Clinical trial NCT05484622: Study of Vorasidenib and Pembrolizumab Combination in Recurrent or Progressive IDH-1 Mutant Glioma
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 IDH-1 Mutant Glioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Astrocytoma
Oligodendroglioma
Keywords: Vorasidenib
AG-881
Pembrolizumab
IDH-1
Astrocytoma
Oligodendroglioma
Enchancing
Non-enchancing
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2022-08-02
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential design for safety lead-in and randomized perioperative phases, parallel design within randomized perioperative phase.
Primary purpose: TREATMENT

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

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.

Eligibility 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 glioma (per the 2016 or 2021 World Health Organization \[WHO\] Classification of Tumors of the central nervous system)
4. Have:

   1. Documented IDH1-R132H gene mutation; and
   2. 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 institutional 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. OR (in the absence of measurable enhancing disease) measurable, MRI-evaluable, unequivocal non enhancing disease as determined by institutional radiologist/Investigator at Screening on either 2D or 3D T2-weighted image or FLAIR. Per RANO 2.0 criteria, measurable lesion is defined as at least 1 non enhancing lesion measuring ≥ 1 cm × ≥ 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.

Primary outcomes:
measure: Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: First 21 days of dosing (Cycle 1) in safety lead-in phase
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: approximately up to 19 months
measure: Percentage of Tumor-infiltrating Lymphocyte (TIL) Cells in Surgically Resected Tumors Following Treatment With Vorasidenib + Pembrolizumab Compared to Untreated Control Tumors
timeFrame: approximately 2 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 55 months
measure: AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib
timeFrame: approximately 16 months
measure: Cmax: Maximum Observed Plasma Concentration of Vorasidenib
timeFrame: approximately 16 months
measure: Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors
timeFrame: approximately 2 months
measure: Concentration of Vorasidenib in Surgically Resected Tumors
timeFrame: approximately 2 months
measure: Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria
timeFrame: Up to approximately 16 months
measure: Time to response
timeFrame: Up to approximately 55 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California, Los Angeles (Site: 840113)
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (Site: 840149)
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Miami
country: United States
facility: University of Miami (Site: 840129)
state: Florida
city: Chicago
country: United States
facility: Northwestern University (Site: 840123)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital (Site: 840104)
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute (Site: 840139)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (Site: 840117)
state: New York
city: Durham
country: United States
facility: Duke University (Site: 840110)
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Cleveland
country: United States
facility: Mayo Clinic Florida
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center (Site: 840102)
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Center
state: Utah
Study officials:
References:
citation: Wen P, Peters K, de la Fuente M, Mellinghoff I, Arrillaga-Romany I, Kumthekar P, Clarke J, Puduvalli V, de Groot J, Zhang J, Chisamore M, Abshire M, Mahboub P, Hassan I, Knipstein J, Cloughesy T. Phase 1 Safety Lead-in and Randomized Open-label Perioperative Study of Vorasidenib Combined with Pembrolizumab in Recurrent or Progressive Enhancing IDH1-mutant Astrocytomas: Safety Lead-in Results. Neuro Oncol. 2023 Nov 10;25(Supplement_5):V65. doi: https://doi.org/10.1093/neuonc/noad179.0254