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

Primary Purpose

Astrocytoma

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Vorasidenib

Pembrolizumab

About this trial

This is an interventional treatment trial for Astrocytoma focused on measuring Vorasidenib, AG-881, Pembrolizumab, IDH-1, Astrocytoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 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) 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.

Sites / Locations

University of California, Los Angeles (Site: 840113)Recruiting
University of California, San Francisco (Site: 840149)Recruiting
University of Miami (Site: 840129)Recruiting
Northwestern University (Site: 840123)Recruiting
Massachusetts General Hospital (Site: 840104)Recruiting
Dana-Farber Cancer Institute (Site: 840139)Recruiting
Memorial Sloan Kettering Cancer Center (Site: 840117)Recruiting
Duke University (Site: 840110)Recruiting
MD Anderson Cancer Center (Site: 840102)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

No Intervention

Arm Label

Safety Lead-In Phase: Vorasidenib + Pembrolizumab

Randomized Perioperative Phase: Vorasidenib + Pembrolizumab

Randomized Perioperative Phase: Vorasidenib Only

Randomized Perioperative Phase: Untreated Control Group

Arm Description

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.

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.

Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery.

Participants will not receive any treatment prior to surgery.

Outcomes

Primary Outcome Measures

Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs)

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Secondary Outcome Measures

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.

AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib

Cmax: Maximum Observed Plasma Concentration of Vorasidenib

Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors

Concentration of Vorasidenib in Surgically Resected Tumors

Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria

Full Information

NCT ID

NCT05484622

First Posted

July 21, 2022

Last Updated

September 14, 2023

Sponsor

Institut de Recherches Internationales Servier

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT05484622

Brief Title

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

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 Astrocytomas

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 20, 2023 (Actual)

Primary Completion Date

March 28, 2024 (Anticipated)

Study Completion Date

August 30, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut de Recherches Internationales Servier

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Astrocytoma

Keywords

Vorasidenib, AG-881, Pembrolizumab, IDH-1, Astrocytoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

Sequential design for safety lead-in and randomized perioperative phases, parallel design within randomized perioperative phase.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Safety Lead-In Phase: Vorasidenib + Pembrolizumab

Arm Type

Experimental

Arm Description

Arm Title

Randomized Perioperative Phase: Vorasidenib + Pembrolizumab

Arm Type

Experimental

Arm Description

Arm Title

Randomized Perioperative Phase: Vorasidenib Only

Arm Type

Experimental

Arm Description

Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery.

Arm Title

Randomized Perioperative Phase: Untreated Control Group

Arm Type

No Intervention

Arm Description

Participants will not receive any treatment prior to surgery.

Intervention Type

Drug

Intervention Name(s)

Vorasidenib

Other Intervention Name(s)

S095032, AG-881

Intervention Description

Administered orally as tablets.

Intervention Type

Drug

Intervention Name(s)

Pembrolizumab

Other Intervention Name(s)

MK-3475, KNB39

Intervention Description

Administered as IV infusion.

Primary Outcome Measure Information:

Title

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

Title

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame

approximately up to 19 months

Title

Percentage of Tumor-infiltrating Lymphocyte (TIL) Cells in Surgically Resected Tumors Following Treatment With Vorasidenib + Pembrolizumab Compared to Untreated Control Tumors

Description

TIL is defined as the percentage of tumor-infiltrating lymphocyte cells on a logarithmic scale.

Time Frame

approximately 2 months

Secondary Outcome Measure Information:

Title

Overall Survival (OS)

Description

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.

Time Frame

Up to approximately 55 months

Title

AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib

Time Frame

approximately 16 months

Title

Cmax: Maximum Observed Plasma Concentration of Vorasidenib

Time Frame

approximately 16 months

Title

Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors

Time Frame

approximately 2 months

Title

Concentration of Vorasidenib in Surgically Resected Tumors

Time Frame

approximately 2 months

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Institut de Recherches Internationales Servier Clinical Studies Department

Phone

+33 1 55 72 43 66

scientificinformation@servier.com

Facility Information:

Facility Name

University of California, Los Angeles (Site: 840113)

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Individual Site Status

Recruiting

Facility Contact:

shwiles@mednet.ucla.edu

Facility Name

University of California, San Francisco (Site: 840149)

City

San Francisco

State/Province

California

ZIP/Postal Code

94013

Country

United States

Individual Site Status

Recruiting

Facility Contact:

NeuroOncNewPatientCoord@ucsf.edu

Facility Name

University of Miami (Site: 840129)

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Individual Site Status

Recruiting

Facility Contact:

yxp303@med.miami.edu

Facility Name

Northwestern University (Site: 840123)

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60045

Country

United States

Individual Site Status

Recruiting

Facility Contact:

cancertrials@northwestern.edu

Facility Name

Massachusetts General Hospital (Site: 840104)

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Individual Site Status

Recruiting

Facility Contact:

lmhibyan@mgb.org

Facility Name

Dana-Farber Cancer Institute (Site: 840139)

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Individual Site Status

Recruiting

Facility Contact:

Patrick_wen@dfci.harvard.edu

Facility Name

Memorial Sloan Kettering Cancer Center (Site: 840117)

City

New York

State/Province

New York

ZIP/Postal Code

10017

Country

United States

Individual Site Status

Recruiting

Facility Contact:

KeithN@mskcc.org

Facility Name

Duke University (Site: 840110)

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27705

Country

United States

Individual Site Status

Recruiting

Facility Contact:

dukebrain1@dm.duke.edu

Facility Name

MD Anderson Cancer Center (Site: 840102)

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Individual Site Status

Recruiting

Facility Contact:

Egachimova@mdanderson.org

hsal@mdanderson.org

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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 URL

https://clinicaltrials.servier.com/

Learn more about this trial

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

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