Methods of treating brain tumors using combination therapy
Inventors
MURTIE, Joshua • NAGARAJA, NELAMANGALA • NICOLAY, Brandon • SCHENKEIN, David • Yen, Katharine
Assignees
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Publication Number
US-12064436-B2
Publication Date
2024-08-20
Expiration Date
Abstract
Provided are methods of treating a brain tumor in a patient in need thereof comprising administering to the patient a compound described herein and radiation therapy and/or one or more additional therapeutic agents.
Core Innovation
The invention relates to a method for treating glioma characterized by the presence of an IDH1 mutation or an IDH2 mutation, wherein the mutation results in accumulation of R(-)-2-hydroxyglutarate. The method administers a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof for treating glioma in patients with IDH mutation-driven R(-)-2-hydroxyglutarate accumulation.
A central feature is the combination of the compound of formula (I) with radiation therapy, with administration defined as concurrent or sequential. The disclosure further includes combination-therapy approaches in which the compound of formula (I) is co-administered concurrently or sequentially with one or more additional therapeutic agents selected from temozolomide, bevacizumab, and gemcitabine.
The examples and in vivo study results reported in the disclosure indicate that Compound A combined with radiation yields smaller tumor volumes and improved survival versus monotherapies. The disclosure characterizes that no antagonism is observed when Compound A is combined with radiation.
Claims Coverage
The document includes two independent claims. The first independent claim covers glioma treatment using the compound of formula (I) together with radiation therapy, administered concurrently or sequentially; it is grounded in IDH1/IDH2 mutation-associated R(-)-2-hydroxyglutarate accumulation. The second independent claim covers glioma treatment using the compound of formula (I) together with one or more additional therapeutic agents selected from temozolomide, bevacizumab, and gemcitabine, also administered concurrently or sequentially.
Glioma with IDH1/IDH2 mutation-driven R(-)-2-hydroxyglutarate accumulation treated with compound of formula (I) and radiation
A method for treating glioma characterized by the presence of an IDH1 mutation or an IDH2 mutation, wherein the IDH1 or IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and radiation therapy, wherein the compound and the radiation are administered concurrently or sequentially.
Glioma with IDH1/IDH2 mutation-driven R(-)-2-hydroxyglutarate accumulation treated with compound of formula (I) and additional agents
A method for treating a glioma characterized by the presence of an IDH1 mutation or an IDH2 mutation, wherein the IDH1 or IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from temozolomide, bevacizumab and gemcitabine, wherein the compound and the additional therapeutic agents are administered concurrently or sequentially.
Overall, the claim coverage is centered on combination therapy for glioma defined by IDH1/IDH2 mutation-associated R(-)-2-hydroxyglutarate accumulation. The first independent claim focuses on combination with radiation therapy, while the second independent claim focuses on combination with temozolomide, bevacizumab, and/or gemcitabine, with concurrent or sequential administration.
Stated Advantages
Improved survival versus monotherapies when Compound A is combined with radiation therapy.
Smaller tumor volumes versus monotherapies when Compound A is combined with radiation therapy.
No observed antagonism when Compound A is combined with radiation therapy.
Documented Applications
Treatment of glioma, including mutant-IDH1 and mutant-IDH2 glioma characterized by IDH-driven R(-)-2-hydroxyglutarate accumulation, using Compound A with radiation therapy and/or additional therapeutic agents.
In vivo orthotopic mutant IDH1 glioma mouse model testing Compound A in combination with radiation, using tumor volume and survival endpoints.
Subcutaneous glioma model combination reporting tumor-volume and lifespan endpoints.
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