JP7093764B2 - How to treat myelodysplastic syndrome - Google Patents

Description

を有する。 Related Applications This application is in the interest of US Provisional Patent Application Nos. 62 / 370,673 filed on August 3, 2016 and No. 62 / 429,649 filed on December 2, 2016. It is alleged that the entire content of each of these is incorporated herein by reference.
Provided herein are methods of treating myelodystrophy syndrome characterized by the presence of a variant allogen of IDH2 and a variant allogen of a second gene, the second gene comprising ASXL1 and SRSF2. Selected from the group, or myelodystrophy syndrome, is characterized by the presence of a variant allogen of IDH2 and the absence of a variant allelic gene of at least one other gene, the other genes being KRAS, TP53, SETBP1 and. Selected from the group consisting of U2AF1, or myelodystrophy syndrome, is characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of the second gene, the second gene from the group consisting of ASXL1 and SRSF2. Be selected. Myelodysplastic syndrome is also characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodystrophy syndrome characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of at least one second gene. Two genes are selected from the group consisting of ASXL1, SRSF2, KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL, or myelodystrophy syndrome is the presence of a variant allogen of IDH2 and at least one other gene. Characterized by the absence of the variant allogen of the gene, other genes are selected from the group consisting of ASXL1, SRSF2, KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF, or myelodystrophy syndrome. Is characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of at least one second gene, the second gene consisting of ASXL1, SRSF2, DNMT3A, MPL, CSF3R, FAT3, and CBL. Is selected from. Myelodysplastic syndrome is also characterized by the absence of a mutant allele of at least one other gene, the other gene being a group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Is selected from. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. Gene is selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Also provided herein is Compound 1 for use in such methods of treating myelodysplastic syndrome, wherein Compound 1 is 2-methyl-1-[(4- [6- (trifluoromethyl) pyridine). -2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5-triazine-2-yl) amino] propane-2-ol or its pharmaceutically Acceptable salts, solvates, tautomers, stereoisomers, isotope molecular species, prodrugs, metabolites, or polymorphs. 2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) amino] propane-2-ol is expressed by the following formula:

Have.

Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitric acid to 2-oxoglutaric acid (ie, α-ketoglutaric acid). These enzymes belong to two different subclasses, one utilizing NAD (+) as an electron acceptor and the other utilizing NADP (+). Five isocitrate dehydrogenases have been reported, three of which are NAD (+) -dependent isocitrate dehydrogenases localized in the mitochondrial matrix and two of which are NADP (+) -dependent isocitrate dehydrogenases. One is mitochondrial type and the other is mainly cytosol type. Each NADP (+) -dependent isozyme is a homodimer.

IDH2 (isocitrate dehydrogenase 2 (NADP +), mitochondrial type) is also known as IDH, IDP, IDHM, IDPM, ICD-M, or mNADP-IDH. The protein encoded by this gene is the NADP (+) -dependent isocitrate dehydrogenase found in mitochondria. It is involved in intermediate metabolism and energy production. This protein may be closely associated with or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein consisting of 452 amino acids. The nucleotide sequence and amino acid sequence of IDH2 can be recognized as GenBank registration numbers NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences of human IDH2 are also described, for example, in Huh et al. , Submitted (NOV-1922) to the EMBL / GenBank / DDBJ databases, and The MGC Project Team, Genome Res. It is also described in 14: 2121-2127 (2004).

Non-mutants, such as wild-type IDH2, can, for example, in a positive reaction, NADH (NADP ⁺ ) by catalyzing the oxidative decarboxylation of isocitric acid to α-ketoglutaric acid (α-KG) ^. Reduce to NADPH):
Isocitric acid + NAD ⁺ (NADP ⁺ ) → α-KG + CO ₂ + NADH (NADPH) + H ⁺ .

It was discovered that mutations in IDH2 present in certain cancer cells lead to a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutaric acid to R (-) -2-hydroxyglutarate (2HG). Was done. 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 462: 739-44, 2009).

The development of selective inhibitors of IDH2 mutant enzymes has provided potential therapeutic benefits for cancer patients with IDH2 mutations. Improved therapies are needed to treat cancer patients with IDH2 mutations.

を有する。 In the present specification, 2-methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino}- 1,3,5-Triazine-2-yl) amino] propane-2-ol or a pharmaceutically acceptable salt thereof, a solvate, a metabolite, a stereoisomer, an isotope molecular species, a prodrug, Compound 1 is provided, which is a metabolite or a polymorph. 2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) amino] propane-2-ol is expressed by the following formula:

Have.

In the present specification, 2-methyl-1-[(4- [6- (trifluoromethyl) pyridine-2-yl] -6-{[2- (trifluoromethyl) pyridine-4-yl] amino}- Compound A, which is a mesylate salt of 1,3,5-triazine-2-yl) amino] propane-2-ol, is provided.

In certain embodiments, as used herein, a therapeutically effective amount of 2-methyl-1-[(4- [6- (trifluoromethyl) pyridine-2-yl] -6-{[2- (tri)) is given to the subject. Fluoromethyl) pyridine-4-yl] amino} -1,3,5-triazine-2-yl) amino] propan-2-ol or a pharmaceutically acceptable salt thereof, a solvent, a tautomer, A method of treating myelodysplastic syndrome in a subject comprising administering a steric isomer, an isotope molecular species, a prodrug, a metabolite, or a polymorph (Compound 1) is provided, wherein the myelodysplastic syndrome is IDH2. The second gene is selected from the group consisting of ASXL1 and SRSF2, characterized by the presence of the variant allogen of the gene and the variant allogen of the second gene. Accordingly, herein, compound 1 is provided for use in a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of the compound 1. Characterized by the presence of a mutant allele of IDH2 and a mutant allele of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of the second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of at least one other gene. Characterized by the absence of a gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. Accordingly, herein, compound 1 is provided for use in a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, which is described as Myelodysplastic Syndrome. Characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is at least one other gene. Characterized by the absence of the variant allogen of the gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and the absence of mutant allogens of at least one other gene, the other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. Accordingly, provided herein is a compound 1 for use in a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of the compound 1. Characterized by the presence of a mutant allelic gene for IDH2 and the absence of a mutant allelic gene for at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome, characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. The gene 2 is selected from the group consisting of ASXL1, SRSF2, KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL. Accordingly, herein, compound 1 for use in the method of treating myelodysplastic syndrome, characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. The second gene provided is selected from the group consisting of ASXL1, SRSF2, KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome, characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Other genes are selected from the group consisting of ASXL1, SRSF2, KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Accordingly, in the present specification, compound 1 for use in the method of treating myelodysplastic syndrome, characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Is provided, and other genes are selected from the group consisting of ASXL1, SRSF2, KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome, wherein the myelodysplastic syndrome is the presence of a variant allogen of IDH2 and a variant allelic gene of at least one second gene. The second gene is selected from the group consisting of ASXL1, SRSF2, DNMT3A, MPL, CSF3R, FAT3, and CBL, and myelodysplastic syndrome is the absence of a variant allogen of at least one other gene. The other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Accordingly, herein, compound 1 is provided for use in that method of treating myelodysplastic syndrome, where myelodysplastic syndrome is a variant of the IDH2 variant allelic gene and a variant of at least one second gene. Characterized by the presence of allelic genes, the second gene is selected from the group consisting of ASXL1, SRSF2, DNMT3A, MPL, CSF3R, FAT3, and CBL, and myelodysplastic syndrome is a variant of at least one other gene. Characterized by the absence of allelic genes, the other genes are selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. Gene is selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL. Accordingly, provided herein is Compound 1 for use in the method of treating myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. The second gene is selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Accordingly, herein, compound 1 for use in the method of treating myelodysplastic syndrome, characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. The other genes provided are selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R140 or mIDH2-R172.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140Q, mIDH2-R140W, mIDH2-R140L, mIDH2-R172K, or mIDH2-R172G.

It is an X-ray powder diffractogram of compound 1 form 1.

It is an X-ray powder diffractogram of compound 1 form 2.

It is an X-ray powder diffractogram of compound 1 form 3.

It is an X-ray powder diffractogram of compound 1 form 4.

It is an X-ray powder diffractogram of compound 1 form 5.

It is an X-ray powder diffractogram of compound 1 form 6.

It is an X-ray powder angstrom of compound A form 3.

The duration of treatment, first response, time to best response, and test results for the study of Compound A monotherapy in patients with MDS and mIDH2 are shown.

The most frequently co-occurring known somatic gene mutations selected by response for the study of Compound A monotherapy in patients with MDS and mIDH2 are shown.

The treatment period and test results for the study of compound A monotherapy in patients with MDS and IDH2 mutant alleles are shown.

Overall survival is shown for a study of compound A monotherapy in patients with MDS and IDH2 mutant alleles.

Shown are co-occurring somatic gene mutations and clinical responses for testing Compound A monotherapy in MDS patients with IDH2 mutant alleles. Fill tiles indicate the presence of mutations and tiles of different colors are used to highlight the mutations associated with response: green = response, and red = no response.

The frequency of co-mutation in MDS patients with the IDH2 mutant allele is shown.

The details of the configurations and the arrangement of the components described in the following description or shown in the drawings are not meant to be limited. Explicitly include other embodiments and different methods for carrying out the methods and compounds. Also, the expressions and terms used herein are for illustration purposes only and should not be considered limiting. The use of "inclusion," "comprising," or "having," "contining," "involving," and variations thereof herein is thereafter. Means to include the items listed in and their equivalents as well as additional items.

Definitions As used herein, the terms "comprising" and "inclating" may be used interchangeably. The terms "comprising" and "inclusion" are to be construed as specifying the existence of a described feature or component as referred to, but one or more features or components. , Or the existence or addition of those groups is not excluded. Further, the terms "comprising" and "inclusion" are intended to include examples encapsulated by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "inclusion" to provide more specific embodiments.

The term "consisting of" means that an object has at least 90%, 95%, 97%, 98%, or 99% of the described features or components that make up it. do. In another embodiment, the term "consisting of" is any other feature or configuration from the scope of any subsequent description, except that it is not essential for the technical effect to be achieved. Exclude the element.

As used herein, the term "or" is construed as a comprehensive "or" meaning any one or any combination. Therefore, "A, B, or C" means any of the following "A, B, C, A and B, A and C, B and C, A and B and C". Exceptions to this definition only occur if the combination of elements, functions, steps, or actions is somehow essentially mutually exclusive.

As used herein, the term "wild-type" is typical or most common of naturally occurring features (eg, gene sequences or beings, or protein sequences, beings, levels, or activities). Refers to a morphology, and a reference to which all others are compared. As will be appreciated by those of skill in the art, wild-type, as used herein, refers to the most commonly occurring, typical gene sequence (s) or gene expression levels in nature.

The term "elevated 2HG level" is more than 10%, 20%, 30%, 50%, 75%, 100%, 200%, 500% more than present in subjects without the mutant IDH2 allele. 2HG is present in a subject carrying the mutant IDH2 allele. The term "elevated 2HG level" can refer to the amount of 2HG in cells, intratumor, organs containing tumors, or body fluids.

The term "body fluid" refers to sheep water, tufts, blood (eg plasma), serum, cerebrospinal fluid, ear stains, keems, cowper gland fluid, vaginal fluid, interstitial fluid, lymph fluid, breast milk, mucus (eg, plasma) that wraps the fetus. , Nasal or sputum), pleural effusion, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal discharge, or vaginal discharge.

The terms "inhibit" or "prevent" include both full and partial inhibition and prevention. Inhibitors can completely or partially inhibit the intended target.

The term "subject" is intended to include humans and non-human animals. Exemplary human subjects include disabilities, such as human patients (referred to as patients) or normal subjects with the disabilities described herein. The term "non-human animal" in one embodiment refers to all vertebrates such as non-mammals (chicken, amphoteric, reptiles, etc.) and non-human primates, reared and / or agricultural animals such as sheep, dogs, etc. Includes mammals such as cats, cows and pigs. In one aspect, the patient is an adult patient.

The term "treat" refers to myelodysplastic syndrome (MDS) characterized by the presence of a disease / disorder (eg, a variant allogen of IDH2 and a second gene, eg, a variant allogen of ASXL1 and SRSF2). , Or myelodysplastic syndrome, characterized by the presence of a variant allogen of IDH2 and the absence of a variant allogen of at least one other gene selected from the group consisting of KRAS, TP53, SETBP1, and U2AF1. Or the presence of a variant allogen of IDH2 and a second gene, eg, a variant allelic of ASXL1 and SRSF2, and mutations of at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. Reduces, suppresses, alleviates, reduces, arrests, or stabilizes the onset or progression of (myelodysplastic syndrome), characterized by the absence of allogeneic genes, reduces the severity of the disease / disorder, or the disease / disorder Means to improve the symptoms associated with.

Amounts of compounds, including pharmaceutically acceptable salts, admixtures, tethers, steric isomers, isotope molecular species, prodrugs, or polymorphs that are effective in treating the disorder, or A "therapeutically effective dose" or "therapeutically effective dose" is the failure of such treatment in treating, alleviating, alleviating, or ameliorating a subject with cells or a disordered subject upon administration of a single or multiple doses to the subject. Of a compound, including its pharmaceutically acceptable salts, solvates, tautomers, steric isomers, isotope molecular species, prodrugs, or polymorphs that are more effective than currently expected. Refers to the quantity.

As used herein, the term "substantially free of other stereoisomers" is at least about 60%, 65% of compounds having a selected stereochemistry in one or more selected stereocenters. , 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% enriched preparations.

The term "enrichment" means that at least a specified percentage of the preparation is a compound having the selected stereochemistry at one or more selected stereocenters.

The term "crystalline" refers to a solid with a highly regular chemical structure. In particular, crystalline compound 1 can be produced as one or more single crystal forms of compound 1. For the purposes of this application, the terms "crystal morphology", "single crystal morphology", and "polymorph" are synonyms, and the terms have different properties (eg, different XRPD patterns and / or different DSC scans). Results) to distinguish crystals with. The term "polymorph" includes quasi-polymorphs, which are typically solvates of different materials and therefore have different properties from each other. Therefore, each separate polymorph and pseudopolymorph of Compound 1 is considered herein as a separate single crystal form.

The term "substantially crystalline" refers to a form that can be at least a particular weight percent crystalline. Specific weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%. , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage from 10% to 100%. In some embodiments, substantially crystalline compound 1 refers to compound 1 which is at least 70% crystalline. In other embodiments, substantially crystalline compound 1 refers to compound 1 which is at least 90% crystalline.

The term "isolated" refers to a form that can be a particular crystalline form of at least a particular weight percent of a compound. Specific weight percentages range from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 90%. Any percentage of 100%.

The term "solvate or solvate" means the physical association of one or more solvent molecules with a compound comprising its crystalline form, provided herein. This physical association involves hydrogen bonds. In certain examples, the solvate could be isolated, for example, if one or more solvent molecules are incorporated into the crystalline lattice of a crystalline solid. "Solvate or solvate" includes both solution phase solvates and separable solvates. Representative solvates include, for example, hydrates, ethanolates, or metanolates.

The term "hydrate" is a solvent mixture in which the solvent molecule is _H2O present in a defined amount of chemical quantity, eg, hemihydrate, monohydrate, dihydrate, etc. Or it may contain trihydrate.

The term "mixture" is used to refer to the combined elements of a mixture, regardless of the phase state of the combination (eg, liquid or liquid / crystal).

The term "seeding" is used to refer to the addition of crystalline material to initiate recrystallization or crystallization.

The term "poor solvent" is used to refer to a solvent in which the compound containing its crystalline form is sparingly soluble.

The term "pharmaceutically acceptable carrier or adjuvant" refers to its pharmacological activity when administered to a subject with a compound of one embodiment and at a dose sufficient to deliver a therapeutic amount of the compound. Refers to a carrier or adjuvant that is intact and non-toxic.

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid or base addition salt of the compound referred to by the term. Examples of pharmaceutically acceptable salts are described in Berge et al. , 1977, "Pharmaceutically Accptable Salts." J. Mol. Pharm. Sci. Vol. 66, pp. Considered in 1-19. In one embodiment, the pharmaceutically acceptable salt is a mesylate salt.

The term "about" means approximately within that range, roughly, or before or after. When the term "about" is used with a numerical range, it modifies the range by extending the boundary above and below the stated numerical value. In general, the term "about" is used herein to modify a number above and below the value indicated by a 10% variance. As used herein, and unless otherwise specified, the terms "about" and "approximately" are values or ranges of values provided to characterize a particular solid form, such as, for example, melting, dehydration. , Desolvination, or solvent in terms of mass change, eg, mass or percentage, such as mass change as a function of temperature or humidity, such as those describing a glass transition temperature. Alternatively, when used in connection with the water content, or, for example, in the analysis by IR or Raman spectroscopy or XRPD, the value or range of values still describes the solid form, while still describing the solid form. Show that it can deviate to the extent that it is considered reasonable to those skilled in the art. Techniques for characterizing crystal morphology and amorphous solids include thermal weight analysis (TGA), differential scanning calorific value measurement (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and vibration spectroscopy. For example, infrared (IR) and Raman spectroscopy, solid state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hotstage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis. , Particle size analysis (PSA), surface area analysis, solubility test, and dissolution test, but are not limited thereto. In certain embodiments, the terms "about" and "approximately", when used in this context, indicate that the value or range of values is 30%, 20%, 15% of the listed value or range of values. Can vary within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% Show that. For example, in some embodiments, the value of the XRPD peak position can fluctuate up to ± 0.1 ° 2θ (or ± 0.2 ° 2θ), still explaining the particular XRPD peak.

を有する、２－メチル－１－［（４－［６－（トリフルオロメチル）ピリジン－２－イル］－６－｛［２－（トリフルオロメチル）ピリジン－４－イル］アミノ｝－１，３，５－トリアジン－２－イル）アミノ］プロパン－２－オール、またはその薬学的に許容される塩、溶媒和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、代謝産物、もしくは多形体である。 Compound 1
In one embodiment, compound 1 has the following formula:

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1, 3,5-Triazine-2-yl) amino] propane-2-ol or a pharmaceutically acceptable salt thereof, a solvate, a metabolite, a stereoisomer, an isotope molecular species, a prodrug, a metabolism. It is a product or a polymorph.

Compound 1 may also contain one or more isotope substitutions (“isotope molecular species”). For example, H can be any isotopic form, including ¹ H, ² H (D or deuterium), and ³ H (T or tritium), and C can be ¹² C, ¹³ C, and ¹⁴ C. Can be any isotope form, including, and O can be any isotope form, including ¹⁶ O and ¹⁸ O. For example, compound 1 contains at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, specific isotopic forms of H, C, and / or O. Enriched by 97%, 98%, or 99%.

Compound 1 in a particular embodiment may also be represented in multiple tautomeric forms, in such examples where only a single tautomeric form may be represented (eg, keto-enol tautomer). ), One embodiment explicitly includes all tautomeric forms of compound 1 described herein. All such isomeric forms of Compound 1 are expressly included herein. The synthesis of Compound 1 is described in US Patent Application Publication No. US2013 / 0190287 (A1) published July 25, 2013, which is incorporated herein by reference in its entirety.

It may be convenient or desirable to prepare, purify, and / or process the corresponding salt of compound 1, eg, a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are described in Berge et al. , 1977, "Pharmaceutically Accptable Salts." J. Mol. Pharm. Sci. Vol. 66, pp. Considered in 1-19.

For example, if compound 1 is anionic or has a functional group that can be anionic (eg, -NH- can be -N-- ⁾ , the salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Al ³⁺ . Examples of some suitable substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumin, and tromethamine, as well as lysine and Some are derived from amino acids such as arginine. An example of a common quaternary ammonium ion is ^N (CH ₃ ) ₄₊ .

If compound 1 is cationic or has a functional group that can be cationic (eg, -NHR can be -NH ₂ R ⁺ ), the salt can be formed with a suitable anion. Examples of suitable inorganic anions include those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodide, sulfuric acid, sulfite, nitrate, nitrite, phosphoric acid, and phosphoric acid. , Not limited to these.

Examples of suitable organic anions include the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, asparagic acid, benzoic acid, camphorsulfonic acid, silica skin acid, citric acid, edetonic acid, ethandisulfonic acid, ethane. Sulphonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mutinic acid, Derived from oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvate, salicylic acid, stearic acid, succinic acid, sulfanic acid, tartrate acid, toluenesulfonic acid, and valeric acid. However, it is not limited to these. In one embodiment, compound 1 is 2-methyl-1-[(4- [6- (trifluoromethyl) pyridine-2-yl] -6-{[2- (trifluoromethyl) pyridine-4-yl]. ] Amino} -1,3,5-triazine-2-yl) Amino] Propane-2-ol contains a mesylate salt (Compound A). Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Compound 1 for use in the methods and pharmaceutical compositions provided herein is therefore compound 1 itself and its pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof. , Isomeric molecular species, prodrugs, metabolites, or polymorphs. The metabolites of Compound 1 are disclosed in Japanese Patent Application Publication No. WO2015 / 006592, which is incorporated herein by reference in its entirety. Compound 1 provided herein can be modified and converted to a prodrug by adding appropriate functionality to improve selected biological properties, eg, targeting to a particular tissue. .. Such modifications (ie, prodrugs) are known in the art and increase biological penetration into a given biological compartment (eg, blood, lymphatic system, central nervous system). Includes those that increase the possibility of oral administration, those that increase the solubility that allows administration by injection, those that alter metabolism, and those that alter excretion rates. Examples of prodrugs include esters (eg, phosphoric acid, amino acids (eg, valine) esters), carbamate, and other pharmaceutically acceptable derivatives capable of providing the active compound after administration to a subject. Be done.

It has been found that compound 1 can be present in various solid forms. In one embodiment, a solid form is provided herein, including a neat crystalline form. In another embodiment, the present specification provides solid forms, including solvated and amorphous forms. The present disclosure provides a particular solid form of compound 1. In certain embodiments, the present disclosure provides a composition comprising Compound 1 in the form described herein. In some embodiments of the provided composition, compound 1 is present as a mixture in one or more solid forms, and in some embodiments of the provided composition, compound 1 is in a single form. Exists in.

In one embodiment, compound 1 is either a single crystal form or one of the single crystal forms described herein. The synthesis of the crystalline form of Compound 1 is incorporated herein by reference in its entirety, International Patent Application Publication No. WO 2015/017821 published on February 5, 2015 and published August 11, 2016. It is described in International Patent Application No. WO2016 / 126798. Pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier or diluent and compound 1 are also provided, wherein compound 1 is either in single crystal form or in crystalline form as described herein. It is one. The use of compound 1 for preparing pharmaceutical compositions is also provided, wherein compound 1 is either in single crystal form or in one of the single crystal forms described herein.

Provided herein is a combination of characterization information for describing the crystalline morphology of Compound 1. However, one of ordinary skill in the art will not need all such information to determine that such a particular form is present in a given composition, and one of ordinary skill in the art will confirm the existence of the particular form. Any part of the characterization information that will be recognized as sufficient for can be used to achieve a particular morphological determination, for example even a single characteristic peak, such as this. It should be understood that it may be sufficient for one of ordinary skill in the art to recognize the existence of a particular form.

In one embodiment, at least a particular weight percentage of compound 1 is crystalline. Specific weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%. , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage from 10% to 100%. If a particular weight percentage of compound 1 is crystalline, the rest of compound 1 is in the amorphous form of compound 1. Non-limiting examples of crystalline compound 1 include single crystal forms of compound 1 or mixtures of different single crystal forms. In some embodiments, compound 1 is at least 90% by weight crystalline. In some other embodiments, compound 1 is at least 95% by weight crystalline.

In another embodiment, a particular weight percentage of crystalline compound 1 refers to a particular weight percentage of a particular single crystal form or a combination of single crystal forms. Specific weight percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%. , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage from 10% to 100%. In another embodiment, compound 1 is in at least 90% by weight single crystal form. In another embodiment, compound 1 is in at least 95% by weight single crystal form.

In the following description of Compound 1, embodiments may be described with reference to specific crystalline forms of Compound 1, characterized by one or more of the properties discussed herein. The description characterizing the crystalline morphology can also be used to describe a mixture of different crystalline morphologies that may be present in the crystalline compound 1. However, a particular crystalline form of compound 1 may also be characterized by one or more of the crystalline morphological features described herein with or without reference to a particular crystalline morphology.

The crystal morphology will be further described by the detailed description and exemplary examples described below. The XRPD peaks listed in Tables 1-6a can vary by ± 0.2 ° depending on the equipment used to acquire the data. The intensities of the XRPD peaks listed in Tables 1-6a can vary by 10%.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 1
In one embodiment, a single crystal form of compound 1, form 1 features the X-ray powder diffraction (XRPD) pattern shown in FIG. 1 and the data shown in Table 1 obtained using CuKα radiation. .. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 1, as shown in Table 1. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 1.
Table 1

In another embodiment, embodiment 1 may feature peaks identified at 2θ angles of 8.9, 13.0, 18.9, 23.8, and 28.1 °. In another embodiment, embodiment 1 may feature peaks identified at 2θ angles of 8.9, 18.9, and 23.8 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 2
In one embodiment, the single crystal form of compound 1, form 2 is characterized by the XRPD pattern shown in FIG. 2 and the data shown in Table 2 obtained using CuKα radiation. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 2, as shown in Table 2. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 2.
Table 2

In another embodiment, embodiment 2 may feature peaks identified at 2θ angles of 12.7, 17.1, 19.2, 23.0, and 24.2 °. In another embodiment, embodiment 2 may feature peaks identified at 2θ angles of 12.7, 19.2, and 24.2 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 3
In one embodiment, a single crystal form of compound 1, form 3 is characterized by the XRPD pattern shown in FIG. 3 and the data shown in Table 3 obtained using CuKα radiation. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 3, as shown in Table 3. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 3.
Table 3

In another embodiment, embodiment 3 may feature peaks identified at 2θ angles of 6.8, 10.6, 13.6, 14.2, and 19.2 °. In another embodiment, embodiment 3 may feature peaks identified at 2θ angles of 10.6, 14.2, and 19.2 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 4
In one embodiment, a single crystal form of compound 1, form 4 is characterized by the XRPD pattern shown in FIG. 4 and the data shown in Table 4 obtained using CuKα radiation. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 4, as shown in Table 4. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 4.
Table 4

In another embodiment, embodiment 4 may feature peaks identified at 2θ angles of 7.2, 13.6, 18.5, 19.3, 21.9, and 23.5 °. In another embodiment, embodiment 4 may feature peaks identified at 2θ angles of 13.6, 18.5, and 23.5 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 5
In one embodiment, a single crystal form of compound 1, form 5 is characterized by the XRPD pattern shown in FIG. 5 and the data shown in Table 5 obtained using CuKα radiation. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 5, as shown in Table 5. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 5.
Table 5

In another embodiment, embodiment 5 may feature peaks identified at 2θ angles of 6.4, 8.4, 9.8, 17.8, and 19.7 °. In another embodiment, embodiment 5 may be characterized by peaks identified at 2θ angles of 8.4 and 9.8 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) Amino] Propane-2-ol Form 6
In one embodiment, a single crystal form of compound 1, form 6 is characterized by the XRPD pattern shown in FIG. 6 and the data shown in Table 6 obtained using CuKα radiation. In certain embodiments, the polymorph may be characterized by one or more of the peaks obtained from FIG. 6, as shown in Table 6. For example, the polymorph may be characterized by one or two or three or four or five or six or seven or eight of the peaks shown in Table 6.
Table 6

In another embodiment, embodiment 6 may feature peaks identified at 2θ angles of 8.1, 14.1, 16.4, 17.3, 20.5, and 24.1 °. In another embodiment, embodiment 6 may be characterized by peaks identified at 2θ angles of 8.1, 16.4, 17.3, and 24.1 °.

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3,5 -Triazine-2-yl) amino] Propane-2-ol mesylate salt form 3 (Compound A)
In one embodiment, 2-methyl-1- [(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl]] methanesulfonic acid Form 3 of amino} -1,3,5-triazine-2-yl) amino] propane-2-ol is an X-ray powder diffraction (XRPD) pattern shown in FIG. 7 obtained using CuKα radiation. , And the data shown in Table A. In certain embodiments, the polymorph is characterized by one or more of the peaks obtained from FIG. 7, as shown in Table A. For example, polymorphs are characterized by one or two or three or four or five or six or seven or eight or nine or ten of the peaks shown in Table A.
Table A

In another embodiment, Form 3 features peaks identified at 2θ angles of 7.5, 9.3, 14.5, 18.8, 21.3, and 24.8 °. In a further embodiment, Form 3 features peaks identified at 2θ angles of 7.5, 14.5, 18.8, and 24.8 °. In another embodiment, Form 3 features peaks identified at 2θ angles of 7.5, 14.5, and 24.8 °.

Compositions and Routes of Administration In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a mutant IDH2 inhibitor is provided herein. In one embodiment, the mutant IDH2 inhibitor is compound 1.

In one embodiment, the compounds utilized in the methods provided herein are formulated into a pharmaceutically acceptable composition with a pharmaceutically acceptable carrier or adjuvant prior to administration to the subject. obtain. In another embodiment, such a pharmaceutically acceptable composition comprises an additional therapeutic agent in an amount effective to achieve control of the disease or disease symptoms, including those described herein. Further included.

The pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in one aspect of the pharmaceutical composition are, but are not limited to, ion exchangers, aluminas, aluminum stearate, lecithin, d-α-tocopherol succinic acid. Surfactants used in pharmaceutical dosage forms such as self-emulsifying drug delivery systems (SEDDS) such as polyethylene glycol acid 1000, TWEEN or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffers such as , Phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salts, or polymers such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts. , Colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives are also available. It can be advantageously used to improve the delivery of the compound 1 described herein.

In one embodiment, the pharmaceutical composition comprises compound 1 and an excipient. In one embodiment, the pharmaceutical composition comprising Compound 1 and the excipient is for oral administration. In one embodiment, the excipient is a diluent, binder, disintegrant, wetting agent, stabilizer, flow enhancer, or lubricant.

In one embodiment, the diluent is microcrystalline cellulose.

In one embodiment, the binder is hydroxypropyl cellulose.

In one embodiment, the disintegrant is sodium starch glycolate.

In one embodiment, the wetting agent is sodium lauryl sulfate.

In one embodiment, the stabilizer is hypromellose acetate succinate.

In one embodiment, the flow accelerator is colloidal silicon dioxide.

In one embodiment, the lubricant is magnesium stearate.

The oral delivery form of Compound 1 includes, but is not limited to, tablets, capsules, caplets, solutions, suspensions, and multiple granules, beads, powders, or may or may not be encapsulated. Pellets may also be included. Such a form may also be referred to herein as a "drug core" containing compound 1.

Certain embodiments herein provide solid oral dosage forms that are tablets or capsules. In certain embodiments, the pharmaceutical product is a tablet containing compound 1. In certain embodiments, the pharmaceutical product is a capsule containing compound 1. In certain embodiments, the tablets or capsules provided herein are optionally such as flow promoters, diluents, lubricants, colorants, disintegrants, granulators, binders, polymers, and coatings. Contains one or more excipients such as agents. In certain embodiments, the pharmaceutical product is an immediate release tablet. In certain embodiments, the pharmaceutical product is a controlled release tablet that releases the active ingredient (API), eg, substantially in the stomach. In certain embodiments, the formulation is a hard gelatin capsule. In certain embodiments, the formulation is a soft gelatin capsule. In certain embodiments, the capsule is a hydroxypropylmethylcellulose (HPMC) capsule. In certain embodiments, the pharmaceutical product is an immediate release capsule. In certain embodiments, the pharmaceutical product is an immediate or controlled release capsule that releases the API, eg, substantially in the stomach. In certain embodiments, the pharmaceutical product is a fast-disintegrating tablet that dissolves substantially by mouth after administration. The specific embodiments provided herein comprise the use of compound 1 for the preparation of a pharmaceutical composition for treating myelodysplastic syndrome in a subject, where myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of a somatic allogen and a variant allogen of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2 and the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1 and. Selected from the group consisting of U2AF1, the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of the second gene, the second gene being selected from the group consisting of ASXL1 and SRSF2. Myelodysplastic syndrome is characterized by the absence of a mutant allelic gene of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1, the composition for oral administration. Prepared for. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene, the second gene being ASXL1, SRSF2, KRAS, DNMT3A. , MPL, CSF3R, FAT3, and CBL, the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene, the other genes being ASXL1, SRSF2, KRAS, TP53. , SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF, the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a variant allogen of IDH2 and a variant allelic gene of at least one second gene, the second gene being ASXL1, SRSF2, DNMT3A, MPL. , CSF3R, FAT3, and CBL, myelodysplastic syndrome is characterized by the absence of a mutant allelic gene of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, Selected from the group consisting of TCF3, STAG2, NRAS, JAK2, and BRAF, the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene, the second gene being MPL, DNMT3A, CSF3R, FAT3. , Or selected from the group consisting of CBL, the composition is prepared for oral administration. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene, the other genes being TP53, SETBP1, U2AF1, TCF3. , STAG2, NRAS, JAK2, and BRAF, the composition is prepared for oral administration.

A particular embodiment herein is a compound 1 that achieves a particular AUC value (eg, AUC (0-t) or AUC (0-∞)) in a subject (eg, human) to which the formulation is orally administered. Provided are pharmaceutical formulations comprising (eg, immediate release oral formulations and / or formulations that substantially release the API in the stomach). Specific embodiments are at least about 25 ng-hr / mL, at least about 50 ng-hr / mL, at least about 75 ng-hr / mL, at least about 100 ng-hr / mL, at least about 150 ng-hr / mL, at least about 200 ng-. hr / mL, at least about 250 ng-hr / mL, at least about 300 ng-hr / mL, at least about 350 ng-hr / mL, at least about 400 ng-hr / mL, at least about 450 ng-hr / mL, at least about 500 ng-hr / mL, at least about 550 ng-hr / mL, at least about 600 ng-hr / mL, at least about 650 ng-hr / mL, at least about 700 ng-hr / mL, at least about 750 ng-hr / mL, at least about 800 ng-hr / mL, At least about 850 ng-hr / mL, at least about 900 ng-hr / mL, at least about 950 ng-hr / mL, at least about 1000 ng-hr / mL, at least about 1100 ng-hr / mL, at least about 1200 ng-hr / mL, at least about about. 1300 ng-hr / mL, at least about 1400 ng-hr / mL, at least about 1500 ng-hr / mL, at least about 1600 ng-hr / mL, at least about 1700 ng-hr / mL, at least about 1800 ng-hr / mL, at least about 1900 ng- Provided are oral formulations that achieve AUC values of hr / mL, at least about 2000 ng-hr / mL, at least about 2250 ng-hr / mL, or at least about 2500 ng-hr / mL. In certain embodiments, the AUC determination is obtained from a time-concentration pharmacokinetic profile obtained from a blood sample of an animal or human volunteer after administration.

A particular embodiment herein is a pharmaceutical formulation (eg, immediate release oral formulation and / or API) comprising compound 1 that achieves a particular maximum plasma concentration (“Cmax”) in the subject to which the formulation is orally administered. A formulation that is substantially released in the stomach). Specific embodiments are at least about 25 ng / mL, at least about 50 ng / mL, at least about 75 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 250 ng / mL, at least about about. 300 ng / mL, at least about 350 ng / mL, at least about 400 ng / mL, at least about 450 ng / mL, at least about 500 ng / mL, at least about 550 ng / mL, at least about 600 ng / mL, at least about 650 ng / mL, at least about 700 ng / mL mL, at least about 750 ng / mL, at least about 800 ng / mL, at least about 850 ng / mL, at least about 900 ng / mL, at least about 950 ng / mL, at least about 1000 ng / mL, at least about 1100 ng / mL, at least about 1200 ng / mL, At least about 1300 ng / mL, at least about 1400 ng / mL, at least about 1500 ng / mL, at least about 1600 ng / mL, at least about 1700 ng / mL, at least about 1800 ng / mL, at least about 1900 ng / mL, at least about 2000 ng / mL, at least about about. Provided are oral formulations that achieve a Cmax of compound 1 of 2250 ng / mL, or at least about 2500 ng / mL.

A particular embodiment herein is a pharmaceutical formulation comprising compound 1 that achieves a particular maximum plasma concentration arrival time (“Tmax”) in a subject to which the formulation is orally administered (eg, an immediate release oral formulation and / or. Alternatively, a preparation that releases API substantially in the stomach) is provided. Specific embodiments are less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes. Less than about 55 minutes, less than about 60 minutes, less than about 65 minutes, less than about 70 minutes, less than about 75 minutes, less than about 80 minutes, less than about 85 minutes, less than about 90 minutes, less than about 95 minutes, less than about 100 minutes Less than about 105 minutes, less than about 110 minutes, less than about 115 minutes, less than about 120 minutes, less than about 130 minutes, less than about 140 minutes, less than about 150 minutes, less than about 160 minutes, less than about 170 minutes, less than about 180 minutes Provided is an oral preparation that achieves the Tmax of compound 1 of less than about 190 minutes, less than about 200 minutes, less than about 210 minutes, less than about 220 minutes, less than about 230 minutes, or less than about 240 minutes. In certain embodiments, the Tmax value is measured from the time the pharmaceutical product is orally administered.

Certain embodiments herein provide an oral dosage form comprising Compound 1, the oral dosage form having an enteric coating. Certain embodiments provide a permeable or partially permeable (eg, "leaky") enteric coating with pores. In certain embodiments, the permeable or partially permeable enteric coated tablet releases compound 1 substantially in the stomach in an immediate release mode.

Provided herein are dosage forms designed to maximize absorption and / or effective delivery of Compound 1 upon oral administration, eg, for release substantially in the stomach. Accordingly, certain embodiments herein provide, for example, a solid oral dosage form of Compound 1 using a pharmaceutical excipient designed for immediate release of API upon oral administration, substantially in the stomach. do. The particular immediate release formulation comprises a particular amount of compound 1 and optionally one or more excipients. In certain embodiments, the pharmaceutical product can be an immediate release tablet or an immediate release capsule (eg, HPMC capsule).

In the present specification, there is a method for making a preparation provided herein (eg, an immediate release oral preparation and / or a preparation which substantially releases API in the stomach) containing the compound 1 provided herein. Provided. In certain embodiments, the formulations provided herein can be prepared using, for example, conventional methods known to those of skill in the art of pharmaceutical formulations, as described in the relevant texts. For example, Remington, The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams & Wilkins, (2000), Ansel et al. , Pharmaceutical Dose Form and Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, (1999), Gibson, Pharmaceutical Press (1999), Gibson, Pharmaceutical Press.

In certain embodiments, the formulations provided herein (eg, an immediate release oral formulation, a formulation that releases the API substantially in the stomach, or a fast disintegrating formulation that dissolves substantially in the mouth) are compound 1. Is included in a specific amount. In a particular embodiment, the particular amount of compound 1 in the formulation is, for example, about 10 mg. In one embodiment, the specific amount is about 20 mg. In one embodiment, the specific amount is about 40 mg. In one embodiment, the specific amount is about 60 mg. In one embodiment, the specific amount is about 80 mg. In one embodiment, the specific amount is about 100 mg. In one embodiment, the specific amount is about 120 mg. In one embodiment, the specific amount is about 140 mg. In one embodiment, the specific amount is about 150 mg. In one embodiment, the specific amount is about 160 mg. In one embodiment, the specific amount is about 180 mg. In one embodiment, the specific amount is about 200 mg. In one embodiment, the specific amount is about 220 mg. In one embodiment, the specific amount is about 240 mg. In one embodiment, the specific amount is about 260 mg. In one embodiment, the specific amount is about 280 mg. In one embodiment, the specific amount is about 300 mg. In one embodiment, the specific amount is about 320 mg. In one embodiment, the specific amount is about 340 mg. In one embodiment, the specific amount is about 360 mg. In one embodiment, the specific amount is about 380 mg. In one embodiment, the specific amount is about 400 mg. In one embodiment, the specific amount is about 420 mg. In one embodiment, the specific amount is about 440 mg. In one embodiment, the specific amount is about 460 mg. In one embodiment, the specific amount is about 480 mg. In one embodiment, the specific amount is about 500 mg. In one embodiment, the specific amount is about 600 mg. In one embodiment, the specific amount is about 700 mg. In one embodiment, the specific amount is about 800 mg. In one embodiment, the specific amount is about 900 mg. In one embodiment, the specific amount is about 1000 mg. In one embodiment, the specific amount is about 1100 mg. In one embodiment, the specific amount is about 1200 mg. In one embodiment, the specific amount is about 1300 mg. In one embodiment, the specific amount is about 1400 mg. In one embodiment, the specific amount is about 1500 mg. In one embodiment, the specific amount is about 1600 mg. In one embodiment, the specific amount is about 1700 mg. In one embodiment, the specific amount is about 1800 mg. In one embodiment, the specific amount is about 1900 mg. In one embodiment, the specific amount is about 2000 mg. In one embodiment, the specific amount is about 2100 mg. In one embodiment, the specific amount is about 2200 mg. In one embodiment, the specific amount is about 2300 mg. In one embodiment, the specific amount is about 2400 mg. In one embodiment, the specific amount is about 2500 mg. In one embodiment, the specific amount is about 3000 mg. In one embodiment, the specific amount is about 4000 mg. In one embodiment, the specific amount is about 5000 mg.

In certain embodiments, the pharmaceutical product is a tablet, and the tablet is manufactured using standard, art-recognized tablet processing procedures and equipment. In certain embodiments, the method for forming a tablet comprises powdering, crystallizing compound 1 alone or in combination with one or more excipients such as carriers, additives, polymers and the like. And / or direct compression of the granular composition. In certain embodiments, as an alternative to direct compression, tablets can be prepared using wet or dry granulation processes. In certain embodiments, the tablets are molded rather than compressed, starting with a damp or otherwise manageable material. In certain embodiments, compression and granulation techniques are used.

In certain embodiments, the pharmaceutical product is a capsule, which can be manufactured using standard, art-recognized capsule processing procedures and equipment. In certain embodiments, soft gelatin capsules may be prepared in which the capsule contains a mixture of compound 1 and a vegetable oil or a non-aqueous, water-miscible material such as, for example, polyethylene glycol. In certain embodiments, hard, comprising granules of compound 1 combined with a solid powdered carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. Gelatin capsules can be prepared. In certain embodiments, the hard gelatin capsule shell can be prepared from a capsule composition comprising a plasticizer such as gelatin and a small amount of glycerol. In certain embodiments, as an alternative to gelatin, the capsule shell can be made of a carbohydrate material. In certain embodiments, the capsule composition may further comprise a polymer, a colorant, a flavoring agent, and a milky whitening agent, if desired. In certain embodiments, the capsule comprises HPMC.

In certain embodiments, the formulation of compound 1 is prepared with an aqueous solvent without causing significant hydrolysis of the compound. In a particular embodiment, the formulation of compound 1 is a tablet containing a coating applied to the drug core using an aqueous solvent without causing significant hydrolysis of the compound in the formulation. In certain embodiments, water is utilized as a solvent for coating the drug core. In certain embodiments, the oral dosage form of Compound 1 is a tablet containing a film coat applied to the drug core using an aqueous solvent. In certain embodiments, water is utilized as a solvent for film coating. In certain embodiments, the tablets containing compound 1 are film coated with an aqueous solvent without causing decomposition of the pharmaceutical composition. In certain embodiments, water is used as the film coating solvent without causing decomposition of the pharmaceutical composition. In certain embodiments, the oral dosage form comprising Compound 1 and an aqueous film coating causes immediate drug release upon oral delivery. In certain embodiments, the oral dosage form comprising Compound 1 and an aqueous film coating causes controlled drug release into the upper gastrointestinal tract, eg, the stomach, upon oral administration. In certain embodiments, tablets with an aqueous film coating contain Compound 1 as the API.

In certain embodiments, a controlled release pharmaceutical formulation for oral administration of Compound 1 is provided herein in which the release occurs substantially in the stomach, a) a particular amount of Compound 1 and b) substantially. It comprises a drug release control component for controlling the release of compound 1 in the upper gastrointestinal tract, eg, stomach, and c) optionally one or more excipients. In certain embodiments, the oral dosage form comprising Compound 1 is prepared as a controlled release tablet or capsule comprising a pharmaceutical composition and a drug core comprising any excipient. Optionally, a "seal coat" or "shell" is applied. In certain embodiments, the formulations provided herein comprising Compound 1 provided herein substantially control the release of a therapeutically effective amount of Compound 1, in the stomach upon oral administration. A controlled release tablet or capsule containing a drug release control component and optionally one or more excipients.

Certain embodiments provide a drug release control component that is a polymer matrix that swells upon exposure to gastric fluid and causes gastric retention of the pharmaceutical product and substantially sustained release of Compound 1 from the polymer matrix in the stomach. In certain embodiments, such formulations can be prepared by incorporating compound 1 into a suitable polymer matrix during formulation. Examples of such formulations are known in the art. For example, Shell et al., Which is incorporated herein by reference in its entirety. , U.S. Patent Application Publication No. 2002/0051820 (Application No. 09/990,061), Shell et al. , U.S. Patent Application Publication No. 2003/0039688 (Application No. 10 / 045, 823), Gussler et al. , U.S. Patent Application Publication No. 2003/0104053 (Application No. 10/029, 134).

In certain embodiments, the drug release control component can include a shell that encloses the drug-containing core, the shell being compounded from the core, for example, by swelling to a size that is retained in the stomach upon exposure to gastric fluid. Compound 1 is released from the core by allowing diffusion of 1 and promoting gastric retention of the pharmaceutical product. In certain embodiments, such a formulation first compresses a mixture of compound 1 with one or more excipients to form a drug core, and then compresses another powdered mixture onto the drug core to shell. It can be prepared by forming the drug core or wrapping the drug core in a capsule shell made of a suitable material. Examples of such formulations are known in the art. For example, Berner et al., Which is incorporated herein by reference in its entirety. , U.S. Patent Application Publication No. 2003/0104062 (Application No. 10 / 213,823).

In certain embodiments, the pharmaceutical formulations provided herein contain compound 1 and optionally one or more excipients to form a "drug core." Optional excipients include, for example, diluents (bulking agents), lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, colorants, flavoring agents known in the art. Examples include agents, binders, excipient aids, flow promoters, permeation-enhancing excipients, plasticizers and the like. It will be appreciated by those skilled in the art that some substances serve more than one purpose in pharmaceutical compositions. For example, some substances are binders that help pack the tablets together after compression, as well as disintegrants that help break the tablets apart when they reach the target delivery site. The choice of excipients and amounts to be used can be readily determined by the pharmaceutical scientist based on experience and consideration of standard procedures and reference studies available in the art.

In certain embodiments, the formulations provided herein comprise one or more binders. Binders can be used, for example, to impart cohesiveness to the tablet and thus ensure that the tablet remains intact after compression. Suitable binders include, among other things, starch (including corn starch and pregelatinized starch), gelatin, sugar (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, wax, and natural and synthetic gums. , For example, acacia, sodium alginate, polyvinylpyrrolidone, cellulose polymers (including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, etc.), bee gum, carbomer (eg, carbopole), sodium, dextrin, etc. Examples include, but are not limited to, guar gum, hydride vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylate, povidone (eg, KOLLIDON, PLASSONE), microcrystalline cellulose. Examples of the binder include acacia, agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate, seratonia, chitosan, starch powder, copovidone, dexstrad, dextrin, dextrose, ethyl cellulose, gelatin, glyceryl behenate, and guar gum. , Hydroxyethyl Cellulose, Hydroxyethyl Methyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Starch, Hypromellose, Inulin, Lactose, Aluminum Magnesium Silica, Malt Dextrin, Martose, Methyl Cellulose, Poroxamar, Polycarbophyll, Polydexstrose, Polyethylene Oxide, Polymethylacrylate, Also included are povidone, sodium alginate, sodium carboxymethyl cellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein. The binder, if determined to be appropriate for the drug core, is about 2% by weight / weight% of the drug core, about 4% by weight / weight% of the drug core, about 6% by weight / weight% of the drug core, the drug. About 8% by weight / weight% of core, about 10% by weight / weight% of drug core, about 12% by weight / weight% of drug core, about 14% by weight / weight% of drug core, about 16% by weight / weight% of drug core, drug About 18% by weight / weight% of core, about 20% by weight / weight% of drug core, about 22% by weight / weight% of drug core, about 24% by weight / weight% of drug core, about 26% by weight / weight% of drug core, drug About 28 weight / weight% of core, about 30 weight / weight% of drug core, about 32 weight / weight% of drug core, about 34 weight / weight% of drug core, about 36 weight / weight% of drug core, drug About 38% by weight / weight% of core, about 40% by weight / weight% of drug core, about 42% by weight / weight% of drug core, about 44% by weight / weight% of drug core, about 46% by weight / weight% of drug core, drug. About 48% by weight / weight% of core, about 50% by weight / weight% of drug core, about 52% by weight / weight% of drug core, about 54% by weight / weight% of drug core, about 56% by weight / weight% of drug core, drug About 58% by weight / weight% of core, about 60% by weight / weight% of drug core, about 62% by weight / weight% of drug core, about 64% by weight / weight% of drug core, about 66% by weight / weight% of drug core, drug About 68% by weight / weight% of core, about 70% by weight / weight% of drug core, about 72% by weight / weight% of drug core, about 74% by weight / weight% of drug core, about 76% by weight / weight% of drug core, drug About 78% by weight / weight% of core, about 80% by weight / weight% of drug core, about 82% by weight / weight% of drug core, about 84% by weight / weight% of drug core, about 86% by weight / weight% of drug core, drug About 88% by weight / weight% of core, about 90% by weight / weight% of drug core, about 92% by weight / weight% of drug core, about 94% by weight / weight% of drug core, about 96% by weight / weight% of drug core, drug It can be about 98 weight /% by weight or more of the core. In certain embodiments, the appropriate amount of a particular binder will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations provided herein comprise one or more diluents. Diluents can be used, for example, to increase bulk so that tablets of practical size are finally provided. Suitable diluents include, among other things, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dried starch, microcrystalline cellulose (eg AVICEL), fine cellulose, pregelatinized starch, calcium carbonate, etc. Calcium Sulfate, Sugar, Dextrate, Dextrin, Dextrose, Dibasic Calcium Phosphate Dihydrate, Tribasic Calcium Phosphate, Kaolin, Magnesium Carbonate, Magnesium Oxide, Maltodextrin, Mannitol, Polymethacrylate (eg, EUDRAGIT), Potassium Chloride, Examples include sodium chloride, sorbitol, and talc. Examples of the diluent include ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, powdered sugar, dextrin, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, and the like. Isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, malt dextrin, maltose, medium chain triglyceride, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, polydextrose, polymethylacrylate, simethicone. , Sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutyl ether-β-cyclodextrin, talc, tragacanth, trehalose, and xylitol. The diluent can be used in an amount calculated to obtain the desired volume in a tablet or capsule, and in certain embodiments, the diluent is about 5% by weight / weight% or more, about 10% by weight / weight% of the drug core. About 15% by weight / weight% or more, about 20% by weight / weight% or more, about 22% by weight / weight% or more, about 24% by weight / weight% or more, about 26% by weight / weight% or more, about 28% by weight / weight% or more, About 30 weight / weight% or more, about 32 weight / weight% or more, about 34 weight / weight% or more, about 36 weight / weight% or more, about 38 weight / weight% or more, about 40 weight / weight% or more, about 42 Weight / weight% or more, about 44 weight / weight% or more, about 46 weight / weight% or more, about 48 weight / weight% or more, about 50 weight / weight% or more, about 52 weight / weight% or more, about 54 weight / weight Weight% or more, about 56 weight / weight% or more, about 58 weight / weight% or more, about 60 weight / weight% or more, about 62 weight / weight% or more, about 64 weight / weight% or more, about 68 weight / weight% About 70% by weight / weight% or more, about 72% by weight / weight% or more, about 74% by weight / weight% or more, about 76% by weight / weight% or more, about 78% by weight / weight% or more, about 80% by weight / weight% or more, About 85% by weight / weight% or more, about 90% by weight / weight% or more, or about 95% by weight / weight% or more, about 10% by weight / weight% to about 90% by weight / weight% of the drug core, about 20% by weight / weight of the drug core. It is used in an amount of about 80% by weight / weight%, about 30% by weight / weight% to about 70% by weight / weight% of the drug core, and about 40% by weight / weight% to about 60% by weight / weight% of the drug core. In certain embodiments, the appropriate amount of a particular diluent will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations provided herein include one or more lubricants. Lubricants can be used, for example, to facilitate tablet production, and examples of suitable lubricants include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil. Examples include glycerin, magnesium stearate, calcium stearate, and stearic acid. In certain embodiments, stearate, if present, represents about 2% by weight or less of the drug-containing core. Further examples of lubricants include, for example, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, magnesium lauryl sulfate, magnesium stearate, myristic acid, palmitic acid, poroxamer, polyethylene glycol, potassium benzoate. , Sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. In certain embodiments, the lubricant is magnesium stearate. In certain embodiments, the lubricant is about 0.2% by weight / weight of the drug core, about 0.4% by weight / weight of the drug core, about 0.6% by weight / weight of the drug core, relative to the drug core. %, About 0.8% by weight / weight% of drug core, about 1.0% by weight / weight% of drug core, about 1.2% by weight / weight% of drug core, about 1.4% by weight / weight% of drug core, About 1.6% by weight / weight% of drug core, about 1.8% by weight / weight% of drug core, about 2.0% by weight / weight% of drug core, about 2.2% by weight / weight% of drug core, drug core About 2.4% by weight / weight%, about 2.6% by weight / weight% of drug core, about 2.8% by weight / weight% of drug core, about 3.0% by weight / weight% of drug core, about about 3.0% by weight / weight% of drug core. 3.5% by weight / weight%, about 4% by weight / weight% of drug core, about 4.5% by weight / weight% of drug core, about 5% by weight / weight% of drug core, about 6% by weight / weight% of drug core, About 7% by weight / weight% of drug core, about 8% by weight / weight% of drug core, about 10% by weight / weight% of drug core, about 12% by weight / weight% of drug core, about 14% by weight / weight% of drug core, About 16% by weight / weight% of drug core, about 18% by weight / weight% of drug core, about 20% by weight / weight% of drug core, about 25% by weight / weight% of drug core, about 30% by weight / weight% of drug core, About 35% by weight / weight% of drug core, about 40% by weight / weight% of drug core, about 0.2% by weight / weight% to about 10% by weight / weight% of drug core, about 0.5% by weight / weight% of drug core. It is present in an amount of ~ about 5% by weight /% by weight, or about 1% by weight /% by weight to about 3% by weight / weight% of the drug core. In certain embodiments, the appropriate amount of a particular lubricant will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations provided herein comprise one or more disintegrants. The disintegrant can be used, for example, to facilitate the disintegration of tablets and can be, for example, starch, clay, cellulose, algin, gum, or crosslinked polymers. Examples of the disintegrant include alginic acid, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose (for example, AC-DI-SOL, PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (for example, KOLLIDON, POLYPLASSONE), guar gum, and the like. Also included are magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, potassium polarcrylin, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (eg EXPLOTAB), and starch. Additional disintegrants include, for example, calcium alginate, chitosan, sodium doxart, hydroxypropyl cellulose, and povidone. In certain embodiments, the disintegrant is about 1% by weight / weight of the drug core, about 2% by weight / weight of the drug core, about 3% by weight / weight of the drug core, about 3% by weight / weight of the drug core, relative to the drug core. 4 weight / weight%, drug core about 5 weight / weight%, drug core about 6 weight / weight%, drug core about 7 weight / weight%, drug core about 8 weight / weight%, drug core about 9% by weight / weight%, about 10% by weight / weight% of drug core, about 12% by weight / weight% of drug core, about 14% by weight / weight% of drug core, about 16% by weight / weight% of drug core, about 16% by weight / weight% of drug core. 18 weight / weight%, drug core about 20 weight / weight%, drug core about 22 weight / weight%, drug core about 24 weight / weight%, drug core about 26 weight / weight%, drug core about 28% by weight /% by weight, about 30% by weight /% by weight of drug core, about 32% by weight /% by weight of drug core, more than about 32% by weight /% by weight of drug core, about 1% by weight /% by weight of drug core to about 10% by weight. / %%, drug core about 2% / weight% to about 8% / weight%, drug core about 3% / weight% to about 7% / weight%, or drug core about 4% / weight% to about It is present in an amount of 6 weight /% by weight. In certain embodiments, the appropriate amount of a particular disintegrant will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations provided herein comprise one or more stabilizers. Stabilizers (also called absorption enhancers) can be used, for example, to inhibit or delay drug degradation reactions, including oxidation reactions, for example. Stabilizers include, for example, d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), acacia, albumin, alginate, aluminum stearate, ammonium alginate, ascorbic acid, ascorbyl palmitate, bentonite, hydroxytoluene butylated. , Calcium alginate, calcium stearate, carboxymethyl cellulose calcium, carrageenan, seratonia, colloidal silicon dioxide, cyclodextrin, diethanolamine, edetate, ethyl cellulose, ethylene glycol palmitostearate, glycerin monostearate, guar gum, hydroxypropyl cellulose, hypromerose , Converted sugar, lecithin, magnesium aluminum silicate, monoethanolamine, pectin, poroxamer, polyvinyl alcohol, potassium alginate, potassium poraclyrine, povidone, propyl acidorate, propylene glycol, propylene glycol alginate, raffinose, sodium acetate, sodium alginate, Examples thereof include sodium borate, sodium carboxymethyl cellulose, sodium stearyl fumarate, sorbitol, stearyl alcohol, sulfobutyl-b-cyclodextrin, trehalose, white wax, xanthan gum, xylitol, yellow wax, and zinc acetate. In certain embodiments, the stabilizer is about 1% by weight / weight of the drug core, about 2% by weight / weight of the drug core, about 3% by weight / weight of the drug core, about 3% by weight / weight of the drug core, relative to the drug core. 4 weight / weight%, drug core about 5 weight / weight%, drug core about 6 weight / weight%, drug core about 7 weight / weight%, drug core about 8 weight / weight%, drug core about 9% by weight / weight%, about 10% by weight / weight% of drug core, about 12% by weight / weight% of drug core, about 14% by weight / weight% of drug core, about 16% by weight / weight% of drug core, about 16% by weight / weight% of drug core. 18 weight / weight%, drug core about 20 weight / weight%, drug core about 22 weight / weight%, drug core about 24 weight / weight%, drug core about 26 weight / weight%, drug core about 28 weight / weight%, drug core about 30 weight / weight%, drug core about 32 weight / weight%, drug core about 1 weight / weight% to about 10 weight / weight%, drug core about 2 weight / weight% It is present in an amount of% to about 8% by weight /% by weight, about 3% by weight /% by weight to about 7% by weight /% by weight of the drug core, or about 4% by weight /% by weight to about 6% by weight /% by weight of the drug core. In certain embodiments, the appropriate amount of a particular stabilizer will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations provided herein include one or more flow promoters. Flow enhancers can be used, for example, to improve the flow properties of powder compositions or granulations, or to improve the accuracy of administration. Excipients that can function as flow promoters include, for example, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, calcium silicate, powdered cellulose, colloidal silicon dioxide, kay. Examples include magnesium acid, magnesium trisilicate, silicon dioxide, starch, tribasic calcium phosphate, and talc. In certain embodiments, the flow promoter is less than about 1% by weight / weight% of the drug core, about 1% by weight / weight% of the drug core, about 2% by weight / weight% of the drug core, and the drug core. About 3% by weight / weight%, about 4% by weight / weight% of drug core, about 5% by weight / weight% of drug core, about 6% by weight / weight% of drug core, about 7% by weight / weight% of drug core, about 7% by weight / weight% of drug core. About 8% by weight / weight%, about 9% by weight / weight% of drug core, about 10% by weight / weight% of drug core, about 12% by weight / weight% of drug core, about 14% by weight / weight% of drug core, about 14% by weight / weight% of drug core. About 16% by weight / weight%, about 18% by weight / weight% of drug core, about 20% by weight / weight% of drug core, about 22% by weight / weight% of drug core, about 24% by weight / weight% of drug core, about 24% by weight / weight% of drug core. About 26% by weight / weight%, about 28% by weight / weight% of drug core, about 30% by weight / weight% of drug core, about 32% by weight / weight% of drug core, about 1% by weight / weight% of drug core to about 10 Weight / weight%, drug core about 2 weight / weight% to about 8 weight / weight%, drug core about 3 weight / weight% to about 7 weight / weight%, or drug core about 4 weight / weight% It is present in an amount of about 6 weight /% by weight. In certain embodiments, the appropriate amount of a particular flow enhancer will be determined by one of ordinary skill in the art.

In certain embodiments, the formulations for use in the methods provided herein are all about 20-30% Compound 1 and about 30-45% microcrystalline cellulose, based on the total weight of the tablets. , About 2% hydroxypropyl cellulose, about 6% sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about. Intragranular excipients containing 0.75% magnesium stearate, about 5-50% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0. .Tablets containing extragranular excipients containing 75% magnesium stearate. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are all about 20-30% Compound 1 and about 30-45% microcrystalline cellulose, based on the total weight of the tablets. , About 2% hydroxypropyl cellulose, about 6% sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about. Intragranular excipients containing 0.75% magnesium stearate, about 9-25% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0. .Tablets containing extragranular excipients containing 75% magnesium stearate. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are about 20% to about 30% amount of Compound 1 and about 34.5% by weight based on the total weight of the tablets. Intragranular excipients selected from 44.5% and ~ about 39.5% microcrystalline cellulose, about 2% hydroxypropyl cellulose, and about 6% sodium starch glycolate, and about 20%. A tablet comprising microcrystalline cellulose and an extragranular excipient selected from about 2% sodium starch glycolate. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are about 30% compound 1, about 45% microcrystalline cellulose, about 2% hydroxypropyl cellulose, about 6%. Intragranular excipient containing sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. Extragranular excipient containing formant and about 9.5% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. A tablet containing an agent. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are about 30% compound 1, about 34.50% microcrystalline cellulose, about 2% hydroxypropyl cellulose, about 6. Granules containing% sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. Excipients containing internal excipients and about 20% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. A tablet containing an agent. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are about 20% compound 1, about 44.50% microcrystalline cellulose, about 2% hydroxypropyl cellulose, about 6. Granules containing% sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. Excipients containing internal excipients and about 20% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. A tablet containing an agent. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are about 25% compound 1, about 39.50% microcrystalline cellulose, about 2% hydroxypropyl cellulose, about 6. Granules containing% sodium starch glycolate, about 1% sodium lauryl sulfate, about 1% hypromellose acetate succinate, about 1.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. Excipients containing internal excipients and about 20% microcrystalline cellulose, about 2% sodium starch glycolate, about 0.5% colloidal silicon dioxide, and about 0.75% magnesium stearate. A tablet containing an agent. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the formulations for use in the methods provided herein are compound 1, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose acetate succinate, iron yellow oxide, magnesium stearate, fine. Tablets containing crystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch glycolate, talc, and titanium dioxide. In one embodiment, compound 1 is compound A. In one embodiment, compound 1 is a polymorphic form 3 of compound A. In one embodiment, the tablet for use in the methods provided herein is a film coated tablet.

In certain embodiments, the pharmaceutical compositions provided herein are preferably by oral, parenteral, inhalation spray, via topical, rectal, nasal, oral, vaginal, or implantable reservoirs. Can be administered by oral administration or administration by injection. In one embodiment, the pharmaceutical composition may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to improve the stability of the formulated compound or its delivery form. As used herein, the term parenteral is subcutaneous, intradermal, intravenous, intramuscular, intraarterial, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion. Including techniques.

In certain embodiments, the pharmaceutical compositions provided herein can be in the form of sterile injectable preparations, eg, as sterile injectable aqueous or oily suspensions. The suspension can be formulated according to techniques known in the art using suitable dispersants or wetting agents (eg, TWEEN80, etc.) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, eg, as a solution in 1,3-butanediol. Acceptable vehicles and solvents available include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as solvents or suspension media. Any non-irritating fixed oil may be utilized for this purpose, including synthetic monos or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated versions, are useful in the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions are also commonly used in the formulation of long chain alcohol diluents or dispersants, or pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. It may contain methyl cellulose or a similar dispersant. Other commonly used surfactants such as TWEEN or SPAN and / or other similar emulsifiers or bios commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms. Availability enhancers can also be used for formulation purposes.

In certain embodiments, the pharmaceutical compositions provided herein can also be administered in the form of a suppository for rectal administration. These compositions are prepared by mixing Compound 1 with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus dissolves in the rectum to release the active ingredient. Can be prepared. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

Topical administration of the pharmaceutical compositions provided herein is useful when the desired treatment involves areas or organs readily reachable by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in the carrier. In certain embodiments, carriers for topical administration of the compounds provided herein include mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsified wax, and water. However, it is not limited to these. Alternatively, the pharmaceutical composition can be formulated with the appropriate lotion or cream containing the active compound suspended or dissolved in the carrier with the appropriate 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 compositions provided herein can also be applied topically to the lower gastrointestinal tract with a rectal suppository or a suitable enema. Topical transdermal patches are also included herein.

In certain embodiments, the pharmaceutical compositions provided herein can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations, such as benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or in the art. It can be prepared as a solution in physiological saline using other known solubilizers or dispersants.

In certain embodiments, the compositions provided herein are described, for example, by injection into intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneous, or oral, oral, nasal, transmucosal. Topically, by ophthalmic preparation, or by inhalation, at doses ranging from about 0.5 to about 100 mg / kg body weight, or at doses of 1 mg to 1000 mg / dose, every 4 to 120 hours, or for a particular drug. It can be administered according to requirements. The methods herein are intended to administer an effective amount of a compound or compound composition in order to achieve the desired or specified effect. In one embodiment, the pharmaceutical composition is administered about 1 to about 6 times per day, or as a continuous infusion. Such administration can be used as chronic or acute therapy. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Typical preparations contain from about 5% to about 95% active compound (weight / weight). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those listed above may be required. Specific dosages and treatment regimens for any particular subject are the activity, age, weight, general health, gender, diet, duration of administration, excretion rate, drug combination of the specific compounds used. Depends on a variety of factors, including the severity and course of the disease, condition, or condition, the subject's predisposition to the disease, condition, or condition, and the judgment of the treating physician.

Maintenance doses of the compounds, compositions, or combinations provided herein may be administered as needed during improvement of the subject's condition. The dose, frequency, or both may then be reduced, depending on the condition, to a level at which the improved condition is retained if the symptoms are reduced to the desired level. Subjects, however, may require long-term intermittent treatment at the time of any recurrence of disease symptoms.

Compound 1 for use in therapeutic methods
Compound 1 can be used in all methods of treating myelodysplastic syndrome in the subjects provided herein.

In addition to IDH2, the mutated state of the second gene selected from the group consisting of ASXL1 and SRSF2 has a response in myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 when treated with compound 1. It was observed to be related. Although not intended to be bound by any particular theory of behavior, the mutation in the second gene selected from the group consisting of ASXL1 and SRSF2 is a compound of MDS characterized by the presence of a mutant allele of IDH2. It may be related to the positive clinical outcome in the treatment at 1.

In addition to IDH2, the mutated state of at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1 is characterized by the presence of a mutant allele of IDH2 when treated with compound 1. It was further observed to be associated with response in myelodysplastic syndrome. Although not intended to be bound by any particular behavioral theory, the presence of mutations in at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1 is a mutant allele of IDH2. May be associated with resistance to treatment with compound 1 of MDS characterized by the presence of.

The mutant state of ASXL1 was observed to be associated with a response in myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 when treated with compound 1. The mutational state of SRSF2 was observed to be associated with a response in myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 when treated with compound 1. Although not intended to be bound by any particular theory of behavior, mutations in ASXL1 and / or SRSF2 result in positive clinical outcomes in treatment with compound 1 of MDS characterized by the presence of a mutant allele of IDH2. Can be related.

In addition to IDH2, the mutational state of at least one second gene selected from the group consisting of ASXL1, SRSF2, KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL is a mutation in IDH2 when treated with compound 1. It was observed to be associated with a response in myelodysplastic syndrome characterized by the presence of alleles. Although not intended to be bound by any particular behavioral theory, mutations in at least one second gene selected from the group consisting of ASXL1, SRSF2, KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL , May be associated with positive clinical outcomes in treatment with compound 1 of MDS characterized by the presence of a mutant allele of IDH2.

In addition to IDH2, mutational states of at least one other gene selected from the group consisting of ASXL1, SRSF2, KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF are treated with compound 1. It was further observed that it was associated with a response in myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2. Not intended to be bound by any particular theory of motion, but at least one other selected from the group consisting of ASXL1, SRSF2, KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. The presence of a mutation in the gene of MDS may be associated with resistance to treatment with compound 1 of MDS characterized by the presence of a mutant allele of IDH2.

In addition to IDH2, the mutational state of at least one second gene selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL is the presence of a mutant allele of IDH2 when treated with compound 1. It was observed to be associated with a response in the characteristic myelodysplastic syndrome. Although not intended to be bound by any particular theory of behavior, mutations in at least one second gene selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL are mutant alleles of IDH2. It may be associated with positive clinical outcomes in treatment with compound 1 of MDS characterized by the presence of the gene.

In addition to IDH2, the mutational state of at least one other gene selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF is a variant of IDH2 when treated with compound 1. It was further observed to be associated with a response in myelodysplastic syndrome characterized by the presence of alleles. The presence of mutations in at least one other gene selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF, although not intended to be bound by any particular behavioral theory. May be associated with resistance to treatment with compound 1 of MDS characterized by the presence of a mutant allele of IDH2.

Specifically, Compound 1 can be used in all methods of treating myelodysplastic syndrome in the subjects provided in the embodiments below.

In certain embodiments, there is provided herein a method of treating myelodysplasia syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplasia syndrome is a variant of IDH2. Characterized by the presence of an allele and a variant of at least one second gene, the second gene is selected from the group consisting of SRSF2, KRAS, and MPL.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allele and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2.

In certain embodiments, there is provided herein a method of treating myelodysplasia syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplasia syndrome is a variant of IDH2. Alleles and variants of the second gene Characterized by the presence of alleles, the second gene is DNMT3A.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allele and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1, SRSF2, and CSF3R.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allele and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1, SRSF2, MPL, FAT3, and CBL.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allelic gene and a variant of at least one second gene, the second gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. ..

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of the second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is one of one or more additional genes. It is further characterized by the presence of the above mutant allogens.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allelic gene and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndromes are MPL, CSF3R, FAT3, and It is further characterized by the presence of one or more mutant allelic genes of one or more additional genes selected from CBL.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of at least one second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is one or more variants of CSF3R. It is further characterized by the presence of myelodysplastic genes.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allogens and variants of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is from MPL, FAT3, and CBL. It is further characterized by the presence of one or more variant allelic genes of the one or more additional genes selected.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of an allelic gene and at least one variant of the second gene, the second gene is selected from the group consisting of ASXL1, SRSF2, and MPL, and myelodysplastic syndrome is from FAT3 and CBL. It is further characterized by the presence of one or more mutant allelic genes of the one or more additional genes selected.

In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and variants of ASXL1 alleles. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.

In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes selected from CSF3R, FAT3, and CBL.

In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and mutants of SRSF2 alleles. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.

In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes selected from MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the second gene is MPL. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Alleles and variants of MPL are characterized by the presence of alleles. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes selected from ASXL1, SRSF2, FAT3, and CBL.

In certain embodiments, the second gene is DNAT3A. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and mutant alleles of DNMT3A.

In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and the absence of mutant allogens of at least one other gene, the other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of the second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of at least one other gene. Characterized by the absence of a gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and variant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of allelic variants of at least one other gene, the other genes being KRAS, TP53, SETBP1, And U2AF1 are selected from the group. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and variants of SRSF2, myelodysplastic syndrome is further characterized by the absence of allelic variants of at least one other gene, the other genes being KRAS, TP53, SETBP1, And U2AF1 are selected from the group. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allogens and variant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of allelic variants of at least one other gene, the other genes being KRAS, TP53, It is selected from the group consisting of SETBP1 and U2AF1.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, And BRAF. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and the absence of mutant allogens of at least one other gene, the other genes are selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Will be done. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allogens and variants of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is associated with at least one other gene. Characterized by the absence of the mutant allogene, other genes are selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.

In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of mutant allogens of at least one other gene, the other genes being KRAS, TP53, SETBP1, It is selected from the group consisting of U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, the additional gene is selected from SRSF2, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of mutant allogens of at least one other gene, the other genes being TP53, SETBP1, U2AF1, It is selected from the group consisting of TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, additional genes are selected from KRAS and MPL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allogens and mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of mutant allogens for at least one other gene, the other genes being KRAS, TP53, It is selected from the group consisting of SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, the additional gene is selected from MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of KRAS, myelodysplastic syndrome is further characterized by the absence of allelic variants of at least one other gene, the other genes being TP53, SETBP1, U2AF1, It is selected from the group consisting of TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, the additional gene is selected from SRSF2 and MPL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of KRAS variant alleles. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of a mutant gene and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of the KRAS variant allogen. Further characterized by absence. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS mutants. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens for SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS mutants. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of mutant allogens for KRAS.

In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the presence of alleles of MPL mutants. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, the additional gene is KRAS. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the presence of mutant allogens for MPL. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the presence of mutant allogens for CSF3R. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant alleles of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the presence of mutant alleles of MPL, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of mutant allogens for TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allelic and variant allogens of the second gene, the second gene was selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome further presents the absence of the allelic variant of TP53. It is a feature. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of mutant allogens for TP53. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some such embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of SETBP1 variant alleles. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allelic and variant allogens of the second gene, the second gene was selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome further absent of the variant allelic of SETBP1. It is a feature. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of SETBP1 mutants. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of SETBP1 mutants. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, additional genes are selected from KRAS and MPL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of SETBP1 mutants. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of U2AF1 variant alleles. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of allelic and variant allogens of the second gene, the second gene was selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome further absent the variant allelic of U2AF1. It is a feature. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of alligators of U2AF1. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of TCF3 variant alleles. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of a mutant gene and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of the TCF3 variant. Further characterized by absence. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of allelic variants of TCF3. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of TCF3 mutants. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from KRAS, DNMT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of allogeneic variants of TCF3. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of STAG2 variant alleles. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of a mutant gene and a variant of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of the STAG2 variant. Further characterized by absence. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens for ASXL1, myelodysplastic syndrome is further characterized by the absence of alligators of STAG2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens for SRSF2, myelodysplastic syndrome is further characterized by the absence of alligators of STAG2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant allogens for ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of mutant allogens for STAG2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of mutant alleles of KRAS and TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of at least one second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is a variant of KRAS and TP53. It is further characterized by the absence of genes. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS and TP53. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens for SRSF2, myelodysplastic syndrome is further characterized by the absence of alligator variants of KRAS and TP53. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS and TP53. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of mutant allogens for KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of the second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndromes are mutations in KRAS, TP53, SETBP1 and U2AF1. It is further characterized by the absence of somatic allogens. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, TCF3, and STAG2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of mutant alleles of KRAS, TP53, TCF3, and STAG2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Allogens and variants of the second gene Characterized by the presence of allogens, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndromes are mutations in KRAS, TP53, TCF3, and STAG2. It is further characterized by the absence of somatic allogens. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of ASXL1, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, TCF3, and STAG2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles and mutant allogens of SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, TCF3, and STAG2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. Characterized by the presence of alleles as well as mutant alligators of ASXL1 and SRSF2, myelodysplastic syndrome is further characterized by the absence of alleles of KRAS, TP53, TCF3, and STAG2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of SETBP1, NRAS, JAK2, and BRAF. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is a variant of IDH2. It is characterized by the presence of alleles and the absence of mutant alleles of SETBP1, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and SETBP1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of TP53 and SETBP1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of TP53 and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of SETBP1 and U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, and SETBP1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, SETBP1, and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of TP53, SETBP1, and U2AF1. In certain embodiments, myelodysplastic syndrome is characterized by the absence of mutant alleles of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, the myelodysplastic syndrome being treated is characterized by a variant allele of IDH2, where the IDH2 mutation is NADPH-dependent for α-ketoglutarate to R (-) -2-hydroxyglutarate in the patient. Brings new capabilities to enzymes that catalyze sex reduction. In certain embodiments, the IDH2 mutant allele has an R140X or R172X mutation. In certain embodiments, the IDH2 mutant allele has an R140X mutation (mIDH2-R140). In certain embodiments, the R140X mutation is an R140Q mutation (mIDH2-R140Q). In certain embodiments, the R140X mutation is an R140W mutation (mIDH2-R140W). In certain embodiments, the R140X mutation is an R140L mutation (mIDH2-R140L). In certain embodiments, the IDH2 mutant allele carries the R172X mutation (mIDH2-R172). In certain embodiments, the R172X mutation is the R172K mutation (mIDH2-R172K). In certain embodiments, the R172X mutation is an R172G mutation (mIDH2-R172G).

In certain embodiments, the mutant allele of IDH2 is mIDH2-R140. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140 and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140 and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140 and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R140. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DBMT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172 and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172 and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172 and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R172. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140Q, mIDH2-R140W, mIDH2-R140L, mIDH2-R172K, or mIDH2-R172G.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R140Q. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140Q and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140Q and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140Q and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R140Q. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140W. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R140W. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140L. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R140L. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172K. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R172K. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172G. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G and A variant of the second gene is characterized by the presence of an allele, the second gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, the second gene is ASXL1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G and It is characterized by the presence of a mutant allele of ASXL1. In certain embodiments, the second gene is SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G and It is characterized by the presence of a mutant allele of SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject, comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is as well as mIDH2-R172G. It is characterized by the presence of mutant alleles of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. .. In certain embodiments, myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R140. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is in mIDH2-R140. Characterized by the presence and absence of a variant allelic of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is in mIDH2-R140. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R140Q. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is described in mIDH2-R140Q. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140W. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is pIDH2-R140W. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is pIDH2-R140W. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140W. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, the IDH2 mutant allele is mIDH2-R140L. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is pIDH2-R140L. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R140L. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172K. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is pIDH2-R172K. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172K. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, the mutant allele of IDH2 is mIDH2-R172G. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. Characterized by the presence of a mutant allogen and the absence of a mutant allogen of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is pIDH2-R172G. Characterized by the presence and absence of a mutant allelic gene of at least one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. In some embodiments, the additional gene is selected from DNAT3A, MPL, CSF3R, FAT3, and CBL. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of KRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of a mutant allele and the absence of a mutant allele of TP53. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of Compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of SETBP1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of U2AF1 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of TCF3 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a STAG2 mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of STAG2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of NRAS mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of JAK2 mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele. In certain embodiments, there is provided herein a method of treating myelodysplastic syndrome in a subject comprising administering to the subject a therapeutically effective amount of compound 1, wherein the myelodysplastic syndrome is mIDH2-R172G. It is characterized by the presence of mutant alleles and the absence of BRAF mutant alleles. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, the other gene being selected from the group consisting of ASXL1 and SRSF2. In certain embodiments, myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, from the group consisting of ASXL1, SRSF2, MPL, DNMT3A, CSF3R, FAT3, and CBL. Be selected.

In certain embodiments, compound 1 for use in the methods disclosed herein is 2-methyl-1-[(4- [6- (trifluoromethyl) pyridine-2-yl] -6-. {[2- (Trifluoromethyl) Pyridine-4-yl] Amino} -1,3,5-Triazine-2-yl) Amino] Propane-2-ol (Compound A) is a mesylate salt.

In certain embodiments, myelodysplastic syndrome (MDS) is MDS that accompanies refractory anemia with excess blast cells (subtype RAEB-1 or RAEB-2). In certain embodiments, MDS is untreated. In certain embodiments, Compound 1 is administered as first-line treatment for MDS. In certain embodiments, Compound 1 is administered as a second, third, or fourth-line treatment for MDS. In certain embodiments, MDS presentation follows AML. In one embodiment, the subject is an adult MDS patient.

In one embodiment, the malignant tumor is sequenced from a cell sample to determine the presence of a mutation in amino acids 140 and / or 172 of IDH2 and the specific properties (eg, of the altered amino acids present therein). Can be analyzed by.

In another aspect, without being bound by theory, certain IDH2 mutations, in particular the R140Q and / or R172K mutations of IDH2, result in a NADPH-dependent reduction of α-ketoglutaric acid to R (-) -2-hydroxyglutarate. Brings new capabilities to catalytic enzymes. Thus, the compounds, compositions, and methods provided herein treat myelodysplastic syndromes characterized by the presence of IDH2 mutant alleles that impart such activity, particularly IDH2R140Q and / or R172K mutations. Useful to do.

In certain embodiments, at least 30, 40, 50, 60, 70, 80, or 90% of cancerous cells have IDH2 mutations, particularly mIDH2-R140Q, mIDH2-R140W, or mIDH2-R140L, at the time of diagnosis or treatment. And / or have mIDH2-R172K or mIDH2-R172G mutations.

In certain embodiments, the effectiveness of treatment for myelodysplastic syndrome is monitored by measuring the level of 2HG in the subject. Typically 2HG levels are measured prior to treatment and elevated levels are indicated for the use of compound 1. Once elevated levels are identified, levels of 2HG are determined during and / or after the end of treatment to confirm efficacy. In certain embodiments, the level of 2HG is determined only during and / or after the end of treatment. Decreased 2HG levels during and after treatment indicate efficacy. Similarly, the determination that 2HG levels are not elevated during or after treatment is also effective. Typically, 2HG measurements reduce the number and size of tumors and / or other cancer-related lesions, improve the overall health of the subject, and change in other biomarkers associated with malignant tumor therapeutic efficacy. Utilized along with other known determinations of efficacy in the treatment of malignant tumors, such as.

2HG can be detected in a sample by the methods of PCT Patent Application Publication No. WO2011 / 050210 and US Patent Application Publication No. US2012 / 0121515, which are incorporated herein by reference in their entirety, or similar methods. In an exemplary method, 2HG can be detected in the sample by LC / MS. The sample is mixed with methanol at 80:20 and centrifuged at 3,000 rpm for 20 minutes at 4 ° C. The resulting supernatant can be recovered prior to LC-MS / MS assessing 2-hydroxyglutaric acid levels and stored at −80 ° C. A variety of different liquid chromatography (LC) separation methods can be used. Each method is a triple quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode with MS parameters optimized for infused metabolite standard solution by negative electrospray ionization (ESI, -3.0 kV). Can be linked to. Metabolites can be separated by reverse phase chromatography using 10 mM tributyl-amine as the ion pairing agent in the aqueous mobile phase according to a variant of the previously reported method (Luo et al. J Chromatogr A 1147, 153-. 64,2007). One method allows for redissolution of TCA metabolites: t = 0, 50% B, t = 5, 95% B, t = 7, 95% B, t = 8, 0% B, where B is 100. % Refers to the organic mobile phase of methanol. Another method is specific for 2-hydroxyglutaric acid and forms a fast linear gradient of 50% -95% B (buffer as defined above) over 5 minutes. Synergy Hydro-RP, 100 mm × 2 mm, 2.1 μm particle size (Phenomonex) can be used as a column as described above. Metabolites can be quantified by comparing peak areas with known concentrations of pure metabolite standards. ¹³ Metabolite flux tests from C-glutamine can be described, for example, in Munger et al. It can be carried out as described in Nat Biotechnol 26, 1179-86, 2008.

In certain embodiments, 2HG is directly evaluated.

In certain embodiments, the derivative of 2HG formed in the process of performing the analytical method is evaluated. As an example, such a derivative can be a derivative formed in MS analysis. Derivatives can include, for example, salt adducts, eg Na adducts, hydrated variants, or similarly salt adducts, eg, hydrated variants that are Na adducts, formed in MS analysis.

In certain embodiments, 2HG metabolic derivatives are evaluated. Examples include species that accumulate, increase, or decrease as a result of the presence of 2HG, such as glutaric acid or glutamic acid that correlates with 2HG, eg, R-2HG.

などの脱水誘導体が挙げられる。 Exemplary 2HG derivatives include the compounds provided below or salt adducts thereof:

Dehydrated derivatives such as.

2HG is known to accumulate in hereditary metabolic disorders 2-hydroxyglutaric aciduria. The disease is caused by a deficiency of the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to α-KG (Struis, EA et al. Am. J. Hum. Genet. 76, 358-60 (2005). ). Patients with 2-hydroxyglutarate dehydrogenase deficiency accumulate 2HG in the brain as assessed by MRI and CSF analysis, develop leukoencephalopathy, and have an increased risk of developing brain tumors (Aghili, M., Zahedi). , F. & Rafiee, J Neurooncol 91,233-6 (2009), Kolker, S., Mayatepek, E. & Hoffmann, GF Neuropeditrics 33, 225-31 (2002), Wajner, M., Latini, A. , AT & Dutra-Filho, CSJ Inherit Meterb Dis27, 427-48 (2004)). In addition, elevated 2HG brain levels resulted in increased ROS levels (Kolker, S. et al. Eur J Neurosci 16, 21-8 (2002), Latini, A. et al. Eur J Neurosci 17, 2017-22 (). 2003)), which contributes to the potentially increased risk of cancer. The ability of 2HGs to act as NMDA receptor agonists can contribute to this effect (Kolker, S. et al. Eur J Neurosci 16, 21-8 (2002)). 2HG can also be toxic to cells by competitively inhibiting glutamate and / or αKG-utilizing enzymes. These include transaminase, which allows the utilization of nitrogen glutamate for amino and nucleic acid biosynthesis, as well as αKG-dependent procollagen-hydroxylase, such as those that regulate Hif1-α levels.

The treatment methods described herein can further include various evaluation steps prior to and / or after treatment with Compound 1.

In one embodiment, before and / or after treatment with Compound 1, the method further comprises assessing the growth, size, weight, invasiveness, stage, and / or other genotypes of myelodysplastic syndrome. ..

In certain embodiments, before and / or after treatment with Compound 1, the method further comprises the step of assessing the IDH2 genotype of myelodysplastic syndrome. This can be achieved by conventional methods in the art such as DNA sequencing, immunoassay and / or assessment of the presence, distribution, or level of 2HG.

In one embodiment, the method further comprises the step of determining 2HG levels in the subject before and / or after treatment with Compound 1. This is achieved by spectroscopic analysis, eg magnetic resonance based analysis, eg, sample analysis of body fluids such as MRI and / or MRS measurements, serum or spinal fluid analysis, or analysis of surgical materials, eg, by mass analysis. be able to.

In certain embodiments, compound 1 is oral, parenteral (eg, intramuscular, intraperitoneal, intravenous, CIV, intracapsular or infusion, subcutaneous injection, or implantation, depending on the disease being treated and the condition of the subject. It can be administered by injection), inhalation, intranasal, intravaginal, rectal, sublingual, or topical (eg, transdermal or topical) route of administration. Compound 1 may be used alone or in a suitable dosage unit containing a pharmaceutically acceptable excipient, carrier, adjuvant, and vehicle suitable for each route of administration, together with one or more activators (s). Can be formulated.

In certain embodiments, the amount of compound 1 administered in the methods provided herein can be, for example, in the range of about 5 mg / day to about 2,000 mg / day. In one embodiment, the range is from about 10 mg / day to about 2,000 mg / day. In one embodiment, the range is from about 20 mg / day to about 2,000 mg / day. In one embodiment, the range is from about 50 mg / day to about 1,000 mg / day. In one embodiment, the range is from about 100 mg / day to about 1,000 mg / day. In one embodiment, the range is from about 100 mg / day to about 500 mg / day. In one embodiment, the range is from about 150 mg / day to about 500 mg / day. In one embodiment, the range is from about 150 mg / day to about 250 mg / day. In certain embodiments, the particular dose is, for example, about 10 mg / day. In one embodiment, the dose is about 20 mg / day. In one embodiment, the dose is about 50 mg / day. In one embodiment, the dose is about 60 mg / day. In one embodiment, the dose is about 75 mg / day. In one embodiment, the dose is about 100 mg / day. In one embodiment, the dose is about 120 mg / day. In one embodiment, the dose is about 150 mg / day. In one embodiment, the dose is about 200 mg / day. In one embodiment, the dose is about 250 mg / day. In one embodiment, the dose is about 300 mg / day. In one embodiment, the dose is about 350 mg / day. In one embodiment, the dose is about 400 mg / day. In one embodiment, the dose is about 450 mg / day. In one embodiment, the dose is about 500 mg / day. In one embodiment, the dose is about 600 mg / day. In one embodiment, the dose is about 700 mg / day. In one embodiment, the dose is about 800 mg / day. In one embodiment, the dose is about 900 mg / day. In one embodiment, the dose is about 1,000 mg / day. In one embodiment, the dose is about 1,200 mg / day. In one embodiment, the dose is, or about 1,500 mg / day. In certain embodiments, the particular dose is, for example, up to about 10 mg / day. In one embodiment, the particular dose is up to about 20 mg / day. In one embodiment, the particular dose is up to about 50 mg / day. In one embodiment, the particular dose is up to about 60 mg / day. In one embodiment, the particular dose is up to about 75 mg / day. In one embodiment, the particular dose is up to about 100 mg / day. In one embodiment, the particular dose is up to about 120 mg / day. In one embodiment, the particular dose is up to about 150 mg / day. In one embodiment, the particular dose is up to about 200 mg / day. In one embodiment, the particular dose is up to about 250 mg / day. In one embodiment, the particular dose is up to about 300 mg / day. In one embodiment, the particular dose is up to about 350 mg / day. In one embodiment, the particular dose is up to about 400 mg / day. In one embodiment, the particular dose is up to about 450 mg / day. In one embodiment, the particular dose is up to about 500 mg / day. In one embodiment, the particular dose is up to about 600 mg / day. In one embodiment, the particular dose is up to about 700 mg / day. In one embodiment, the particular dose is up to about 800 mg / day. In one embodiment, the particular dose is up to about 900 mg / day. In one embodiment, the particular dose is up to about 1,000 mg / day. In one embodiment, the particular dose is up to about 1,200 mg / day. In one embodiment, the particular dose is up to about 1,500 mg / day.

In certain embodiments, Compound 1 for the methods described herein is administered at a dose of about 20-2000 mg / day. In certain embodiments, compound 1 is administered at a dose of about 50-500 mg / day. In certain embodiments, the dose is about 50 mg / day. In certain embodiments, the dose is about 60 mg / day. In certain embodiments, the dose is about 100 mg / day. In certain embodiments, the dose is about 150 mg / day. In certain embodiments, the dose is about 200 mg / day. In certain embodiments, the dose is about 300 mg / day.

In one embodiment, the amount of compound 1 in a pharmaceutical composition or dosage form according to the method provided herein can be, for example, in the range of about 5 mg to about 2,000 mg. In one embodiment, the range is from about 10 mg to about 2,000 mg. In one embodiment, the range is from about 20 mg to about 2,000 mg. In one embodiment, the range is from about 50 mg to about 1,000 mg. In one embodiment, the range is from about 50 mg to about 500 mg. In one embodiment, the range is from about 50 mg to about 250 mg. In one embodiment, the range is from about 100 mg to about 500 mg. In one embodiment, the range is from about 150 mg to about 500 mg. In one embodiment, the range is from about 150 mg to about 250 mg. In certain embodiments, the particular amount is, for example, about 10 mg. In one embodiment, the specific amount is about 20 mg. In one embodiment, the specific amount is about 30 mg. In one embodiment, the specific amount is about 50 mg. In one embodiment, the specific amount is about 60 mg. In one embodiment, the specific amount is about 75 mg. In one embodiment, the specific amount is about 100 mg. In one embodiment, the specific amount is about 120 mg. In one embodiment, the specific amount is about 150 mg. In one embodiment, the specific amount is about 200 mg. In one embodiment, the specific amount is about 250 mg. In one embodiment, the specific amount is about 300 mg. In one embodiment, the specific amount is about 350 mg. In one embodiment, the specific amount is about 400 mg. In one embodiment, the specific amount is about 450 mg. In one embodiment, the specific amount is about 500 mg. In one embodiment, the specific amount is about 600 mg. In one embodiment, the specific amount is about 650 mg. In one embodiment, the specific amount is about 700 mg. In one embodiment, the specific amount is about 800 mg. In one embodiment, the specific amount is about 900 mg. In one embodiment, the specific amount is about 1,000 mg. In one embodiment, the specific amount is about 1,200 mg. In one embodiment, the particular amount is, or about 1,500 mg. In certain embodiments, the particular amount is, for example, up to about 10 mg. In one embodiment, the specific amount is up to about 20 mg. In one embodiment, the specific amount is up to about 50 mg. In one embodiment, the specific amount is up to about 60 mg. In one embodiment, the specific amount is up to about 75 mg. In one embodiment, the specific amount is up to about 100 mg. In one embodiment, the specific amount is up to about 120 mg. In one embodiment, the specific amount is up to about 150 mg. In one embodiment, the specific amount is up to about 200 mg. In one embodiment, the specific amount is up to about 250 mg. In one embodiment, the specific amount is up to about 300 mg. In one embodiment, the specific amount is up to about 350 mg. In one embodiment, the specific amount is up to about 400 mg. In one embodiment, the specific amount is up to about 450 mg. In one embodiment, the specific amount is up to about 500 mg. In one embodiment, the specific amount is up to about 600 mg. In one embodiment, the specific amount is up to about 700 mg. In one embodiment, the specific amount is up to about 800 mg. In one embodiment, the specific amount is up to about 900 mg. In one embodiment, the specific amount is up to about 1,000 mg. In one embodiment, the specific amount is up to about 1,200 mg. In one embodiment, the specific amount is up to about 1,500 mg.

In one embodiment, Compound 1 can be delivered as a single dose, eg, a single bolus injection, or an oral tablet or pill, or over a long period of time, for example, a long-term continuous infusion or a long-term divided bolus dose. In one embodiment, Compound 1 can be administered repeatedly, if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or their lack, such as patient symptom assessment, physical examination, x-ray, CAT, PET, or visualization of tumors imaged using MRI scanning and other generally accepted assessment modalities. , Determined by methods known in the art.

In certain embodiments, compound 1 for the methods described herein is administered once daily.

In certain embodiments, Compound 1 is administered to the patient in a cycle (eg, daily administration for 1 week followed by a washout period of up to 3 weeks without administration). Cycling therapy involves administration of the active drug for a period of time, followed by a period of withdrawal, and this continuous administration. Cycling therapy can reduce the development of tolerance, avoid or reduce side effects, and / or improve the effectiveness of treatment.

In one embodiment, the method provided herein comprises compound 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or Includes administration in more than 40 cycles. In certain embodiments, compound 1 for the methods described herein is administered over 1-25 cycles. In one embodiment, the median number of cycles administered in a group of patients is about 1. In one embodiment, the median number of cycles administered in a group of patients is about 2. In one embodiment, the median number of cycles administered in a group of patients is about 3. In one embodiment, the median number of cycles administered in a group of patients is about 4. In one embodiment, the median number of cycles administered in a group of patients is about 5. In one embodiment, the median number of cycles administered in a group of patients is about 6. In one embodiment, the median number of cycles administered in a group of patients is about 7. In one embodiment, the median number of cycles administered in a group of patients is about 8. In one embodiment, the median number of cycles administered in a group of patients is about 9. In one embodiment, the median number of cycles administered in a group of patients is about 10. In one embodiment, the median number of cycles administered in a group of patients is about 11. In one embodiment, the median number of cycles administered in a group of patients is about 12. In one embodiment, the median number of cycles administered in a group of patients is about 13. In one embodiment, the median number of cycles administered in a group of patients is about 14. In one embodiment, the median number of cycles administered in a group of patients is about 15. In one embodiment, the median number of cycles administered in a group of patients is about 16. In one embodiment, the median number of cycles administered in a group of patients is about 17. In one embodiment, the median number of cycles administered in a group of patients is about 18. In one embodiment, the median number of cycles administered in a group of patients is about 19. In one embodiment, the median number of cycles administered in a group of patients is about 20. In one embodiment, the median number of cycles administered in a group of patients is about 21. In one embodiment, the median number of cycles administered in a group of patients is about 22. In one embodiment, the median number of cycles administered in a group of patients is about 23. In one embodiment, the median number of cycles administered in a group of patients is about 24. In one embodiment, the median number of cycles administered in a group of patients is about 25. In one embodiment, the median number of cycles administered in a group of patients is about 26. In one embodiment, the median number of cycles administered in a group of patients is about 27. In one embodiment, the median number of cycles administered in a group of patients is about 28. In one embodiment, the median number of cycles administered in a group of patients is about 29. In one embodiment, the median number of cycles administered in a group of patients is about 30. In one embodiment, the median number of cycles administered in a group of patients is greater than about 30 cycles.

In certain embodiments, the treatment cycle is optionally followed by treatment holidays (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) for subjects in need thereof. , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or more than 28 days), followed by multiple days (eg, 1). , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 14 or more days) comprising multiple doses of Compound 1.

In certain embodiments, compound 1 for the methods described herein is administered in a 28-day cycle.

In certain embodiments, compound 1 for the methods described herein is orally administered.

In certain embodiments, Compound 1 for the methods described herein is administered once daily in a 28-day cycle at a dose of about 100 mg / day.

In certain embodiments, compound A is used in a method for treating myelodysplastic syndrome in a subject, the method comprising orally administering to the subject a therapeutically effective amount of compound A, myelodysplastic syndrome. , IDH2 variant allogen and at least one second gene variant allelic gene, the second gene being selected from the group consisting of ASXL1 and SRSF2, compound A once daily. , 28 day cycle, administered at doses of 5, 10, 25, 50, 100, 150, or 200 mg. In one embodiment, Compound A is administered at a dose of 100 mg / day.

In certain embodiments, compound A is used in a method for treating myelodysplastic syndrome in a subject, the method comprising orally administering to the subject a therapeutically effective amount of compound A, which is a myeloid dysplasia syndrome. , IDH2 variant allele and at least one second gene variant allelic, the second gene being selected from the group consisting of ASXL1 and SRSF2, compound A once daily. , In a 28-day cycle, administered at doses of 5, 10, 25, 50, 100, 150, or 200 mg, myelodysplastic syndromes are acute myeloid leukemia, preferably comprising recurrent AML or refractory AML or untreated AML. It follows sex leukemia (AML). In one embodiment, compound A is administered at a dose of 100 mg / day and myelodysplastic syndrome is followed by acute myeloid leukemia (AML), preferably comprising recurrent AML or refractory AML or untreated AML. Occur.

In a more specific embodiment, compound A is used in a method for treating myelodysplastic syndrome in a subject, the method comprising orally administering to the subject a therapeutically effective amount of compound A for myeloid dysplasia. The syndrome is characterized by the presence of a variant allele of IDH2 and a variant allelic of at least one second gene, the second gene being selected from the group consisting of ASXL1 and SRSF2, compound A daily. Once administered in a 28-day cycle at doses of 5, 10, 25, 50, 100, 150, or 200 mg, in one embodiment at a dose of 100 mg / day, myelodysplastic syndrome is a recurrent AML or It follows acute myeloid leukemia (AML), including refractory AML or untreated AML, and myelodysplastic syndrome occurs with refractory anemia.

In a more specific embodiment, compound A is used in a method for treating myelodysplastic syndrome in a subject, the method comprising orally administering to the subject a therapeutically effective amount of compound A for myeloid dysplasia. The syndrome is characterized by the presence of a variant allele of IDH2 and a variant allelic of at least one second gene, the second gene being selected from the group consisting of ASXL1 and SRSF2, compound A daily. Once administered in a 28-day cycle at doses of 5, 10, 25, 50, 100, 150, or 200 mg, in one embodiment at a dose of 100 mg / day, myelodysplastic syndrome is a recurrent AML or It follows acute myeloid leukemia (AML), including refractory AML or untreated AML, and myelodysplastic syndrome occurs with refractory anemia with excess blast cells, subtype RAEB-1 or RAEB-2.

In certain embodiments, compound A is used in a method for treating myelodysplastic syndrome in a subject, the method comprising orally administering to the subject a therapeutically effective amount of compound A, myelodysplastic syndrome. , IDH2 variant allelic and at least one second gene variant allelic, the second gene being selected from the group consisting of ASXL1 and SRSF2, compound A once daily. , In a 28-day cycle, at doses of 5, 10, 25, 50, 100, 150, or 200 mg, in one embodiment at a dose of 100 mg / day, the subject to previous myelodysplastic syndrome therapy. Was relapsed or refractory, or was not a candidate for standard therapy.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodysplastic syndrome, and (b). ) Biological samples are screened for IDH2 mutations and mutations in a second gene selected from the group consisting of ASXL1 and SRSF2, and (c) Myelodysplastic syndrome is the presence of IDH2 mutant allelic genes, as well as ASXL1 and When characterized by the presence of a mutant allogen of the second gene selected from the group consisting of SRSF2, identifying the subject as a suitable cancer subject for treatment using the methods described herein. include. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodysplastic syndrome, and (b). ) Screening of biological samples for IDH2 mutations and mutations in at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1 and (c) Myelodysplastic syndrome is a variant of IDH2. If the subject is characterized by the presence of a gene and the absence of a mutant allelic gene of at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1, the method described herein is used. Includes identifying suitable cancer targets for treatment. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodysplastic syndrome, and (b). ) Screening of biological samples for IDH2 mutations and mutations in at least one other gene selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF, and (c). Myelodysplastic syndrome is the presence of a mutant allogene for IDH2, as well as a mutant allogeneic for at least one other gene selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. When characterized by the absence of a gene, it comprises identifying the subject as a suitable cancer subject for treatment using the methods described herein. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodysplastic syndrome, and (b). ) Screening of biological samples for IDH2 mutations and mutations in at least one other gene selected from the group consisting of SETBP1, NRAS, JAK2, and BRAF, and (c) Myelodysplastic syndrome is a variant of IDH2. If the subject is characterized by the presence of a gene and the absence of a mutant allelic gene of at least one other gene selected from the group consisting of SETBP1, NRAS, JAK2, and BRAF, the method described herein is used. Includes identifying suitable cancer targets for treatment. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodystrophy syndrome, and (b). ) The biological sample is an IDH2 mutation, a mutation in a second gene selected from the group consisting of ASXL1 and SRSF2, and a variant allele of at least one other gene selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. Screening for the absence of the gene and (c) the presence of a mutant allogene for IDH2, the presence of a mutant allelic gene for a second gene selected from the group consisting of ASXL1 and SRSF2, and KRAS. , TP53, SETBP1, and U2AF1, if characterized by the absence of a mutant allelic gene of at least one other gene selected from the group, the subject is a cancer suitable for treatment using the methods described herein. Includes identifying as a target. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In one embodiment, there is provided herein a method of identifying a subject suitable for the treatment method described herein, (a) obtaining a biological sample from a subject having myelodystrophy syndrome, and (b). ) Biological samples are selected from the group consisting of IDH2 mutations, at least one second gene mutation selected from the group consisting of ASXL1 and SRSF2, and the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Screening for the absence of a mutant allogen of at least one other gene, and (c) at least one of the myeloid dysplasia syndrome selected from the group consisting of the presence of a mutant allogen of IDH2, ASXL1 and SRSF2. The presence of a mutant alligator gene for the second gene and the absence of a mutant alligator gene for at least one other gene selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. Features include identifying the subject as a suitable cancer subject for treatment using the methods described herein. In another embodiment, a subject identified as a suitable subject for the therapeutic methods described herein is treated with Compound 1.

In another embodiment, treatment with compound 1 using the methods provided herein from a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 herein. A method for identifying one or more subjects suitable for the disease is provided. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by a mutation in at least one second gene from a plurality of subjects suitable for treatment with compound 1. Genes are selected from the group consisting of ASXL1 and SRSF2. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, treatment with compound 1 using the methods provided herein from a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 herein. A method for identifying one or more subjects suitable for the disease is provided. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by a mutation in at least one second gene from a plurality of subjects suitable for treatment with compound 1. Genes are selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, from a plurality of subjects having myelodysplastic syndrome characterized herein by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Methods are provided for identifying one or more subjects suitable for treatment with compound 1 using the methods provided herein, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. Will be done. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, from a plurality of subjects having myelodysplastic syndrome characterized herein by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Methods are provided for identifying one or more subjects suitable for treatment with compound 1 using the methods provided herein, the other genes being KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS. , JAK2, and BRAF. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, from a plurality of subjects having myelodysplastic syndrome characterized herein by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Methods are provided for identifying one or more subjects suitable for treatment with compound 1 using the methods provided herein, the other gene being selected from the group consisting of SETBP1, NRAS, JAK2, and BRAF. Will be done. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of SETBP1, NRAS, JAK2, and BRAF. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, from a plurality of subjects having myelodysplastic syndrome characterized herein by the presence of a mutant allele of IDH2 and the absence of a mutant allele of at least one other gene. Methods are provided for identifying one or more subjects suitable for treatment with compound 1 using the methods provided herein, the other genes being TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2. , And BRAF. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, provided herein by a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of a second gene. A method for identifying one or more subjects suitable for treatment with compound 1 using the method described above is provided, and the second gene is selected from the group consisting of ASXL1 and SRSF2. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, herein, from a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. A method for identifying one or more subjects suitable for treatment with compound 1 using the method provided in the book is provided, and the second gene is selected from the group consisting of ASXL1 and SRSF2. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the absence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with Compound 1. , Other genes are selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, and STAG2. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, herein, from a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. A method for identifying one or more subjects suitable for treatment with compound 1 using the method provided in the book is provided, and the second gene is selected from the group consisting of ASXL1 and SRSF2. The method comprises identifying one or more subjects with myelodysplastic syndrome characterized by the presence of a mutant allele of at least one other gene from a plurality of subjects suitable for treatment with compound 1. , Other genes are selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL. In one embodiment, one or more suitable subjects are treated with Compound 1.

In another embodiment, herein, from a plurality of subjects having myelodysplastic syndrome characterized by the presence of a mutant allele of IDH2 and a mutant allele of at least one second gene. A method for identifying one or more subjects suitable for treatment with compound 1 using the method provided in the book is provided, and the second gene is selected from the group consisting of ASXL1 and SRSF2. The method comprises identifying one or more subjects with myelodysplastic syndrome from multiple subjects suitable for treatment with compound 1, where myelodysplastic syndrome is a variant of at least one other gene. Characterized by the presence of the gene, other genes are selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL, and myelodysplastic syndrome is characterized by the absence of a mutant allogene for at least one additional gene. The additional gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. In one embodiment, one or more suitable subjects are treated with Compound 1.

In certain embodiments, the inhibitory activity of Compound 1 against the IDH2 variant is tested by the method described in US Patent Application Publication No. US2013 / 0190287, or a similar method, which is incorporated herein by reference in its entirety. Can be done.

Patient Population In certain embodiments of the methods provided herein, the subject to be treated is an animal, eg, a mammal or a non-human primate. In certain embodiments, the subject is a human patient. The subject can be male or female.

In particular, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is a variant of the IDH2 variant allele and a variant of the second gene. Characterized by the presence of alleles, the second gene is selected from the group consisting of ASXL1 and SRSF2.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is the presence of a mutant allogene for IDH2 and at least. A variant of one other gene is characterized by the absence of an allelic gene, the other gene being selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is the presence of a mutant allogene for IDH2 and at least. Characterized by the absence of a mutant allelic gene of one other gene, the other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is the presence of a mutant allogene for IDH2 and at least. Characterized by the absence of a mutant allelic gene of one other gene, the other gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is the presence of a mutant allogene for IDH2 and at least. Mutant of one other gene Characterized by the absence of an allelic gene, the other gene is selected from the group consisting of SETBP1, NRAS, JAK2, and BRAF.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, wherein the myelodysplastic syndrome is a variant allogen of IDH2 and a second. Characterized by the presence of variant allogens of the gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is further characterized by the absence of variant allelics of at least one other gene. The other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is a variant allogen of IDH2 and at least one. Characterized by the presence of a variant allogen of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is the absence of a variant allelic of at least one other gene. The other gene is selected from the group consisting of KRAS, TP53, SETBP1, U2AF1, TCF3, and STAG2.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is a variant allogen of IDH2 and at least one. Characterized by the presence of a variant allogen of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is the absence of a variant allelic of at least one other gene. The other gene is selected from the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF.

In certain embodiments, subjects that can be treated according to the methods provided herein include subjects with myelodysplastic syndrome, where myelodysplastic syndrome is a variant allogen of IDH2 and at least one. Characterized by the presence of a variant allogen of the second gene, the second gene is selected from the group consisting of ASXL1 and SRSF2, and myelodysplastic syndrome is the presence of a variant allogen of at least one other gene. The other gene is selected from the group consisting of MPL, DNMT3A, CSF3R, FAT3, or CBL.

Some diseases or disorders are more common in a particular age group, but also include methods of treating a subject regardless of the subject's age. In some embodiments, the subject is a human patient at least 18 years old. In some embodiments, the patient is 10, 15, 18, 21, 24, 35, 40, 45, 50, 55, 65, 70, 75, 80, or 85 years or older.

In certain embodiments, the methods provided herein comprise the treatment of a subject who has not previously been treated for myelodysplastic syndrome. In other embodiments, the method comprises treating a subject previously treated for myelodysplastic syndrome but not responding to standard therapy, as well as a subject currently being treated. For example, the subject may or is currently being treated with standard treatment regimens for myelodysplastic syndrome known to those of skill in the art.

It is understood that the above detailed description and accompanying examples are merely exemplary and should not be construed as a limitation to the scope of the subject. Various changes and modifications to the disclosed embodiments will be apparent to those of skill in the art. Such changes and modifications, including but not limited to those related to the usage provided herein, may be made without departing from their gist and scope. Patents, patent application publications, and other publications referenced herein are incorporated herein by reference.

When used, the symbols and practices used in the examples are used in modern scientific literature, such as the Journal of the American Chemical Society or Journal of Biological Chemistry, regardless of the specific abbreviations defined. Consistent with what is done. Specifically, but not limited to, the following abbreviations may be used in the Examples and throughout the specification: MDS = Myelodysplastic Syndrome, ASXL1 = Additional Sex Combs-like 1, BRAF = B-Raf proto-oncogene, Serin. / Treonine kinase, CBL = Casitas B-series lymphoma proto-oncogene, CSF3R = colony stimulator 3 receptor, DNMT3A = DNA cytosine-5-methyltransferase 3α, FAT3 = FAT atypical cadoherin 3, JAK2 = Janus kinase 2, KRAS = Carsten rat sarcoma virus cancer gene homolog, mIDH2 = mutant isocitrate dehydrogenase 2, MPL = myelodysplastic leukemia protein, NRAS = neuroblastoma RAS virus cancer gene homolog, SETBP1 = SET binding protein 1, SRSF2 = serine / Arginine-rich splicing factor 2, STAG2 = interstitial antigen 2, TCF = transcription factor 3, TP53 = tumor protein p53, U2AF1 = U2 small nucleus RNA cofactor 1, CR = complete response, HI = hematological improvement, mCR = Complete myelodysplastic response, NR = no response, and PR = partial response.
Example 1. Phase 1/2, multicenter, open-label, dose escalation and expansion, safety, pharmacokinetics, pharmacodynamics, and clinical activity studies of orally administered compound A in subjects with advanced hematological malignancies with IDH2 mutations.

Phase 1 (dose escalation and part 1 expansion) Objective:

Main purpose

To evaluate the safety and resistance of treatment with compound A, which is administered continuously as a single agent orally administered on days 1-28 of a 28-day cycle in subjects with advanced hematological malignancies.

To determine the maximum resistant dose (MTD) or maximum dose (MAD) and / or recommended Phase 2 dose (RP2D) of Compound A in subjects with advanced hematological malignancies, eg, MDS.

Secondary purpose

Explain the dose limiting toxicity (DLT) of Compound A in subjects with advanced hematological malignancies, eg, MDS.

To characterize the pharmacokinetics (PK) of compound A and its metabolites in subjects with advanced hematological malignancies, eg, MDS.

To characterize the PK / pharmacodynamic (PD) relationship between compound A and 2-hydroxyglutaric acid (2-HG).

To characterize the clinical activity associated with compound A in a subject with advanced hematological malignancies, eg, MDS.

Phase 2 Objective:

Main purpose

To evaluate the efficacy of Compound A as a treatment for subjects with relapsed or refractory AML with IDH2 mutations.

Secondary purpose

To further evaluate the safety profile of Compound A in subjects with relapsed or refractory AML with IDH2 mutations.

To characterize the pharmacokinetics (PK) of compound A and its metabolites in subjects with relapsed or refractory AML with IDH2 mutations.

To characterize the PK / pharmacodynamic (PD) relationship between compound A and 2-hydroxyglutaric acid (2-HG).

Test design:

This is Phase 1/2, multicenter, open-label, 3 parts (Phase 1 dose escalation, Phase 1 Part 1) of orally administered compound A in advanced hematological malignancies with IDH2 mutations, eg, MDS. Expansion and Phase 2), safety, PK / PD, and clinical activity assessment. The study included a dose escalation phase to determine MTD / MAD and / or RP2D, an expansion phase (Part 1) to further assess the safety, resistance, and clinical activity of Compound A, and Compound A in RP2D. Phase 2 was included to assess clinical efficacy and further assess safety in subjects with refractory and recurrent AML with IDH2 mutations.

In the Phase 1 part, the study is a dose escalation phase to determine MTD / MAD and / or RP2D, and an extended phase to further assess the safety, tolerance, and clinical activity of Compound A in the selected population (Part 1). Enlarged) was included. The Phase 2 part (formerly Part 2 Expansion) provided further information on the efficacy, safety, resistance, and clinical activity of Compound A in subjects with refractory or recurrent AML with IDH2 mutations.

Dose escalation phase: The dose escalation phase utilized a standard "3 + 3" design. During the dose escalation phase, relapsed or refractory acute myeloid leukemia (AML), untreated AML over 60 years of age who was not a candidate for standard therapy, or myelodysplastic syndrome with refractory anemia with excess blast cells Consent-eligible subjects with had were enrolled in a continuous cohort in which the dose of compound A was increased without exceeding the 650 mg QD dose. A minimum of 3 subjects were enrolled in each dose cohort. The first three subjects enrolled in each dosing cohort during the dose-escalation portion of the study received a single dose of study drug on day 3 (ie, 3 days prior to the start of daily dosing) 72. Safety and PK / PD assessments were performed over time to assess drug concentrations as well as 2-HG and α-KG levels. The next dose of study drug was on day 1 of cycle 1 (C1D1), at which point daily dosing was started. The initial dosing schedule was twice daily (approximately every 12 hours). A once-daily dosing schedule was also performed based on the data generated. Alternative dosing schedules (eg, once-daily dosing following the loaded dose) could be continuously investigated during the dose escalation and expansion phase as approved by the clinical trial team. If there were multiple subjects in the screening process when the third subject in the cohort began treatment, up to two additional subjects could be enrolled with medical monitor approval. For these additional subjects, the PK / PD evaluation from the 3rd day to the 1st day was optional after consideration with the medical monitor.

The safety of administration during the dose escalation phase was assessed by a clinical trial team consisting of a client-designated person (the responsible medical officer), the study medical monitor, and the investigator. The clinical trial team reviewed the safety data generated from each cohort to determine whether dose escalation should be performed.

Toxicity severity was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) 4.03. DLT was defined as outlined below.

Non-blood:

All clinically significant non-hematological toxic CTCAE ≧ grade except ≧ grade 3 blood bilirubin increase in subjects with UDP (uridine diphosphate) -glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) mutation 3. In subjects with the UGT1A1 mutation, an increase in blood bilirubin> 5 x upper normal limit (ULN) could be considered a DLT.

blood:

At least 42 days after the start of cycle 1 therapy (NCI CTCAE, 4.03 edition, leukemia-specific criteria, ie, with myelocytopenia <5% after day 28 from study drug initiation without evidence of leukemia) ≧ Grade 3 Long-term myelosuppression, defined as persistence of neutropenia or thrombocytopenia. Leukemia-specific grading was used for cytopenia (based on baseline reduction percentage: 50-75% = grade 3,> 75% = grade 4).

Due to the high frequency of comorbidity and concomitant administration in the study population, it was difficult to identify adverse events (AEs) to specific drugs. Therefore, all AEs that could not be explicitly determined to be unrelated to Compound A were considered to be related to the determination of DLT and were reviewed by the clinical trial team. The clinical trial team also reviewed any other outbreak toxicity that was not explicitly defined by the DLT criteria and determined which one justified the DLT designation.

If no DLT was observed after the third subject completed the 28-day DLT evaluation period (ie, cycle 1), the study was dose-escalated to the next cohort after safety review by the clinical study team. Proceeded to. If 1 in 3 subjects experienced DLT during the first cycle, 3 additional subjects were enrolled in the cohort. If none of the three additional subjects experienced DLT, dose escalation continued to the next cohort after safety review by the clinical trial team. If two or more subjects in the cohort experienced DLT during the first cycle, dose escalation was discontinued and the next lower dose level was declared MTD. If the MTD cohort included only 3 subjects, an additional 3 subjects were enrolled at that dose level, confirming that <2 out of 6 subjects experienced DLT at that dose. Alternatively, an intermediate dose level between the non-tolerant dose level and the previous tolerant dose level could be investigated and MTD could be declared if <2 out of 6 subjects experienced DLT at that dose.

The dose increase of Compound A for each dose cohort is guided by an accelerated escalation design, and the dose is until NCI CTCAE grade 2 or higher toxicity associated with Compound A is observed in any subject within the cohort. It was doubled (100% increase) from one cohort to the next. After evaluation by the clinical trial team, subsequent dose increases were less than 50% until MTD was determined. The absolute percentage increase in dose was determined by the clinical trial team based on the type and severity of all toxicity seen in previous dose cohorts. MTD was the highest dose to cause DLT in <2 of 6 subjects.

Intra-subject dose escalation was observed with medical monitor approval to optimize the number of subjects treated at doses that may be clinically appropriate.

Part 1 expansion phase

During the Part 1 expansion phase, safety, PK / PD, and preliminary clinical activity data were continuously reviewed by the clinical trial team.

In Part 1, we enrolled four non-randomized cohorts of approximately 25 subjects per arm with IDH2 mutant hematological malignancies as follows:

Arm 1: Subjects with relapsed or refractory AML and AML relapsed after age 60 years or older, or after bone marrow transplantation (BMT) at any age.

Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML relapsed after BMT.

Arm 3: Untreated AML who declined standard-of-care chemotherapy and age 60 years or older.

Arm 4: IDH2 mutant advanced hematological malignancies not eligible for Arms 1-3.

Phase 2

Phase 2, a crucial part of the study, is the compound at the recommended Phase 2 dose (RP2D) determined during the ongoing dose escalation phase in patients with IDH2 mutation relapse or refractory AML as defined below. Further constructed A efficacy and safety profile:

Subjects who relapsed after allogeneic transplantation,

Targets during the second and subsequent recurrences,

Subjects who were refractory to initial or reintroduction treatment,

Subjects who relapsed within 1 year of initial treatment, excluding patients with low-risk conditions according to NCCN guidelines (NCCN2015, NCCN2015 National Comprehensive Cancer Network Myeloid Leukemia (Version1.2015) /cw.cw.cwt.cwt. /Professionals/physician_gls/PDF/aml.pdf). Low-risk cytogenetics: inv (16), + (16; 16), t (8; 21), t (15; 17).

Approximately 125 subjects were enrolled in this part of the study.

Conducting general tests:

After explanation and consent, all subjects underwent screening procedures within 28 days prior to C1D1 to determine eligibility. All subjects needed to have confirmation of IDH2 mutant disease from bone marrow aspiration and peripheral blood. For subjects in the dose escalation phase and Part 1 expansion, documentation of IDH2 mutation status could be based on local institutional studies along with retrospective central laboratory studies. Subjects in Phase 2 were required to have an IDH2 mutant state based on a central laboratory study during pretreatment screening. Additional screening procedures include medical history, surgical history, and drug history, oral mucosal sampling for reproductive line mutation analysis, physical examination, vital sign, US East Coast Cancer Clinical Trials Group (ECOG) Performance Status (PS), 12-lead ECG (ECG), left ventricular ejection rate (LVEF) assessment, clinical laboratory assessment (hematology, chemistry, coagulation, and serum pregnancy tests), bone marrow biopsy and puncture fluid, 2-HG and α-KG Blood and bone marrow samples for measurement and blood for determination of UGT1A1 mutation status were included. In addition, subjects in Part 1 expansion were taken during screening a urine sample for 2-HG and α-KG measurements and a blood sample for cholesterol and 4β-OH-cholesterol levels.

Dose escalation and Part 1 expansion

The first 3 subjects enrolled in each cohort in the dose escalation phase and the first 15 enrolled in each arm of Part 1 expansion 3 days prior to the start of daily administration of Compound A (3rd day). Subject received a single dose of Compound A at the facility, Compound A, its metabolites (6-(6- (trifluoromethyl) pyridine-2-yl) -N2- (2- (trifluoromethyl) pyridine). Obtain a series of blood and urine samples to determine blood and urine concentrations of -4-yl) -1,3,5-triazine-2,4-diamine), 2-HG, and α-KG. did. A full 72-hour PK / PD profile was performed: Subjects stayed in the test facility for 10 hours on day 3-day, -2, -1, and 1 day for 24, 48, and 72-hour samples, respectively. I had to go back to my eyes. -Clinical observations and continuous 12-lead ECG and vital sign assessments were performed during the institutional period on day 3. Daily treatment with compound A was started at C1D1 and clinically for subjects in the dose escalation phase and part 1 expansion without PK / PD evaluation on day 3 for 8 hours after the first administration of compound A to C1D1. Observations and continuous 12-lead ECG and vital sign evaluations were performed.

Subjects in the dose escalation phase and Part 1 expansion were PK / PD evaluated over 10 hours on C1D15, C2D1, and C4D1. Pre-administration blood samples (troughs) were taken from C1D1 (for subjects who did not undergo PK / PD evaluation on day -3), C1D8, C1D22, C2D15, C3D1, C3D15, C5D1, and day 1 of all subsequent cycles. Obtained for determination of compound 1, 2-HG, and α-KG concentrations. These subjects had urine collected for PK / PD assessment at screening, before administration of C1D15, C2D1 and all subsequent cycles on day 1 and at the end of treatment visit. Available bone marrow biopsy samples were also evaluated for 2-HG and α-KG levels.

Phase 2

Subjects in Phase 2 of the study did not need to be evaluated on day -3, and these subjects underwent an 8-hour PK / PD profile on days 1 and 2 of cycles 1 and 2 and PK / PD for 24 hours. Pre-dose blood samples (troughs) of C1D2 and C2D2 were obtained to assess PD. Additional blood samples for PK / PD evaluation were taken before administration on day 1 of cycle 3 (within 30 minutes) and at the end of treatment visit. Time-matched 12-lead ECG was performed triple on the first day of cycles 1 and 2, and triple ECG was also obtained at the end of treatment visit. A single 12-lead ECG was performed starting at cycle 3 on the first day of each cycle and at follow-up visits. Available bone marrow biopsy samples were evaluated for 2-HG and α-KG levels.

Other safety assessments (all phases)

All subjects undergo safety assessments during treatment, including physical examination, vital signs, ECOG PS, 12-lead ECG, LVEF assessments, and clinical laboratory assessments (hematology, chemistry, coagulation, and urinalysis). rice field.

Clinical activity evaluation:

Phase 1 (dose escalation and part 1 expansion)

Subjects in the dose escalation phase and Part 1 expansion were at screening, C1D15, C2D1, and C3D1, regardless of delay and / or discontinuation, followed by every 28 days (peripheral blood only) or every 56 days (bone marrow) during study drug treatment. Bone marrow biopsy and / or bodily fluid and peripheral blood), and / or at any time when disease progression was suspected, were assessed, including bone marrow biopsy and / or bodily fluid and peripheral blood. Responses and treatment decisions for treatment in all subjects were determined by the investigator based on the Modified International Working Group (IWG) Response Criteria for Malignant Tumors Under Study or other appropriate response criteria. Choson et. al. J. Clin. Oncol. 21 (24): 4642-9 (2003).

Phase 2

For subjects enrolled in Phase 2 of the study, the extent of the disease, including bone marrow biopsy and / or puncture fluid and peripheral blood, was 12 months thereafter, regardless of C2D1, delay and / or discontinuation at screening. It was assessed every 28 days over and then every 56 days during study drug treatment, and / or at any time when disease progression was suspected. Eligibility, treatment decisions, and response to treatment were determined by the investigator based on the Revised International Working Group (IWG) Response Criteria. Responses were also retrospectively assessed by the Independent Response Judgment Committee (IRAC).

End of treatment and follow-up:

Subjects were able to continue treatment with Compound A until disease progression or the development of unacceptable toxicity.

Evidence supports that cancer-related IDH mutations block normal cell differentiation and promote tumorigenesis through 2-HG, aberrant production of potential cancer metabolites. Compound A was able to produce an antitumor effect by restoring the differentiation block induced by the IDH2 mutation and promoting appropriate cell differentiation.

Due to the unique mechanism of action of Compound A, the clinical response was different from that observed with cytotoxic agents. Responses with compound A can occur after more than two cycles of therapy, and in rare cases the corresponding clinical signs and symptoms of fever, fluid retention, hypoxia, and skin rash, referred to as differentiation-like syndrome. Could occur after the onset period of leukocytosis in peripheral blood and / or bone marrow.

Therefore, standard criteria developed based on experience with cytotoxic chemotherapeutic agents did not provide a complete and accurate response assessment for this new class of IDH2 inhibitors. Therefore, attention should be paid to the discontinuation of study drug in situations where the subject's assessment shows signs of progression within the first two cycles, especially the subject's clinical condition, but not limited to disease progression and /. Or it needed to be considered with a medical monitor in a stable situation, as supported by the absence of signs and symptoms of rapid deterioration indicating that the general condition was stable or improved. ..

Subjects who have experienced disease progression (PD) according to applicable response criteria will be evaluated for disease on 28 days to confirm PD with the option to continue treatment as described above while waiting for confirmation. Repeated later. If repeated assessments confirmed PD, the subject discontinued study treatment and proceeded to the survival follow-up phase.

Subjects with stable or progressive disease were able to continue study treatment with Compound A, with the discretion of the investigator and the approval of the medical monitor.

All subjects underwent end-of-treatment assessment (within approximately 5 days after the final dose of study drug), and a follow-up safety assessment was scheduled 28 days after the final dose. In addition, all subjects were followed monthly for disease status, overall survival, and initiation of non-trial antitumor therapy until death, withdrawal of consent, or end of study, whichever came first.

Subjects who achieved an appropriate response to treatment with Compound A and met the other criteria required to undergo hematopoietic stem cell transplantation (HSCT) were able to proceed to HSCT after discontinuation of study therapy. Those subjects were followed up in the study for results until recurrence or end of study to support the overall clinical benefit of Compound A in this situation.

Subjects who relapsed after HSCT confirmed recurrent IDH2 variant-positive disease and were used in the course of HSCT other than HSCT (pretreatment regimen or induction regimen, etc.) and antitumor used in anti-GVHD prevention after the final administration of compound A. If no other cancer treatment is given (except for therapy [ie, methotrexate]), the subject meets the safety parameters listed in the selection / exclusion criteria, and the study is open, medical monitor approval and study conduct. At his discretion, he was able to qualify for resuming treatment with Compound A. Subjects resumed Compound A therapy at the same dose and schedule as when Compound A treatment was discontinued prior to HSCT.

All subjects were followed monthly for assessment of survival and non-study antitumor therapy from study drug discontinuation to death or study termination, including those that relapsed after HSCT and were determined not to resume treatment.

Number of (planned) targets:

A total of at least about 291 subjects were planned to be enrolled in the study (ie, dose escalation, Part 1 expansion, and Phase 2 part of the study).

Assuming that MTD / MAD identification required evaluation of 13 dose levels / schedules of Compound A in up to 5 subjects per dose level, except that MTD / MAD required 6 subjects. Then, 66 subjects were enrolled during the dose escalation part of the study. Cohort expansion during dose escalation, PK / PD, safety, or replacement of subjects whose clinical activity was not evaluable to optimize RP2D and regimen (s), or planned escalation scheme or MTD / Additional subjects may be required to evaluate alternative dosing regimens other than MAD. Five dose levels (range 30 mg to 150 mg) were assessed on the BID schedule and eight dose levels (range 50 mg to 650 mg) were assessed on the QD schedule.

Four cohorts of a minimum of 25 additional subjects (a total of a minimum of 100 subjects) in a particular hematological malignancies subset were enrolled in Part 1 Expansion of the study.

The Phase 2 part of the study enrolled approximately 125 subjects with relapsed or refractory AML with IDH2 mutations. Additional subjects may be required to evaluate replacement or alternative dosing regimens of subjects that were not evaluable for PK / PD, safety, and / or clinical activity. The final total sample size could be adjusted according to the observed toxicity rate and the number of subjects enrolled for expanded evaluation.

Selection criteria

To be enrolled in the exam, the subject had to meet all of the following criteria:
1. 1. Subjects had to be 18 years of age or older.
2. 2. Subjects had to have advanced hematological malignancies including:
Phase 1 / dose escalation:
Diagnosis of AML according to World Health Organization (WHO) standards (Swedlow et. Al. WHO Classication of Tumors of Haematopoietic and Lymphoid Tips. 4th ed.Lyon, France; France: IARCPre
o Refractory or recurrent disease (defined as> 5% blast reappearance in bone marrow).
o Untreated AML, which was not a candidate for standard therapy due to age 60 years or older, and age, performance status, and / or adverse risk factors, according to the treating physician and with the approval of the medical monitor.
It occurs with refractory anemia with excess blast cells (subtype RAEB-1 or RAEB-2) according to the WHO classification, according to the treating physician and with the approval of the medical monitor, or the revised International Prognosis Scoring System (revised international prognosis scoring system). IPSS-R, Greenberg et.al.Blood.120 (12): 2454-65 (2012)) for the diagnosis of relapsed or refractory MDS, or clinical for its pathology. Subjects who were intolerant to established therapies known to provide benefits (ie, subjects who should not have been candidates for a regimen known to provide clinical benefits). (Other relapsed and / or primary refractory hematological malignancies that meet the selection / exclusion criteria, such as subjects with CMML, could be considered individually with the approval of the Medical Monitor.)
Phase 1 / Part 1 expansion:
Arm 1: Subjects with either relapsed or refractory AML and AML over 60 years of age or relapsed after BMT at any age.
Arm 2: Relapsed or refractory AML and age <60 years, excluding subjects with AML relapsed after BMT.
Arm 3: Untreated AML who declined standard-of-care chemotherapy and age 60 years or older.
Arm 4: IDH2 mutant advanced hematological malignancies not eligible for Arms 1-3.
Phase 2:
Diagnosis of AML according to World Health Organization (WHO) standards and relapsed or refractory disease as defined by:
o Subjects who have relapsed after allogeneic transplantation,
o Targets during recurrence after the second time,
o Subjects who were refractory to initial or reintroduction treatment,
Subjects who relapsed within 1 year of initial treatment, excluding patients with low-risk conditions according to the oNCCN guidelines. Low-risk cytogenetics: inv (16), + (16; 16), t (8; 21), t (15; 17).
3. 3. Subjects had to have a documented IDH2 gene mutation disease:
For subjects in the dose escalation phase and Part 1 expansion, IDH2 mutations could be based on local assessment. (The centralized test was conducted retroactively).
4. Central testing of IDH2 mutations in bone marrow aspiration and peripheral blood samples was required during screening to confirm eligibility for subjects in Phase 2 of the study. Subjects had to be capable of continuous bone marrow sampling, peripheral blood sampling, and urine sampling during the test.
Diagnosis and evaluation of AML or MDS was performed by bone marrow aspiration and biopsy. If the puncture fluid was not available (ie, "dry tap"), the diagnosis was made from a core biopsy.
Screening of bone marrow aspirations and peripheral blood samples was required for all subjects. A bone marrow biopsy had to be taken if proper puncture fluid was not achievable unless:
o Bone marrow aspiration and biopsy were performed as part of standard treatment within 28 days prior to the start of study treatment, and o Bone marrow aspiration, biopsy, and stained peripheral blood smear slides were local and central pathology. It was available to both judges,
5. Subject had to be able to understand the explanation and consent and be willing to sign. If approved and approved by the institution and / or the Institutional Review Board (IRB) / Institutional Review Board (IEC), the legal representative would otherwise not be able to provide explanation and consent. I was able to agree instead of.
6. The subject must have 0-2 ECOG PS (Oken et. Al. Am. J. Clin. Oncol. 5: 649-655 (1982)).
7. Platelet count ≥20,000 / μL (Transfusions to achieve this level were allowed.) Subjects with a baseline platelet count of <20,000 / μL due to the underlying malignancies were approved by the Medical Monitor. It was eligible.
8. Subjects had to have adequate liver function as demonstrated by:
After approval by the medical monitor, serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), unless considered to be due to Gilbert's disease, a genetic mutation in UGT1A1, or a leukemic organ lesion.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 x ULN, unless considered to be due to leukemic organ lesions.
9. Subjects had to have adequate renal function as demonstrated by:
Serum creatinine ≤ 2.0 x ULN
Or creatinine clearance based on Cockrovt-Gault glomerular filtration rate (GFR) estimation> 40 mL / min:
(140-age) x (weight kg) x (0.85 for women) / 72 x serum creatinine 10. Subjects had to recover from any clinically relevant toxic effects of any previous surgery, radiation therapy, or other therapy intended to treat the cancer. (Subjects with residual Grade 1 toxicity, such as Grade 1 peripheral neuropathy or sequelae alopecia, were approved with medical monitor approval.)
11. Female subjects with fertility had to agree to undergo a medically controlled pregnancy test before starting the study drug. The first pregnancy test is performed at screening (within 7 days prior to the first study drug administration) and on the day of the first study drug administration, with a negative result before administration and on the first day before administration of all subsequent cycles. confirmed.
12. Female subjects with fertility had to undergo a negative serum pregnancy test within 7 days prior to the start of therapy. Fertility subjects had not undergone hysterectomy, bilateral oophorectomy, or tubal blockage, or were not spontaneously postmenopausal (ie, amenorrhea) for at least 24 consecutive months (ie, amenorrhea). It was defined as a sexually mature woman (who had menstruation at any point during the previous 24 consecutive months). Fertility women and their fertile men and their partners who were fertility women were in study and for 120 days (female and male) after the last dose of Compound A, from the time of explanation and consent. He had to refrain from sexual intercourse or agree to use two highly effective forms of contraception. Highly effective forms of contraception include oral hormone contraceptives, injections, patches, intrauterine devices, double barrier methods (eg, synthetic condoms, pessaries, or cervical caps and spermicide foams, creams, or jellies), or It was defined as a male partner's sterilization.
13. The study visit schedule (ie, study facility visits were mandatory unless otherwise stated for a particular study visit) and other protocol requirements could be observed.

Exclusion Criteria Subjects who meet any of the following criteria were not enrolled in the study:
1. 1. Subjects who received hematopoietic stem cell transplantation (HSCT) within 60 days of the first dose of Compound A, or received post-HSCT immunosuppressive therapy at screening, or clinically significant graft-versus-host disease (GVHD) Targets that have. (The use of oral steroids after a stable dose of HSCT and / or topical steroids for ongoing skin GVHD was approved with the approval of the Medical Monitor.)
2. 2. Subjects who received systemic anticancer therapy or radiation therapy <14 days before the date of administration of the first study drug. (Pre-registration and post-initiation hydroxyurea of compound A were allowed for the control of peripheral leukemic blast cells in subjects with leukocytosis (leukocytosis [WBC] count> 30,000 / μL)).
3. 3. Subjects who received a small molecule study drug <14 days before the date of administration of the first study drug. In addition, the first dose of Compound A should not be given before the ≥5 half-life of the study drug has elapsed.
4. Subjects taking the following susceptible CYP substrate agents with a narrow therapeutic range were excluded from the study as long as they were unable to switch to other agents within ≥5 half-life prior to administration: paclitaxel. (CYP2C8) Warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2).
5. Subjects taking P-gp and BCRP transporter-sensitive substrates digoxin and rosuvastatin were excluded from the study as long as they were unable to transfer to other agents within ≥5 half-life prior to administration.
6. Subjects for whom potentially curative anticancer therapy was available.
7. Subjects who were pregnant or breastfeeding.
8. Subjects with active severe infections requiring anti-infective therapy during screening visits or on the day of initial study drug administration, or unexplained fever above 38.5 ° C (tumors at the discretion of the investigator) Subjects with fever could be registered).
9. Subjects with known high susceptibility to any of the components of compound A.
10. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiography (ECHO) or multigate collection (MUGA) scans obtained within approximately 28 days of C1D1.
11. Subjects with a history of myocardial infarction within the last 6 months of screening.
12. Subjects with uncontrolled hypertension during screening (systolic blood pressure [BP]> 180 mmHg or diastolic BP> 100 mmHg) were excluded. Subjects who required more than one drug to control hypertension were eligible with medical monitor approval.
13. Subjects with known instability or uncontrolled angina.
14. Subjects with a known history of severe and / or uncontrolled ventricular arrhythmia.
15. QTcF (QT corrected based on Fridericia's equation) interval ≥ 450 msec at screening or other factors that increase the risk of QT prolongation or arrhythmia events (eg, family history of heart failure, hypokalemia, QT interval prolongation syndrome) Target to have. Subjects with bundle branch block and extended QTc interval had to be examined by a medical monitor for potential selection.
16. Subjects taking drugs known to prolong the QT interval as long as they could not switch to other drugs within ≥5 half-life before dosing.
17. Subjects with a known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
18. Subjects with any other medical or psychological condition that the investigator has determined in the study to interfere with the ability of the subject to sign, cooperate, or participate in the explanation and consent.
19. Subjects with known dysphagia, short bowel syndrome, gastroparesis, or other conditions that limit the intake or gastrointestinal absorption of orally administered drugs.
20. Subjects with clinical manifestations of active central nervous system (CNS) leukemia or known CNS leukemia. Cerebrospinal fluid assessment was required only if there was clinical suspicion of a CNS lesion due to leukemia during screening.
21. Subjects with immediate and life-threatening complications of leukemia, such as uncontrolled bleeding, hypoxia or pneumonia with shock, and / or disseminated intravascular coagulation.
22. Subjects previously treated with an IDH2 inhibitor in only Phase 2 part of the study.

Test drug, dosage, and mode of administration:

Compound A (2-methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1, 3,5-Triazine-2-yl) amino] propane-2-ol (mesylate salt) is 5, 10, 25, 50, 100, 150, and 200 mg of orally administered base-free equivalent strength tablets. Provided as.

Phase 1 / dose escalation

The first 3 subjects in each cohort of the dose-escalation portion of the study and the first 15 subjects in each arm of Part 1 expansion received a single dose of study drug on day 3 and the next dose of study. The drug was administered to C1D1, at which point the subject began daily dosing on days 1-28 of the 28-day cycle. Starting with C1D1, administration was continuous and there was no intra-cycle withdrawal period. Subjects who did not need to undergo a PK / PD evaluation on day 3 started daily administration of compound A to C1D1.

Subjects needed to fast for 2 hours prior to study drug administration and 1 hour after study drug administration (water allowed).

The dose of Compound A administered to the subject depended on which dose cohort was available for enrollment when the subject was eligible for the study. The starting dose of compound A administered to the subject of the first cohort was 30 mg orally administered twice daily, and the maximum dose of compound A administered was 650 mg orally administered once daily. there were.

Phase 1 / Part 1 Expansion and Phase 2

The starting dose of compound A recommended for evaluation was 100 mg QD. This was based on the safety, PK, pharmacodynamics, and clinical activity of compound A previously observed in AG221-C-001. Assessment of pharmacodynamic response showed sustained reduction and up to 98% inhibition of 2-HG plasma levels by day 1 of cycle 2 in most subjects with the R140Q mutation at all doses. Increased doses have been associated with higher exposure and inhibition of 2-HG in subjects with the R172K mutation. Importantly, preliminary efficacy data for 44 subjects treated with 100 mg QD showed an overall response rate of 36.4%. Thus, a dose of 100 mg should sufficiently achieve inhibition of 2-HG in subjects with either the R140Q or R172K mutations. Also, the safety profile at 100 mg, including ≧ Grade 3, was consistent with the lower doses.

It was possible to gradually increase the dose within the subject.

Treatment period:

Subjects were able to continue treatment with Compound A until disease progression or the development of unacceptable toxicity. Subjects who experienced disease progression according to applicable response criteria and who, in the opinion of the investigator, benefited from treatment could be allowed to continue study with medical monitor approval.

End of test:

Exam end was defined as:
All subjects discontinued treatment with Compound A and were followed for survival for at least 12 months, died, became unfollowable, or withdrew consent before at least 12 months of follow-up. The date of receipt of the last data point from the last subject that required primary, secondary, and / or exploratory analysis, as previously specified in the Protocol and / or Statistical Analysis Plan (SAP). The slower one.

Evaluation criteria:

safety:

Monitoring of AEs, safety laboratory parameters, physical examination findings, vital signs, 12-lead ECG, LVEF, and ECOG PS, including DLT determination, serious adverse events (SAEs), and AEs leading to discontinuation.

The severity of AE was assessed by NCI CTCAE, Edition 4.03.

Pharmacokinetics and pharmacodynamics:

Compound A and its metabolites (6- (6- (trifluoromethyl) pyridin-2-yl) -N2- (2- (trifluoromethyl) pyridin-4-yl) -1,3,5-triazine-2 , 4-Diamine) Concentration-Continuous blood sampling for time profile determination. Compound A and its metabolites (6- (6- (trifluoromethyl) pyridin-2-yl) -N2- (2- (trifluoromethyl) pyridin-4-yl) -1,3,5-triazine-2 , 4-Diamine) urine sampling for determination of concentration (dose escalation and Part 1 expansion subjects only). Blood and bone marrow sampling for determination of 2-HG and α-KG levels.

Clinical activity:

Continuous blood and bone marrow sampling to determine response to treatment based on the modified IWG response criteria or other appropriate response criteria based on the malignant tumor under study.

Statistical method:

Overall response rate (ORR), primary efficacy endpoint is complete remission (CR), CR (CRp) with incomplete platelet recovery, bone marrow CR (mCR) (morphologically leukemia in subjects with AML) It was defined as the percentage of respondents who included non-state [MLFS]), CR (CRi) in incomplete hematological recovery, and partial remission (PR). Other indicators of clinical activity were summarized, including complete remission rate (CRR), remission / duration of response, event-free survival, overall survival, and time to reach remission / response.

For Phase 1 dose escalation / Part 1 expansion, response rate efficacy analysis evaluated by institutional researchers using the Revised International Working Group (IWG) Response Criteria is appropriate for the largest population analyzed. Was performed for each dose level, expansion arm, and overall. Analysis of the Part 1 magnifying arm could include subjects from the dose escalation phase that received the same dose / regimen as the subject in the magnifying arm and met the eligibility criteria for the individual arm.

For Phase 2 part of the study, the primary efficacy analysis of Compound A was determined by the investigator based on the Modified International Working Group (IWG) Response Criteria. Responses were also retrospectively assessed by the Independent Response Judgment Committee (IRAC) using the largest analyzed population (FAS). An important supportive analysis was based on an independent central review of response in FAS.
Example 2. A study of compound A monotherapy in patients with MDS and mIDH2.

In this example, a subset of clinical samples from the test described in Example 1 were analyzed.

The IDH2 mutation (mIDH2) relapses in about 5% of patients with MDS and in about 15% of patients with acute myeloid leukemia (AML). The mIDH2 protein has neoplasmic enzyme activity and is associated with DNA and histone hypermethylation, modified gene expression, and differentiation block of hematopoietic precursor cells. Compound A is a small molecule allosteric inhibitor of the mIDH2 protein that induces a hematological response in patients with mIDH2-positive AML, including relapsed or refractory (R / R) AML. Current analysis evaluates the safety and clinical efficacy of Compound A monotherapy in patients with MDS and mIDH2.

METHODS: This analysis participated in a Phase 1 study (see Example 1), which included a dose setting (dose escalation) period followed by an expansion phase in which all patients received daily oral compound A 100 mg QD in a 28-day cycle, mIDH2 positive. Included were patients aged 18 years and older with MDS. The patient was relapsed or refractory prior to MDS therapy (Tx) or was not a candidate for standard therapy. Responses were measured using peripheral blood (PB) and bone marrow (BM) samples at days 15, 29, 57, and every 56 days thereafter, as well as by objective investigator reports. Overall response rate (ORR) is the best response achieved by individual patients, including complete remission (CR), partial remission (PR), bone marrow CR (mCR), and any hematological improvement (HI). (IWG2006MDS standard). Cheson et al. , Blood. 108: 419-425 (2006). Evaluable patients required or discontinued response assessment after day 1 of cycle 2. Overall survival (OS) was estimated using the Kaplan-Meier method. Next-generation sequencing uses the FoundationOne Heme test on purified mononuclear cells from BM or PB to assess the relationship between comutation status and clinical response, using existing co-occurring gene modifications. Identified. For example, http: // foundationone. com / docks / FM_TechnicalOverview_HEM-I-001-20150105. pdf? __Hstc = 197910000.0f2b8af9a5295b09fb8f9c286e3d9952.14666609126039.1469725363136.14690808635757.8 & __hssc = 197910000.5.1469808635757 & __hsfp = 965007364h com / docks / ONE-B-001-2014430. See Foundation Medicine, FoundationOne® Heme, Technical Information and Test Overview, available in pdf (last visit August 2, 2016).

RESULTS: Of the 16 patients with MDS in the study, 12 patients with intermediate database locks were discontinued and 4 patients continued to receive compound A. Reasons for discontinuation included disease progression (n = 1), adverse events (AE, n = 1), death (n = 4), investigator judgment (n = 2), and others (n = 1). Three patients proceeded to transplant. The median age was 67 years (range 45-78) (see Table 7). The R140 mutation was more common than the R172 mutation (88% vs. 12%). At enrollment, 3 patients (19%) had relapsed after allogeneic stem cell transplantation and 11 patients (69%) had failed pretherapy (Tx) with hypomethylating agents (HMA). Six patients (38%) received ≧ 2 precancerous Tx for MDS. MDS patients in the dose setting phase received daily Compound A doses of 60 mg (n = 1), 150 mg (1), 200 mg (3), or 300 mg (1), and 10 patients received Compound A 100 mg QD. .. The median number of Tx cycles was 3 (range 1-25), with 5 patients (31%) receiving ≧ 6 compound A cycles and 4 patients (25%) receiving ≧ 12 cycles. Grade 3-4 treatment-induced AE (TEAE) was reported in 13 patients (81%), the most frequent being hyperbilirubinemia (n = 5, non-conjugation), pneumonia (n = 4). , Thrombocytopenia (n = 3), and hypokalemia (n = 3). Seven patients (44%) had 3-4 drug-related TEAEs. One patient was not evaluated for response. The ORR included one patient who achieved CR and was 53% (8/15) (showing duration of treatment, first response, time to best response, and study results) Table 8 and Figure. See 8). Of the 10 evaluable patients who received pre-HMA Tx, 5 (50%) included patients with CR and had a response to compound A. Responses for 4 patients without pre-MDS Tx were PR and mCR (1 each). The median time to reach CR, PR, or mCR (lasting 4 weeks or longer) was 24 days (range 17-87) from the start of Tx for compound A, and HI (lasting 8 weeks or longer) was 11 days (range 11). It was ~ 60). Two patients were reported to have disease progression in Tx. Median OS was also not achieved after a median follow-up of 4.7 months. FoundationOne data were available for 12 patients, and the most frequently observed known somatic co-occurrence mutations in these MDS patients were ASXL1 and SRSF2. (See Figure 9 showing the most frequently co-occurring known somatic gene mutations screened by response).

表８．全奏効

実施例３． ＭＤＳ及びｍＩＤＨ２を有する患者における化合物Ａ単剤療法の試験 Discussion: Daily Tx on oral compound A monotherapy is well tolerated and induces response in more than half of MDS patients with these mIDH2, 50% of whom have higher risk disease. 2/3 had failed the previous HMA Tx. In particular, half of the evaluable MDS patients who failed pre-HMA Tx had a response, including CR, on compound A monotherapy. Only two patients experienced disease progression during Tx. Mutation testing is rapidly becoming essential for diagnosis and prognosis in MDS, and assessment of IDH2 mutations can identify MDS patients who can benefit from the target Tx in compound A. ..
Table 7. Baseline characteristics of MDS patients treated with compound A

Table 8. All effects

Example 3. Study of Compound A monotherapy in patients with MDS and mIDH2

In this example, a subset of clinical samples from the test described in Example 1 were analyzed.

METHODS: This analysis participated in a Phase 1 study (see Example 1), which included a dose setting (dose escalation) period followed by an expansion phase in which all patients received daily oral compound A 100 mg QD in a 28-day cycle, mIDH2 positive. Included were patients aged 18 years and older with MDS. The patient was relapsed or refractory prior to MDS therapy (Tx) or was not a candidate for standard therapy. Responses were measured using peripheral blood (PB) and bone marrow (BM) samples at days 15, 29, 57, and every 56 days thereafter, as well as by objective investigator reports. Overall response rate (ORR) is the best response achieved by individual patients, including complete remission (CR), partial remission (PR), bone marrow CR (mCR), and any hematological improvement (HI). (IWG2006MDS standard). Cheson et al. , Blood. 108: 419-425 (2006). Evaluable patients required or discontinued response assessment after day 1 of cycle 2. Overall survival (OS) was estimated using the Kaplan-Meier method. Next-generation sequencing uses the FoundationOne Heme test on purified mononuclear cells from BM or PB to assess the relationship between comutation status and clinical response, using existing co-occurring gene modifications. Identified. For example, http: // foundationone. com / docks / FM_TechnicalOverview_HEM-I-001-20150105. pdf? __Hstc = 197910000.0f2b8af9a5295b09fb8f9c286e3d9952.14666609126039.1469725363136.14690808635757.8 & __hssc = 197910000.5.1469808635757 & __hsfp = 965007364h com / docks / ONE-B-001-2014430. See Foundation Medicine, FoundationOne® Heme, Technical Information and Test Overview, available in pdf (last visit August 2, 2016).

RESULTS: For 17 patients with MDS in the study, the median age was 67 years (range 45-78) (see Table 9). The R140 mutation was more common than the R172 mutation (88% vs. 12%). Of the 17 patients, 13 (76%) had 0-1 US Eastern Cooperative Oncology Group (ECOG) performance and 4 (24%) had 2 ECOG performance. .. At enrollment, 4 (24%) patients did not have precancerous therapy, 7 (41%) patients received one precancerous regimen, and 6 (35%). The patient had more than two precancerous regimens. Patients were receiving the following pre-anticancer treatments: 13 (76%) patients were previously treated with hypomethylating agents (HMA) and 2 (12%) patients were treated with renalidemid. Eight (47%) patients previously had other anti-cancer agents (soraphenib (2 patients), bossaloxin (1 patient), procrit (1 patient), plushnostat (1 patient). ), Citalabin + clofarabin (1 patient), luxolitinib (1 patient), ligoseltib (1 patient)), and 4 patients did not receive any prior anticancer treatment. The average time from patient diagnosis was 16.8 months (SD = 14.5). Additional baseline characteristics of MDS patients treated with compound A are provided in Table 9.
Table 9. Baseline characteristics of MDS patients treated with compound A

Grade 3-4 treatment-induced AEs (TEAEs) have been reported in 14 patients (82%), with the most frequent being hyperbilirubinemia (n = 5, non-conjugated. Hyperbilirubinemia and blood). (Including increased bilirubin), pneumonia (n = 4), thrombocytopenia (n = 4), anemia (n = 3), hypopotassemia (n = 3), respiratory distress (n = 2), and tumors. It was a collapse syndrome (n = 2). Six patients had 3-4 drug-related TEAEs. Severe TEAEs associated with compound A were reported in 4 patients (tumor lysis syndrome [2], increased blood bilirubin, hypertransaminaseemia). No treatment-related deaths were reported (see Table 10).
Table 10: Grade 3-4 Treatment-induced adverse events

Of the 13 patients who received previous HMA therapy, 7 (54%) responded to compound A. Of the patients who achieved HI, 2 had triblood cell system improvement and 2 had diblood cell system improvement. The median time to reach response in treated patients was 21 days (range 10-87). Table 11 provides an overview of response in patients. FIG. 10 shows the treatment period and test results. The median number of treatment cycles was 3. FIG. 10 shows overall survival in treated patients, showing that a median follow-up of 7.5 months did not achieve a median overall survival.
Table 11. All effects

FoundationOne data were available for 13 of 17 patients, and the most frequently observed known somatic co-occurrence mutations in these MDS patients were ASXL1 and SRSF2. (See Figure 12, showing clinical response to co-occurrence mutations and compound A monotherapy). FIG. 13 shows the co-mutation frequency in MDS patients with mIDH2.

Analysis of MDS patients regarding the association between the genetic mutations observed and overall response rate (ORR) was performed on patients who received Compound A, and clinical responses were captured at at least one time point during treatment. (Table 12). An average of 2.6 genes were mutated across IDH2 in each patient.
Table 12: Association of known and possible somatic mutations identified by the FoundationOne Heme panel with response to compound A

を有する２－メチル－１－［（４－［６－（トリフルオロメチル）ピリジン－２－イル］－６－｛［２－（トリフルオロメチル）ピリジン－４－イル］アミノ｝－１，３，５－トリアジン－２－イル）アミノ］プロパン－２－オール、
またはその薬学的に許容される塩、溶媒和物、互変異性体、同位体分子種、プロドラッグ、代謝産物、もしくは多形体（化合物１）を投与することを含み、前記骨髄異形成症候群が、ＩＤＨ２の変異体対立遺伝子及び少なくとも１つの第２の遺伝子の変異体対立遺伝子の存在を特徴とし、前記第２の遺伝子が、ＡＳＸＬ１及びＳＲＳＦ２からなる群から選択される、前記方法。
（態様２）
前記骨髄異形成症候群が、１つ以上の追加の遺伝子の１つ以上の変異体対立遺伝子の存在をさらに特徴とする、態様１に記載の方法。
（態様３）
前記第２の遺伝子が、ＡＳＸＬ１である、態様１または２のいずれか１項に記載の方法。
（態様４）
前記第２の遺伝子が、ＳＲＳＦ２である、態様１または２のいずれか１項に記載の方法。
（態様５）
前記骨髄異形成症候群が、ＡＳＸＬ１及びＳＲＳＦ２の変異体対立遺伝子の存在を特徴とする、態様１～４のいずれか１項に記載の方法。
（態様６）
前記追加の遺伝子が、ＭＰＬである、態様２～５のいずれか１項に記載の方法。
（態様７）
前記１つ以上の追加の遺伝子が、ＭＰＬ、ＤＮＭＴ３Ａ、ＣＳＦ３Ｒ、ＦＡＴ３、またはＣＢＬである、態様２～６のいずれか１項に記載の方法。
（態様８）
前記骨髄異形成症候群が、少なくとも１つの他の遺伝子の変異体対立遺伝子の不在をさらに特徴とし、前記他の遺伝子が、ＫＲＡＳ、ＴＰ５３、ＳＥＴＢＰ１、及びＵ２ＡＦ１からなる群から選択される、態様１～８のいずれか１項に記載の方法。
（態様９）
前記骨髄異形成症候群が、少なくとも１つの他の遺伝子の変異体対立遺伝子の不在をさらに特徴とし、前記他の遺伝子が、ＴＰ５３、ＳＥＴＢＰ１、Ｕ２ＡＦ１、ＴＣＦ３、ＳＴＡＧ２、ＮＲＡＳ、ＪＡＫ２、及びＢＲＡＦからなる群から選択される、態様１～８のいずれか１項に記載の方法。
（態様１０）
前記骨髄異形成症候群が、ＫＲＡＳの変異体対立遺伝子の不在を特徴とする、態様１～９のいずれか１項に記載の方法。
（態様１１）
前記骨髄異形成症候群が、ＴＰ５３の変異体対立遺伝子の不在を特徴とする、態様１～１０のいずれか１項に記載の方法。
（態様１２）
前記骨髄異形成症候群が、ＳＥＴＢＰ１の変異体対立遺伝子の不在を特徴とする、態様１～１１のいずれか１項に記載の方法。
（態様１３）
前記骨髄異形成症候群が、Ｕ２ＡＦ１の変異体対立遺伝子の不在を特徴とする、態様１～１２のいずれか１項に記載の方法。
（態様１４）
前記骨髄異形成症候群が、ＫＲＡＳ及びＴＰ５３の変異体対立遺伝子の不在を特徴とする、態様１～１３のいずれか１項に記載の方法。
（態様１５）
前記骨髄異形成症候群が、ＫＲＡＳ、ＴＰ５３、ＳＥＴＢＰ１、及びＵ２ＡＦ１の変異体対立遺伝子の不在を特徴とする、態様１～１４のいずれか１項に記載の方法。
（態様１６）
前記骨髄異形成症候群が、ＴＣＦ３の変異体対立遺伝子の不在を特徴とする、態様１～１５のいずれか１項に記載の方法。
（態様１７）
前記骨髄異形成症候群が、ＳＴＡＧ２の変異体対立遺伝子の不在を特徴とする、態様１～１６のいずれか１項に記載の方法。
（態様１８）
前記骨髄異形成症候群が、ＮＲＡＳの変異体対立遺伝子の不在を特徴とする、態様１～１７のいずれか１項に記載の方法。
（態様１９）
前記骨髄異形成症候群が、ＪＡＫ２の変異体対立遺伝子の不在を特徴とする、態様１～１８のいずれか１項に記載の方法。
（態様２０）
前記骨髄異形成症候群が、ＢＲＡＦの変異体対立遺伝子の不在を特徴とする、態様１～１９のいずれか１項に記載の方法。
（態様２１）
前記骨髄異形成症候群が、ＫＲＡＳ、ＴＰ５３、ＴＣＦ３、及びＳＴＡＧ２の変異体対立遺伝子の不在を特徴とする、態様１～７のいずれか１項に記載の方法。
（態様２２）
前記骨髄異形成症候群が、ＳＥＴＢＰ１、ＮＲＡＳ、ＪＡＫ２、及びＢＲＡＦの変異体対立遺伝子の不在を特徴とする、態様１～７のいずれか１項に記載の方法。
（態様２３）
対象において骨髄異形成症候群を治療する方法であって、前記対象に治療有効量の下記式：
（化２）

を有する２－メチル－１－［（４－［６－（トリフルオロメチル）ピリジン－２－イル］－６－｛［２－（トリフルオロメチル）ピリジン－４－イル］アミノ｝－１，３，５－トリアジン－２－イル）アミノ］プロパン－２－オール、
またはその薬学的に許容される塩、溶媒和物、互変異性体、同位体分子種、プロドラッグ、代謝産物、もしくは多形体（化合物１）を投与することを含み、前記骨髄異形成症候群が、ＩＤＨ２の変異体対立遺伝子の存在及び少なくとも１つの他の遺伝子の変異体対立遺伝子の不在を特徴とし、前記他の遺伝子が、ＫＲＡＳ、ＴＰ５３、ＳＥＴＢＰ１、及びＵ２ＡＦ１からなる群から選択される、前記方法。
（態様２４）
対象において骨髄異形成症候群を治療する方法であって、前記対象に治療有効量の下記式：
（化３）

を有する２－メチル－１－［（４－［６－（トリフルオロメチル）ピリジン－２－イル］－６－｛［２－（トリフルオロメチル）ピリジン－４－イル］アミノ｝－１，３，５－トリアジン－２－イル）アミノ］プロパン－２－オール、
またはその薬学的に許容される塩、溶媒和物、互変異性体、同位体分子種、プロドラッグ、代謝産物、もしくは多形体（化合物１）を投与することを含み、前記骨髄異形成症候群が、ＩＤＨ２の変異体対立遺伝子の存在及び少なくとも１つの他の遺伝子の変異体対立遺伝子の不在を特徴とし、前記他の遺伝子が、ＫＲＡＳ、ＴＰ５３、ＳＥＴＢＰ１、Ｕ２ＡＦ１、ＴＣＦ３、ＳＴＡＧ２、ＮＲＡＳ、ＪＡＫ２、及びＢＲＡＦからなる群から選択される、前記方法。
（態様２５）
前記骨髄異形成症候群が、１つ以上の追加の遺伝子の１つ以上の変異体対立遺伝子の存在をさらに特徴とする、態様２３または２４に記載の方法。
（態様２６）
前記骨髄異形成症候群が、ＫＲＡＳの変異体対立遺伝子の不在を特徴とする、態様２３～２５のいずれか１項に記載の方法。
（態様２７）
前記骨髄異形成症候群が、ＴＰ５３の変異体対立遺伝子の不在を特徴とする、態様２３～２６のいずれか１項に記載の方法。
（態様２８）
前記骨髄異形成症候群が、ＳＥＴＢＰ１の変異体対立遺伝子の不在を特徴とする、態様２３～２７のいずれか１項に記載の方法。
（態様２９）
前記骨髄異形成症候群が、Ｕ２ＡＦ１の変異体対立遺伝子の不在を特徴とする、態様２３～２８のいずれか１項に記載の方法。
（態様３０）
前記骨髄異形成症候群が、ＫＲＡＳ及びＴＰ５３の変異体対立遺伝子の不在を特徴とする、態様２３～２９のいずれか１項に記載の方法。
（態様３１）
前記骨髄異形成症候群が、Ｕ２ＡＦ１の変異体対立遺伝子の不在を特徴とする、態様２３～３０のいずれか１項に記載の方法。
（態様３２）
前記骨髄異形成症候群が、ＴＣＦ３の変異体対立遺伝子の不在を特徴とする、態様２３～３１のいずれか１項に記載の方法。
（態様３３）
前記骨髄異形成症候群が、ＳＴＡＧ２の変異体対立遺伝子の不在を特徴とする、態様２３～３２のいずれか１項に記載の方法。
（態様３４）
前記骨髄異形成症候群が、ＮＲＡＳの変異体対立遺伝子の不在を特徴とする、態様２３～３３のいずれか１項に記載の方法。
（態様３５）
前記骨髄異形成症候群が、ＪＡＫ２の変異体対立遺伝子の不在を特徴とする、態様２３～３４のいずれか１項に記載の方法。
（態様３６）
前記骨髄異形成症候群が、ＢＲＡＦの変異体対立遺伝子の不在を特徴とする、態様２３～３５のいずれか１項に記載の方法。
（態様３７）
前記骨髄異形成症候群が、第２の遺伝子の変異体対立遺伝子の存在を特徴とし、前記第２の遺伝子が、ＡＳＸＬ１及びＳＲＳＦ２からなる群から選択される、態様２３～３６のいずれか１項に記載の方法。
（態様３８）
前記骨髄異形成症候群が、ＡＳＸＬ１の変異体対立遺伝子の存在を特徴とする、態様２３～３７のいずれか１項に記載の方法。
（態様３９）
前記骨髄異形成症候群が、ＳＲＳＦ２の変異体対立遺伝子の存在を特徴とする、態様２１～３７のいずれか１項に記載の方法。
（態様４０）
前記骨髄異形成症候群が、ＡＳＸＬ１及びＳＲＳＦ２の変異体対立遺伝子の存在を特徴とする、態様２３～３９のいずれか１項に記載の方法。
（態様４１）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０またはｍＩＤＨ２－Ｒ１７２である、態様１～４０のいずれか１項に記載の方法。
（態様４２）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０である、態様４１に記載の方法。
（態様４３）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１７２である、態様４１に記載の方法。
（態様４４）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０Ｑ、ｍＩＤＨ２－Ｒ１４０Ｗ、ｍＩＤＨ２－Ｒ１４０Ｌ、ｍＩＤＨ２－Ｒ１７２Ｋ、またはｍＩＤＨ２－Ｒ１７２Ｇである、態様４１に記載の方法。
（態様４５）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０Ｑである、態様４１に記載の方法。
（態様４６）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０Ｗである、態様４１に記載の方法。
（態様４７）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１４０Ｌである、態様４１に記載の方法。
（態様４８）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１７２Ｋである、態様４１に記載の方法。
（態様４９）
ＩＤＨ２の前記変異体対立遺伝子が、ｍＩＤＨ２－Ｒ１７２Ｇである、態様４１に記載の方法。
（態様５０）
化合物１が、約２０～２０００ｍｇ／日の用量で投与される、態様１～４９のいずれか１項に記載の方法。
（態様５１）
化合物１が、約５０～５００ｍｇ／日の用量で投与される、態様１～４８のいずれか１項に記載の方法。
（態様５２）
前記用量が、約６０ｍｇ／日である、態様５１に記載の方法。
（態様５３）
前記用量が、約１００ｍｇ／日である、態様５１に記載の方法。
（態様５４）
前記用量が、約１５０ｍｇ／日である、態様５１に記載の方法。
（態様５５）
前記用量が、約２００ｍｇ／日である、態様５１に記載の方法。
（態様５６）
前記用量が、約３００ｍｇ／日である、態様５１に記載の方法。
（態様５７）
化合物１が、１日１回投与される、態様１～５６のいずれか１項に記載の方法。
（態様５８）
化合物１が、１～２５サイクルにわたって投与される、態様１～５７のいずれか１項に記載の方法。
（態様５９）
化合物１が、２８日サイクルで投与される、態様１～５８のいずれか１項に記載の方法。
（態様６０）
化合物１が、経口投与される、態様１～５９のいずれか１項に記載の方法。
（態様６１）
化合物１が、１日１回、２８日サイクルで、約１００ｍｇ／日の用量で経口投与される、態様６０に記載の方法。
（態様６２）
化合物１が、２－メチル－１－［（４－［６－（トリフルオロメチル）ピリジン－２－イル］－６－｛［２－（トリフルオロメチル）ピリジン－４－イル］アミノ｝－１，３，５－トリアジン－２－イル）アミノ］プロパン－２－オールのメシラート塩である、態様１～６１のいずれか１項に記載の方法。
（態様６３）
前記骨髄異形成症候群が、過剰芽細胞、サブタイプＲＡＥＢ－１またはＲＡＥＢ－２を伴う、態様１～６２のいずれか１項に記載の方法。
（態様６４）
前記骨髄異形成症候群が、未治療である、態様１～６３のいずれか１項に記載の方法。
（態様６５）
化合物１が、ＭＤＳの第一選択治療として投与される、態様１～６４のいずれか１項に記載の方法。
（態様６６）
化合物１が、前記骨髄異形成症候群の第二、第三、または第四選択治療として投与される、態様１～６４のいずれか１項に記載の方法。
（態様６７）
前記骨髄異形成症候群が、急性骨髄性白血病に続いて起こる、態様１～６６のいずれか１項に記載の方法。
In certain embodiments, there are high levels of covariant heterogeneity in MDS patients. In certain embodiments, 16 different additional genes other than IDH2 are present containing the mutation, with an average of 2.6 genes mutated per patient. In certain embodiments, a clinical response (≧ HI) to compound A in MDS patients is observed in the presence of all mutations except TP53, U2AF1, SETBP1, TCF3, STAG2, NRAS, JAK2, and BRAF. In certain embodiments, patients with mutations in SRSF2, MPL, and ASXL1 are more abundant in MDS patients with a clinical response (≧ HI) to compound A.
The present application provides the invention of the following aspects.
(Aspect 1)
A method for treating myelodysplastic syndrome in a subject, the following formula of a therapeutically effective amount for the subject:
(Chemical 1)

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3 , 5-Triazine-2-yl) Amino] Propane-2-ol,
Or the administration of a pharmaceutically acceptable salt thereof, an admixture, an allele, an isotope molecular species, a prodrug, a metabolite, or a polymorph (Compound 1), wherein the myelodysplastic syndrome is present. , IDH2 variant allele and at least one second gene variant allele, wherein the second gene is selected from the group consisting of ASXL1 and SRSF2.
(Aspect 2)
The method of aspect 1, wherein the myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.
(Aspect 3)
The method according to any one of aspects 1 or 2, wherein the second gene is ASXL1.
(Aspect 4)
The method according to any one of aspects 1 or 2, wherein the second gene is SRSF2.
(Aspect 5)
The method according to any one of aspects 1 to 4, wherein the myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2.
(Aspect 6)
The method according to any one of aspects 2 to 5, wherein the additional gene is MPL.
(Aspect 7)
The method according to any one of aspects 2 to 6, wherein the one or more additional genes are MPL, DNMT3A, CSF3R, FAT3, or CBL.
(Aspect 8)
The myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, wherein the other gene is selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1. The method according to any one of 8.
(Aspect 9)
The myelodysplastic syndrome is further characterized by the absence of a mutant allele of at least one other gene, the group consisting of TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and BRAF. The method according to any one of aspects 1 to 8, which is selected from.
(Aspect 10)
The method according to any one of aspects 1 to 9, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS.
(Aspect 11)
The method according to any one of aspects 1 to 10, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53.
(Aspect 12)
The method according to any one of aspects 1 to 11, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1.
(Aspect 13)
The method according to any one of aspects 1 to 12, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1.
(Aspect 14)
The method according to any one of aspects 1 to 13, wherein the myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and TP53.
(Aspect 15)
The method according to any one of aspects 1-14, wherein the myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, SETBP1 and U2AF1.
(Aspect 16)
The method according to any one of aspects 1 to 15, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3.
(Aspect 17)
The method according to any one of aspects 1 to 16, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of STAG2.
(Aspect 18)
The method according to any one of aspects 1 to 17, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS.
(Aspect 19)
The method according to any one of aspects 1 to 18, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2.
(Aspect 20)
The method according to any one of aspects 1 to 19, wherein the myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele.
(Aspect 21)
The method according to any one of aspects 1 to 7, wherein the myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS, TP53, TCF3, and STAG2.
(Aspect 22)
The method according to any one of aspects 1 to 7, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1, NRAS, JAK2, and BRAF.
(Aspect 23)
A method for treating myelodysplastic syndrome in a subject, the following formula of a therapeutically effective amount for the subject:
(Chemical 2)

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3 , 5-Triazine-2-yl) Amino] Propane-2-ol,
Or the administration of a pharmaceutically acceptable salt thereof, an admixture, an allele, an isotope molecular species, a prodrug, a metabolite, or a polymorph (Compound 1), wherein the myeloid dysplasia syndrome is present. , IDH2, characterized by the presence of a mutant allele and the absence of a mutant allele of at least one other gene, wherein the other gene is selected from the group consisting of KRAS, TP53, SETBP1, and U2AF1. Method.
(Aspect 24)
A method for treating myelodysplastic syndrome in a subject, the following formula of a therapeutically effective amount for the subject:
(Chemical 3)

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3 , 5-Triazine-2-yl) Amino] Propane-2-ol,
Or the administration of a pharmaceutically acceptable salt thereof, an admixture, an allele, an isotope molecular species, a prodrug, a metabolite, or a polymorph (Compound 1), wherein the myeloid dysplasia syndrome is present. , IDH2 variant alleles and the absence of at least one other gene variant allele, wherein the other genes are KRAS, TP53, SETBP1, U2AF1, TCF3, STAG2, NRAS, JAK2, and The method described above, selected from the group consisting of BRAF.
(Aspect 25)
23 or 24. The method of aspect 23 or 24, wherein the myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes.
(Aspect 26)
The method according to any one of aspects 23 to 25, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS.
(Aspect 27)
The method according to any one of aspects 23-26, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53.
(Aspect 28)
The method according to any one of aspects 23-27, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1.
(Aspect 29)
The method according to any one of aspects 23-28, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1.
(Aspect 30)
The method according to any one of aspects 23-29, wherein the myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and TP53.
(Aspect 31)
The method according to any one of aspects 23 to 30, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1.
(Aspect 32)
The method according to any one of aspects 23 to 31, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of TCF3.
(Aspect 33)
The method according to any one of aspects 23 to 32, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of STAG2.
(Aspect 34)
The method according to any one of aspects 23 to 33, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of NRAS.
(Aspect 35)
The method according to any one of aspects 23 to 34, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of JAK2.
(Aspect 36)
The method according to any one of aspects 23 to 35, wherein the myelodysplastic syndrome is characterized by the absence of a BRAF mutant allele.
(Aspect 37)
In any one of embodiments 23-36, the myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, wherein the second gene is selected from the group consisting of ASXL1 and SRSF2. The method described.
(Aspect 38)
The method according to any one of aspects 23 to 37, wherein the myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1.
(Aspect 39)
The method according to any one of aspects 21 to 37, wherein the myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2.
(Aspect 40)
The method according to any one of aspects 23 to 39, wherein the myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2.
(Aspect 41)
The method according to any one of aspects 1 to 40, wherein the mutant allele of IDH2 is mIDH2-R140 or mIDH2-R172.
(Aspect 42)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R140.
(Aspect 43)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R172.
(Aspect 44)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R140Q, mIDH2-R140W, mIDH2-R140L, mIDH2-R172K, or mIDH2-R172G.
(Aspect 45)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R140Q.
(Aspect 46)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R140W.
(Aspect 47)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R140L.
(Aspect 48)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R172K.
(Aspect 49)
41. The method of aspect 41, wherein the mutant allele of IDH2 is mIDH2-R172G.
(Aspect 50)
The method according to any one of aspects 1-49, wherein compound 1 is administered at a dose of about 20-2000 mg / day.
(Aspect 51)
The method according to any one of aspects 1-48, wherein compound 1 is administered at a dose of about 50-500 mg / day.
(Aspect 52)
51. The method of aspect 51, wherein the dose is about 60 mg / day.
(Aspect 53)
51. The method of aspect 51, wherein the dose is about 100 mg / day.
(Aspect 54)
51. The method of aspect 51, wherein the dose is about 150 mg / day.
(Aspect 55)
51. The method of aspect 51, wherein the dose is about 200 mg / day.
(Aspect 56)
51. The method of aspect 51, wherein the dose is about 300 mg / day.
(Aspect 57)
The method according to any one of aspects 1 to 56, wherein compound 1 is administered once daily.
(Aspect 58)
The method according to any one of aspects 1 to 57, wherein compound 1 is administered over 1 to 25 cycles.
(Aspect 59)
The method according to any one of aspects 1 to 58, wherein compound 1 is administered in a 28-day cycle.
(Aspect 60)
The method according to any one of aspects 1 to 59, wherein compound 1 is orally administered.
(Aspect 61)
60. The method of embodiment 60, wherein compound 1 is orally administered once daily in a 28-day cycle at a dose of about 100 mg / day.
(Aspect 62)
Compound 1 is 2-methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1). , 3,5-Triazine-2-yl) Amino] The method according to any one of aspects 1 to 61, which is a mesylate salt of propane-2-ol.
(Aspect 63)
The method according to any one of aspects 1 to 62, wherein the myelodysplastic syndrome is associated with excess blast cells, subtype RAEB-1 or RAEB-2.
(Aspect 64)
The method according to any one of aspects 1 to 63, wherein the myelodysplastic syndrome is untreated.
(Aspect 65)
The method according to any one of aspects 1 to 64, wherein compound 1 is administered as a first-line treatment for MDS.
(Aspect 66)
The method according to any one of aspects 1 to 64, wherein compound 1 is administered as a second, third, or fourth-line treatment for the myelodysplastic syndrome.
(Aspect 67)
The method according to any one of aspects 1 to 66, wherein the myelodysplastic syndrome follows acute myeloid leukemia.

Claims (37)

A pharmaceutical composition for treating myelodysplastic syndrome in a subject, the following formula:

2-Methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1,3 , 5-Triazine-2-yl) Amino] Propane-2-ol,
Alternatively, the myeloid dysplasia syndrome comprising a pharmaceutically acceptable salt, an admixture, a mutant or isotope molecular species (Compound 1), the presence of a variant allele of IDH2 and at least one. Mutant alleles of other genes Characterized by the absence of alleles, said other genes are selected from the group consisting of KRAS, TP53, SETBP1 and U2AF1 , and said mutant alleles of IDH2 are mIDH2-R140 or The pharmaceutical composition of mIDH2-R172 . The pharmaceutical composition according to claim 1, wherein the myelodysplastic syndrome is further characterized by the presence of one or more mutant alleles of one or more additional genes. The pharmaceutical composition according to claim 1 or 2, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of KRAS. The pharmaceutical composition according to any one of claims 1 to 3, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of TP53. The pharmaceutical composition according to any one of claims 1 to 4, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of SETBP1. The pharmaceutical composition according to any one of claims 1 to 5, wherein the myelodysplastic syndrome is characterized by the absence of a mutant allele of U2AF1. The pharmaceutical composition according to any one of claims 1 to 6, wherein the myelodysplastic syndrome is characterized by the absence of mutant alleles of KRAS and TP53. One of claims 1 to 7, wherein the myelodysplastic syndrome is characterized by the presence of a mutant allele of the second gene, wherein the second gene is selected from the group consisting of ASXL1 and SRSF2. The pharmaceutical composition according to. The pharmaceutical composition according to any one of claims 1 to 8, wherein the myelodysplastic syndrome is characterized by the presence of a mutant allele of ASXL1. The pharmaceutical composition according to any one of claims 1 to 8, wherein the myelodysplastic syndrome is characterized by the presence of a mutant allele of SRSF2. The pharmaceutical composition according to any one of claims 1 to 10, wherein the myelodysplastic syndrome is characterized by the presence of mutant alleles of ASXL1 and SRSF2. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R140. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R172. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R140Q, mIDH2-R140W, mIDH2-R140L, mIDH2-R172K, or mIDH2-R172G. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R140Q. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R140W. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R140L. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R172K. The pharmaceutical composition according to claim 1 , wherein the mutant allele of IDH2 is mIDH2-R172G. The pharmaceutical composition according to any one of claims 1 to 19 , wherein Compound 1 is indicated for administration at a dose of about 20 to 2000 mg / day. The pharmaceutical composition according to any one of claims 1 to 20 , wherein Compound 1 is indicated for administration at a dose of about 50 to 500 mg / day. 21. The pharmaceutical composition of claim 21 , wherein the dose is about 60 mg / day. 21. The pharmaceutical composition of claim 21 , wherein the dose is about 100 mg / day. 21. The pharmaceutical composition of claim 21 , wherein the dose is about 150 mg / day. 21. The pharmaceutical composition of claim 21 , wherein the dose is about 200 mg / day. 21. The pharmaceutical composition of claim 21 , wherein the dose is about 300 mg / day. The pharmaceutical composition according to any one of claims 1 to 26 , wherein compound 1 is indicated for once-daily administration. The pharmaceutical composition according to any one of claims 1 to 27 , wherein compound 1 is indicated for administration over 1 to 25 cycles. The pharmaceutical composition according to any one of claims 1 to 28 , wherein Compound 1 is indicated for administration in a 28-day cycle. The pharmaceutical composition according to any one of claims 1 to 29 , wherein compound 1 is indicated for oral administration. 30. The pharmaceutical composition of claim 30 , wherein Compound 1 is indicated for once-daily oral administration in a 28-day cycle at a dose of about 100 mg / day. Compound 1 is 2-methyl-1-[(4- [6- (trifluoromethyl) pyridin-2-yl] -6-{[2- (trifluoromethyl) pyridin-4-yl] amino} -1). , 3,5-Triazine-2-yl) Amino] The pharmaceutical composition according to any one of claims 1 to 31 , which is a mesylate salt of propane-2-ol. The pharmaceutical composition according to any one of claims 1 to 32 , wherein the myelodysplastic syndrome is accompanied by excess blast cells, subtype RAEB-1 or RAEB-2. The pharmaceutical composition according to any one of claims 1 to 33 , wherein the myelodysplastic syndrome has not been treated. The pharmaceutical composition according to any one of claims 1 to 34 , wherein compound 1 is indicated for administration as a first-line treatment for MDS. The pharmaceutical composition according to any one of claims 1 to 35 , wherein compound 1 is indicated for administration as a second, third, or fourth-line treatment for the myelodysplastic syndrome. The pharmaceutical composition according to any one of claims 1 to 36 , wherein the myelodysplastic syndrome follows acute myeloid leukemia.

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