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

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 Glioma

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

Study Overview

• Status: Recruiting
• Conditions: Astrocytoma
• Intervention / Treatment: Drug: Vorasidenib; Drug: Pembrolizumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier Clinical Studies Department; Phone Number: +33 1 55 72 43 66; Email: scientificinformation@servier.com

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles (Site: 840113)
      • Contact: Email: shwiles@mednet.ucla.edu
    • San Francisco, California, United States, 94013
      • Recruiting
      • University of California, San Francisco (Site: 840149)
      • Contact: Email: NeuroOncNewPatientCoord@ucsf.edu
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami (Site: 840129)
      • Contact: Email: yxp303@med.miami.edu
  • Illinois
    • Chicago, Illinois, United States, 60045
      • Recruiting
      • Northwestern University (Site: 840123)
      • Contact: Email: cancertrials@northwestern.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital (Site: 840104)
      • Contact: Email: lmhibyan@mgb.org
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute (Site: 840139)
      • Contact: Email: Patrick_wen@dfci.harvard.edu
  • New York
    • New York, New York, United States, 10017
      • Recruiting
      • Memorial Sloan Kettering Cancer Center (Site: 840117)
      • Contact: Email: KeithN@mskcc.org
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke University (Site: 840110)
      • Contact: Email: dukebrain1@dm.duke.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center (Site: 840102)
      • Contact: Email: Egachimova@mdanderson.org
      • Contact: Email: hsal@mdanderson.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: AG-881; S095032; 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: AG-881; S095032; 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: AG-881; S095032
No Intervention: Randomized Perioperative Phase: Untreated Control Group; Participants will not receive any treatment prior to surgery.

What is the study measuring?

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
Time to response	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.	Up to approximately 55 months

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2023
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): August 30, 2027

Study Registration Dates

• First Submitted: July 21, 2022
• First Submitted That Met QC Criteria: August 1, 2022
• First Posted (Actual): August 2, 2022

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Pembrolizumab; Astrocytoma; Vorasidenib; AG-881; IDH-1
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Astrocytoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: CL1-95032-005; MK-3475-B39 (Other Identifier: Merck Sharp & Dohme LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• Used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• Where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• Sponsored by Servier
• With a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No