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

Astrocytoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05484622
• Other study ID #: CL1-95032-005
• Secondary ID: MK-3475-B39
• Status: Recruiting
• Phase: Phase 1
• Start date: January 20, 2023
• Est. completion date: August 30, 2027

Study information

• Verified date: June 2024
• Source: Servier
• Contact: Institut de Recherches Internationales Servier Clinical Studies
• Phone: +33 1 55 72 43 66
• Email: scientificinformation[@]servier.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: August 30, 2027
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Astrocytoma

Intervention

Drug:
• Vorasidenib
Administered orally as tablets.
• Pembrolizumab
Administered as IV infusion.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Dana-Farber Cancer Institute (Site: 840139)	Boston	Massachusetts
United States	Massachusetts General Hospital (Site: 840104)	Boston	Massachusetts
United States	Northwestern University (Site: 840123)	Chicago	Illinois
United States	Duke University (Site: 840110)	Durham	North Carolina
United States	MD Anderson Cancer Center (Site: 840102)	Houston	Texas
United States	University of California, Los Angeles (Site: 840113)	Los Angeles	California
United States	University of Miami (Site: 840129)	Miami	Florida
United States	Memorial Sloan Kettering Cancer Center (Site: 840117)	New York	New York
United States	University of California, San Francisco (Site: 840149)	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs)		First 21 days of dosing (Cycle 1) in safety lead-in phase
Primary	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)		approximately up to 19 months
Primary	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	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
Secondary	AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib		approximately 16 months
Secondary	Cmax: Maximum Observed Plasma Concentration of Vorasidenib		approximately 16 months
Secondary	Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors		approximately 2 months
Secondary	Concentration of Vorasidenib in Surgically Resected Tumors		approximately 2 months
Secondary	Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria		Up to approximately 16 months
Secondary	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