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

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ClinicalTrials.gov Identifier: NCT05484622
Recruitment Status : Recruiting
First Posted : August 2, 2022
Last Update Posted : May 8, 2024
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Servier ( Institut de Recherches Internationales Servier )

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

Condition or disease Intervention/treatment Phase
Astrocytoma Drug: Vorasidenib Drug: Pembrolizumab Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 20, 2023
Estimated Primary Completion Date : February 28, 2025
Estimated Study Completion Date : August 30, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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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:
  • 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.


Outcome Measures
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Primary Outcome Measures :
  1. Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: First 21 days of dosing (Cycle 1) in safety lead-in phase ]
  2. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: approximately up to 19 months ]
  3. Percentage of Tumor-infiltrating Lymphocyte (TIL) Cells in Surgically Resected Tumors Following Treatment With Vorasidenib + Pembrolizumab Compared to Untreated Control Tumors [ Time Frame: approximately 2 months ]
    TIL is defined as the percentage of tumor-infiltrating lymphocyte cells on a logarithmic scale.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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.

  2. AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib [ Time Frame: approximately 16 months ]
  3. Cmax: Maximum Observed Plasma Concentration of Vorasidenib [ Time Frame: approximately 16 months ]
  4. Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors [ Time Frame: approximately 2 months ]
  5. Concentration of Vorasidenib in Surgically Resected Tumors [ Time Frame: approximately 2 months ]
  6. Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria [ Time Frame: Up to approximately 16 months ]
  7. Time to response [ Time Frame: 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05484622


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

Locations
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United States, California
University of California, Los Angeles (Site: 840113) Recruiting
Los Angeles, California, United States, 90095
Contact       shwiles@mednet.ucla.edu   
University of California, San Francisco (Site: 840149) Recruiting
San Francisco, California, United States, 94013
Contact       NeuroOncNewPatientCoord@ucsf.edu   
United States, Florida
University of Miami (Site: 840129) Recruiting
Miami, Florida, United States, 33136
Contact       yxp303@med.miami.edu   
United States, Illinois
Northwestern University (Site: 840123) Recruiting
Chicago, Illinois, United States, 60045
Contact       cancertrials@northwestern.edu   
United States, Massachusetts
Massachusetts General Hospital (Site: 840104) Recruiting
Boston, Massachusetts, United States, 02114
Contact       lmhibyan@mgb.org   
Dana-Farber Cancer Institute (Site: 840139) Recruiting
Boston, Massachusetts, United States, 02215
Contact       Patrick_wen@dfci.harvard.edu   
United States, New York
Memorial Sloan Kettering Cancer Center (Site: 840117) Recruiting
New York, New York, United States, 10017
Contact       KeithN@mskcc.org   
United States, North Carolina
Duke University (Site: 840110) Recruiting
Durham, North Carolina, United States, 27705
Contact       dukebrain1@dm.duke.edu   
United States, Texas
MD Anderson Cancer Center (Site: 840102) Recruiting
Houston, Texas, United States, 77030
Contact       Egachimova@mdanderson.org   
Contact       hsal@mdanderson.org   
Sponsors and Collaborators
Institut de Recherches Internationales Servier
Merck Sharp & Dohme LLC
More Information
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Responsible Party: Institut de Recherches Internationales Servier
ClinicalTrials.gov Identifier: NCT05484622    
Other Study ID Numbers: CL1-95032-005
MK-3475-B39 ( Other Identifier: Merck Sharp & Dohme LLC )
First Posted: August 2, 2022    Key Record Dates
Last Update Posted: May 8, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
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.
URL: https://clinicaltrials.servier.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Servier ( Institut de Recherches Internationales Servier ):
Vorasidenib
AG-881
Pembrolizumab
IDH-1
Astrocytoma
Additional relevant MeSH terms:
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Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
 Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action