Methods of treating brain tumors using combination therapy

Abstract

Provided herein 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.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: June 12, 2018; application number: 201880048131.3 (International application number: PCT / US2018 / 037062); invention name: Method for treating brain tumors using combination therapy). Background Art

[0002] Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two different subclasses, one of which utilizes NAD(+) as an electron acceptor and the other utilizes NADP(+) as an electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which are localized to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other is predominantly cytoplasmic. Each NADP(+)-dependent isozyme is a homodimer.

[0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for peroxisomal reduction (e.g., conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA), as well as in peroxisomal reactions that consume 2-oxoglutarate (i.e., α-hydroxylation of phytanic acid). The cytoplasmic enzyme plays an important role in cytoplasmic NADPH production.

[0004] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide sequence and amino acid sequence of human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences of IDH1 are also described, for example, in Nekrutenko et al., Mol. Biol. Evol. 15: 1674-1684 (1998); Geisbrecht et al., J. Biol. Chem. 274: 30527-30533 (1999); Wiemann et al., Genome Res. 11: 422-435 (2001); The MGC Project Team, Genome Res. 14: 2121-2127 (2004); submitted by Lubec et al. (December 2008) to UniProtKB; submitted by Kullmann et al. (June 1996) to the EMBL / GenBank / DDBJ database; and Sjoeblom et al., Science 314: 268-274 (2006).

[0005] Non-mutant, such as wild-type IDH1, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate.

[0006] It has been found that mutations in IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is thought to contribute to the development and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).

[0007] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD M; or mNADP IDH. The protein encoded by this gene is a NADP(+)-dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediary metabolism and energy production. The protein may be tightly bound to or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein of 452 amino acids. The nucleotide sequence and amino acid sequence of IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2, respectively. The nucleotide sequence and amino acid sequence of human IDH2 are also described, for example, in: Huh et al. submitted (November 1992) to the EMBL / GenBank / DDBJ database; and The MGC Project Team, Genome Res. 14: 2121-2127 (2004).

[0008] Non-mutant, such as wild-type IDH2, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG).

[0009] It has been found that mutations in IDH2 present in certain cancer cells result in a new ability for the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44)

[0010] Mutations in IDH1 or IDH2 occur in more than 70% of diffuse low-grade glioma (LGG) tumors. IDH mutations lead to the accumulation of 2-HG, which is thought to promote tumorigenesis through DNA hypermethylation, increased repressive histone methylation, and inhibition of differentiation processes. Studies using a tool compound called AGI-5198, which has been shown to inhibit mutant IDH1 (mIDH1) but not mutant IDH2 (mIDH2), have shown that in some model systems (D. Rohle et al. Science 340: 626-630 (2013)), inhibition of mIDH1 protein can suppress the growth of mIDH1-driven gliomas. However, recent in vitro studies in a mIDH1 glioma model showed that mIDH1 cells treated with AGI-5198 were desensitized to radiotherapy, and the authors of these studies suggested that administration of mIDH1 inhibitors during radiotherapy may lead to adverse clinical outcomes (RJ Molenaar et al., Cancer Research 75:4790-4802 (2015)).

[0011] U.S. Publication No. 2015 / 0018328A1 discloses a novel pyridine-containing compound having the chemical name 6-(6-chloropyridin-2-yl)-N 2 ,N 4 -Bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine Compounds are described which have been shown to act as inhibitors of mutant IDH1 and IDH2 proteins in biochemical and cellular assays. Summary of the invention

[0012] The present invention provides methods for 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.

[0013] In one aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0014]

[0015] or a pharmaceutically acceptable salt thereof; and (b) radiation therapy; in an amount effective for treating brain tumors.

[0016] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0017]

[0018] or a pharmaceutically acceptable salt thereof; and (b) one or more additional therapeutic agents; in an amount effective for treating a brain tumor.

[0019] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0020]

[0021] or a pharmaceutically acceptable salt thereof; (b) radiation therapy; and (c) one or more additional therapeutic agents; in an amount effective for treating a brain tumor. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a graph of median tumor volume versus time during treatment with vehicle, radiation therapy, Compound A, and a combination of radiation therapy and Compound A in the IHD1m glioma mouse model.

[0023] Figure 2 is a graph of median tumor volume versus time during treatment with vehicle, temozolomide, Compound A, and the combination of temozolomide and Compound A in an IDH1m glioma mouse model. DETAILED DESCRIPTION

[0024] In one aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0025]

[0026] or a pharmaceutically acceptable salt thereof; and (b) radiation therapy; in an amount effective for treating brain tumors.

[0027] In some embodiments, the compound of Formula (I) is administered in non-salt (ie, free base) form.

[0028] Radiotherapy can be administered simultaneously or sequentially (before or after) with the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof and radiotherapy are administered simultaneously. In other embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof and radiotherapy are administered sequentially. For example, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered before radiotherapy. In other embodiments, radiotherapy is administered before a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0029] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0030]

[0031] or a pharmaceutically acceptable salt thereof; and (b) one or more additional therapeutic agents; in an amount effective for treating a brain tumor.

[0032] In some embodiments, the compound of Formula (I) is administered in non-salt (ie, free base) form.

[0033] One or more additional therapeutic agents can be administered together with the compound of formula (I) or its pharmaceutically acceptable salt in a single dosage form (e.g., pharmaceutical composition) or as a separate dosage form. If administered as a separate dosage form, one or more additional therapeutic agents can be administered simultaneously or sequentially (before or after) with the administration of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and one or more additional therapeutic agents are administered simultaneously. In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and one or more additional therapeutic agents are administered sequentially. For example, in some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered before one or more additional therapeutic agents. In other embodiments, one or more additional therapeutic agents are administered before the compound of formula (I) or its pharmaceutically acceptable salt.

[0034] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0035]

[0036] or a pharmaceutically acceptable salt thereof; (b) radiation therapy; and (c) one or more additional therapeutic agents; in an amount effective for treating a brain tumor.

[0037] In some embodiments, the compound of Formula (I) is administered in non-salt (ie, free base) form.

[0038] One or more additional therapeutic agents can be administered together with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in a single dosage form (e.g., a pharmaceutical composition) or as separate dosage forms. If a compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are administered in a single dosage form, the single dosage form can be administered simultaneously or sequentially (before or after) with the administration of radiation therapy.

[0039] If the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are administered as separate dosage forms, the compound of formula (I) or a pharmaceutically acceptable salt thereof, one or more additional therapeutic agents, and radiation therapy may be administered simultaneously with each other or sequentially in any order.

[0040] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0041]

[0042] or a pharmaceutically acceptable salt thereof; and (b) a DNA-reactive agent; in an amount effective for treating brain tumors.

[0043] In some embodiments, the compound of Formula (I) is administered in non-salt (ie, free base) form.

[0044] The DNA-reactive agent can be administered together with the compound of formula (I) or its pharmaceutically acceptable salt in a single dosage form (e.g., a pharmaceutical composition) or as a separate dosage form. If administered as a separate dosage form, the DNA-reactive agent can be administered simultaneously or sequentially (before or after) with the administration of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and the DNA-reactive agent are administered simultaneously. In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and the DNA-reactive agent are administered sequentially. For example, in some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered before the DNA-reactive agent. In other embodiments, the DNA-reactive agent is administered before the compound of formula (I) or its pharmaceutically acceptable salt.

[0045] In another aspect, the present invention provides a method for treating a brain tumor in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0046]

[0047] or a pharmaceutically acceptable salt thereof; (b) radiation therapy; and (c) a DNA-reactive agent; in an amount effective for treating a brain tumor.

[0048] In some embodiments, the compound of Formula (I) is administered in non-salt (ie, free base) form.

[0049] The DNA-reactive agent can be administered together with the compound of formula (I) or a pharmaceutically acceptable salt thereof, in a single dosage form (e.g., a pharmaceutical composition) or as separate dosage forms. If the compound of formula (I) or a pharmaceutically acceptable salt thereof and the DNA-reactive agent are administered in a single dosage form, the single dosage form can be administered simultaneously or sequentially (before or after) with the administration of radiation therapy.

[0050] If the compound of formula (I) or a pharmaceutically acceptable salt thereof and the DNA-reactive agent are administered as separate dosage forms, the compound of formula (I) or a pharmaceutically acceptable salt thereof, the DNA-reactive agent, and radiation therapy may be administered simultaneously with each other or sequentially in any order.

[0051] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0052] In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any of the methods described herein.

[0053] As used herein, the phrase "effective amount" refers to the amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and radiotherapy and / or one or more additional therapeutic agents (e.g., DNA reactive agents), which, when administered in combination, is sufficient to achieve a therapeutic benefit for treating brain tumors in the methods described herein. The effective amount in the methods described herein may be the same or different from the effective amount when the compound of formula (I) or its pharmaceutically acceptable salt, radiotherapy, or one or more additional therapeutic agents (e.g., DNA reactive agents) are administered as a monotherapy. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt that is effective in the methods described herein is the same, smaller, or greater than the amount of the compound of formula (I) or its pharmaceutically acceptable salt that is effective when the compound of formula (I) or its pharmaceutically acceptable salt is administered as a monotherapy. In some embodiments, the amount of radiotherapy that is effective in the methods described herein is the same, smaller, or greater than the amount of radiotherapy that is effective when radiotherapy is administered as a monotherapy. In some embodiments, the amount of one or more additional therapeutic agents (e.g., DNA-reactive agents) that is effective in the methods described herein is the same, less, or greater than the amount of one or more additional therapeutic agents (e.g., DNA-reactive agents) that is effective when the one or more additional therapeutic agents (e.g., DNA-reactive agents) are administered as a monotherapy.

[0054] As used herein, the term "treat" when referring to a brain tumor means having a therapeutic effect on a brain tumor, alleviating one or more symptoms of a brain tumor, altering the progression of a brain tumor, eradicating a brain tumor, reducing the size of a brain tumor, slowing or inhibiting the growth of a brain tumor, delaying or minimizing one or more symptoms associated with a brain tumor, reducing the malignancy of a brain tumor, or inducing stagnation of a brain tumor, or alleviating or minimizing one or more side effects associated with another therapy that is administered or applied to treat a brain tumor. In some embodiments, "treat" includes reducing the size of a brain tumor or slowing or inhibiting the growth of a brain tumor. In some embodiments, "treat" includes reducing the size of a brain tumor or slowing or inhibiting the growth of a brain tumor for a period of time, followed by stagnation of the brain tumor. In some embodiments, "treat" includes having a therapeutic effect on a brain tumor, alleviating the symptoms of a brain tumor, altering the progression of a brain tumor, or inducing stagnation of a brain tumor, without affecting the size of a brain tumor. In some embodiments, "treat" includes reducing the number or percentage of malignant cells in a brain tumor.

[0055] In one embodiment, the methods provided herein provide a complete response, partial response, or stable disease in a patient with glioma.

[0056] In one embodiment, the methods provided herein increase overall survival in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, the methods provided herein increase the complete remission rate in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the methods provided herein increase the objective response rate in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the methods provided herein increase the time to progression in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the methods provided herein increase recurrence-free survival in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the methods provided herein increase progression-free survival in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the methods provided herein increase event-free survival in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment, the methods provided herein increase the duration of remission in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the methods provided herein increase the duration of response in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the methods provided herein increase the time of remission / response in patients with glioma when treated with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to patients not treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, the methods provided herein increase overall survival in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0067] In one embodiment, the methods provided herein increase the complete remission rate in patients suffering from glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0068] In one embodiment, the methods provided herein increase the objective response rate in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0069] In one embodiment, the methods provided herein increase the time to progression in patients with glioma compared to patients individually treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0070] In one embodiment, the methods provided herein increase relapse-free survival in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0071] In one embodiment, the methods provided herein increase progression-free survival in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0072] In one embodiment, the methods provided herein increase event-free survival in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0073] In one embodiment, the methods provided herein increase the duration of remission in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0074] In one embodiment, the methods provided herein increase the duration of response in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0075] In one embodiment, the methods provided herein increase the duration of remission / response in patients with glioma compared to patients treated individually with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, or one or more additional therapeutic agents.

[0076] As used herein, the term "complete response" refers to the disappearance of all signs of cancer in response to treatment. This does not necessarily mean that the cancer is cured. The term is also interchangeable with "complete remission" in the art.

[0077] As used herein, the term "partial response" refers to a decrease in tumor size or extent of cancer in the body in response to treatment. The term is also interchangeable with "partial remission" in the art.

[0078] As used herein, the term "stable disease" refers to a cancer that is neither increasing nor decreasing in extent or severity.

[0079] As used herein, the term "overall survival" (OS) means the time from randomization in a clinical trial until death due to any cause.

[0080] As used herein, the term "complete remission rate" refers to the complete disappearance of all such manifestations of the disease.

[0081] As used herein, the term "objective response rate" (ORR) refers to the proportion of patients with a predetermined amount and a reduction in tumor size for a minimum time period. The duration of response is usually measured from the time of the initial response until the tumor progression recorded. Generally, the U.S. FDA has defined ORR as the sum of a partial response plus a complete response. When defined in this way, ORR is a direct measure of the anti-tumor activity of a drug, which can be evaluated in a single-arm study. Stable disease should not be a component of ORR. Stable disease can reflect the selection of the natural history of the disease, and tumor reduction is a direct therapeutic effect. The importance of ORR is evaluated by its magnitude and duration, as well as the percentage of complete response (no detectable tumor evidence).

[0082] As used herein, the term "time to progression" (TPP) refers to the time from randomization until objective tumor progression; TTP does not include death.

[0083] As used herein, the term "recurrence-free survival" (RFS) refers to the length of time after the initial treatment for cancer ends that a patient survives without any signs or symptoms of the cancer. In clinical trials, measuring recurrence-free survival is a way to see how well a new treatment works. The term is also interchangeable with disease-free survival (DFS) in the art.

[0084] As used herein, the term "progression-free survival" (PFS) means the time from randomization in a clinical trial until progression or death.

[0085] As used herein, the term "event-free survival" (EFS) means the time from study entry until any treatment failure, including disease progression, treatment discontinuation for any reason, or death.

[0086] As used herein, the term "duration of response" (DoR) is the time from achievement of response until relapse or disease progression.

[0087] As used herein, the term "patient" refers to a mammal having a brain tumor (eg, glioma), including mice, rats, dogs, and humans. In some embodiments, the patient is a human.

[0088] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied in an amount of 1 to 100mg / days, 2 to 50mg / days, 3 to 30mg / days, 4 to 20mg / days, 5 to 15mg / days, 8 to 12mg / days or about 10mg / days. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied in an amount of 1 to 500mg / days, 1 to 250mg / days, 5 to 100mg / days, 8 to 75mg / days, 10 to 50mg / days, 15 to 40mg / days, 20 to 30mg / days or about 25mg / days. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied in an amount of 1 to 500mg / days, 10 to 250mg / days, 20 to 100mg / days, 30 to 80mg / days, 40 to 60mg / days, 45 to 55mg / days or about 50mg / days. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied in an amount of 1 to 500 mg / day, 20 to 400 mg / day, 40 to 200 mg / day, 50 to 150 mg / day, 75 to 125 mg / day, 85 to 115 mg / day, 90 to 110 mg / day or about 100 mg / day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied in an amount of 1 to 500 mg / day, 50 to 400 mg / day, 100 to 300 mg / day, 150 to 250 mg / day, 175 to 225 mg / day, 185 to 215 mg / day, 190 to 210 mg / day or about 200 mg / day. In certain embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is used in an amount of 1 to 500 mg / day, 100 to 500 mg / day, 200 to 400 mg / day, 250 to 350 mg / day, 275 to 375 mg / day, 285 to 315 mg / day, 290 to 310 mg / day or about 300 mg / day. In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is used in an amount of 0.01 to 10 mg / kg body weight / day, 0.2 to 8.0 mg / kg body weight / day, 0.4 to 6.0 mg / kg body weight / day, 0.6 to 4.0 mg / kg body weight / day, 0.8 to 2.0 mg / kg body weight / day, 0.1 to 1 mg / kg body weight / day, 0.2 to 1.0 mg / kg body weight / day, 0.15 to 1.5 mg / kg body weight / day or 0.1 to 0.5 mg / kg body weight / day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day or more than once a day (e.g., twice a day, three times a day, four times a day, etc.) to achieve the aforementioned amount / day of administration. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day to achieve the aforementioned amount / day of administration.In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied twice a day to achieve the aforementioned amount / day application. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied once a day with 30-70mg, 35-65mg, 40-60mg, 45-55mg or about 50mg / applied. In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied once a day with about 10mg, about 25mg, about 50mg, about 100mg, about 200mg or about 300mg / applied. In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied twice a day with 5-35mg, 5-20mg, 5-15mg or about 10mg / applied. The amount of the compound of formula (I) described herein or its pharmaceutically acceptable salt is based on the amount of the compound of formula (I). The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the subject's predisposition to the disease, condition or symptom, and the judgment of the treating physician.

[0089] In some embodiments, radiation therapy is administered in a manner consistent with the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (eg, administration doses and schedules), Version 1.2016, available at nccn.org. In some embodiments, the radiation therapy is administered at a cumulative dose of 20-100 Gy, or 30-80 Gy, or 30-60 Gy, or 40-70 Gy, or 40-60 Gy, or 30-40 Gy, or 40-50 Gy, or 50-60 Gy, or 45-55 Gy in 1.0-5.0 Gy fractions, or 1.5-3.0 Gy fractions, or 1.0-1.5 Gy fractions, or 1.5-2.0 Gy fractions, or 2.0-2.5 Gy fractions, or 2.5-3.0 Gy fractions, or 1.8-2.0 Gy fractions, or 1.8 Gy fractions, or 2.0 Gy fractions. In some embodiments, the radiation therapy is administered at a cumulative dose of 50-70 Gy in 1.5-2.5 Gy fractions or 60 Gy in 2.0 Gy fractions. Cumulative dose refers to the sum of all divided doses given during treatment.

[0090] The dose of radiotherapy can be selected based on the properties of the brain tumor. In some embodiments where the brain tumor is a low-grade glioma, radiotherapy is administered with a cumulative dose of 40-50Gy in 1.5-2.5Gy fractions, or a cumulative dose of 45-54Gy in 1.8-2.0Gy fractions, or a cumulative dose of 45.5Gy in 1.8-2.0Gy fractions. In some embodiments where the brain tumor is a high-grade glioma, radiotherapy is administered with a cumulative dose of 50-70Gy in 1.5-2.5Gy fractions, or a cumulative dose of 59.4Gy in 1.8Gy fractions, or a cumulative dose of 55.8-59.4Gy in 1.8Gy fractions, or a cumulative dose of 57Gy in 1.9Gy fractions, or a cumulative dose of 60Gy in 1.8-2.0Gy fractions, or a cumulative dose of 25Gy in 5.0Gy fractions. In some embodiments where the brain tumor is a glioblastoma, radiation therapy is administered at a cumulative dose of 30-60 Gy in 2.0-4.0 Gy fractions, or 34 Gy in 3.4 Gy fractions, or 35-45 Gy in 2.5-3.0 Gy fractions, or 50 Gy in 2.5 Gy fractions.

[0091] Additional therapeutic agents

[0092] As used herein, "one or more additional therapeutic agents" employed in the methods described herein include those agents known to be useful for treating brain tumors, i.e., have a therapeutic effect on brain tumors, alleviate one or more symptoms of brain tumors, alter the progression of brain tumors, eradicate brain tumors, reduce the size of brain tumors, slow or inhibit the growth of brain tumors, delay or minimize one or more symptoms associated with brain tumors, reduce the malignancy of brain tumors, or induce stasis of brain tumors, or alleviate or minimize one or more side effects associated with another therapy that is administered or applied to treat brain tumors.

[0093] In some embodiments, the one or more additional therapeutic agents include one or more of a DNA-reactive agent, a PARP inhibitor, an antiemetic, an anticonvulsant or anti-epileptic drug, a checkpoint inhibitor, PVC chemotherapy, bevacizumab, and gemcitabine.

[0094] In certain embodiments, one or more additional therapeutic agents are DNA reactive agents. As used herein, "DNA reactive agents" are those agents that interact covalently or non-covalently with cellular DNA, such as alkylating agents, cross-linking agents, and DNA intercalators. For example, DNA reactive agents include adolesin, hexamethylmelamine, biszelexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, heptanediol diaminosulfonate (hepsulfam), ifosfamide, improsulfan, ilofven, lomustine, nitrogen mustard, melphalan, mitozolamide, nedaplatin, oxaliplatin, piposulfan, procarbazine, semustine, streptozotocin, temozolomide, thiotepa, trioxosulfan, diethylnitrosamine, benzo(a)pyrene, doxorubicin, mitomycin C, etc. Many of these DNA-reactive agents can be used as DNA-reactive chemotherapeutic agents in the treatment of cancer.

[0095] In some embodiments, the DNA-reactive agent is temozolomide (TMZ). In one aspect of these embodiments, TMZ is administered in a manner consistent with the National Comprehensive Cancer Network Oncology Clinical Practice Guidelines (e.g., administration doses and schedules), Version 1.2016, available at nccn.org. ... (Temozolomide) capsules and injections TMZ is administered in a manner consistent with the prescribing information for temozolomide. In some aspects of these embodiments, 100-250 mg / m2 of temozolomide is administered based on the patient's body surface area. 2 , or 100-150 mg / m 2 , or 150-200 mg / m 2 , or 200-250 mg / m 2 In some aspects of these embodiments, TMZ is administered at a daily dose of 50-100 mg / m based on the patient's body surface area. 2 , or 50-75 mg / m 2 , or 75-100 mg / m 2 , or 60-90 mg / m 2 , or 65-85 mg / m 2 , or 70-80 mg / m 2 In some aspects of these embodiments, TMZ is administered at a daily dose of 125-175 mg / m based on the patient's body surface area for 5 consecutive days of a 28-day treatment cycle. 2 In some aspects of these embodiments, TMZ is administered at a daily dose of 50-100 mg / m based on the patient's body surface area. 2 , or 50-75 mg / m 2 , or 75-100 mg / m 2, or 60-90 mg / m 2 , or 65-85 mg / m 2 , or 70-80 mg / m 2 TMZ is administered in combination with radiation therapy at a daily dose of 70-80 mg / m based on the patient's body surface area. 2 TMZ is administered in combination with radiation therapy for 42 days at a daily dose of 70-80 mg / m based on the patient's body surface area. 2 TMZ is administered in combination with radiation therapy for 42 days at a daily dose of 125-175 mg / m2 based on the patient's body surface area for 5 consecutive days of a 28-day treatment cycle. 2 In some aspects of these embodiments where the brain tumor is an anaplastic astrocytoma, TMZ is administered at a daily dose of 175-225 mg / m based on the patient's body surface area for 5 consecutive days of a 28-day treatment cycle. 2 Administer TMZ at a daily dose of .

[0096] In some embodiments, one or more additional therapeutic agents are PARP inhibitors. As used herein, "PARP inhibitors" refers to inhibitors of poly ADP ribose polymerase (PARP). Examples of PARP inhibitors include pamiparib, olaparib, rucaparib, veliparib, iniparib, talazoparib, niraparib, and the like.

[0097] In some embodiments, one or more additional therapeutic agents are antiemetics. As used herein, "antiemetic" refers to a drug that is effective in reducing symptoms of vomiting and nausea. Examples of antiemetics include 5-HT 3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, mirtazapine, etc.), dopamine agonists (e.g., domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, chlorpromazine, prochlorperazine, alizapride, prochlorperazine, metoclopramide, etc.), NK1 receptor antagonists (e.g., aprepitant, casopitant, rolapitant, etc.), antihistamines (e.g., cinnarizine, cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine, etc.), benzodiazepines (e.g., midazolam, lorazepam, etc.), anticholinergics (e.g., scopolamine, etc.), steroids (e.g., dexamethasone, etc.), trimethobenzamide, ginger, propofol, glucose / fructose / phosphate (which is sold under the trade name for sale), mint, muscimol, ajwain, etc.

[0098] In some embodiments, one or more additional therapeutic agents are anticonvulsants or antiepileptic drugs. As used herein, "anticonvulsants or antiepileptic drugs" refer to drugs that are effective in treating or preventing epileptic seizures (including epileptic seizures). Examples of anticonvulsants include paraldehyde, stiripentol, phenobarbital, methylphenobarbital, barbexalon, clobazam, clonazepam, chlorphenacate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam, potassium bromide, felbamate, carbamazepine, oxcarbazepine, eslicarbazepine acetate, valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide, tiagabine, topiramate, gabapentin, pregabalin, acetaminophen, phenobarbital ... Phenytoin, phenytoin, mephenytoin, fosphenytoin, methylethyldione, trimethyldione, ethadione, becloamide, primidone, brivaracetam, ethyltiracetam, levetiracetam, seletracetam, ethosuximide, phensuximide, methsuximide, acetazolamide, sulthiamide, methazolamide, zonisamide, lamotrigine, phenylbutyrylamide, phenylacetylurea, valproamide, valproamide, perampanel, stiripentol, pyridoxine, etc.

[0099] In some embodiments, one or more additional therapeutic agents are checkpoint inhibitors. As used herein, "checkpoint inhibitors" refer to therapeutic agents that inhibit immune checkpoints (e.g., CTLA-4, PD-1 / PD-L1, etc.), which otherwise prevent immune system attacks on cancer cells, thereby allowing the immune system to attack cancer cells. Examples of checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, pembrolizumab, atezolizumab, avelumab, durvalumab, BGB-A317, spartalizumab, etc.

[0100] In some embodiments, the one or more additional therapeutic agents are PVC chemotherapy. As used herein, "PVC chemotherapy" refers to a combination of procarbazine, lomustine (which is marketed under the trade name and vincristine (which is sold under the trade name PCV chemotherapy is a chemotherapy regimen that is administered in combination with vincristine (sold as ) and procarbazine (sold as ). Typically, vincristine is administered intravenously, while procarbazine and lomustine are administered orally. PCV chemotherapy is often administered in cycles, where each cycle includes a single administration of vincristine and lomustine, and a 10-day course of treatment with procarbazine.

[0101] In some embodiments, the one or more additional therapeutic agents is bevacizumab. Bevacizumab is sold as a recombinant humanized monoclonal antibody.

[0102] In some embodiments, the one or more additional therapeutic agents is gemcitabine. Gemcitabine is sold as a pyrimidine nucleoside analog.

[0103] Brain tumors treated by the methods of the present invention

[0104] The method of the present invention can be used to treat brain tumors. This includes all tumors inside the human skull (cranium) or in the central spinal canal. Tumors can originate from the brain itself, or from lymphoid tissue, blood vessels, cranial nerves, brain capsule (meninges), skull, pituitary gland, or pineal gland. Within the brain itself, the affected cells can be neurons or glial cells (which include astrocytes, oligodendrocytes, and ependymal cells). Brain tumors can also spread from cancers primarily located in other organs (metastatic tumors).

[0105] In certain embodiments, brain tumor is glioma, for example ependymoma, astrocytoma, oligoastrocytoma, oligodendroglioma, ganglioglioma, glioblastoma (also referred to as multiforme glioblastoma) or mixed glioma.Glioma is a primary brain tumor, and based on its appearance under the microscope, and in particular the presence of atypical cells, mitosis, endothelial cell proliferation and necrosis, is divided into four grades (I, II, III and IV).Grade I and II tumors referred to as "low-grade glioma" do not have any of these features or have one of these features, and include diffuse astrocytoma, pilocytic astrocytoma, low-grade astrocytoma, low-grade oligoastrocytoma, low-grade oligodendroglioma, ganglioglioma, dysembryoplastic neuroepithelioma, pleomorphic xanthoastrocytoma and mixed glioma. Grade III and IV tumors, referred to as "high-grade gliomas," have two or more of these characteristics and include anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, anaplastic ependymomas, and glioblastomas (including giant cell glioblastomas and gliosarcoma). In one aspect of these embodiments, the glioma is a low-grade glioma. In another aspect of these embodiments, the glioma is a high-grade glioma. In another aspect of these embodiments, the glioma is a glioblastoma.

[0106] In some embodiments, the brain tumor to be treated (e.g., glioma) is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in the accumulation of R(-)-2-hydroxyglutaric acid in the patient. In one aspect of these embodiments, the IDH1 mutation results in the accumulation of R(-)-2-hydroxyglutaric acid in the patient by providing an enzyme-catalyzed NADPH-dependent α-ketoglutaric acid reduction to R(-)-2-hydroxyglutaric acid in the patient. In another aspect of these embodiments, the IDH1 mutation is an R132X mutation. In another aspect of these embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another aspect of these embodiments, the R132X mutation is R132H or R132C. In another aspect of these embodiments, the R132X mutation is R132H. In yet another aspect of these embodiments, at the time of diagnosis or treatment, at least 30, 40, 50, 60, 70, 80 or 90% of brain tumor (e.g., glioma) cells carry an IDH1 R132X mutation, such as an R132H, R132C, R132L, R132V, R132S or R132G mutation. Brain tumors (e.g., gliomas) can be analyzed by sequencing cell samples to determine the presence and specific nature (e.g., altered amino acid present) of a mutation at amino acid 132 of IDH1.

[0107] In other embodiments, the brain tumor to be treated (e.g., glioma) is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in the accumulation of R(-)-2-hydroxyglutaric acid in the patient. In one aspect of these embodiments, the IDH2 mutation results in the accumulation of R(-)-2-hydroxyglutaric acid in the patient by providing an enzyme in the patient to catalyze the reduction of NADPH-dependent α-ketoglutaric acid to R(-)-2-hydroxyglutaric acid. In another aspect of these embodiments, the mutant IDH2 has an R140X mutation. In another aspect of these embodiments, the R140X mutation is an R140Q mutation. In another aspect of these embodiments, the R140X mutation is an R140W mutation. In another aspect of these embodiments, the R140X mutation is an R140L mutation. In another aspect of these embodiments, the mutant IDH2 has an R172X mutation. In another aspect of these embodiments, the R172X mutation is an R172K mutation. In another aspect of these embodiments, the R172X mutation is an R172G mutation. In yet another aspect of these embodiments, at the time of diagnosis or treatment, at least 30, 40, 50, 60, 70, 80 or 90% of brain tumor (e.g., glioma) cells carry IDH2 R140X and / or R172X mutations, such as R140Q, R140W or R140L and / or R172K or R172G mutations. Brain tumors (e.g., gliomas) can be analyzed by sequencing cell samples to determine the presence and specific nature (e.g., altered amino acids present) of mutations at amino acids 140 and / or 172 of IDH2.

[0108] In other embodiments, the brain tumor to be treated (e.g., glioma) is characterized by the presence of IDH1 mutations and IDH2 mutations, wherein the IDH1 and IDH2 mutations together result in the accumulation of R (-) -2-hydroxyglutaric acid in the patient. In one aspect of these embodiments, by providing an enzyme in the patient to catalyze the reduction of NADPH-dependent α-ketoglutaric acid to R (-) -2-hydroxyglutaric acid, IDH1 and IDH2 mutations result in the accumulation of R (-) -2-hydroxyglutaric acid in the patient. In various aspects of these embodiments, the IDH1 mutation is an R132X mutation selected from R132H, R132C, R132L, R132V, R132S and R132G. In various aspects of these embodiments, the IDH2 mutation is a R140Q, R140W, R140L, R172K or R172G mutation. In various other aspects of these embodiments, the brain tumor (e.g., glioma) to be treated is characterized by any combination of the aforementioned IDH1 and IDH2 mutations. In other aspects of these embodiments, at least 30, 40, 50, 60, 70, 80, or 90% of brain tumor (e.g., glioma) cells carry IDH1 R132X mutations, such as R132H, R132C, R132L, R132V, R132S, or R132G mutations, and IDH2 R140X and / or R172X mutations, such as R140Q, R140W, or R140L, and / or R172K or R172G mutations, at the time of diagnosis or treatment. Brain tumors (e.g., gliomas) can be analyzed by sequencing cell samples to determine the presence and specific properties (e.g., the altered amino acids present) of mutations at amino acid 132 of IDH1 and at amino acid 140 and / or 172 of IDH2.

[0109] In yet other embodiments, the brain tumor (e.g., glioma) to be treated is characterized by the presence of an IDH1 allele that does not include an R132X mutation, and an IDH2 allele that does not include an R140X or R172X mutation. In one aspect of these embodiments, at the time of diagnosis or treatment, at least 90% of brain tumor (e.g., glioma) cells do not include a mutation at amino acid 132 of IDH1, or at amino acid 140 or 172 of IDH2. Brain tumors (e.g., gliomas) can be analyzed by sequencing cell samples to determine the presence or absence of mutations at amino acid 132 of IDH1 and at amino acids 140 and / or 172 of IDH2.

[0110] Compounds and pharmaceutically acceptable salts thereof used in the methods of the present invention

[0111] The compound of formula (I) used in the methods described herein is referred to as 6-(6-chloropyridin-2-yl)-N 2 ,N 4-bis((R)-1,1,1-trifluoropropane-2-yl)-1,3,5-triazine-2,4-diamine, and is referred to as Compound A in the examples.

[0112] The compounds of formula (I) can be prepared by the methods described in paragraphs

[1032] -

[1036] of U.S. Publication No. 2015 / 0018328A1, which are incorporated herein by reference.

[0113] As used herein, when referring to compounds of Formula (I) and pharmaceutically acceptable salts thereof, the terms "compound" and "pharmaceutically acceptable salt" include the specified compounds and pharmaceutically acceptable salts in any form, including any tautomers or rotational isomers thereof, any solid form thereof (including any polymorphs thereof), any solvate or hydrate form thereof, any co-crystals thereof, and any solutions thereof.

[0114] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" of compounds of formula (I) include any non-toxic salts that, upon administration to a recipient, can directly or indirectly provide a compound of formula (I). Pharmaceutically acceptable salts are described in detail in SM Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, which reference is incorporated herein by reference.

[0115] As used herein, the term "co-crystal" refers to a crystalline solid composed of two or more neutral chemical species in a defined stoichiometric ratio, which has unique crystallographic and spectroscopic properties when compared to the individual species. "Co-crystals" are distinguished from "salts", which are composed of charged species that are charge balanced. The species that make up the co-crystal are typically linked by hydrogen bonding and other non-covalent and non-ionic interactions. Thus, pharmaceutical co-crystals of a drug typically comprise the drug and one or more coformers.

[0116] In the specification and claims, each atom of the compound of formula (I) is intended to represent any stable isotope of the specified element. In the example, no effort is made to enrich any atom of compound A in a specific isotope, and therefore each atom is likely to exist with a natural abundance isotopic composition close to the specified element.

[0117] As used herein, the term "stable" when referring to an isotope means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, isotopes for which no decay mode has been identified in VS Shirley & C. M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0118] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises each constituent atom in an isotopic composition close to the natural abundance of a designated element.

[0119] Compositions and administration routes of compounds of formula (I) or pharmaceutically acceptable salts thereof

[0120] Before administration to a subject, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition together with a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0121] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a carrier, adjuvant or vehicle that can be administered to a subject together with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and that does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0122] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α, β and γ cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance the delivery of compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0123] The pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or by injection. The pharmaceutical composition can contain any conventional nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the preparation can be adjusted with pharmaceutically acceptable acid, alkali or buffer to enhance the stability of the compound or its delivery form of the formulation. As used herein, the term parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0124] The pharmaceutical composition can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oily suspension. Such suspensions can be prepared using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersing agents, which are commonly used to prepare pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween or Span and / or other similar emulsifiers or bioavailability enhancers, which are commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms may also be used for formulation purposes.

[0125] The pharmaceutical composition can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, conventional carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dried corn starch. When oral administration of aqueous suspensions and / or emulsions, the active ingredient can be suspended or dissolved in an oil phase and mixed with an emulsifier and / or a suspending agent. When necessary, certain sweeteners and / or flavoring agents and / or coloring agents can be added.

[0126] The pharmaceutical composition can also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0127] The pharmaceutical composition can be topically applied to the skin. The pharmaceutical composition should be formulated with a suitable ointment containing an active component suspended or dissolved in a carrier. Carriers for topical application of the compound of one aspect of the present invention include, but are not limited to, mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing an active compound suspended or dissolved in a carrier and a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of one aspect of the present invention can also be topically applied to the lower intestinal tract via a rectal suppository or with a suitable enema formulation. Topical transdermal patches are also included in one aspect of the present invention.

[0128] The pharmaceutical compositions can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0129] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the patient being treated and the specific mode of administration. Typical preparations contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0130] The pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may also comprise another therapeutic agent useful in the treatment of cancer, such as a DNA reactive agent (defined above).

[0131] The pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may further comprise one or more additional therapeutic agents (eg, DNA reactive agents).

[0132] Routes of administration of radiation therapy

[0133] Radiation therapy involves the use of high-energy radiation (e.g., X-rays, gamma rays, or charged particles) to damage and / or kill cancer cells and shrink tumors. In the methods of the present invention, radiation can be delivered to a brain tumor (e.g., a glioma) by a machine placed outside the body (external beam radiation therapy), by radioactive materials placed inside the body near the brain tumor (internal radiation therapy, also called brachytherapy), or by systemically administered radioactive substances (e.g., radioactive iodine) that travel to the brain tumor through the bloodstream. Alternatively, these delivery methods can be used in combination.

[0134] In some embodiments, radiation therapy includes external radiation therapy (e.g., external beam radiation therapy including fractionated external beam radiation therapy, stereotactic radiation therapy such as or Gamma External radiation therapy can be given as several treatment sessions over several days or weeks. In one aspect of these embodiments, the radiation is administered in the form of X-rays.

[0135] In other embodiments, radiation therapy includes internal radiation therapy, wherein the radiation comes from an implant or material (liquid, solid, semi-solid or other substance) placed in the body. In one aspect of these embodiments, internal radiation therapy is brachytherapy, wherein a solid radiation source is placed near a brain tumor in the body. In another aspect of these embodiments, internal radiation therapy includes systemic administration of a radiation source, which is typically a radionuclide (radioisotope or unsealed source). The radiation source can be administered orally or can be injected into a vein.

[0136] Additional treatments and therapeutic agents

[0137] In some embodiments, the methods described herein further comprise the additional step of administering to the patient an additional cancer therapeutic agent or an additional cancer treatment.

[0138] For example, the methods described herein can be practiced in combination with existing standard of care treatments for gliomas. The standard of care for patients diagnosed with gliomas takes into account tumor location, potential symptoms, and the potential benefits of different treatment options (modalities) relative to risks. After the initial diagnosis of gliomas, standard treatment consists of maximal surgical resection, radiation therapy, and / or concomitant and adjuvant chemotherapy (e.g., using temozolomide (TMZ)). For patients over 70 years of age, less aggressive therapies are sometimes used, using radiation or TMZ alone. (See generally the National Comprehensive Cancer Network Clinical Practice Guidelines for Oncology, Version 1.2016, available at nccn.org)

[0139] For example, the current scheme for treating primary grade IV glioblastoma (GBM) is surgical resection in combination with radiotherapy and chemotherapy. The chemotherapy for primary grade IV GBM tumors approved by the U.S. FDA at present includes nitrosoureas (lomustine and carmustine) and TMZ. The postoperative care standard treatment of glioma consists of radiation and TMZ as anti-tumor treatment, and dexamethasone (DEX) for neurological symptom relief. Recently, antibodies against vascular endothelial growth factor (VEGF), bevacizumab, are more often used for tumor recurrence. Numerous experimental reagents are in various stages of preclinical, and clinical applications are under development, and may lead to changes in the care standard of glioblastoma.

[0140] The methods described herein can be combined with radiotherapy or surgery. In certain embodiments, the method is practiced in patients who are undergoing radiotherapy, have previously undergone radiotherapy, or are about to undergo radiotherapy. In certain embodiments, the method is practiced in patients who have undergone brain tumor resection surgery. Also provided herein is a method for treating a patient who has previously been treated for a brain tumor, but has no response to, for example, standard therapy with temozolomide, and a patient who has not been treated previously. Also provided herein is a method for treating a patient who has undergone surgery in an attempt to treat the condition in question, and a method for a patient who has not undergone surgery. Because brain tumor patients can have different clinical manifestations and different clinical outcomes, the treatment given to the patient can be different depending on the patient's prognosis. Without excessive experimentation, a skilled clinician can easily determine the specific secondary agents, surgical types, and non-drug-based standard treatment types that can be effectively used to treat each patient with a brain tumor. In some embodiments, the method described herein additionally includes the administration of temozolomide. In some such embodiments, the brain tumor is temozolomide-resistant.

[0141] Exemplary additional cancer therapeutics include, for example, chemotherapy, targeted therapy, immunotherapy, anti-epileptic drugs, steroids, checkpoint inhibitors, CAR-Ts, (Carmustine Implant) and (bevacizumab). Other cancer treatments include, for example, surgery and radiation therapy.

[0142] In some embodiments, additional cancer therapeutic agents are targeted therapeutic agents. Targeted therapy constitutes the use of drugs specific for the dysregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutations, overexpression or other key proteins in cancer cells. Outstanding examples are tyrosine kinase inhibitors, such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semasanib, sorafenib, sunitinib and vandetanib, and cyclin-dependent kinase inhibitors, such as avosidic and celecoxib. In some embodiments, targeted therapy can be used in combination with the methods described herein, such as biguanides, such as metformin or phenformin, preferably phenformin.

[0143] Targeted therapies can also involve small peptides that act as "homing devices" that can bind to cell surface receptors or the extracellular matrix surrounding affected cells. Radionuclides attached to these peptides (e.g., RGD) ultimately kill cancer cells if the nuclide decays in the vicinity of the cell. Examples of such therapies include

[0144] In some embodiments, the additional cancer therapeutic is an immunotherapeutic agent.Cancer immunotherapy refers to a collection of various treatment strategies designed to induce a subject's own immune system to fight tumors.

[0145] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy because the donor's immune cells often attack the tumor with a graft-versus-tumor effect.In some embodiments, immunotherapeutic agents can be used in combination with the methods described herein.

[0146] Other possible additional treatment modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.

[0147] Examples

[0148] abbreviation

[0149] Unless otherwise stated, or when the context indicates otherwise, the following abbreviations shall be understood to have the following meanings:

[0150] abbreviation meaning

[0151] IDH1 isocitrate dehydrogenase 1

[0152] IDH1m mutant isocitrate dehydrogenase 1

[0153] R132H Arginine to histidine point mutation at codon 132 of IDH1 IDH1R132H IDH1 with R132H point mutation EGF Epidermal Growth Factor

[0154] bFGF basic fibroblast growth factor

[0155] MRI Magnetic Resonance Imaging

[0156] 2HG 2-Hydroxyglutaric acid

[0157] PO Per Os (oral administration)

[0158] SARRP Small Animal Radiation Research Platform Platform)

[0159] QD Quaque Die (apply once a day)

[0160] QDxN Quaque Die (apply once a day) for N days Q12H every 12 hours

[0161] Q12Hx2 every 12 hours, 2 times (Q12Hx2) QDx17 every 12 hours, 2 times a day, for 17 days (34 times total), also Can be written as "Q12Hx34" or "12 hours for 17 days")

[0162] (Q12Hx2) QDxN Administer every 12 hours, 2 times / day, for N days BID Bis in Die (applied twice a day)

[0163] T2w T2 weighted rcf relative centrifugal force

[0164] TMZ Temozolomide

[0165] Gy

[0166] RT Radiation therapy

[0167] BED biologically effective dose

[0168] mm Millimeters

[0169] mg milligram

[0170] ng

[0171] kg kilogram

[0172] mL milliliters

[0173] min

[0174] MAD Median Absolute Distribution

[0175] SEM Standard error of the mean

[0176] Example 1

[0177] Combination of Compound A and Radiation Therapy in the IDH1m Glioma Model

[0178] Purpose of the study:

[0179] The aim of this study was to evaluate the potential efficacy of Compound A, administered twice daily, alone and in combination with focused beam radiation, against established orthotopic human neurosphere-derived grade III glioma cells carrying the IDH1R132H mutation in female mice using magnetic resonance imaging (MRI).

[0180] Study Design:

[0181] Study mice were imaged by MRI on days 37 and 38 post-inoculation and divided into five study groups based on MRI estimates of tumor burden. Staging values ​​were recorded on day 38. Treatment was initiated on day 39 post-inoculation, with the treatment schedule summarized in Table 1.

[0182] Table 1. Study design / treatment schedule

[0183]

[0184]

[0185] The scheme deviations reflected in Table 1 are as follows:

[0186] * For Groups 1, 3, 4 and 5, the administration of Compound A or vehicle control was extended until the study was terminated. The dosing schedule ((Q12Hx2)QDx17) specified in Table 1 is the dosing schedule planned for each group. However, for each group, dosing continued until there were no animals left in the group. Dosing continued for the duration of the time period specified for each group in Table 1.

[0187] **For groups 2, 4, and 5, the SARRP unit failed after the third day of treatment (Day 41), resulting in a 2-day delay in radiation therapy for study animals 6-10 in group 2 and study animals 1-10 in groups 4 and 5. No treatment delay occurred for study animals 1-5 in group 2. As is common in clinical practice, if a patient misses a radiation session, the radiation exposure is modified for the delayed study animals by using the calculation of the biologically effective dose (BED), which explains the dose exposure fraction from the two-day interval in the therapy. After a 2-day SARRP treatment delay, the adjusted radiation exposure was calculated to give a biologically effective dose (BED) over the same time period. For 2Gy to the tumor, QDx5 treatment (tissue α / β=10), BED10=12Gy. Therefore, in order to achieve this BED, the last two doses were delivered at 2.1Gy.

[0188] The aforementioned protocol deviations are not believed to have affected the study results.

[0189] Materials and methods:

[0190] On day 0 of the study, R132H Mutation 5x 10 4 The cells were implanted intracranially into study animals (female mice obtained from Envigo). The cell line is a primary human glioma cell line generated by the Mellinghoff laboratory (Memorial Sloan Kettering Cancer Institute / NYC) and identified as the TS603 cell line. The cell line was cultured in StemCell Technologies NeuroCult medium with Neurocult NS supplement, 0.0002% heparin, 20 ng / mL EGF, and 10 ng / mL bFGF. Tumors were normal with small tumor volumes (average 9.1 mm) at day 38. 3 ) were selected for staging.

[0191] Compound A was prepared to meet the dosage level requirements. The compound was formulated at a concentration of 5 mg / mL in a vehicle of 0.5% methylcellulose, 0.2% Tween 80 and water. A polytron was used for approximately 30-60 seconds to dissolve any clots. The resulting formulation was a fine white suspension with a pH of 2.8. The formulation was prepared fresh daily and stirred for at least one hour prior to dosing. The dosing formulation was stored at 4°C between doses.

[0192] For Groups 3-5, Compound A was orally dosed twice daily at 50 mg / kg (based on the amount of Compound A). The dose of Compound A was selected based on historical data that at this dose, 2HG production was inhibited to >98% in brain tumors when compared to healthy brain tissue.

[0193] Radiation therapy was administered via Xstrahl Life Sciences Small Animal Radiation Research Platform or SARRP. The system has been designed to allow highly targeted irradiation, which simulates that applied in human patients. The X-ray tube on the SARRP has a variable output and is used for computed tomography (CT) imaging to guide treatment, as well as for treatment delivery with single or multiple beams. For Groups 2, 4, and 5, the total amount of radiation delivered to the tumor was 10 Gy / mouse (2 Gy, QDx5).

[0194] Group 1 was anesthetized on the same treatment schedule.

[0195] All study animals received subcutaneous infusions (Lactated Ringer's) beginning on day 44. Beginning on day 39, hydrogel supplements were added to all cages.

[0196] T2-weighted (T2w) magnetic resonance images (MRI) were acquired so that volumetric measurements could be evaluated to determine disease progression. Brain tumor volume was assessed via MRI on days 38, 45, 49, 52, 56, 59, 63, 66, and 71.

[0197] result:

[0198] There was no Compound A or radiation-related mortality. Treatment with vehicle was well tolerated and resulted in no treatment-related mortality. Treatment was associated with a 25.1% weight loss, most of which appeared to be due to tumor burden progression rather than vehicle or anesthesia. Study animals began to show clinical signs from day 42. Most study animals developed rough fur, hunched posture, and dehydration from day 49.

[0199] Treatment with radiation therapy alone (Group 2), Compound A alone (Group 3), concurrent administration of Compound A and radiation therapy (Group 4), and radiation therapy followed by sequential administration of Compound A (Group 5) were compared. Tumor volume estimates from MRI found that when each group was compared to vehicle-treated mice (Group 1), mice receiving the combination therapy (Groups 4 and 5) demonstrated significantly smaller tumor burdens compared to the monotherapy alone (Groups 2 and 3). In Tables 2 and Figure 1 The median measured tumor volume (in mm) for each group of animals up to and including day 59 is reported in 3 count). Figure 1Tumor volumes measured on days 63, 66, and 71 were not included in the data because Group 1 was terminated after day 59 and thus comparison with vehicle control was not possible for later time points. Figure 1 The error bars in correspond to the median absolute distribution of each data point.

[0200] Table 2. Measured tumor volumes

[0201]

[0202] As shown in Table 3, the differences in tumor burden at day 59 between the designated groups were statistically significant. Data points were included throughout the study to allow for the incorporation of tumor volumes from all mice as they withdrew at different stages of the study due to disease burden. Statistical significance of the final data was performed using an unpaired Mann-Whitney test between groups.

[0203] Table 3. Statistical analysis of median tumor volume

[0204] Compare P-value Group 2 relative to Group 1 0.0001 Group 3 relative to Group 1 0.011 Group 4 relative to Group 1 <0.0001 Group 5 relative to Group 1 <0.0001 Group 4 relative to Group 2 0.052 Group 5 relative to Group 2 0.002 Group 4 relative to Group 3 0.0015 Group 5 relative to Group 3 0.0021

[0205] Therefore, although it has been suggested from in vitro experiments that administration of mIDH1 inhibitors during radiotherapy desensitizes mIDH1 cells to radiotherapy (RJ Molenaar et al., Cancer Research 75:4790-4802 (2015)), Figure 1 The results shown in demonstrate that the combination of Compound A and radiation therapy did not show an antagonistic effect in vivo in an orthotopic mutant IDH1 glioma brain tumor model.

[0206] Example 2

[0207] Combination of Compound A and Temozolomide Treatment in the IDH1m Glioma Model

[0208] Purpose of the study:

[0209] The aim of this study was to evaluate the potential efficacy of Compound A, administered twice daily, alone and in combination with temozolomide, against established subcutaneous human neurosphere-derived glioma cells carrying the IDH1 R132H mutation in male mice.

[0210] Study Design:

[0211] Study mice were divided into six study groups, which were treated according to the treatment schedule summarized in Table 4.

[0212] Table 4. Study design

[0213]

[0214]

[0215] Materials and methods

[0216] IDH1-carrying cells were used in growth hormone / heparin-free medium with Matrigel (final, 1:1) R132H Mutated 1X10 6 Ninety (90) 5-6 week old male mice (obtained from Taconic Biosciences) were implanted subcutaneously with cells. This cell line is a primary human glioma cell line generated by the Mellinghoff laboratory (Memorial Sloan Kettering Cancer Institute / NYC) and is identified as the TS603 cell line. The cell line was cultured in StemCell Technologies NeuroCult medium with Neurocult NS supplement, 0.0002% heparin, 20 ng / mL EGF, and 10 ng / mL bFGF. An excess of mice was inoculated to account for tumor variability. Tumor volume and body weight were monitored twice weekly until tumors reached ~200 mm 3 Once the tumor reaches ~200 mm 3 Animals were randomized into 6 groups based on digital caliper estimates of tumor burden.

[0217] The vehicle control formulation (Group 1) contained 0.5% methylcellulose and 0.1% Tween 80 in water and was adjusted to pH 3.5 with hydrochloric acid.

[0218] TMZ (2 mg / mL) formulations (Groups 2, 4, 5, and 6) were prepared as follows:

[0219] 1) Weigh 24 mg TMZ into a transparent vial.

[0220] 2) Add 12 ml of an aqueous solution of 0.5% methylcellulose and 0.1% Tween 80.

[0221] 3) Vortex the vial for 1-2 minutes, sonicate if necessary, and store on ice until use.

[0222] Compound A (10 mg / mL) formulations (Groups 3 and 6) were prepared as follows:

[0223] 1) Weigh 120 mg of Compound A into a transparent vial.

[0224] 2) Add 12 ml of an aqueous solution of 0.5% methylcellulose and 0.1% Tween 80.

[0225] 3) Vortex the vial for 1-2 minutes, sonicate if necessary, and store on ice until use.

[0226] Compound A (2 mg / mL) formulation (Group 5) was prepared as follows:

[0227] 1) Transfer 1.4 mL of the 10 mg / mL formulation into a clear vial.

[0228] 2) Add 5.6 mL of an aqueous solution of 0.5% methylcellulose and 0.1% Tween 80.

[0229] 3) Vortex the vial for 1-2 minutes, sonicate if necessary, and store on ice until use.

[0230] Compound A (0.4 mg / mL) formulation (Group 4) was prepared as follows:

[0231] 1) Transfer 1.2 mL of 2 mg / mL formulation into a clear vial.

[0232] 2) Add 4.8 mL of an aqueous solution of 0.5% methylcellulose and 0.1% Tween 80.

[0233] 3) Vortex the vial for 1-2 minutes, sonicate if necessary, and store on ice until use.

[0234] As shown in Table 4, each formulation was administered at 5 ml / kg via oral gavage based on the most recent body weight. Starting from the first day after the animals were randomly grouped, vehicle controls and compound A formulations were administered BID, 7 days / week. Starting from the first day after the animals were randomly grouped, TMZ formulations were administered once a day from Monday to Thursday, followed by 3 days of rest. For the administration of TMZ, animals were administered at least 1 hour apart from the administration of compound A to allow mice to recover from the initial gavage dose. The study continued for 55 days.

[0235] result:

[0236] Comparison was made with TMZ alone (Group 2), Compound A alone (Group 3), and simultaneous administration of TMZ and Compound A (Groups 4-6). Tumor volumes were measured by digital calipers on days 44, 47, 50, 54, 57, 60, and 64. As shown in Tables 5 and Figure 2 As shown in , the combination treatment paradigm of Compound A and TMZ (Groups 4-6) produced comparable effects on tumor volume when compared to either treatment alone (Groups 2 and 3). Figure 2 The error bars in the graph correspond to the standard error of the mean for each data point.

[0237] Table 5. Measured tumor volume (mm 3 )

[0238]

[0239]

[0240] As shown in Table 6, TMZ (Group 2) and Compound A (Group 3) individually produced statistically significant tumor growth inhibition relative to vehicle (Group 1). However, there were no statistically significant differences between any single agent (Groups 2 and 3) and the combination (Groups 4, 5, and 6). Statistical analysis was performed by comparing tumor volumes from the final tumor measurement at day 54 using an unpaired Student's T test between groups.

[0241] Table 6. Statistical comparison of tumor growth inhibition by monotherapy

[0242] Compare P-value Group 2 relative to Group 1 <0.02 Group 3 relative to Group 1 <0.02

[0243] therefore, Figure 2 The results shown in demonstrate that the combination of Compound A and TMZ did not result in a loss of anti-tumor activity when compared to each monotherapy.

[0244] Example 3

[0245] Combination of Compound A and Radiation Therapy in IDH1m Gliomas

[0246] Purpose of the study:

[0247] The aim of this study was to evaluate the potential efficacy of Compound A, administered twice daily, alone and in combination with focused beam radiation, against established orthotopic human neurosphere-derived grade III glioma cells carrying the IDH1 R132H mutation in female mice, using survival as an endpoint.

[0248] Study Design:

[0249] Study mice were imaged by MRI on days 37 and 38 post-inoculation and divided into five study groups based on MRI estimates of tumor burden. Staging values ​​were recorded on day 38. Treatment was initiated on day 40 post-inoculation, with the treatment schedule summarized in Table 7.

[0250] Table 7. Study design / treatment schedule

[0251]

[0252]

[0253]

[0254] The scheme deviations reflected in Table 7 are as follows:

[0255] * For Groups 1, 3, 4 and 5, the administration of Compound A was extended until the study was terminated. The dosing schedule ((Q12Hx2)QDx17) specified in Table 7 is the dosing schedule planned for each group. However, for each group, dosing continued until there were no animals left in the group. Dosing continued for the duration of the time period specified for each group in Table 7. Extension of dosing is common in in vivo studies. In the case of this study, tumor volume was still within the range of allowing mice to receive treatment with vehicle or Compound A, which was beyond what was expected before the study.

[0256] The aforementioned protocol deviations are not believed to have affected the study results.

[0257] Materials and methods:

[0258] On day 0 of the study, R132H Mutation 5x 10 4 The cells were implanted intracranially into research animals (female mice obtained from Envigo). The cell line is a primary human glioma cell line generated by the Mellinghoff laboratory (Memorial Sloan Kettering Cancer Institute / NYC) and identified as the TS603 cell line. The cell line was cultured in StemCell Technologies NeuroCult medium with Neurocult NS supplement, 0.0002% heparin, 20 ng / mL EGF, and 10 ng / mL bFGF.

[0259] T2-weighted (T2w) magnetic resonance images (MRI) are acquired so that volumetric measurements can be evaluated to determine disease progression.

[0260] All mice were assigned to study groups based on MRI estimates of tumor burden. Mice were assigned to ensure that the mean tumor burden of all groups was within 10% of the overall mean tumor burden of the study population. The overall mean tumor burden was 9.8 mm from day 40 of treatment. 3 (The group average range is 9.7-9.8mm 3 On the treatment day, all mice were dosed according to individual body weight (0.2 mL / 20 g) or in a fixed volume.

[0261] At the beginning of the study (Day 40), Supplements were added to all cages of all study mice and replenished daily until the study was terminated. Starting on day 44, all mice were given subcutaneous infusions (Lactated Ringer's solution). Mice with less than 20% weight loss received a total of 1.5 mL per day, while mice with more than 20% weight loss received a total of 2 mL per day. Subcutaneous infusions for all mice continued until the study was terminated.

[0262] Compounds were formulated in a vehicle of 0.5% methylcellulose, 0.2% Tween 80 and water. A polytron was used for approximately 30-60 seconds to dissolve any clots. The resulting formulation was a fine white suspension at a pH of 4.5 and a concentration of 5 mg / mL. The formulation was prepared fresh daily and stirred for at least one hour prior to dosing. Dosing formulations were stored at 4°C between dosings.

[0263] Radiation therapy was administered via Xstrahl Life Sciences Small Animal Radiation Research Platform or SARRP. The system has been designed to allow highly targeted irradiation, which simulates that applied in human patients. The X-ray tube on the SARRP has a variable output and is used for computed tomography (CT) imaging to guide treatment, as well as for treatment delivery with single or multiple beams. For Groups 2, 4, and 5, the total amount of radiation delivered to the tumor was 10 Gy / mouse (2 Gy, QDx5).

[0264] Group 1 was anesthetized on the same treatment schedule.

[0265] Six hours after the morning dose of Compound A, mice exceeding euthanasia criteria (greater than 30% weight loss, skull expansion, severely impaired locomotion, severe respiratory distress and / or loss of righting reflex) were euthanized via overexposure to carbon dioxide for blood and brain collection.

[0266] Measurements and Endpoints:

[0267] The primary endpoint for efficacy was increased lifespan.

[0268] Side Effect Evaluation. All animals were observed for clinical signs at least once daily. Animals were weighed at the time of daily treatment. Individual body weights were recorded 3 times per week. Animals were euthanized due to any one or combination of the following events: weight loss greater than 30%, skull expansion, severe motor impairment, severe respiratory distress, and / or loss of righting reflex.

[0269] Treatment-related weight loss and net treatment-related weight loss were also determined. Net weight loss was calculated by subtracting the vehicle control average treatment-related weight change from the weight change on the day for each treated animal. Treatment-related weight was monitored only according to the protocol measures approved by the Institutional Animal Care and Use Committee (IACUC). Treatment-related weight loss was concurrent with disease burden progression and was unrelated to the treatment in the study.

[0270] Median life span. The life span of each animal (Kaplan-Meier Survival-Log-Rank) was measured from the day of the first treatment of each animal (not the day of tumor implantation) and used to calculate the median life span of each group. This calculation is based on the death day of all animals, which either died or were euthanized for disease or treatment-related reasons. Animals euthanized for sampling or treatment-related reasons were excluded from this calculation.

[0271] The median lifespan of each group was used to calculate the % increase in lifespan (%ILS). %ILS is the group endpoint. It is calculated as follows:

[0272] %ILS = {[(median treatment lifespan) - (median control lifespan) / (median control lifespan)} * 100

[0274] P values ​​and statistical significance for comparisons of treatment groups (Groups 2-5) to the control group (Group 1) were determined using SigmaPlot 12.5 software.

[0275] result:

[0276] On the first day of treatment, the mean estimated tumor burden for all groups in the study was 9.8 mm 3 , and all groups in the experiment were well matched (group means ranged from 9.7-9.8 mm 3 At the start of treatment, all animals weighed at least 16.1 g. The mean group body weights at the first treatment were also well matched (group mean range 19.0-19.3 g).

[0277] Table 8 reports the median lifespan and %ILS for Groups 2-5.

[0278] Table 8. Median lifespan and percentage increase in lifespan

[0279]

[0280] As shown in Table 8, the treatment groups that received focused radiation (Group 2) and the combination therapy involving Compound A and focused radiation (Groups 4 and 5) experienced a significant increase in lifespan. Although not statistically significant, the treatment groups that received the combination therapy (Groups 4 and 5) experienced a greater increase in lifespan than the group that received focused radiation (Group 2).

[0281] Thus, although in vitro experiments have suggested that administration of mIDH1 inhibitors during radiotherapy desensitizes mIDH1 cells to radiotherapy (RJ Molenaar et al., Cancer Research 75:4790-4802 (2015)), the results shown in Table 8 confirm that the combination of Compound A and radiotherapy did not show an antagonistic effect in vivo in an orthotopic mutant IDH1 glioma brain tumor model.

[0282] This application specifically relates to the following implementation schemes:

[0283] 1. A method for treating glioma in a patient in need thereof, comprising administering to the patient (a) a compound of formula (I)

[0284]

[0285] or a pharmaceutically acceptable salt thereof; and (b) radiation therapy; in an amount effective for treating glioma.

[0286] 2. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and radiation therapy are administered simultaneously.

[0287] 3. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and radiation therapy are administered sequentially.

[0288] 4. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 50 mg / day.

[0289] 5. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 25 mg, 50 mg, 100 mg, 200 mg or 300 mg / administration.

[0290] 6. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 50 mg / administration.

[0291] 7. The method according to embodiment 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day in an amount of about 10 mg / administration.

[0292] 8. The method according to any one of embodiments 1 to 7, wherein the compound of formula (I) is administered in non-salt form.

[0293] 9. The method of any one of embodiments 1 to 8, wherein the radiation therapy is administered in the form of X-ray radiation.

[0294] 10. The method of any one of embodiments 1 to 9, wherein the radiation therapy is administered at a cumulative dose of 30 to 60 Gy.

[0295] 11. The method according to any one of embodiments 1 to 10, wherein the glioma is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in the accumulation of R(-)-2-hydroxyglutarate in the patient.

[0296] 12. The method of embodiment 11, wherein the IDH1 mutation is an R132X mutation.

[0297] 13. The method according to embodiment 11, wherein the IDH1 mutation is a R132H or R132C mutation.

[0298] 14. The method of any one of embodiments 1 to 10, wherein the glioma is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.

[0299] 15. The method of embodiment 14, wherein the IDH2 mutation is an R140X mutation.

[0300] 16. The method of embodiment 14, wherein the IDH2 mutation is a R140Q, R140W or R140L mutation.

[0301] 17. The method of embodiment 14, wherein the IDH2 mutation is an R172X mutation.

[0302] 18. The method of embodiment 14, wherein the IDH2 mutation is a R172K or R172G mutation.

[0303] 19. The method of any one of embodiments 1 to 10, wherein the glioma is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations together lead to accumulation of R(-)-2-hydroxyglutarate in the patient.

[0304] 20. A method for treating glioma in a patient in need thereof, comprising administering to said patient (a) a compound of formula (I)

[0305]

[0306] or a pharmaceutically acceptable salt thereof; and (b) one or more additional therapeutic agents; in an amount effective for treating glioma.

[0307] 21. A method according to embodiment 20, wherein the one or more additional therapeutic agents are DNA-reactive agents.

[0308] 22. A method according to embodiment 21, wherein the DNA-reactive reagent is temozolomide.

[0309] 23. The method according to embodiment 22, wherein the temozolomide is administered at a dosage of 150-200 mg / m based on the body surface area of ​​the patient. 2 The daily dose is administered.

[0310] 24. The method of embodiment 20, wherein the one or more additional therapeutic agents is a PARP inhibitor.

[0311] 25. The method of embodiment 20, wherein the one or more additional therapeutic agents is an antiemetic.

[0312] 26. The method of embodiment 20, wherein the one or more additional therapeutic agents is an anticonvulsant or an anti-epileptic drug.

[0313] 27. The method of embodiment 20, wherein the one or more additional therapeutic agents are checkpoint inhibitors.

[0314] 28. The method of embodiment 20, wherein the one or more additional therapeutic agents is PVC chemotherapy.

[0315] 29. The method of embodiment 20, wherein the one or more additional therapeutic agents is bevacizumab.

[0316] 30. The method of embodiment 20, wherein the one or more additional therapeutic agents is gemcitabine.

[0317] 31. The method according to any one of embodiments 20-30, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are administered simultaneously.

[0318] 32. The method according to any one of embodiments 20-30, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are administered sequentially.

[0319] 33. The method according to any one of embodiments 20-32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 50 mg / day.

[0320] 34. The method according to any one of embodiments 20-32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 25 mg, 50 mg, 100 mg, 200 mg or 300 mg / administration.

[0321] 35. The method according to any one of embodiments 20-32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 50 mg / administration.

[0322] 36. The method according to any one of embodiments 20-32, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 10 mg / administration.

[0323] 37. The method according to any one of embodiments 20 to 36, wherein the compound of formula (I) is administered in non-salt form.

[0324] 38. The method of any one of embodiments 20-37, wherein the glioma is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.

[0325] 39. The method of embodiment 38, wherein the IDH1 mutation is an R132X mutation.

[0326] 40. The method of embodiment 38, wherein the IDH1 mutation is a R132H or R132C mutation.

[0327] 41. The method of any one of embodiments 20-37, wherein the glioma is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.

[0328] 42. The method of embodiment 41, wherein the IDH2 mutation is an R140X mutation.

[0329] 43. The method of embodiment 41, wherein the IDH2 mutation is a R140Q, R140W or R140L mutation.

[0330] 44. The method of embodiment 41, wherein the IDH2 mutation is an R172X mutation.

[0331] 45. The method of embodiment 41, wherein the IDH2 mutation is a R172K or R172G mutation.

[0332] 46. ​​A method according to any one of embodiments 20-37, wherein the glioma is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations together lead to the accumulation of R(-)-2-hydroxyglutarate in the patient.

[0333] 47. A method for treating glioma in a patient in need thereof, comprising administering to said patient (a) a compound of formula (I)

[0334]

[0335] or a pharmaceutically acceptable salt thereof; (b) radiation therapy; and (c) one or more additional therapeutic agents; in an amount effective for treating glioma.

[0336] 48. A method according to embodiment 47, wherein the one or more additional therapeutic agents are DNA-reactive reagents.

[0337] 49. A method according to embodiment 48, wherein the DNA-reactive reagent is temozolomide.

[0338] 50. The method according to embodiment 49, wherein the temozolomide is administered at a dosage of 150-200 mg / m based on the body surface area of ​​the patient. 2 The daily dose is administered.

[0339] 51. The method of embodiment 47, wherein the one or more additional therapeutic agents is a PARP inhibitor.

[0340] 52. The method of embodiment 47, wherein the one or more additional therapeutic agents is an antiemetic.

[0341] 53. The method of embodiment 47, wherein the one or more additional therapeutic agents is an anticonvulsant or an anti-epileptic drug.

[0342] 54. The method of embodiment 47, wherein the one or more additional therapeutic agents are checkpoint inhibitors.

[0343] 55. The method of embodiment 47, wherein the one or more additional therapeutic agents is PVC chemotherapy.

[0344] 56. The method of embodiment 47, wherein the one or more additional therapeutic agents is bevacizumab.

[0345] 57. The method of embodiment 47, wherein the one or more additional therapeutic agents is gemcitabine.

[0346] 58. The method of any one of embodiments 47-57, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, and one or more additional therapeutic agents are administered simultaneously.

[0347] 59. The method according to any one of embodiments 47-57, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof, radiation therapy, and one or more additional therapeutic agents are administered sequentially.

[0348] 60. The method according to any one of embodiments 47-59, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 50 mg / day.

[0349] 61. The method of any one of embodiments 47-59, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 25 mg, 50 mg, 100 mg, 200 mg or 300 mg / administration.

[0350] 62. The method according to any one of embodiments 47-59, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in an amount of about 50 mg / administration.

[0351] 63. The method according to any one of embodiments 47-59, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 10 mg / administration.

[0352] 64. The method according to any one of embodiments 47 to 63, wherein the compound of formula (I) is administered in non-salt form.

[0353] 65. The method of any one of embodiments 47-64, wherein the radiation therapy is administered in the form of X-ray radiation.

[0354] 66. A method according to any one of embodiments 47-65, wherein the radiation therapy is administered at a cumulative dose of 30 to 60 Gy.

[0355] 67. The method of any one of embodiments 47-66, wherein the glioma is characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.

[0356] 68. The method of embodiment 67, wherein the IDH1 mutation is an R132X mutation.

[0357] 69. The method of embodiment 67, wherein the IDH1 mutation is a R132H or R132C mutation.

[0358] 70. The method of any one of embodiments 47-66, wherein the glioma is characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in accumulation of R(-)-2-hydroxyglutarate in the patient.

[0359] 71. The method of embodiment 70, wherein the IDH2 mutation is an R140X mutation.

[0360] 72. The method of embodiment 70, wherein the IDH2 mutation is a R140Q, R140W or R140L mutation.

[0361] 73. The method of embodiment 70, wherein the IDH2 mutation is an R172X mutation.

[0362] 74. The method of embodiment 70, wherein the IDH2 mutation is a R172K or R172G mutation.

[0363] 75. A method according to any one of embodiments 47-66, wherein the glioma is characterized by the presence of an IDH1 mutation and an IDH2 mutation, wherein the IDH1 and IDH2 mutations together lead to accumulation of R(-)-2-hydroxyglutarate in the patient.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of radiotherapy treatment for glioma in a patient in need thereof, wherein the glioma is characterized by the presence of an IDH1 mutation or an IDH2 mutation, wherein the IDH1 mutation or the IDH2 mutation results in the accumulation of R(-)-2-hydroxyglutarate, and wherein the compound of formula (I) is: Wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and radiotherapy are administered simultaneously or sequentially.

2. The use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 50 mg / day.

3. The use according to claim 1, wherein the radiation therapy is administered in the form of X-ray radiation.

4. The use according to claim 1, wherein the radiation therapy is administered at a cumulative dose of 30 to 60 Gy.

5. The use according to claim 1, wherein the IDH1 mutation is an R132X mutation.

6. The use according to claim 5, wherein the IDH1 mutation is R132H or R132C mutation.

7. The use according to claim 1, wherein the IDH2 mutation is R140X or R172X mutation.

8. The use according to claim 7, wherein the IDH2 mutation is R140Q, R140W or R140L mutation.

9. The use according to claim 7, wherein the IDH2 mutation is R172K or R172G mutation.

10. The use according to any one of claims 1 to 9, wherein the compound of formula (I) is administered in non-salt form.

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