
scientificinformation@servier.com

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.