EA039805B1 - Combination therapy for treating malignancies - Google Patents

Abstract

Provided are methods and compositions for treating cancers in patients carrying an IDH1 mutation using a combination of an inhibitor of a mutant IDH1 enzyme and an AML induction and consolidation therapy.

Description

This application claims priority from the U.S.S.N. 62/242267 filed October 15, 2015

g., and U.S.S.N. 62/255253, filed November 13, 2015 a, each of which is incorporated into this application by reference in its entirety.

The field to which the invention relates

This application provides combination therapies for the treatment of acute myeloid leukemia. In one embodiment, therapies include treatment with an IDH1 inhibitor and induction and consolidation therapy.

Prerequisites for the creation of the invention

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2oxoglutarate (i.e. α-ketoglutarate). These enzymes belong to two different subclasses, one using NAD(+) as an electron acceptor and the other using NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases that are localized in the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal guide signal sequence. The presence of this enzyme in peroxisomes suggests roles in NADPH regeneration for intraperoxisomal reductions, such as the conversion of 2,4dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme plays an essential role in the production of cytoplasmic NADPH.

The human IDH1 gene encodes a 414 amino acid protein. The nucleotide and amino acid sequences for human IDH1 can be found in GenBank number NM_005896.2 and NP 005887.2, respectively. The nucleotide and amino acid sequences for IDH1 are also described, for example, in Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN1996) to the EMB L/GenB ank/DDB J databases; and Sjoeblom et al, Science 314:268-274 (2006).

Wild-type, for example, IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, thus reducing NAD+ (NADP+) to NADH (NADPH), for example, in a forward reaction:

Isocitrate + NAD ⁺ (NADP +) ^ a-KG + CO ₂ + NADH (NADPH) + H +.

IDH1 mutations present in some cancer cells have been found to result in a novel ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2hydroxyglutarate (2HG). The production of 2HG is believed to promote the formation and progression of cancer (Dang, L et al., Nature 2009, 462: 739-44).

The development of selective inhibitors of the IDH1 mutant enzyme has provided the potential for therapeutic benefit in AML patients with an IDH1 mutation. This has led to successful clinical responses with a reduced blast population and a beneficial effect on differentiated functional blood cells. However, genetic load is present in patients even with a good overall response. Therefore, there is a need for improved therapies for the treatment of acute myeloid leukemia with IDH1 mutations.

The essence of the invention

In one embodiment, the present application provides methods for treating acute myeloid leukemia (AML) characterized by the presence of a mutant IDH1 allele by administering to a subject a therapeutically effective amount of a combination of a mutant IDH1 inhibitor and induction and consolidation therapy. In one embodiment, AML characterized by the presence of a mutant IDH1 allele is refractory or recurrent AML.

In one embodiment, the mutant IDH1 inhibitor is (S)-N-((S)-1-(2chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine -2-yl)-N-(5-fluoropyridin3-yl)-5-oxopyrrolidine-2-carboxamide or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug or polymorph thereof (Compound 2).

In one embodiment, the method includes administering to the subject a therapeutically effective amount of Compound 2 and induction and consolidation therapy.

In some embodiments, induction therapy for the treatment of AML comprises administering cytarabine with either daunorubicin or idarubicin. In some embodiments, the implementation of induction therapy includes the introduction of cytarabine with daunorubicin. In some embodiments, the induction therapy comprises administering cytarabine with idarubicin.

- 1 039805

In some embodiments, consolidation therapy for the treatment of AML comprises administering i) mitoxantrone with etoposide or ii) cytarabine. In some embodiments, consolidation therapy comprises administering mitoxantrone with etoposide. In some embodiments, the implementation of consolidation therapy includes the introduction of cytarabine.

In one embodiment, the present application provides methods of treating AML characterized by the presence of a mutant IDH allele by administering to a subject a combination of a therapeutically effective amount of an inhibitor of the mutant IDH1 and induction and consolidation therapy, where a) the induction therapy comprises administering cytarabine with either daunorubicin or idarubicin and b) consolidation therapy includes the administration of i) mitoxantrone with etoposide or ii) cytarabine. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

In one embodiment, the present application provides methods of treating AML characterized by the presence of a mutant IDH1 allele by administering to the subject a combination of a therapeutically effective amount of an inhibitor of the mutant IDH1 and induction and consolidation therapy, where a) induction therapy comprises the administration of cytarabine with daunorubicin, and b) consolidation therapy includes administration of mitoxantrone with etoposide. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

In one embodiment, the present application provides methods of treating AML characterized by the presence of a mutant IDH1 allele by administering to the subject a combination of a therapeutically effective amount of an inhibitor of the mutant IDH1 and induction and consolidation therapy, where a) induction therapy comprises the administration of cytarabine with daunorubicin, and b) consolidation therapy includes the administration of cytarabine. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

In one embodiment, the present application provides methods of treating AML characterized by the presence of a mutant IDH1 allele by administering to a subject a combination of a therapeutically effective amount of an inhibitor of the mutant IDH1 and induction and consolidation therapy, where a) induction therapy comprises the administration of cytarabine with idarubicin, and b) consolidation therapy includes administration of mitoxantrone with etoposide. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

In one embodiment, the present application provides methods of treating AML characterized by the presence of a mutant IDH1 allele by administering to a subject a combination of a therapeutically effective amount of an inhibitor of the mutant IDH1 and induction and consolidation therapy, where a) induction therapy comprises the administration of cytarabine with idarubicin, and b) consolidation therapy includes the administration of cytarabine. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

In one embodiment, the present application provides methods for treating AML characterized by the presence of a mutant IDH1 allele by administering to a subject a combination of a pharmaceutical composition comprising a therapeutically effective amount of Compound 2 and induction and consolidation therapy for AML.

In one embodiment, the present application provides a method of treating AML, wherein the AML is selected from newly diagnosed AML, untreated AML, AML arising from myelodysplastic syndrome (MDS), AML arising from a pre-existing hematological disorder (AHD), and AML arising after genotoxic defeat. In some embodiments, the implementation of genotoxic damage occurs as a result of radiation and/or chemotherapy. In one embodiment, the present application provides a method of treating AML that occurs after a genotoxic lesion resulting from radiation and/or chemotherapy.

Brief description of the drawings

Fig. 1 represents X-ray powder diffraction (XPRD) of Compound 2 Form 1.

Fig. 2 is a Differential Scanning Calorimetry (DSC) profile of Compound 2 Form 1.

Fig. 3 is a thermogravimetric analysis (TGA) profile of Compound 2 Form 1.

Fig. 4 is an X-ray powder diffraction (XPRD) of Form 2 Compound 2.

Fig. 5 is a Differential Scanning Calorimetry (DSC) profile of Compound 2 Form 2.

Fig. 6 is a thermogravimetric analysis (TGA) profile of Compound 2 Form 2.

Detailed description of the invention

Details regarding the construction and arrangement of the components described hereinafter in the description or illustrated in the drawings should not be construed as limiting. Other embodiments and other ways of practicing the present invention are expressly included. Also, the phraseology and terminology used in this application is for the purposes of description, and should not be construed as limiting. The use in this application of the terms including, including, or having, containing, including, and variations thereof is intended to cover the elements listed thereafter and their equivalents, as well as additional elements.

Definitions

The term IDH1 mutant inhibitor or IDH1 mutant(s) inhibitor means a molecule, e.g., a polypeptide, peptide or small molecule (e.g., a molecule less than 1000 daltons) or an aptomer, that binds to an IDH1 mutant subunit and inhibits neoactivity, e.g., by inhibiting dimer formation eg, a homodimer of mutant IDH1 subunits or a heterodimer of mutant and wild-type subunits. In some embodiments, the inhibition of neoactivity is at least about 60%, 70%, 80%, 90%, 95%, or 99% of the activity in the absence of the mutant IDH1 inhibitor. In one embodiment, the mutant IDH1 inhibitor is Compound 2.

The term elevated levels of 2HG means that 10, 20 30, 50, 75, 100, 200, 500% or more of 2HG is present in a subject with a mutant IDH1 allele compared to a subject lacking a mutant IDH1 allele. The term elevated 2HG levels can refer to the amount of 2HG in a cell, in a tumor, in an organ containing the tumor, or in body fluid.

The term body fluid includes one or more of the amniotic fluid surrounding the fetus, intraocular fluid, blood (eg, blood plasma), serum, cerebrospinal fluid, cerumen, chyme, pre-ejaculate, female ejaculate, interstitial fluid, lymph, breast milk, mucus ( e.g. a runny nose or cough), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretions, or vomit.

The terms inhibit or prevent include both complete and partial inhibition and prevention. The inhibitor may completely or partially inhibit the intended target.

The term subject is intended to include human and non-human animals. Examples of human subjects include a human patient (referred to as a patient) having a disorder, such as the disorder described herein, or a healthy subject. The term non-human animals, in accordance with one aspect of the invention, includes all vertebrate animals, for example, non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agricultural animals, e.g. sheep, dog, cat, cow, pig, etc.

The term "treatment" means reducing, suppressing, attenuating, reducing the severity, arresting or stabilizing the development or progression of a disease/disorder (e.g., advanced hematologic malignancy such as acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN). ), chronic myelomonocytic leukemia (CMML), acute B-cell lymphoblastic leukemias (B-ALL), or lymphoma (eg, T-cell lymphoma), each characterized by the presence of a mutant IDH1 allele), reduction in the severity of the disease/disorder or improvement in symptoms, associated with the disease/disorder.

An amount of a compound, including a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug, or polymorph thereof, effective to treat a disorder, or a therapeutically effective amount or a therapeutically effective dose refers to an amount of a compound, or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable salt thereof , solvate, tautomer, stereoisomer, isotopologue, prodrug, or polymorph, which is effective, when administered to a subject in one or more doses, to treat a cell or to treat, relieve symptoms, alleviate or improve a condition in a subject suffering from a disorder, better than that would be expected in the absence of such treatment.

The term co-administration as used herein in relation to additional cancer therapeutics means that the additional cancer therapeutic can be administered together with a compound provided herein as part of a single dosage form (such as a composition, containing the compound and the second therapeutic agent, as described above) or in the form of several separate dosage forms. Alternatively, an additional therapeutic agent for the treatment of cancer can be entered before, sequentially or after the introduction of the compounds presented in this application. In such combination therapy, both the compounds provided herein and the second therapeutic agent(s) are administered by conventional means. Administration of a composition containing both a compound provided herein and a second therapeutic agent to a subject does not preclude separate administration of the same therapeutic agent, any other second therapeutic agent, or any compound provided herein, to the subject at another time during the course of treatment. . The term co-administration, as used herein in relation to adjunctive cancer treatment, means that

- 3 039805 additional cancer treatment can occur before, sequentially, simultaneously or after the introduction of the compounds presented in this application.

The term substantially free of other stereoisomers, as used herein, means a preparation enriched in a compound having the selected stereochemistry at one or more selected stereocenters by at least about 60, 65, 70, 75, 80, 85, 90, 95, 96%, 97, 98 or 99%.

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

The term crystalline refers to a solid having a highly regular chemical structure. In particular, crystalline Compound 2 can be obtained as one or more separate crystalline forms of compound 2. For the purposes of this application, the terms crystalline form, single crystalline form, and polymorph are synonymous; the terms reflect differences between crystals that have different properties (eg, different XRPD patterns and/or different DSC scan results). The term "polymorph" includes pseudopolymorphs, which are usually different solvates of the substance, and therefore their properties differ from each other. Thus, each individual polymorph and pseudopolymorph of Compound 2 is considered to be a separate crystal form.

The term substantially crystalline refers to forms that may be at least a certain percentage by weight crystalline. Specific mass percentages include 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 between 10 and 100%. In some embodiments, substantially crystalline refers to Compound 2 that is at least 70% crystalline. In other embodiments, substantially crystalline refers to Compound 2 that is at least 90% crystalline.

The term isolated refers to forms that can, at least to a certain percentage by weight, consist of a particular crystalline form of the compound. Specific mass percentages are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 90% and 100%.

The term solvate or solvated means the physical association of a compound, including its crystalline form, of the present invention with one or more solvent molecules. This physical association includes the formation of hydrogen bonds. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. Solvate or solvated covers both in the solution phase and isolated solvates. Typical solvates include, for example, hydrate, ethanolates or methanolates.

The term hydrate means a solvate in which the solvent molecule is H ₂ O, which is present in a certain stoichiometric amount, and may, for example, include hemihydrate, monohydrate, dihydrate or 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/crystalline).

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

The term antisolvent is used to refer to a solvent in which compounds, including their crystalline forms, are poorly soluble.

The term pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that can be administered to a subject along with a compound of one aspect of the present invention and that does not interfere with its pharmacological activity and is non-toxic when administered at doses sufficient to deliver a therapeutic amount of the compound.

The term pharmaceutically acceptable salt as used herein refers to non-toxic acid or base addition salts of the compound to which the term refers. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, Pharmaceutically Acceptable Salts. J Pharm. sci. Vol. 66, pp. 1-19.

The term acute myeloid leukemia (AML), as used herein, refers to a cancer of the myeloid blood cell lineage characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. In one embodiment, AML is selected from newly diagnosed AML, untreated AML, AML arising from myelodysplastic syndrome (MDS), AML arising from a pre-existing hematological disorder (AHD), and AML arising after a genotoxic lesion.

The term refractory AML, as used herein, refers to AML in which high levels of white blood cells do not decrease in response to treatment.

The term recurrent AML, as used herein, refers to AML that is not

- 4 039805 responds to treatment.

The term AML induction therapy, as used herein, refers to therapy used to rapidly restore normal bone marrow function, ie to induce remission.

The term AML consolidation therapy, as used herein, refers to therapy used to maintain remission achieved as a result of induction therapy.

The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The term about means approximately, of the order of, roughly, or approximately. When the term about is used in conjunction with a numerical range, it modifies that range by extending the limits above and below the set numerical values. Typically, the term about is used in this application to change a numerical value above and below the claimed value by 10%.

Connections

Compound 2 is (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2oxoethyl)-1-(4-cyanopyridin-2-yl) -N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug or polymorph thereof. Compound 2 has the following chemical structure:

Compound 2 may also include one or more isotopic substitutions. For example, H can be in any isotopic form (isotopologues) including 1H, 2H ⁽ D or deuterium), and ^3H (T or tritium); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; The O may be in any isotopic form, including ¹⁶ O and ¹⁸ O; etc. For example, Compound 2 is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% enriched in a particular H, C, and/or O isotopic form.

Compound 2 may also be present in multiple tautomeric forms in some embodiments, in such cases one aspect of the invention specifically includes all tautomeric forms of Compound 2 described herein, even if only one tautomeric form may be present (e.g., keto-enol tautomers ). All such isomeric forms of Compound 2 are expressly included in the present invention. The synthesis of Compound 2 is described in US Published Application ^-2013-0190249^1 published July 25, 2013, which is incorporated by reference in its entirety.

It may be convenient or desirable to prepare, purify and/or process the corresponding salt of Compound 2, eg a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, Pharmaceutically Acceptable Salts. J Pharm. sci. Vol. 66, pp. 1-19.

For example, if Compound 2 is anionic or contains a functional group that may be anionic (eg, -NH- may be -N- ^- ), then a salt may 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 metal cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Al ³⁺ . Examples of some suitable substituted ammonium ions include ions derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH ₃ ) ₄ ⁺ -.

If Compound 2 is cationic or has a functional group that may be cationic (eg, -NHR may be -NH ₂ R ⁺ ), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, derivatives of the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulphurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, compounds derived from the following organic acids: 2-acetyloxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic , glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucinic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, tartaric , toluenesulfonic and valeric. Examples of suitable polymeric organic anions include, but are not limited to, compounds derived from

- 5 039805 the following polymeric acids: tannic acid, carboxymethyl cellulose.

Thus, Compound 2 for use in the methods and pharmaceutical compositions provided herein includes Compound 2 as such, as well as pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, isotopologues, prodrugs, or polymorphs thereof. Compound 2 provided in this application can be modified and converted into a prodrug by adding appropriate functional groups to enhance certain biological properties, for example, targeting a specific tissue. Such modifications (e.g., prodrugs) are known in the art and include those that increase biological penetration into a particular biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow injection, alter metabolism and change the rate of excretion. Examples of prodrugs include esters (eg, phosphates, esters of amino acids (eg, valine)), carbamates, and other pharmaceutically acceptable derivatives which, when administered to a subject, are capable of providing active compounds.

Compound 2 has been found to exist in various solid forms. In one embodiment, solid forms are provided which include pure crystalline forms. In another embodiment, solid forms are provided herein, which include solvated forms and amorphous forms. The present disclosure provides certain solid forms of Compound 2. In some embodiments, the present disclosure provides compositions containing Compound 2 in the form described herein. In some embodiments of the provided compositions, Compound 2 is present as a mixture of one or more solid forms; in some embodiments of the present compositions, Compound 2 is present in one form.

In one embodiment of the invention, Compound 2 is a single crystal form or any of the individual crystal forms described herein. The synthesis of crystalline forms of Compound 2 is described in WO 2015/138837 and WO 2015/138839, published September 17, 2015, which are incorporated herein by reference in their entirety. Also provided are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier or diluent; and Compound 2, where Compound 2 is a single crystalline form or any of the crystalline forms described herein. Also contemplated are the uses of Compound 2 wherein Compound 2 is a single crystal form or any of the individual crystal forms described herein for the preparation of a pharmaceutical composition.

This description provides a selection of illustrative information to describe the crystalline forms of Compound 2. However, it should be understood that not all such information is required by a person skilled in the art to determine that such a particular form is present in a given composition, but that determination of a specific form can be done using any piece of illustrative information that a person skilled in the art finds sufficient to establish the presence of a particular form, for example, even one characteristic peak may be sufficient for a person skilled in the art to understand that such a particular form is present.

In one embodiment, at least a certain percentage by weight of Compound 2 is crystalline. The specific weight percent can be 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 between 10 and 100%. When a certain percentage by weight of Compound 2 is crystalline, the remainder of Compound 2 is an amorphous form of Compound 2. Non-limiting examples of crystalline Compound 2 include a single crystalline form of Compound 1 or a mixture of different individual crystalline forms. In some embodiments, Compound 2 is at least 90% by weight crystalline. In some other embodiments, the implementation of Compound 2 is at least 95 wt.% crystalline.

In another embodiment, a certain proportion, expressed as a percentage by weight, of the crystalline Compound 2 is one particular crystalline form or a combination of individual crystalline forms. The specific weight percent can be 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 between 10 and 100%. In another embodiment, Compound 2 is at least 90% by weight of a single crystalline form. In another embodiment, Compound 2 is at least 95% by weight of a single crystalline form.

In the following description of Compound 2, embodiments of the invention may be described with reference to a specific crystalline form of Compound 2 that is characterized by one or more of the properties as discussed herein. Descriptions characterizing the crystalline forms can also be used to describe a mixture of different crystalline forms that may be present in the crystalline Compound 2. However, specific crystalline forms of Compound 2 can also be characterized by one or more characteristics.

- 6 039805 crystal form described in this application, with or without reference to a specific crystal form.

The crystalline forms are further illustrated in the detailed descriptions and illustrative examples below. XRPD peaks described in Table. 1-2 may vary within ±0.2° depending on the instrument used to acquire the data. The intensity of the XRPD peaks described in Table. 1-2 may vary by 10%.

Form 1.

In one embodiment, a single crystalline form, form 1, of Compound 2 is characterized by the X-ray powder diffraction pattern (XRPD) shown in FIG. 1, and the data shown in table. 1 obtained using CuKa radiation. In a particular embodiment, the polymorph may be characterized by one or more peaks taken from FIG. 1, as shown in table. 1. For example, a polymorph can 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. one.

Table 1

In another embodiment, Form 1 can be characterized by peaks identified at 2Θ angles of 8.6, 15.6, 18.5, 20.6, 21.6, and 26.4°. In another embodiment, Form 1 can be characterized by peaks identified at 2θ angles of 8.6, 15.6, 18.5, and 21.6°.

In another embodiment Form 1 can be characterized by Differential Scanning Calorimetry (DSC), the data is shown in FIG. 2. The DSC plot represents heat flow as a function of temperature from the sample, with a temperature change rate of about 10°C/min. The profile is characterized by an endothermic transition with a transition start temperature of about 140.1°C with a melting point at about 149.9°C.

In another embodiment Form 1 can be characterized by thermogravimetric analysis (TGA) shown in FIG. 3. The TGA profile graphically represents the percentage weight loss of a sample as a function of temperature, with a temperature change rate of about 10°C/min. The weight loss is about 0.44% weight loss of the sample as the temperature changes from about 29.0 to 125.0°C.

Form 2.

In one embodiment, a single crystalline form, form 2, of Compound 2 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 4, and the data shown in table. 2 obtained using CuKa radiation. In a particular embodiment, the polymorph may be characterized by one or more peaks taken from FIG. 4, as shown in table. 2. For example, a polymorph can be 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. 2.

table 2

- 7 039805

In another embodiment, Form 2 can be characterized by peaks identified at 2Θ angles of 9.8, 11.6, 19.6, 22.5, 23.0, and 31.4°. In another embodiment, Form 2 can be characterized by peaks identified at 2Θ angles of 9.8, 11.6, 19.6, and 23.0°.

In another embodiment Form 2 can be characterized by Differential Scanning Calorimetry (DSC), the data is shown in FIG. 5. The DSC plot represents heat flow as a function of temperature from the sample, with a temperature change rate of about 10°C/min. The profile is characterized by an endothermic transition with a transition start temperature of about 62.7°C with a melting point at about 72.5°C and an endothermic transition with a transition start temperature of about 145.6°C with a melting point at about 153.6°C.

In another embodiment Form 2 can be characterized by thermogravimetric analysis (TGA) shown in FIG. 6. The TGA profile graphically represents the percentage weight loss of a sample as a function of temperature, with a temperature change rate of about 10°C/min. The weight loss is about 0.57% weight loss of the sample when the temperature changes from about 29.3 to 170.3°C.

Other embodiments relate to a single crystalline form of Compound 2 having a combination of the above characteristics of any of the individual crystalline forms described. The characterization may include any combination of one or more of the XRPD, TGA, and DSC described for a particular polymorph. For example, a single crystalline form of Compound 2 can be characterized by any combination of XRPD results regarding major peak positions in an XRPD scan; and/or any combination of one or more parameters derived from the XRPD scan data. This one crystalline form of Compound 2 can also be characterized by TGA data on sample-associated mass loss over a given temperature range; and/or the temperature at which a particular transition to weight loss begins. DSC determinations of the temperature associated with maximum heat flux during heat transfer and/or the temperature at which the sample begins to undergo heat transfer can also characterize the crystalline form. Sample weight change and/or change in water sorption/desorption per molecule of Compound 2, as determined by measuring water sorption/desorption over a relative humidity range (e.g., 0 to 90%), can also be indicative of a single crystalline form of Compound 2.

Compositions and routes of administration

In one embodiment, the pharmaceutical composition includes Compound 2 and an excipient. In one embodiment, the pharmaceutical composition, which includes Compound 2 and an excipient, is for oral administration. In one embodiment, the excipient is a diluent, binder, disintegrant, wetting agent, stabilizer, glidant and/or lubricant.

In one embodiment, the pharmaceutical composition includes cytarabine and a diluent or solvent. In one embodiment, the pharmaceutical composition, which includes cytarabine and a diluent or solvent, is for intravenous injection.

In one embodiment, the pharmaceutical composition includes daunorubicin and a diluent or solvent. In one embodiment, the pharmaceutical composition, which includes daunorubicin and a diluent or solvent, is for intravenous injection.

In one embodiment, the pharmaceutical composition includes idarubicin and a diluent or solvent. In one embodiment, the pharmaceutical composition, which includes idarubicin and a diluent or solvent, is for intravenous injection.

In one embodiment, the pharmaceutical composition includes mitoxantrone and a diluent or solvent. In one embodiment, the pharmaceutical composition, which includes mitoxantrone and a diluent or solvent, is for intravenous injection.

In one embodiment, the pharmaceutical composition includes etoposide and a diluent or solvent. In one embodiment, the pharmaceutical composition, which includes etoposide and a diluent or solvent, is for intravenous injection.

Pharmaceutically acceptable carriers, adjuvants, and excipients that may be used in the pharmaceutical compositions of one aspect of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying

- 8 039805 drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin , buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, trisilicate magnesium, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrins or other solubilized derivatives can also be advantageously used to increase the delivery of Compound 2, described in this application.

In one embodiment, the pharmaceutical composition includes Compound 2 and an excipient. In one embodiment, the pharmaceutical composition, which includes Compound 2 and an excipient, is for oral administration. In one embodiment, the excipient is a diluent, binder, disintegrant, wetting agent, stabilizer, glidant, or lubricant.

In one embodiment, the pharmaceutical compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral administration or administration by injection. In one embodiment, the pharmaceutical compositions may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or excipients. In some instances, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases, or buffers to improve the stability of the formulated compound or delivery form.

In one embodiment, the pharmaceutical compositions provided herein may be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oily suspension. This suspension can be prepared according to methods known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersants that are commonly used to formulate pharmaceutically acceptable dosage forms such as emulsions and/or suspensions. Other commonly used surfactants such as Tween or Span and/or other similar emulsifiers or bioavailability agents that are commonly used to prepare pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.

Specific embodiments of the present invention provide solid oral dosage forms that are tablets or capsules. In some embodiments, the formulation is a tablet containing Compound 2. In some embodiments, the formulation is a tablet containing Compound 2. In some embodiments, the formulation is a capsule containing Compound 2. In some embodiments, the tablets or capsules provided herein application, optionally contain one or more excipients, such as, for example, glidants, diluents, lubricants, colorants, disintegrants, granulating agents, binders, polymers, and coating agents. In some embodiments, the formulation is an immediate release tablet. In some embodiments, the formulation is a controlled release tablet that releases the active pharmaceutical ingredient (API), eg, predominantly in the stomach. In some embodiments, the formulation is a hard gelatin capsule. In some embodiments, the formulation is a soft gelatin capsule. In some embodiments, the capsule is a cap

- 9 039805 sulu from hydroxypropyl methylcellulose (HPMC). In some embodiments, the formulation is an immediate release capsule. In some embodiments, the formulation is an immediate or controlled release capsule that releases the API, for example, predominantly in the stomach. In some embodiments, the formulation is a fast disintegrating tablet that substantially dissolves in the mouth upon administration. In some embodiments, the present embodiments cover the use of Compound 2 for the preparation of a pharmaceutical composition for the treatment of a cancer characterized by the presence of a mutant IDH1 allele, wherein the composition is prepared for oral administration.

In some embodiments, the embodiments provided herein cover the use of cytarabine, daunorubicin, idarubicin, mitoxantrone, and/or etoposide for the preparation of a pharmaceutical composition for the treatment of a cancer characterized by the presence of a mutant IDH1 allele, wherein the composition is prepared for intravenous administration.

The methods presented in this application, provide for the introduction of an effective amount of the compound or composition of the compound to achieve the desired or claimed effect. In one embodiment, the pharmaceutical compositions are administered from about 1 to about 6 times per day, or alternatively, as a continuous infusion. Such an introduction can be used for long-term or emergency therapy. The amount of active ingredient that can be combined with carrier materials to form a unit dosage form varies depending on the host being treated and the particular route of administration. A typical formulation contains from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% of the active compound.

A lower or higher dose than those listed above may be required. Specific dosages and administration schedules for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, severity and course of the disease, conditions or symptoms, the subject's predisposition to the disease, condition, or symptoms, and the opinion of the attending physician.

When the condition of the subject improves, if necessary, you can enter a maintenance dose of the compounds, compositions or combinations described in this application, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced depending on the symptoms to a level at which the improved condition is maintained when the symptoms are reduced to the desired level. However, subjects may require intermittent treatment on a long-term basis for any recurrence of disease symptoms.

Solid dispersions Compounds 2

In some embodiments, Compound 2 is administered in compositions comprising Compound 2 and one or more polymers as part of a solid dispersion (eg, an amorphous solid dispersion). In some embodiments, the solid dispersion comprises Compound 2 and one or more polymers. In some embodiments, the solid dispersion comprises Compound 2, one or more polymers, and one or more surfactants. In some embodiments, the solid dispersion comprises Compound 2 and one polymer. In some embodiments, the solid dispersion comprises Compound 2, one polymer, and a surfactant.

In some embodiments, the solid dispersions provided herein, comprising Compound 2, increase the solubility of Compound 2 over the pure crystalline form of Compound 2 (e.g., Form 1 or Form 2) and thus provide better oral exposure to the solid dispersion. subject. In one embodiment, the solid dispersion comprises Compound 2, one or more polymers, and optionally one or more solubilizing surfactants.

For example, the water solubility of Form 1 is from about 0.025 to about 0.035 mg/ml, and the water solubility of Form 2 is from about 0.008 to about 0.010 mg/ml.

Form 2 has a solubility of about 0.018 mg/mL in simulated fasting intestinal juice (FASSIF) at pH 6.1 after 4 hours. 3 o'clock

In some embodiments, the solid dispersion exhibits an exposure of Compound 2 when administered to a subject of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% higher compared to in situ administration of amorphous Compound 2. In some embodiments, the solid dispersion exhibits Compound 2 exposure when administered to a subject at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70 %, at least about 80% or at least about 90% higher compared to the introduction of pure crystalline Compound 2.

In pharmacokinetic studies in rats and monkeys, a modest improvement in exposure was observed with oral dosage forms in the form of solid dispersions compared with in situ administration of an amorphous substance. For example, a solid dispersion containing 50% wt./wt. Compound 2 and 50% w/w, polyvinyl acetate phthalate (PVAP), had approximately two times higher exposure compared to in situ amorphous Compound 2 in male Sprague Dawley rats. There is no significant difference in exposure between the solid dispersion containing 70% wt./wt. Compound 2 and 30% w/w, oral dosage form, and in situ amorphous Compound 2. In male Cynomolgus monkeys, there is no significant difference between exposure to a solid dispersion containing 50% w/w. Compound 2 and 50% wt./wt. hydroxypropyl methylcellulose acetate succinate, also known as hypromelose acetate succinate (HPMCAS), and in situ amorphous Compound 2. Similarly, a solid dispersion containing 50% wt./wt. Compound 2 and 50% wt./wt. hydroxypropyl methylcellulose, also known as hypromellose phthalate (HPMC phthalate), has no significant difference compared to in situ amorphous Compound 2. While in situ amorphous therapeutic compounds are commonly used in research for administration to animals, they are not suitable dosage forms for introduction to people.

As described in the rat pharmacokinetic test in Example 4, Compound 2 exposure is improved when solid dispersion dosage forms are administered compared to pure crystalline Compound 2 Form 2.

In some embodiments, at least a portion of Compound 2 in the solid dispersion is in an amorphous state (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%). In other embodiments, the solid dispersion is substantially free of crystalline Compound 2.

In some embodiments, the composition is an amorphous solid (eg, spray-dried) dispersion comprising Compound 2 and a polymer. The amorphous solid dispersion may include, for example, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%. , less than about 2% or less than about 1% crystalline Compound 2, for example, may be substantially free of crystalline Compound 2.

In one embodiment, the solid dispersion exhibits a desired level of physical and/or chemical stability. For example, a solid dispersion retains about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99% of the amorphous Compound 2 when stored at 25° C. in a closed watertight container, for example, in a dark glass jar, high-density polyethylene (HDPE) container, or double nylon twist-locked polyethylene bags placed in an HDPE container with desiccant.

In some embodiments, the polymer improves the chemical or physical stability (e.g., as measured by a temperature modulated differential scanning calorimeter) of Compound 2 when stored (e.g., at 2-8°C, e.g. 4°C or at room temperature) of at least at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least at least about 70%, at least about 80%, or at least about 90%) compared to amorphous Compound 2 without the presence of polymer.

A solid dispersion typically exhibits a glass transition temperature where the dispersion makes a transition from a solid glassy state to a rubbery composition. Generally, the higher the glass transition temperature, the higher the physical stability of the dispersion. The existence of a glass transition temperature generally indicates that at least most of the composition (eg dispersion) is in an amorphous state. The glass transition temperature (Tg) of a solid dispersion suitable for pharmaceutical applications is typically at least about 50°C. In some embodiments, higher temperatures are preferred. Therefore, in some embodiments, the solid dispersion disclosed herein has a Tg of at least about 100°C (e.g., at least about 100°C, at least about 105°C, at least about 110°C, according to at least about 115°C, at least about 120°C, at least about 125°C, at least about 130°C, at least about 135°C, at least about 140°C, at least about 150°C, at least about 160°C, at least about 170°C, at least about 175°C, at least about 180°C, or at least about 190°C). In some embodiments, the implementation of Tg comes up to about 200°C. In some embodiments, the Tg is up to about 130°C (e.g., at least about 110°C, at least about 111°C, at least about 112°C, at least about 113°C, at least about 114°C, at least about

- 11 039805

115°C, at least about 116°C, at least about 117°C, at least about 118°C, at least about 119°C, at least about 120°C, at least about 121°C C, at least about 122°C, at least about 123°C, at least about 124°C, at least about 125°C, at least about 1216°C, at least about 127°C, at least about 128°C, at least about 129°C, or at least about 130°C). Unless otherwise indicated, the glass transition temperatures disclosed in this application are measured under dry conditions.

In some embodiments, the implementation of the solid dispersion has a higher glass transition temperature than the glass transition temperature of amorphous Compound 2, measured without the presence of polymer(s). In some embodiments, the implementation of the solid dispersion has a relaxation rate that is lower than the relaxation rate of amorphous Compound 2, measured without the presence of polymer(s).

Examples of solid dispersion polymers include cellulose derivatives (e.g., hydroxypropyl methylcellulose, also known as hypromelose succinate (HPMC), hydroxypropyl methylcellulose phthalate, also known as hypromelose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate, also known as hypromelose acetate succinate, (HPMCAS), hydroxypropyl cellulose (HPC)), ethyl cellulose or cellulose acetate phthalate; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); polyvinyl esters such as polyvinyl acetate phthalate (PVAP); acrylates such as polymethacrylate (eg Eudragit. RTM. E); cyclodextrins (eg. beta.-cyclodextrin); poly(D,L-lactide) (PLA), poly(D,L-lactide-co-glycolide (PLGA); and copolymers and derivatives thereof, including, for example, polyvinylpyrrolidone-vinyl acetate (PVP-VA), polyvinylcaprolactam-polyvinyl, and acetate-polyethylene glycol copolymer, methyl acrylate/methacrylic acid copolymer; Soluplus; Copovidone; and mixtures thereof.

In some embodiments, the implementation of the solid dispersion includes a single water-soluble polymer. In some embodiments, the implementation of the solid dispersion includes one partially water-soluble polymer. In some embodiments, the implementation of the polymer is a cellulosic polymer.

In some embodiments, the implementation of the polymer is HPMCAS (for example, various grades of HPMCAS: HPMCAS-M, HPMCAS-MG or HPMCAS-HG). In some embodiments, the polymer is PVAP. In some embodiments, the implementation of the polymer is HPMC (for example, various grades of HPMC: HMPC60SH50, HPMCE50 or HPMCE15). In some embodiments, the polymer is HPMCP (eg, various grades of HPMCP: eg, HMPCP-HP55).

In some embodiments, the implementation of the polymer is a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), HPMCP, HPMCAS, carboxymethyl cellulose (CMC), or a salt thereof (e.g., a sodium salt such as (CMC-Na) ); cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP) and methylcellulose acetate phthalate (MCAP), polymethacrylates (eg Eudragit S) or mixtures thereof.

In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate, also known as hypromelose acetate succinate (HPMCAS), such as HMPCAS-HG.

In another embodiment, the polymer(s) is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (eg, Crospovidone). In another embodiment, the polymer(s) is polyvinylpyrrolidone (PVP).

In some embodiments, one or more polymers are present in the solid dispersion in an amount between about 10 and 90% w/w (e.g., between about 20% w/w and about 80% w/w; between about 30 % w/w and about 70% w/w, between about 40% w/w and about 60% w/w, or between about 15% w/w and about 35% w/w. /wt.). In some embodiments, the implementation of the polymer(s) is present in the solid dispersion in an amount of from about 10 to about 80% wt./wt., for example, from about 30 to about 75% wt./wt. or from about 40 to about 65% w/w, or from about 45 to about 55% w/w, for example about 46% w/w, about 47% w/w, about 48% wt./wt., about 49% wt./wt., about 50% wt./wt., about 51% wt./wt., about 52% wt./wt., about 53% wt./wt. or about 54% wt./wt. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w. /wt., about 50% wt./wt., about 50.5% wt./wt., about 51% wt./wt., about 51.5% wt./wt., about 52% wt./ wt. or about 52.5% wt./wt.

In some embodiments, the implementation of the polymer(s) is present in the solid dispersion in an amount of from about 30 to about 70% wt./wt. In some embodiments, the implementation of the polymer(s) is present in the solid dispersion in an amount of from about 35 to about 65% wt./wt. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of from about 40% to about 60% w/w. In some embodiments, the implementation of the polymer(s) is present in the solid dispersion in an amount of from about 45 to about 55% wt./wt. In some embodiments, the implementation of the polymer(s) is present in the solid dispersion in an amount of about 50% wt./wt.

In some embodiments, the implementation of Compound 2 is present in the solid dispersion in an amount of from about 10 to 90% wt./wt. (for example, between about 20% w/w and about 80% w/w; between about 30% w/w and about 70% w/w; between about 40% w/w. and about 60% w/w, or between about 15% w/w and about 35% w/w). In some embodiments, Compound 2 is present in the solid dispersion in an amount of from about 10 to about 80% w/w, for example from about 30 to about 75% w/w. or from about 40 to about 65% wt./wt. or from about 45 to about 55% w/w, for example about 46% w/w, about 47% w/w, about 48% w/w, about 49% w/w. , about 50% wt./wt., about 51% wt./wt., about 52% wt./wt., about 53% wt./wt. or about 54% wt./wt. In some embodiments, Compound 2 is present in the solid dispersion in an amount of about 48% w/w, about 48.5% w/w, about 49% w/w, about 49.5% w/w ., about 50% w/w, about 50.5% w/w, about 51% w/w, about 51.5% w/w, about 52% w/w. or about 52.5% wt./mass.

In some embodiments, the implementation of Compound 2 is present in the solid dispersion in an amount of from about 30 to about 70% wt./wt. In some embodiments, the implementation of Compound 2 is present in the solid dispersion in an amount of from about 35 to about 65% wt./wt. In some embodiments, the implementation of Compound 2 is present in the solid dispersion in an amount of from about 40 to about 60% wt./wt. In some embodiments, the implementation of Compound 2 is present in the solid dispersion in an amount of from about 45 to about 55% wt./wt. In some embodiments, Compound 2 is present in the solid dispersion in an amount of about 50% w/w.

In another embodiment, the solid dispersion includes from about 20 to about 80% wt./wt. Connection 2 and from about 20% wt./wt. up to about 80% polymer(s). In another embodiment, the solid dispersion comprises from about 25 to about 75% wt./wt. Compound 2 and from about 25% w/w to about 75% polymer(s). In another embodiment, the solid dispersion comprises from about 30 to about 70% wt./wt. Connection 2 and from about 30% wt./wt. up to about 70% polymer(s). In another embodiment, the solid dispersion includes from about 35 to about 65 wt./wt.% Compound 2 and from about 35% wt./wt. up to about 65% polymer(s). In another embodiment, the solid dispersion comprises from about 40 to about 60% wt./wt. Connection 2 and from about 40% wt./wt. up to about 60% polymer(s). In another embodiment, the solid dispersion comprises from about 45 to about 55% wt./wt. Compound 2 and from about 45% w/w to about 55% polymer(s). In another embodiment, the solid dispersion comprises from about 50% wt./wt. Connection 2 and from about 50% wt./wt. polymer(s).

In another embodiment, the solid dispersion comprises from about 45 to about 55% wt./wt. Connection 2 and from about 45 to about 55% wt./wt. HPMCAS (eg HPMCAS-MG or HPMCASHG or other grades such as LF, MF, HF or LG) or PVAP. In another embodiment, the solid dispersion includes about 50% wt./wt. Connection 2 and about 50% wt./wt. HPMCAS.

In some embodiments, the implementation of the solid dispersion also includes a surfactant or an inert pharmaceutically acceptable substance. Examples of solid dispersion surfactants include sodium lauryl sulfate (SLS), vitamin E or a derivative thereof (e.g. vitamin E TPGS), sodium docusate, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, polyoxyethylene-polyoxypropylene block copolymers (eg Pluronic F108, Pluronic P-123) and mixtures thereof. In some embodiments, the surfactant is SLS. In some embodiments, the surfactant is vitamin E or a derivative thereof (eg, vitamin E TPGS).

In some embodiments, the implementation of the surfactant is present in the solid dispersion in an amount of from about 0.1 to about 10% wt./wt., for example, from about 0.5 to about 2% wt./wt. or from about 1 to about 3% wt./wt., from about 1 to about 4% wt./wt. or from about 1 to about 5% wt./wt. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0. 4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w ., about 0.9% wt./wt. or about 1% wt./wt. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w. /wt., about 2.5% wt./wt., about 3% wt./wt., about 3.5% wt./wt., about 4% wt./wt., about 4.5 or about 5% w/w

Methods for obtaining solid dispersions

In some embodiments, the implementation of a solid dispersion can be obtained in accordance with the method described in this application. Typically, methods that can be used are those that include rapidly removing the solvent or mixture of solvents from the mixture, or cooling the molten sample. Such methods include, but are not limited to, evaporation on

- 13 039805 rotary evaporator, freeze-drying (ie freeze-drying), vacuum drying, melt solidification and melt extrusion. One embodiment of the present disclosure includes a spray-dried solid dispersion. In one embodiment, the spray dried product is dried to remove the solvent or mixture of solvents.

The preparations disclosed in this application, for example, a pharmaceutical composition, can be obtained by spray drying a mixture comprising Compound 2, one or more polymers and a suitable solvent or mixture of solvents. Spray drying involves spraying a liquid mixture containing, for example, a solid and a solvent or solvent mixture, and removing the solvent or solvent mixture. The solvent or solvent mixture may also contain a non-volatile solvent such as glacial acetic acid. Atomization can be carried out, for example, through a two-tray or pressurized or ultrasonic nozzle or on a rotating disk.

Spray drying converts a liquid feed material into a dried solid form. Spray drying typically involves spraying a liquid stock solution into a droplet spray and contacting the droplets with hot air or gas in a drying chamber. Sprays are usually obtained using rotating (wheel) or spray nozzles. The evaporation of moisture from the droplets and the formation of dry particles takes place under controlled conditions of temperature and airflow.

Optionally, a secondary drying process such as fluid bed drying or vacuum drying can be used to reduce residual solvents (and other additives such as glacial acetic acid) to pharmaceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid slurry or solution (eg, a spray solution) and a sufficient volume of hot air or gas (eg, nitrogen, such as pure nitrogen) to produce vaporization and drying of the liquid droplets. The formulation to be spray dried may be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be sprayed using the spray dryer of choice. In a standard procedure, the formulation is sprayed into a stream of warm filtered air (or a gas such as nitrogen) which vaporizes the solvent and transfers the dried product to a collector (eg a cyclone). The exhaust air or gas is then exhausted by the solvent (or solvent mixture, including any additives such as glacial acetic acid) (e.g., then filtered) or, alternatively, the exhaust air or gas is sent to a condenser to collect and potentially recycle the solvent or solvent mixture. For example, if a gas (eg, nitrogen) is used, the gas is then optionally recycled, reheated, and returned to the plant in a closed system. Commercially available types of devices can be used to carry out spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (for example, Niro's PSD line of spray dryers).

For spray drying, a material concentration of from about 1% to about 30% or up to about 50% (ie, the therapeutically active compound plus and excipients) is typically used, preferably at least about 10%. In some embodiments, a weight concentration of less than 10% can lead to poor yields and unacceptably long run times. In general, the upper limit of the mass concentration depends on the viscosity (eg pumpability) of the resulting solution and the solubility of the components in the solution. As a rule, the viscosity of the solution can determine the particle size in the resulting powdered product.

Procedures and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H. Perry, D.W. Green & J.O. Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall Atomization and Spray-Drying 50, Chem. Eng. Prog. Mongr. Series 2 (1954). Typically, spray drying is carried out with an inlet temperature of from about 40 to about 200°C, for example from about 70 to about 150°C, preferably from about 40 to about 60°C, from about 50 to about 55°C, or from about 80 to about 110°C, for example about 90°C. Spray drying is typically carried out with an outlet temperature of from about 20 to about 100°C, for example from about 25 to about 30°C (for example, about 26°C), from about 40 to about 50°C, from about 50 up to about 65°C, for example from about 56 to about 58°C.

Removal of the solvent or mixture of solvents may require a subsequent drying step such as tray drying, fluid bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, drum drying, or using a two-cone vacuum dryer. (for example, from about room temperature to about 200°C).

In one embodiment, the spray dryer is a fluid bed spray dryer (FSD). The steps in FSD may include, for example, obtaining a feed liquid solution (eg, containing Compound 2, and optionally polymer(s) and/or surfactant(s) dissolved or suspended in a solvent(s)); atomization (for example, using a pressure nozzle, rotary atomizer or disc, twin-flute nozzle, or other atomization methods) of the supply solution

- 14 039805 when feeding a spray dryer into the drying chamber, for example, operating in FSD mode; drying the feed solution in a drying chamber with heated air or heated gas (e.g. nitrogen) to produce a product where larger product particles are separated, e.g. natural convection) and into the cyclone, and reintroducing (e.g., at the top of the drying chamber or axially in the middle of the chamber) the fines into the drying chamber, where the reintroduced fines can agglomerate with the newly formed product to form an agglomerated product, wherein if the agglomerated product is large enough, it will separate if it is not large enough to separate, the agglomerated product will be carried by convection to the top of the chamber and into the cyclone and reintroduced into the chamber. This process is repeated until an agglomerated product is formed that is large enough to precipitate. Fine particles can be re-introduced from the cyclone to the drying chamber through the feed line.

In some embodiments, instead of drying the feed solution with heated air or heated gas, the feed solution may be spray cured, e.g., the chamber is at room temperature (e.g., 21+4°C) or cooled, e.g., a chilled gas (e.g., nitrogen) is used for the process. ).

The FSD may further include collecting the agglomerated product in the first fluidizing chamber; which may be followed by the discharge of the agglomerated product from the first fluidizing chamber into a second fluidizing chamber, in which a post-drying process may take place.

The agglomerated product (eg, which is separated in the drying chamber) can then be transferred from the second fluidizing chamber to the third fluidizing chamber, where the agglomerated product is cooled. The agglomerated product (eg, a solid dispersion of an amorphous compound) can then be further processed. For example, the product can be immediately pressed. The product may optionally be mixed with a surfactant, excipient or pharmaceutically acceptable carrier, for example prior to direct compression. The product may optionally be subjected to further processing, for example by milling, granulating, blending and/or blending with a melt granulate, surfactant, excipient and/or pharmaceutically acceptable carrier.

FSD can be carried out in a commercial spray dryer operating in a fluid bed spray drying mode (FSD mode). FSD can be carried out either in an open cycle mode or in a closed cycle mode (eg drying gas, eg nitrogen, is recycled). Examples of suitable spray dryers for use in FSD include dryers from Niro (eg PSD line of spray dryers manufactured by Niro: PHARMASD®, chemical dryers or SD lines). FSD can essentially be carried out in any spray dryer that is configured to allow the reintroduction of fines into the dryer chamber.

Additional post-drying, for example in a vacuum or fluid bed or double cone dryer or biconical dryer or drum dryer, can be carried out if necessary/applicable to remove other solvents. In some embodiments, a post-drying step is performed.

Vacuum drying, spray drying, fluid bed spray drying, tray dryer, lyophilization, rotary evaporation, and other drying procedures can be used to remove the solvent or mixture of solvents. The use of any of these methods using the appropriate processing parameters in accordance with the present disclosure will provide Compound 2 in the amorphous state in the final product as a solid dispersion. By using appropriate conditions (e.g. low spray dryer outlet temperatures, use of low boiling solvents, use of heated gas) that result in a dispersion, e.g. powder, with desired properties (e.g. average particle size (d50) 40-200 µm, e.g. 40-150 µm), powder bulk density >0.2 g/mL (e.g. 0.2 to 0.5 g/mL) or >0.25 g/mL, improved powder flow (e.g. low cohesive forces, low interparticle friction); and/or dry powder with low OVI (organic volatile impurities), eg below ICH limits and/or user specifications), the dispersion can be directly compressed into a dosage form.

In some embodiments, the inlet temperature is between about 50 and about 200°C, for example, between about 60 and about 150°C, between about 70 and about 100°C, between about 60 and about 95°C, between about 65 and about 85°C, between about 70 and about 90°C, between about 85 and about 95°C, or between about 70 and about 85°C.

In some embodiments, the outlet temperature is between about room temperature (e.g., room temperature USP (e.g., 21+4°C)) and about 80°C,

- 15 039805 for example, between about 25 and about 75°C, between about 30 and about 65°C, between about 35 and about 70°C, between about 40 and about 65°C, between about 45 and about 60°C, between about 35 and about 45°C, between about and about 40°C, or between about 37 and about 40°C.

In some embodiments, the target temperature of the fluidized beds (the temperature for each bed is selected independently of the temperature selected for the other bed) is between about room temperature (e.g., between room temperature USP (e.g., 21+4°C)) and about 100 °C, for example, between about 30 and about 95°C, between about 40 and about 90°C, between about 50 and about 80°C, between about 60 and about 85°C, between about 65 and about 95°C, or between about 80 and about 95°C.

FSD can be performed on a mixture containing Compound 2. For example, FSD can be performed on a mixture containing Compound 2 and one or more polymers and optionally one or more surfactants and optionally one or more additional excipients) to obtain a solid dispersion of an amorphous Compound 2, for example, which can be directly compressed into an oral dosage form (eg, a tablet). Alternatively, the dispersion may be mixed with one or more excipients prior to compression.

In one embodiment, a process for preparing a solid dispersion of Compound 2 comprises:

a) forming a mixture of Compound 2, one or more polymers and one or more solvents; and

b) rapidly removing the solvent(s) from solution to form a solid amorphous dispersion comprising Compound 2 and one or more polymers. One or more polymers and one or more solvents may be any of those disclosed in this application.

In some embodiments, the solvent is removed by spray drying. In some embodiments, the solid dispersion is tray dried using a convection tray dryer. In some embodiments, the implementation of the solid dispersion is sifted through a sieve.

In one embodiment, Compound 2 is crystalline. In another embodiment, Compound 2 is amorphous.

As will be understood by those skilled in the art, spray drying can be, and often is, carried out in the presence of an inert gas such as nitrogen. In some embodiments, methods that include spray drying can be carried out in the presence of a supercritical fluid comprising carbon dioxide or a mixture comprising carbon dioxide.

In another embodiment, a process for preparing a solid dispersion of Compound 2 comprises:

a) forming a mixture of Compound 2, polymer and solvent, and

b) spray drying the mixture to form a solid dispersion comprising Compound 2 and polymer.

Optionally, the wet spray-dried dispersion can be post-dryed and/or refinished to below the ICH or these specifications for residual solvents.

These methods can be used to obtain the pharmaceutical compositions disclosed in this application. The amounts and characteristics of the components used in the methods may be those disclosed in this application.

In some embodiments, the solvent includes one or more volatile solvents for dissolving or suspending Compound 2 and the polymer(s). In some embodiments, one or more solvents completely dissolve Compound 2 and the polymer(s).

In some embodiments, one or more solvents are volatile solvents (eg, methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof). Examples of suitable volatile solvents include those which dissolve or suspend the therapeutically active compound, either alone or in combination with another co-solvent. In some embodiments, the solvent(s) completely dissolves the therapeutically active compound. In some embodiments, the solvent is acetone. In some embodiments, the solvent is methanol.

In some embodiments, the solvent is a non-volatile solvent (eg, organic acids such as glacial acetic acid, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or water). In some embodiments, the non-volatile solvent is a component in the solvent system. For example, a non-volatile solvent is present as a component in the solvent from about 1 to about 20% wt./wt. (for example, from about 3 to about 15% w/w).

In some embodiments, the solvent is a mixture of solvents. For example, the solvent may include about 0% to about 30% acetone and about 70% to about 100% methanol, or the solvent may include about 0% to about 40% acetone and about 60% to about 100% methanol. Other examples of methanol to acetone ratios include 80:20, 75:25, 70:30, 60:40, 55:45 and 50:50.

- 16 039805

In some embodiments, the implementation of the solvent is a combination of solvents, including at least one non-volatile solvent. For example, a solvent is a combination of components that includes both a volatile solvent and a non-volatile solvent. In some embodiments, the solvent system is a combination of a volatile solvent or a combination of solvents such as methanol and acetone with a non-volatile solvent such as glacial acetic acid. For example, the solvent system includes about 40% to about 80% methanol, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (e.g., about 50% to about 70% methanol, about 25% to about 30% acetone; and about 3 to about 12% glacial acetic acid).

In some embodiments, the solvent system is a combination of a volatile solvent or a combination of solvents such as methanol and acetone with a non-volatile solvent such as water. For example, the solvent system includes about 40% to about 80% methanol, about 20% to about 35% acetone, and about 0.1% to about 15% water (e.g., about 50% to about 70% methanol, about 25% to about 30% acetone and about 1 to about 5% water).

In some embodiments, the pharmaceutical compositions of the solid dispersion can be obtained by the method described in this application. For example, a solid dispersion comprising: (a) Compound 2 and (b) one or more polymers and optionally one or more surfactants and optionally one or more additional excipients.

A. Pharmaceutical compositions containing solid dispersions of Compound 2

In some embodiments, the present application provides pharmaceutical compositions comprising: (a) a solid dispersion comprising Compound 2 and a polymer; and (b) one or more pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers include fillers, disintegrants, wetting agents, glidants, and lubricants.

In some embodiments, pharmaceutical compositions may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

In some embodiments, the pharmaceutical composition is a tablet.

In some embodiments, the pharmaceutical composition comprises a direct compression dosage form of Compound 2.

In some embodiments, the implementation of the pharmaceutical composition also includes a filler. The filler may be, for example, microcrystalline cellulose, lactose, mannitol, ethylcellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicon-containing microcrystalline cellulose, isomalt or mixtures thereof. In some embodiments, the filler is microcrystalline cellulose.

In some embodiments, the implementation of the filler is present in the pharmaceutical composition in an amount between about 10 and 50% wt./wt. (for example, between about 15 and about 45% wt. wt.; between about 20 and about 40% wt./wt.; between about 25 and about 35% wt./wt., or between about 28 and about 32% wt. /wt.). In some embodiments, the implementation of the filler is present in the pharmaceutical composition in an amount of from about 20 to about 35% wt./wt., for example, from about 25 to about 34% wt./wt. or from about 26 to about 33% wt./wt. or from about 27 to about 32% w/w, for example about 28% w/w, about 28.5% w/w, about 29% w/w, about 29.5% w/w ./wt., about 30% wt./wt., about 30.5% wt./wt., about 31% wt./wt. or about 31.5% wt./wt. In some embodiments, the excipient is present in the pharmaceutical composition in an amount of about 29% w/w, about 29.1% w/w, about 29.2% w/w, about 29.3% w/w. , about 29.4% w/w, about 29.5% w/w, about 29.6% w/w, about 29.7% w/w, about 29.8% wt./wt., about 29.9% wt./wt. or about 30% wt./wt. In some embodiments, the implementation of the filler is present in the pharmaceutical composition in an amount between about 25 and about 35% wt./wt. In some embodiments, the implementation of the filler is present in the pharmaceutical composition in an amount of about 29.5% wt./wt.

In some embodiments, the pharmaceutical composition also includes a disintegrant. The disintegrant may be, for example, colloidal silicon dioxide, powdered cellulose, calcium silicate, crospovidone, calcium alginate, methylcellulose, chitosan, carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, sodium alginate, sodium starch glycolate, pregelatinized starch, or mixtures thereof. In some embodiments, the disintegrant is croscarmellose sodium.

In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount between about 1 and 15% w/w. (for example, between about 3 and about 12% w/w; between about 4 and about 10% w/w; between about 5 and about 7% w/w, or between about 6 and about 7% w/w ./wt.). In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 3% w/w, about 3.5% w/w, about 4% w/w, about 49.5% w/w. , about 5% wt./wt., about 5.5% wt./wt., about 6% wt./wt. or about 6.5% w/w, about

- 17 039805

7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about 9% w/w, about

9.5% w/w or about 10% wt./wt. In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount between about 5% and about 7% w/w. In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 6% w/w.

In some embodiments, the implementation of the pharmaceutical composition also includes a wetting agent. The wetting agent may be, for example, sodium lauryl sulfate, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, or mixtures thereof. In some embodiments, the wetting agent is sodium lauryl sulfate.

In some embodiments, the implementation of the wetting agent is present in the pharmaceutical composition in an amount between about 0.1 and 2% wt./wt. (for example, between about 0.5 and about 2% w/w; between about 0.5 and about 1.5% w/w; or between about 1 and about 1.5% w/w. ). In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% wt./wt., about 0.5% wt./wt., about 0.6% wt./wt., about 0.7% wt./wt. or about 0.8% wt./wt., about 0.9% wt./wt., about 1% wt./wt., about 1.1% wt./wt., about 1.2% wt. /wt., about 1.3% wt./wt., about 1.4% wt./wt., about 1.5% wt./wt., about 1.6% wt./wt., about 1 .7% w/w, about 1.8% w/w, about 1.9% w/w. or about 2% wt./wt. In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount between about 0.5 and about 1.5% w/w. In some embodiments, the implementation of the wetting agent is present in the pharmaceutical composition in an amount of about 1% wt./wt.

In some embodiments, the pharmaceutical composition also includes a glidant. The glidant may be, for example, silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, magnesium stearate, magnesium trisilicate, powdered cellulose, talc, starch, and mixtures thereof. In some embodiments, the glidant is fumed silica.

In some embodiments, a glidant is present in the pharmaceutical composition in an amount between about 0.1 and 5% w/w. (eg, between about 1 and about 4% w/w; between about 1 and about 3% w/w, or between about 1.5 and about 2.5% w/w). In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w. ./wt., about 2.5% wt./wt., about 3% wt./wt., about 3.5% wt./wt. or about 4% wt./wt., about 4.5% wt./wt. or about 5% wt./wt. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1 4% w/w, about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w wt., about 1.9% wt./wt., about 2% wt./wt., 2.1% wt./wt., about 2.2% wt./wt., about 2.3% wt. ./wt., about 2.4% wt./wt., about 2.5% wt./wt., about 2.6% wt./wt., about 2.7% wt./wt., about 2.8% w/w, about 2.9% w/w. or about 3% wt./wt. In some embodiments, the glidant is present in the pharmaceutical composition in an amount between about 1% and about 3% w/w. In some embodiments, a glidant is present in the pharmaceutical composition in an amount of about 2% w/w.

In some embodiments, the implementation of the pharmaceutical composition also includes a lubricant. The lubricant may be, for example, magnesium stearate, talc, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, zinc stearate, calcium stearate, sucrose stearate, polyvinyl alcohol, magnesium lauryl sulfate, or mixtures thereof. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the lubricant is present in the pharmaceutical composition in an amount between about 0.1 and 5% w/w. (eg, between about 1% and about 4% w/w; between about 1% and about 3% w/w, or between about 1% and about 2% w/w). In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w ., about 2.5% wt./wt., about 3% wt./wt., about 3.5% wt./wt. or about 4% wt./wt., about 4.5% wt./wt. or about 5% wt./wt. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4%. w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w wt., about 1.4% wt./wt., about 1.5% wt./wt., about 1.6% wt./wt., about 1.7% wt./wt., about 1, 8% w/w, about 1.9% w/w, about 2% w/w, 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w. or about 2.5% wt./wt. In some variants

- 18 039805 implementation of the lubricant is present in the pharmaceutical composition in an amount between about 0.5 and about 2.5% wt./wt. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.5% w/w.

In some embodiments, the implementation of the solid dispersion is about 25-85 wt.% of the total weight of the pharmaceutical composition. In some embodiments, the implementation of the solid dispersion is from about 50 to about 70 wt.% of the total weight of the pharmaceutical composition.

In some embodiments, Compound 2 makes up about 15-45% of the total weight of the pharmaceutical composition and one or more polymers make up about 15-45% of the total weight of the pharmaceutical composition.

In some embodiments, the implementation of Compound 2 is about 20% wt./wt. pharmaceutical composition, one or more polymers make up about 40% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of Compound 2 is about 25% wt./wt. pharmaceutical composition, one or more polymers make up about 35% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of Compound 2 is about 30% wt./wt. pharmaceutical composition, one or more polymers make up about 30% w/w of the pharmaceutical composition.

In some embodiments, the implementation of Compound 2 is about 35% wt./wt. pharmaceutical composition, one or more polymers make up about 25% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of the solid dispersion is from about 50 to about 70% wt./wt. pharmaceutical composition, the filler is from about 25 to about 35% wt./wt. pharmaceutical composition, disintegrant is from about 5 to about 7% wt./wt. pharmaceutical composition, the wetting agent is from about 0.5 to about 1.5% wt./wt. pharmaceutical compositions, a substance that promotes sliding, is from about 1 to about 3% wt./wt. pharmaceutical composition, the lubricant is from about 0.5 to about 2.5% wt./wt. pharmaceutical composition, thus obtaining a total of 100 wt.% of the composition.

In some embodiments, the implementation of the solid dispersion is about 60% wt./mass. pharmaceutical composition, the filler is about 29.5% wt./wt. pharmaceutical composition, disintegrant is about 6% wt./wt. pharmaceutical composition, the wetting agent is about 1% wt./wt. pharmaceutical composition, a substance that promotes sliding is about 2% wt./wt. pharmaceutical composition, the lubricant is about 1.5% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of the pharmaceutical composition includes from about 25 to about 35% wt./wt. Connection 2, from about 25 to about 35% wt./wt. hypromelose acetate succinate (HPMCAS), from about 25 to about 35% wt./wt. microcrystalline cellulose, from about 5 to about 7% wt./wt. sodium croscarmellose, from about 0.5 to about 1.5% wt./wt. sodium lauryl sulfate, about from about 1 to about 3% wt./wt. colloidal silicon dioxide and from about 0.5 to about 2.5% wt./wt. magnesium stearate, thus giving a total of 100% by weight of the composition.

In some embodiments, the implementation of the pharmaceutical composition includes about 30% wt./wt.

Connection 2 about 30% wt./wt. hypromelose acetate succinate (HPMCAS), about 29.5% wt./wt. microcrystalline cellulose, about 6% wt./wt. croscarmellose sodium, about 1% wt./wt. sodium lauryl sulfate, about 2% wt./wt. colloidal silicon dioxide and about 1.5% wt./wt. magnesium stearate.

In some embodiments, the solid dispersion, filler, disintegrant, wetting agent, glidant, and lubricant are added intragranularly. In some embodiments, additional filler, disintegrant, glidant, and lubricant are added extragranularly.

In some embodiments, the implementation of the pharmaceutical composition includes the following intragranularly added components: solid dispersion is from about 50 to about 70% wt./wt. pharmaceutical composition, the filler is from about 18 to about 26% wt./wt. pharmaceutical composition, disintegrant is from about 2 to about 6% wt./wt. pharmaceutical composition, the wetting agent is from about 0.5 to about 1.5% wt./wt. pharmaceutical compositions, a substance that promotes sliding, is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition and lubricant is from about 0.25 to about 1% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of the pharmaceutical composition includes the following extragranular added components: additional amount of filler is from about 4 to about 12% wt./wt. pharmaceutical composition, the additional amount of baking powder is from about 1 to about 3% wt./wt. pharmaceutical composition, additional amount

- 19 039805 glidants is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition and additional amount of lubricant is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition, and they are added extragranularly.

In some embodiments, the implementation of the pharmaceutical composition includes the following intragranularly added components: solid dispersion is about 60% wt./wt. pharmaceutical composition, the filler is about 21.5% wt./wt. pharmaceutical composition, disintegrant is about 4% wt./mass, pharmaceutical composition, wetting agent is about 1% wt./wt. pharmaceutical composition, a substance that promotes sliding is about 1% wt./wt. pharmaceutical composition, and the lubricant is about 0.5% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of the pharmaceutical composition includes the following extragranular added components: the additional amount of filler is about 8% wt./wt. pharmaceutical composition, the additional amount of baking powder is about 2% wt./wt. pharmaceutical composition, the additional amount of substance that promotes sliding is about 1% wt./wt. pharmaceutical composition, and the additional amount of lubricant is about 1% wt./wt. pharmaceutical composition, and they are added extragranularly.

In some embodiments, the implementation of the pharmaceutical composition includes the following intragranularly added components: a solid dispersion, including Compound 2 and hypromelose acetate succinate (HPMCAS), is from about 50 to about 70% wt./wt. pharmaceutical composition, microcrystalline cellulose is from about 18 to about 26% wt./wt. pharmaceutical composition, sodium croscarmellose is from about 2 to about 6% wt./wt. pharmaceutical composition, sodium lauryl sulfate is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition, colloidal silicon dioxide is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition, and magnesium stearate is from about 0.25 to about 1% w/w of the pharmaceutical composition.

In some embodiments, the implementation of the pharmaceutical composition includes the following extragranular added components: additional amount of microcrystalline cellulose is from about 4 to about 12% wt./wt. pharmaceutical composition, the additional amount of sodium croscarmellose is from about 1 to about 3% wt./wt. pharmaceutical composition, the additional amount of colloidal silicon dioxide is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition and an additional amount of magnesium stearate is from about 0.5 to about 1.5% wt./wt. pharmaceutical composition, and they are added extragranularly.

In some embodiments, the implementation of the pharmaceutical composition includes the following intragranularly added components: a solid dispersion, including Compound 2 and hypromelose acetate succinate (HPMCAS), is about 60% wt./wt. pharmaceutical composition, microcrystalline cellulose is about 21.5% wt./wt. pharmaceutical composition, sodium croscarmellose is about 4% wt./wt. pharmaceutical composition, sodium lauryl sulfate is about 1% wt./wt. pharmaceutical composition, colloidal silicon dioxide is about 1% wt./wt. pharmaceutical composition and magnesium stearate is about 0.5% wt./wt. pharmaceutical composition.

In some embodiments, the implementation of the pharmaceutical composition includes the following extragranular added components: the additional amount of microcrystalline cellulose is about 8% wt./wt. pharmaceutical composition, the additional amount of sodium croscarmellose is about 2% wt./wt. pharmaceutical composition, the additional amount of colloidal silicon dioxide is about 1% wt./wt. pharmaceutical composition and an additional amount of magnesium stearate is about 1% wt./wt. pharmaceutical composition, and they are added extragranularly.

B. Pharmaceutical compositions containing cytarabine

In some embodiments, this application provides pharmaceutical compositions comprising cytarabine and a pharmaceutically acceptable carrier, for administration to a patient in need thereof, in the methods presented in this application. In some embodiments, pharmaceutical compositions comprising cytarabine are for parenteral administration. In one embodiment, the pharmaceutical composition comprises cytarabine in a sterile solution for intravenous, intrathecal, or subcutaneous administration.

In some embodiments, the implementation of the pharmaceutical composition includes an aqueous solution containing 20 mg/ml cytarabine. In some embodiments, the implementation of the pharmaceutical composition includes an aqueous solution containing 100 mg/ml cytarabine.

In one embodiment, the pharmaceutical composition comprising cytarabine does not contain a preservative. In one embodiment, the pharmaceutical composition comprising cytarabine further comprises sodium chloride. In one embodiment, sodium chloride is present in an amount of about 0.68% based on the total weight of the composition. In one embodiment, the pharmaceutical composition further comprises hydrochloric acid and/or sodium hydroxide to adjust the pH of the composition to about 7.2-7.8. In one embodiment, the pharmaceutical composition further comprises hydrochloric acid and/or sodium hydroxide to adjust the pH of the composition to about 7.3-7.7. In one embodiment, the pharmaceutical composition further comprises hydrochloric acid and/or sodium hydroxide to adjust the pH of the composition to about 7.4, 7.6, or 7.7.

In one embodiment, the pharmaceutical composition comprising cytarabine contains a preservative. In one embodiment, the preservative is benzyl alcohol. In one embodiment, the amount of benzyl alcohol is about 0.9% based on the total weight of the composition. In one embodiment, the pharmaceutical composition further comprises hydrochloric acid and/or sodium hydroxide to adjust the pH of the composition to about 7.6.

In some embodiments, provided herein is a powder comprising cytarabine, wherein the powder is suitable for reconstitution. In some embodiments, the composition is reconstituted with water containing 0.9% w/v benzyl alcohol.

In some embodiments, the implementation of cytarabine is formulated and administered in accordance with the instructions for use of cytarabine.

C. Pharmaceutical compositions containing daunorubicin

In some embodiments, provided herein are pharmaceutical compositions comprising daunorubicin hydrochloride and a pharmaceutically acceptable carrier. In some embodiments, the compositions are intended for intravenous administration to a patient in need of it, in the methods presented in this application. In some embodiments, the compositions further include sodium chloride. In some embodiments, the compositions further include sodium hydroxide and/or hydrochloric acid to adjust the pH to 3-7. In some embodiments, the compositions have a pH in the range of 3-4, 4-5, or 4.5-6.5. In some embodiments, the compositions include an aqueous solution of daunorubicin hydrochloride equivalent to 5 mg/ml daunorubicin, 9 mg/ml sodium chloride, sodium hydroxide, and/or hydrochloric acid to adjust the pH to 3-4.

In some embodiments, daunorubicin is formulated and administered according to instructions for use.

D. Pharmaceutical compositions containing idarubicin

In some embodiments, provided herein are pharmaceutical compositions comprising idarubicin hydrochloride and a pharmaceutically acceptable carrier. In some embodiments, the compositions include idarubicin hydrochloride as a sterile lyophilized powder for reconstitution and intravenous administration. In some embodiments, the compositions include sterile lyophilized powder of idarubicin hydrochloride in an amount of about 20 mg per disposable vial. In some embodiments, the compositions further comprise lactose NF.

In some embodiments, provided herein are pharmaceutical compositions comprising idarubicin hydrochloride as a sterile semi-synthetic preservative-free intravenous solution. In some embodiments, provided herein are pharmaceutical compositions comprising idarubicin hydrochloride as an isotonic parenteral preservative-free solution. In some embodiments, the compositions are presented in disposable vials.

In one embodiment, the vials contain about 5, 10, or 20 ml of a solution containing idarubicin hydrochloride. In some embodiments, each vial contains 1 mg/mL idarubicin hydrochloride and the following inactive ingredients: USP glycerol 25 mg/mL, water, NF hydrochloric acid to adjust the pH to about 3.5.

In some embodiments, each vial contains about 5 mg idarubicin hydrochloride, 125 mg glycerol, water for injection q.s. up to 5 ml and HCl to pH 3.5.

In some embodiments, each vial contains about 10 mg idarubicin hydrochloride, 250 mg glycerol, water for injection q.s. up to 10 ml and HCl to pH 3.5.

In some embodiments, idarubicin is formulated and administered according to instructions for use.

E. Pharmaceutical compositions containing etoposide

In some embodiments, provided herein are pharmaceutical compositions comprising etoposide phosphate and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions of etoposide phosphate are for intravenous infusion. In one embodiment, the pharmaceutical composition is presented in a single dose vial containing etoposide phosphate equivalent to about 100 mg of etoposide, about 32.7 mg of USP sodium citrate, and about 300 mg of dextran 40.

In some embodiments, the pharmaceutical compositions of etoposide phosphate are for intravenous injection. In one embodiment, the pharmaceutical compositions are presented as 20 mg/ml solutions in 100 mg (5 ml), 200 mg (10 ml), or 500 mg (25 ml) sterile multi-dose vials, where each ml contains about 20 mg of etoposide, about 2 mg citric acid, approx. 80 mg polysorbate 80, approx. 650 mg polyethylene glycol 300 and dehydrated alcohol approx.

33.2% (v/v).

In some embodiments, etoposide is formulated and administered according to instructions for use.

F. Pharmaceutical compositions containing mitoxantrone

In some embodiments, provided herein are pharmaceutical compositions comprising mitoxantrone hydrochloride and a pharmaceutically acceptable carrier. In some embodiments, pharmaceutical compositions of mitoxantrone hydrochloride are for intravenous administration.

In some embodiments, the compositions are presented as a concentrate that requires dilution prior to injection. In some embodiments, the composition is a sterile aqueous solution comprising mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, sodium chloride (about 0.80% w/v), sodium acetate (about 0.005% w/v ), glacial acetic acid (about 0.046% w/v) and water. In one embodiment, the composition has a pH of 3.0-4.5 and contains 0.14 meq. sodium per ml. In some embodiments, the composition does not contain any preservative.

In some embodiments, mitoxantrone is formulated and administered according to instructions for use.

Application methods

In one embodiment, the present application provides methods for treating acute myeloid leukemia (AML) characterized by the presence of a mutant IDH1 allele by administering to a subject a combination of a mutant IDH1 inhibitor and AML induction and consolidation therapy.

In one embodiment, the mutant IDH1 inhibitor is (5)-N-((5)-1-(2chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine -2-yl)-N-(5-fluoropyridin3-yl)-5-oxopyrrolidine-2-carboxamide or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, isotopologue, prodrug or polymorph thereof (Compound 2).

In one embodiment, the present application provides a method of treating AML characterized by the presence of a mutant IDH1 allele, comprising administering to the subject a therapeutically effective amount of Compound 2 and induction therapy and consolidation therapy of AML.

In one embodiment, the present application provides a method of treating AML characterized by the presence of a mutant IDH1 allele, comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of Compound 2, and induction therapy and consolidation therapy of AML.

In one embodiment, the present application provides a method of treating AML selected from newly diagnosed AML, previously untreated AML, AML arising from myelodysplastic syndrome (MDS), AML arising from a pre-existing hematological disorder (AHD), and AML arising after genotoxic defeat. In some embodiments, the genotoxic lesion results from radiation and/or chemotherapy. In one embodiment, the present application provides a method of treating AML that occurs after a genotoxic lesion resulting from radiation and/or chemotherapy.

In one embodiment, the present application provides a method for treating newly diagnosed AML.

In one embodiment, the present application provides a method for the treatment of previously untreated AML.

In one embodiment, the present application provides a method for the treatment of AML arising from myelodysplastic syndrome (MDS).

In one embodiment, the present application provides a method for the treatment of AML arising from a previous hematological disorder (AHD).

In one embodiment, the present application provides a method for the treatment of AML that occurs after a genotoxic injury.

In one embodiment, the AML induction therapy is a combination of cytarabine and daunorubicin. In one embodiment, the AML induction therapy is a combination of cytarabine and idarubicin.

In one embodiment, the AML consolidation therapy is cytarabine. In one embodiment, the AML consolidation therapy is a combination of mitoxantrone and etoposide.

In one embodiment, the method of treating AML provided herein comprises administering a therapeutically effective amount of Compound 2 orally and cytarabine and daunorubicin intravenously during the induction phase, followed by administering a therapeutically effective

- 22 039805 amounts of Compound 2 orally and cytarabine intravenously at the consolidation stage.

In one embodiment, the method of treating AML provided herein comprises administering a therapeutically effective amount of Compound 2 orally and administering cytarabine and idarubicin intravenously at the induction stage, followed by administering a therapeutically effective amount of Compound 2 orally and cytarabine intravenously at the consolidation stage.

In one embodiment, the method of treating AML provided herein comprises administering a therapeutically effective amount of Compound 2 orally and cytarabine and daunorubicin intravenously at the induction stage followed by mitoxantrone and etoposide intravenously at the consolidation stage.

In one embodiment, the method of treating AML provided herein comprises administering a therapeutically effective amount of Compound 2 orally and cytarabine and idarubicin intravenously at the induction stage, followed by administering a therapeutically effective amount of Compound 2 orally and mitoxantrone and etoposide intravenously at the consolidation stage.

In one embodiment, Compound 2, cytarabine and daunorubicin are administered simultaneously. In one embodiment, Compound 2, cytarabine and daunorubicin are administered sequentially. In one embodiment, Compound 2, cytarabine and idarubicin are administered simultaneously. In one embodiment, Compound 2, cytarabine and idarubicin are administered sequentially.

In one embodiment, the cancer being treated is characterized by a mutant IDH1 allele, where the IDH1 mutation results in a novel ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2 hydroxyglutarate in the patient. In one aspect of this embodiment, the mutant IDH1 has the R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H.

Cancer can be analyzed by sequencing cell samples to determine the presence and specific nature (eg, altered amino acid present at) of the mutation at amino acid position 132 of IDH1.

Without being bound by theory, the present inventors have found that mutant alleles of IDH1, where the IDH1 mutation results in a novel ability of the enzyme to catalyze the NAPH-dependent reduction of ketoglutarate to R(-)-2 hydroxyglutarate, and in particular the R132H mutations of IDH1 characterize species of all types cancer, regardless of their cellular nature or localization in the body. Thus, the compounds, compositions and methods provided herein are useful in the treatment of any type of cancer characterized by the presence of a mutant IDH1 allele conferring such activity, and in particular an IDH1 R132H or R132C mutation.

In one embodiment, the cancer is a tumor, where at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.

In one embodiment, the effectiveness of the treatment of malignant disease is monitored by measuring the levels of 2HG in the subject. Typically, 2HG levels are measured prior to treatment, with elevated levels requiring Compound 2. Once elevated levels are established, 2HG levels are measured during and/or after treatment is stopped to determine efficacy. In some embodiments, the implementation of the level of 2HG determine only during and/or after cessation of treatment. A decrease in 2HG levels during and after treatment is indicative of efficacy. Likewise, determining that 2HG levels do not rise during or after treatment is also indicative of efficacy. Typically, 2HG measurements are used in conjunction with other well-known measures of cancer treatment efficacy, such as reduction in the number and size of tumors and/or other cancer-related lesions, improvement in the subject's overall health, and changes in other biomarkers that are associated with cancer treatment efficacy. diseases.

2HG can be detected in the sample by LC/MS.

The sample is mixed 80:20 with methanol and centrifuged at 3000 rpm for 20 min at 4°C. The resulting supernatant can be collected and stored at 80° C. until LCMS/MS to evaluate the levels of 2 hydroxyglutarate. Various liquid chromatography (LC) separation methods can be used. Each method can be coupled with negative electrospray ionization (ESI, 3.0 kV) to triple quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on injected metabolite standard solutions. The metabolites can be separated by reverse phase chromatography using 10 mM tributylamine as the ion pairing agent in the aqueous mobile phase according to a variant of the previously described method (Luo et al., J Chromatogr A 1147, 153, 64, 2007 ) . One method allows the separation of TCA metabolites: t=0.50% B; t=5, 95% B; t=7, 95% B; t=8.0% B, where B refers to the organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate with a fast linear gradient from 50 to 95% B (buffers as defined above) over 5 minutes. Synergi Hydro RP, 100 mm χ 2 mm, particle size 2.1 µm (Phenomonex) can be used as a column as described above. Metabolites can be quantified by comparing peak areas with pure metabolite standards at a known concentration. Metabolite flux studies from 13C-glutamine can be performed as described, for example, in Munger et al. Nat Biotechnol 26, 1179 86, 2008.

In one embodiment, 2HG is directly evaluated.

In another embodiment, the 2HG derivative formed during the implementation of the analytical method is evaluated. As an example, such a derivative may be a derivative formed in MS analysis. The derivatives may include a salt adduct, eg a Na adduct, a hydration variant, or a hydration variant that is also a salt adduct, eg a Na adduct, eg obtained in MS analysis.

In another embodiment, a metabolic derivative of 2HG is evaluated. Examples include species that accumulate or increase or decrease as a result of the presence of 2HG, such as glutarate or glutamate, which will correlate with 2HG, such as R-2HG.

Exemplary 2HG derivatives include dehydrated derivatives such as the compounds below or their salt adduct:

Ltd

L L ⁿ L ⁿ θ o no^\-o no^K^o

A JL >=O )=0 [ )=0

2HG is known to accumulate in the inherited metabolic disorder 2hydroxyglutaric aciduria. This disease is caused by a deficiency in the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to α-KG (Struys E. A. 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 Neuropediatrics 33, 225-31 (2002), Wajner, M., Latini, A., Wyse, AT & Dutra-Filho, CS J Inherit Metab Dis 27, 427-48 (2004)). In addition, elevated levels of 2HG in the brain lead to increased levels of ROS (Kolker S. et al., Eur JN euros ci 16, 21-8 (2002), Latini A. et al., Eur J Neurosci 17, 2017-22 (2003)), which potentially increases the risk of cancer. The ability of 2HG to act as an NMDA receptor agonist may contribute to this effect (Kolker S. et al., Eur J Neurosci 16, 21-8 (2002)). 2HG can also be toxic to cells by competitive inhibition of glutamate and/or aKG using enzymes. These include transaminases, which allow the use of the glutamate nitrogen for amino acid and nucleic acid biosynthesis, and aKG-dependent prolyl hydroxylases, such as those that regulate Hif1-alpha levels.

Thus, in accordance with another embodiment, the present application provides a method of treating 2-hydroxyglutaric aciduria, in particular D-2-hydroxyglutaric aciduria in a subject by administering Compound 2, cytarabine and daunorubicin to the subject. In one embodiment, the present application provides a method of treating 2 hydroxyglutaric aciduria, in particular D-2 hydroxyglutaric aciduria in a subject by administering to the subject Compound 2, cytarabine and idarubicin.

In one embodiment, before and/or after treatment with Compound 2, cytarabine, and daunorubicin, the method further comprises the step of assessing height, size, body weight, invasiveness, stage, and/or other phenotype of the cancer. In one embodiment, before and/or after treatment with Compound 2, cytarabine, and idarubicin, the method further comprises the step of assessing height, size, body weight, invasiveness, stage, and/or other phenotype of the cancer.

In one embodiment, before and/or after treatment with Compound 2, cytarabine, and daunorubicin, the method further comprises the step of assessing the IDH1 genotype of the cancer. In one embodiment, before and/or after treatment with Compound 2, cytarabine, and idarubicin, the method further comprises the step of assessing the IDH1 genotype of the cancer. This can be done by conventional methods known in the art, such as DNA sequencing, immunoassay and/or assessment of the presence, distribution or level of 2HG.

In one embodiment, before and/or after treatment with Compound 2, cytarabine, and daunorubicin, the method further comprises the step of determining a subject's 2HG level. In one embodiment, before and/or after treatment with Compound 2, cytarabine, and idarubicin, the method further comprises the step of determining the subject's 2HG level. This can be done using spectroscopic analysis, such as magnetic resonance analysis, such as MRI and/or

- 24 039805 magnetic resonance spectroscopy, analysis of a body fluid sample, such as analysis of serum or cerebrospinal fluid, or analysis of surgical material, such as mass spectroscopy.

In one embodiment, depending on the disease being treated and the condition of the subject, Compound 2 can be administered orally, parenterally (e.g., using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) administration. Compound 2 can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants and excipients suitable for each route of administration. In one embodiment, Compound 2 is administered orally.

In one embodiment, the amount of Compound 2 administered in the methods provided herein may range, for example, between about 5 and about 2000 mg/day. In one embodiment, in the range between about 10 and about 2000 mg/day. In one embodiment, in the range between about 20 and about 2,000 mg/day. In one embodiment, in the range between about 50 and about 1000 mg/day. In one embodiment, in the range between about 100 and about 1000 mg/day. In one embodiment, in the range between about and about 500 mg/day. In one embodiment, in the range between about 150 and about 500 mg/day. In one embodiment, in the range between about 150 and about 250 mg/day. In some embodiments, the specific amount is, for example, or is 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 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 1000 mg/day. In one embodiment, the dose is about 1200 mg/day. In one embodiment, the dose is 1500 mg/day or so. In some embodiments, specific dosages are, for example, up to about 10 mg/day. In one embodiment, the specific dosage is up to about 20 mg/day. In one embodiment, the specific dosage is up to about 50 mg/day. In one embodiment, the specific dosage is up to about 75 mg/day. In one embodiment, the specific dosage is up to about 100 mg/day. In one embodiment, the specific dosage is up to about 120 mg/day. In one embodiment, the specific dosage is up to about 150 mg/day. In one embodiment, the specific dosage is up to about 200 mg/day. In one embodiment, the specific dosage is up to about 250 mg/day. In one embodiment, the specific dosage is up to about 300 mg/day. In one embodiment, the specific dose is up to about 350 mg/day. In one embodiment, the specific dosage is up to about 400 mg/day. In one embodiment, the specific dosage is up to about 450 mg/day. In one embodiment, the specific dosage is up to about 500 mg/day. In one embodiment, the specific dosage is up to about 600 mg/day. In one embodiment, the specific dose is up to about 700 mg/day. In one embodiment, the specific dosage is up to about 800 mg/day. In one embodiment, the specific dosage is up to about 900 mg/day. In one embodiment, the specific dosage is up to about 1000 mg/day. In one embodiment, the specific dose is up to about 1200 mg/day. In one embodiment, the specific dose is up to about 1500 mg/day.

In one embodiment, the amount of Compound 2 in the pharmaceutical composition or dosage form provided herein may vary, for example between about 5 mg and about 2000 mg. In one embodiment, in the range between about 10 and about 2000 mg. In one embodiment, in the range between about 20 and about 2000 mg. In one embodiment, in the range between about 50 and about 1000 mg. In one embodiment, in the range between about 50 and about 500 mg. In one embodiment, in the range between about 50 and about 250 mg. In one embodiment, in the range between about 100 and about 500 mg. In one embodiment, in the range between about 150 and about 500 mg. In one embodiment, in the range between about 150 and about 250 mg. In some embodiments, specific amounts are, for example, about 10 mg. In one embodiment, the specific amount is about 20 mg. In one embodiment, the specific amount is about 50 mg. AT

- 25 039805 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 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 1200 mg. In one embodiment, the specific amount is 1500 mg or so. In some embodiments, specific amounts are, 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 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 1000 mg. In one embodiment, the specific amount is up to about 1200 mg. In one embodiment, the specific amount is up to about 1500 mg.

In one embodiment, Compound 2 can be delivered as a single dose such as, for example, a single bolus injection or oral tablets or pills; or over a period of time, for example, as a continuous infusion over a period of time or as fractional bolus doses over a period of time. In one embodiment, COMPOUND 2 may be administered on a repeat basis as needed, for example, until the patient experiences stabilization or regression of the disease, or until the patient experiences disease progression or unacceptable toxicity. Stable disease, or the absence of disease, is determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, imaging of the tumor by X-ray, axial computed tomography, PET or MRI scanning, and other conventional assessment methods.

In some embodiments, Compound 2 is administered to the patient in cycles (eg, daily administration for one week, then a break without any administration for up to three weeks). Cyclic therapy involves administering an active agent for a period of time followed by a break for a period of time and repeating this sequential administration. Cyclic therapy may reduce the development of resistance, avoid or reduce side effects, and/or improve treatment efficacy.

In one embodiment, the method presented in this application includes the introduction of Compound 2 using 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 greater than 40 injection cycles. In one embodiment, the average number of administration cycles per patient group is about 1. In one embodiment, the average number of administration cycles per patient group is about 2. In one embodiment, the average number of administration cycles per patient group is about 3. In one embodiment, the average the number of administration cycles in the patient group is about 4. In one embodiment, the average number of administration cycles in the patient group is about 5. In one embodiment, the average number of administration cycles in the patient group is about 6. In one embodiment, the average number of administration cycles in the group patients is about 7. In one embodiment, the average number of administration cycles in a group of patients is about 8. In one embodiment, the average number of administration cycles in a group of patients is about 9. In one embodiment, the average number of administration cycles in a group of patients yents is about 10. In one embodiment, the average number

- 26 039805 administration cycles in a patient group is about 11. In one embodiment, the average number of administration cycles in a patient group is about 12. In one embodiment, the average number of administration cycles in a patient group is about 13. In one embodiment, the average number of administration cycles in a patient group in a patient group is about 14. In one embodiment, the average number of administration cycles in a patient group is about 15. In one embodiment, the average number of administration cycles in a patient group is about 16. In one embodiment, the average number of administration cycles in a patient group is about 17. In one embodiment, the average number of administration cycles per patient group is about 18. In one embodiment, the average number of administration cycles per patient group is about 19. In one embodiment, the average number of administration cycles per patient group is but 20. In one embodiment, the average number of administration cycles in a patient group is about 21. In one embodiment, the average number of administration cycles in a patient group is about 22. In one embodiment, the average number of administration cycles in a patient group is about 23. In one embodiment, the average number of administration cycles in a patient group is about 23. in an embodiment, the average number of administration cycles per patient group is about 24. In one embodiment, the average number of administration cycles per patient group is about 25. In one embodiment, the average number of administration cycles per patient group is about 26. In one embodiment, the average number of administration cycles per patient group is about 26. administration per patient group is about 27. In one embodiment, the average number of administration cycles per patient group is about 28. In one embodiment, the average number of administration cycles per patient group is about 29. In one embodiment, the average number of administration cycles per patient group is The average number of administration cycles in a patient group is about 30. In one embodiment, the average number of administration cycles in a patient group is greater than about 30 cycles.

In some embodiments, treatment cycles comprise multiple doses of Compound 2 administered to a subject in need thereof over several days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more than 14 days), optionally followed by drug holidays (e.g. 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 or more than 28 days).

In one embodiment, depending on the disease being treated and the condition of the subject, cytarabine can be administered by oral, parenteral (eg, using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal , rectal, sublingual, or topical (eg, transdermal or topical) administration, cytarabine can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants, and excipients suitable for each route of administration. In one embodiment, cytarabine is administered intravenously.

In some embodiments, treatment cycles include multiple doses of cytarabine administered to a subject in need over several days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14 or more than 14 days), optionally followed by drug holidays (e.g., 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 or more than 28 days). In one embodiment, treatment cycles include multiple doses of cytarabine administered to a subject in need thereof over a period of 2-10 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 4-8 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 4 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need over a period of 5 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 6 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 7 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 8 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 9 days. In one embodiment, the treatment cycles comprise multiple doses of cytarabine administered to a subject in need thereof over a period of 10 days.

Suitable dosage sizes for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts of cytarabine. For example, in some embodiments, the amount of cytarabine administered during the induction step in the methods provided herein may vary, for example, between about 10 and about 1500 mg/m ² /day. In some embodiments, the amount of cytarabine is in the range between about 50 and about 1000 mg/m ² /day. In some embodiments, the amount of cytarabine is in the range between about 100 and about 500 mg/m ² /day. In some embodiments, the amount of cytarabine is in the range between about 150 and about 300 mg/m ² /day. In some

- 27 039805 In other embodiments, the amount of cytarabine is in the range between about 150 and about 200 mg/m ² /day. In some embodiments, the specific dosage is about mg/m ² /day. In one embodiment, the specific dosage is about 75 mg/m ² /day. In one embodiment, the specific dosage is about 100 mg/m ² /day. In one embodiment, the specific dosage is about 125 mg/m ² /day. In one embodiment, the specific dosage is about 150 mg/m ² /day. In one embodiment, the specific dosage is about 175 mg/m ² /day. In one embodiment, the specific dosage is about 200 mg/m ² /day. In one embodiment, the specific dosage is about 225 mg/m ² /day. In one embodiment, the specific dosage is about 250 mg/m ² /day. In one embodiment, the specific dosage is about 275 mg/m ² /day. In one embodiment, the specific dosage is about 300 mg/m ² /day. In one embodiment, the specific dosage is about 350 mg/m ² /day. In one embodiment, the specific dosage is about 400 mg/m ² /day. In some embodiments, the specific dosage is up to about 100 mg/m ² /day. In one embodiment, the specific dosage is up to about 125 mg/m ² /day. In one embodiment, the specific dosage is up to about 150 mg/m ² /day. In one embodiment, the specific dosage is up to about 175 mg/m ² /day. In one embodiment, the specific dosage is up to about 200 mg/m ² /day. In one embodiment, the specific dosage is up to about 225 mg/m ² /day. In one embodiment, the specific dosage is up to about 250 mg/m ² /day. In one embodiment, the specific dosage is up to about 275 mg/m ² /day. In one embodiment, the specific dosage is up to about 300 mg/m ² /day. In one embodiment, the specific dosage is up to about 350 mg/m ² /day. In one embodiment, the specific dosage is up to about 400 mg/m ² /day.

In some embodiments, the amount of cytarabine administered in the consolidation step in the methods provided herein may vary, for example between about 0.1 and about 25 g/m ² /day. For example, in some embodiments, the amount of cytarabine administered in the methods provided herein may vary, for example, between about 0.5 g/m ² /day and about 15 g/m ² /day. In some embodiments, the amount of cytarabine is between about 1 g/m ² /day and about 10 g/m ² /day. In some embodiments, the amount of cytarabine is between about 1 g/m ² /day and about 5 g/m ² /day. In some embodiments, the amount of cytarabine is between about 1 g/m ² /day and about 3 g/m ² /day. In some embodiments, the amount of cytarabine is between about 1 and about 2 g/m ² /day. In some embodiments, the amount of cytarabine is between about 1 and about 1.5 g/m ² /day. In some embodiments, the amount of cytarabine is in the range between about 2 and about 3 g/m ² /day. In some embodiments, the specific dosage of cytarabine is about 0.1 g/m ² /day. In one embodiment, the specific dosage is about 0.5 g/m ² /day. In one embodiment, the specific dosage is about 1 g/m ² /day. In one embodiment, the specific dosage is about 1.5 g/m ² /day. In one embodiment, the specific dosage is about 2 g/m ² /day. In one embodiment, the specific dosage is about 2.5 g/m ² /day. In one embodiment, the specific dosage is about 3 g/m ² /day. In one embodiment, the specific dosage is about 4 g/m ² /day. In one embodiment, the specific dosage is about 5 g/m ² /day. In some embodiments, the specific dosage of cytarabine is up to about 0.1 g/m ² /day. In one embodiment, the specific dosage is up to about 0.5 g/m ² /day. In one embodiment, the specific dosage is up to about 1 g/m ² /day. In one embodiment, the specific dosage is up to about 1.5 g/m ² /day. In one embodiment, the specific dosage is up to about 2 g/m ² /day. In one embodiment, the specific dosage is up to about 2.5 g/m ² /day. In one embodiment, the specific dosage is up to about 3 g/m ² /day. In one embodiment, the specific dosage is up to about 4 g/m ² /day. In one embodiment, the specific dosage is up to about 5 g/m ² /day.

In one embodiment, depending on the disease being treated and the condition of the subject, daunorubicin can be administered by oral, parenteral (e.g., using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) administration. Daunorubicin can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants and excipients suitable for each route of administration. In one embodiment, daunorubicin is administered intravenously.

In some embodiments, treatment cycles include multiple doses of daunorubicin administered to a subject in need over several days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14 or more than 14 days), optionally followed by a drug holiday

- 28039805 23, 24, 25, 26, 27, 28 or more than 28 days). In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 1-8 days. In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 2-6 days. In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 2 days. In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 3 days. In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 4 days. In one embodiment, the treatment cycles comprise multiple doses of daunorubicin administered to a subject in need thereof over a period of 5 days.

Suitable dosage sizes for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts of daunorubicin. For example, in some embodiments, the amount of daunorubicin administered in the methods provided herein may vary, for example between about 1 and about 500 mg/m ² /day. In some embodiments, the amount of daunorubicin is between about 10 and about 300 mg/m ² /day. In some embodiments, the amount of daunorubicin is in the range between about 20 g/m ² /day and about 200 g/m ² /day. In some embodiments, the amount of daunorubicin is between about 30 and about 150 mg/m ² /day. In some embodiments, the amount of daunorubicin is between about 40 and about 120 mg/m ² /day. In some embodiments, the amount of daunorubicin is in the range between about 50 and about 100 mg/m ² /day. In some embodiments, the amount of daunorubicin is between about 60 and about 90 mg/m ² /day. In some embodiments, the amount of daunorubicin is between about 70 and about 80 mg/m ² /day.

In some embodiments, the specific dosage of daunorubicin is about 10 mg/m ² /day. In one embodiment, the specific dosage is about 15 mg/m ² /day. In one embodiment, the specific dosage is about 20 mg/m ² /day. In one embodiment, the specific dosage is about 25 mg/m ² /day. In one embodiment, the specific dosage is about 30 mg/m ² /day. In one embodiment, the specific dosage is about 35 mg/m ² /day. In one embodiment, the specific dosage is about 40 mg/m ² /day. In one embodiment, the specific dosage is about 45 mg/m ² /day. In one embodiment, the specific dosage is about 50 mg/m ² /day. In one embodiment, the specific dosage is about 55 mg/m ² /day. In one embodiment, the specific dosage is about 60 mg/m ² /day. In one embodiment, the specific dosage is about 65 mg/m ² /day. In one embodiment, the specific dosage is about 70 mg/m ² /day. In one embodiment, the specific dosage is about 80 mg/m ² /day. In one embodiment, the specific dosage is about 90 mg/m ² /day. In one embodiment, the specific dosage is about 100 mg/m ² /day.

In some embodiments, the specific dosage of daunorubicin is up to about 10 mg/m ² /day. In one embodiment, the specific dosage is up to about 15 mg/m ² /day. In one embodiment, the specific dosage is up to about 20 mg/m ² /day. In one embodiment, the specific dosage is up to about 25 mg/m ² /day. In one embodiment, the specific dosage is up to about 30 mg/m ² /day. In one embodiment, the specific dosage is up to about 35 mg/m ² /day. In one embodiment, the specific dosage is up to about 40 mg/m ² /day. In one embodiment, the specific dosage is up to about 45 mg/m ² /day. In one embodiment, the specific dosage is up to about 50 mg/m ² /day. In one embodiment, the specific dosage is up to about 55 mg/m ² /day. In one embodiment, the specific dosage is up to about 60 mg/m ² /day. In one embodiment, the specific dosage is up to about 70 mg/m ² /day. In one embodiment, the specific dosage is up to about 80 mg/m ² /day. In one embodiment, the specific dosage is up to about 90 mg/m ² /day. In one embodiment, the specific dosage is up to about 100 mg/m ² /day.

In one embodiment, depending on the disease being treated and the condition of the subject, idarubicin can be administered by oral, parenteral (e.g., using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) administration. Daunorubicin can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants and excipients suitable for each route of administration. In one embodiment, daunorubicin is administered intravenously.

In some embodiments, the treatment cycles include multiple doses of idarubicin,

- 29 039805 to the subject in need of it for several days (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more than 14 days) , optionally followed by drug holidays (e.g., 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 or more than 28 days). In one embodiment, the treatment cycles comprise multiple doses of idarubicin administered to a subject in need thereof over a period of 1-8 days. In one embodiment, the treatment cycles comprise multiple doses of idarubicin administered to a subject in need over a period of 2-6 days. In one embodiment, the treatment cycles comprise multiple doses of idarubicin administered to a subject in need thereof over a period of 2 days. In one embodiment, the treatment cycles include multiple doses of idarubicin administered to a subject in need thereof over a period of 3 days. In one embodiment, the treatment cycles comprise multiple doses of idarubicin administered to a subject in need thereof over a period of 4 days. In one embodiment, the treatment cycles comprise multiple doses of idarubicin administered to a subject in need thereof over a period of 5 days.

Suitable dosage sizes for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts of idarubicin. For example, in some embodiments, the implementation of the amount of idarubicin administered in the methods presented in this application may vary, for example, in the range between about 0.5 and about 50 mg/m ² /day. In some embodiments, the amount of idarubicin is in the range between about 1 and about 25 mg/m ² /day. In some embodiments, the amount of idarubicin is in the range between about 2 and about 20 mg/m ² /day. In some embodiments, the amount of idarubicin is between about 3 and about 15 mg/m ² /day. In some embodiments, the amount of idarubicin is between about 5 and about 14 mg/m ² /day. In some embodiments, the amount of idarubicin is in the range between about 10 and about 13 mg/m ² /day.

In some embodiments, the specific dosage of idarubicin is about 1 mg/m ² /day. In one embodiment, the specific dosage is about 2 mg/m ² /day. In one embodiment, the specific dosage is about 3 mg/m ² /day. In one embodiment, the specific dosage is about 4 mg/m ² /day. In one embodiment, the specific dosage is about 5 mg/m ² /day. In one embodiment, the specific dosage is about 6 mg/m ² /day. In one embodiment, the specific dosage is about 7 mg/m ² /day. In one embodiment, the specific dosage is about 8 mg/m ² /day. In one embodiment, the specific dosage is about 9 mg/m ² /day. In one embodiment, the specific dosage is about 10 mg/m ² /day. In one embodiment, the specific dosage is about 11 mg/m ² /day. In one embodiment, the specific dosage is about 12 mg/m ² /day. In one embodiment, the specific dosage is about 13 mg/m ² /day. In one embodiment, the specific dosage is about 14 mg/m ² /day. In one embodiment, the specific dosage is about 15 mg/m ² /day. In one embodiment, the specific dosage is about 16 mg/m ² /day. In one embodiment, the specific dosage is about 17 mg/m ² /day. In one embodiment, the specific dosage is about 18 mg/m ² /day. In one embodiment, the specific dosage is about 19 mg/m ² /day. In one embodiment, the specific dosage is about 120 mg/m ² /day.

In some embodiments, the specific dosage of idarubicin is up to about 1 mg/m ² /day. In one embodiment, the specific dosage is up to about 2 mg/m ² /day. In one embodiment, the specific dosage is up to about 3 mg/m ² /day. In one embodiment, the specific dosage is up to about 4 mg/m ² /day. In one embodiment, the specific dosage is up to about 5 mg/m ² /day. In one embodiment, the specific dosage is up to about 6 mg/m ² /day. In one embodiment, the specific dosage is up to about 7 mg/m ² /day. In one embodiment, the specific dosage is up to about 8 mg/m ² /day. In one embodiment, the specific dosage is up to about 9 mg/m ² /day. In one embodiment, the specific dosage is up to about 10 mg/m ² /day. In one embodiment, the specific dosage is up to about 11 mg/m ² /day. In one embodiment, the specific dosage is up to about 12 mg/m ² /day. In one embodiment, the specific dosage is up to about 13 mg/m ² /day. In one embodiment, the specific dosage is up to about 14 mg/m ² /day. In one embodiment, the specific dosage is up to about 15 mg/m ² /day. In one embodiment, the specific dosage is up to about 16 mg/m ² /day. In one embodiment, the specific dosage is up to about 17 mg/m ² /day. In one embodiment, the specific dosage is up to about 18 mg/m ² /day. In one embodiment, the specific dosage is up to about 19 mg/m ² /day. In one embodiment, the specific dosage is up to about 20 mg/m ² /day.

In one embodiment, depending on the disease being treated and the condition of the subject, mitoxantrone can be administered orally, parenterally (eg, using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) administration. Mitoxantrone can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants and excipients suitable for each route of administration. In one embodiment, mitoxantrone is administered intravenously.

In some embodiments, treatment cycles include multiple doses of mitoxantrone administered to a subject in need over several days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14 or more than 14 days), optionally followed by drug holidays (e.g., 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 or more than 28 days). In one embodiment, the treatment cycles include multiple doses of mitoxantrone administered to a subject in need thereof over a period of 1-15 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need thereof over a period of 2-10 days. In one embodiment, the treatment cycles include multiple doses of mitoxantrone administered to a subject in need thereof over a period of 2 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need over a period of 3 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need thereof over a period of 4 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need thereof over a period of 5 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need over a period of 6 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need over a period of 7 days. In one embodiment, the treatment cycles include multiple doses of mitoxantrone administered to a subject in need thereof over a period of 8 days.

Suitable dosage sizes for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts of mitoxantrone. For example, in some embodiments, the implementation of the amount of mitoxantrone administered in the methods presented in this application may vary, for example, in the range between about 0.5 and about 50 mg/m ² /day. In some embodiments, the implementation of the amount of mitoxantrone is in the range between about 1 and about 25 mg/m ² /day. In some embodiments, the implementation of the amount of mitoxantrone is in the range between about 5 and about 20 mg/m ² /day. In some embodiments, the implementation of the amount of mitoxantrone is in the range between about 10 and about 15 mg/m ² /day.

In some embodiments, the specific dosage of mitoxantrone is about 1 mg/m ² /day. In one embodiment, the specific dosage is about 2 mg/m ² /day. In one embodiment, the specific dosage is about 3 mg/m ² /day. In one embodiment, the specific dosage is about 4 mg/m ² /day. In one embodiment, the specific dosage is about 5 mg/m ² /day. In one embodiment, the specific dosage is about 6 mg/m ² /day. In one embodiment, the specific dosage is about 7 mg/m ² /day. In one embodiment, the specific dosage is about 8 mg/m ² /day. In one embodiment, the specific dosage is about 9 mg/m ² /day. In one embodiment, the specific dosage is about 10 mg/m ² /day. In one embodiment, the specific dosage is about 11 mg/m ² /day. In one embodiment, the specific dosage is about 12 mg/m ² /day. In one embodiment, the specific dosage is about 13 mg/m ² /day. In one embodiment, the specific dosage is about 14 mg/m ² /day. In one embodiment, the specific dosage is about 15 mg/m ² /day. In one embodiment, the specific dosage is about 16 mg/m ² /day. In one embodiment, the specific dosage is about 17 mg/m ² /day. In one embodiment, the specific dosage is about 18 mg/m ² /day. In one embodiment, the specific dosage is about 19 mg/m ² /day. In one embodiment, the specific dosage is about 20 mg/m ² /day.

In some embodiments, the specific dosage of mitoxantrone is up to about 1 mg/m ² /day. In one embodiment, the specific dosage is up to about 2 mg/m ² /day. In one embodiment, the specific dosage is up to about 3 mg/m ² /day. In one embodiment, the specific dosage is up to about 4 mg/m ² /day. In one embodiment, the specific dosage is up to about 5 mg/m ² /day. In one embodiment, the specific dosage is up to about 6 mg/m ² /day. In one embodiment, the specific dosage is up to about 7 mg/m ² /day. In one embodiment, the specific dosage is up to about 8 mg/m ² /day. In one embodiment, the specific dosage is up to about 9 mg/m ² /day. In one embodiment, the specific dosage is up to about 10 mg/m ² /day. In one embodiment, the specific dosage is up to about 11 mg/m ² /day. In one embodiment, the specific dosage is up to about 12 mg/m ² /day. In one embodiment, the specific dosage is up to about 13 mg/m ² /day. In one embodiment, the specific dosage is up to about 14 mg/m ² /day. In one embodiment, a specific

- 31 039805 dosage is up to about 15 mg/m ² /day. In one embodiment, the specific dosage is up to about 16 mg/m ² /day. In one embodiment, the specific dosage is up to about 17 mg/m ² /day. In one embodiment, the specific dosage is up to about 18 mg/m ² /day. In one embodiment, the specific dosage is up to about 19 mg/m ² /day. In one embodiment, the specific dosage is up to about 20 mg/m ² /day.

In one embodiment, depending on the disease being treated and the condition of the subject, etoposide can be administered by oral, parenteral (e.g., using intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) administration. Etoposide can be formulated into a suitable dosage unit using pharmaceutically acceptable excipients, carriers, adjuvants and excipients suitable for each route of administration. In one embodiment, etoposide is administered intravenously. In one embodiment, etoposide is administered orally.

In some embodiments, treatment cycles include multiple doses of etoposide administered to a subject in need over several days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14 or more than 14 days), optionally followed by drug holidays (e.g., 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 or more than 28 days). In one embodiment, the treatment cycles comprise multiple doses of etoposide administered to a subject in need thereof over a period of 1-15 days. In one embodiment, the treatment cycles comprise multiple doses of etoposide administered to a subject in need thereof over a period of 2-10 days. In one embodiment, the treatment cycles comprise multiple doses of etoposide administered to a subject in need thereof over a period of 2 days. In one embodiment, the treatment cycles comprise multiple doses of etoposide administered to a subject in need thereof over a period of 3 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need thereof over a period of 4 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need thereof over a period of 5 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need over a period of 6 days. In one embodiment, the treatment cycles comprise multiple doses of mitoxantrone administered to a subject in need over a period of 7 days. In one embodiment, the treatment cycles include multiple doses of mitoxantrone administered to a subject in need thereof over a period of 8 days.

Suitable dosage sizes for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts of etoposide. For example, in some embodiments, the amount of etoposide administered in the methods provided herein may vary, for example between about 10 and about 1000 mg/m ² /day. In some embodiments, the amount of etoposide is between about 50 and about 500 mg/m ² /day. In some embodiments, the amount of etoposide is between about 75 and about 250 mg/m ² /day. In some embodiments, the amount of etoposide is between about 100 and about 200 mg/m ² /day.

In some embodiments, the specific dosage of etoposide is about 10 mg/m ² /day. In one embodiment, the specific dosage is about 25 mg/m ² /day. In one embodiment, the specific dosage is about 50 mg/m ² /day. In one embodiment, the specific dosage is about 75 mg/m ² /day. In one embodiment, the specific dosage is about 100 mg/m ² /day. In one embodiment, the specific dosage is about 125 mg/m ² /day. In one embodiment, the specific dosage is about 150 mg/m ² /day. In one embodiment, the specific dosage is about 175 mg/m ² /day. In one embodiment, the specific dosage is about 200 mg/m ² /day.

In some embodiments, the specific dosage of etoposide is up to about 10 mg/m ² /day. In one embodiment, the specific dosage is up to about 25 mg/m ² /day. In one embodiment, the specific dosage is up to about 50 mg/m ² /day. In one embodiment, the specific dosage is up to about 75 mg/m ² /day. In one embodiment, the specific dosage is up to about 100 mg/m ² /day. In one embodiment, the specific dosage is up to about 125 mg/m ² /day. In one embodiment, the specific dosage is up to about 150 mg/m ² /day. In one embodiment, the specific dosage is up to about 175 mg/m ² /day. In one embodiment, the specific dosage is up to about 200 mg/m ² /day.

In one embodiment, the method provided in this application includes the introduction of Compound 1 and induction therapy using 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 or more than 30 cycles. In one embodiment, the average number of administration cycles per group of patients is about 1. In one embodiment, the average number of cycles is about 2. In one embodiment, the average

- 32 039805 the number of cycles is about 3. In one embodiment, the average number of cycles is about 4. In one embodiment, the average number of cycles is about 5. In one embodiment, the average number of cycles is about 6. In one embodiment, the average number of cycles is about 7. In one embodiment, the average number of cycles is about 8. In one embodiment, the average number of cycles is about 9. In one embodiment, the average number of cycles is about 10. In one embodiment, the average number of cycles is about 11. In one embodiment, In one embodiment, the average number of cycles is about 12. In one embodiment, the average number of cycles is about 13. In one embodiment, the average number of cycles is about 14. In one embodiment, the average number of cycles is about 15. In one embodiment, the average number of cycles cycles is about 16. In one embodiment, the average number of cycles is about 17. In one embodiment, the average number of cycles is about 18. In one embodiment, the average number of cycles is about 19. In one embodiment, the average number of cycles is about 20. In in one embodiment, the average number of cycles is about 21. In one embodiment, the average number of cycles is about 22. In one embodiment, the average number of cycles is about 23. In one embodiment, the average number of cycles is about 24. In one embodiment, the average number of cycles is about 25. In one embodiment, the average number of cycles is about 26. In one embodiment, the average number of cycles is about 27. In one embodiment, the average number of cycles is about 28. In one embodiment, the average number of cycles is is about 29. In one embodiment, the average number of cycles is about 30. In one embodiment, the average number of cycles is greater than about 30 cycles.

In one embodiment, the method provided in this application includes the introduction of Compound 1 and consolidation therapy using 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 or more than 30 cycles. In one embodiment, the average number of administration cycles per group of patients is about 1. In one embodiment, the average number of cycles is about 2. In one embodiment, the average number of cycles is about 3. In one embodiment, the average number of cycles is about 4. In one embodiment, the average number of cycles is about 4. in one embodiment, the average number of cycles is about 5. In one embodiment, the average number of cycles is about 6. In one embodiment, the average number of cycles is about 7. In one embodiment, the average number of cycles is about 8. In one embodiment, the average number of cycles is about 9. In one embodiment, the average number of cycles is about 10. In one embodiment, the average number of cycles is about 11. In one embodiment, the average number of cycles is about 12. In one embodiment, the average number of cycles is about but 13. In one embodiment, the average number of cycles is about 14. In one embodiment, the average number of cycles is about 15. In one embodiment, the average number of cycles is about 16. In one embodiment, the average number of cycles is about 17. In one embodiment, In one embodiment, the average number of cycles is about 18. In one embodiment, the average number of cycles is about 19. In one embodiment, the average number of cycles is about 20. In one embodiment, the average number of cycles is about 21. In one embodiment, the average number of cycles is about 22. In one embodiment, the average number of cycles is about 23. In one embodiment, the average number of cycles is about 24. In one embodiment, the average number of cycles is about 25. In one embodiment, the average number of cycles is about 26. In one embodiment, the average number of cycles is about 27. In one embodiment, the average number of cycles is about 28. In one embodiment, the average number of cycles is about 29. In one embodiment, the average number of cycles is about 30. In one embodiment, the average number of cycles is more than about 30 cycles.

In one embodiment, Compound 2 is administered orally once a day. In one embodiment, Compound 2 is administered on days 1-28 of each 28 day cycle. In one embodiment, 50 mg of Compound 2 is administered orally once a day. In another embodiment, 100 mg of Compound 2 is administered orally once a day. In yet another embodiment, 200 mg of Compound 2 is administered orally once a day.

In one embodiment, the induction therapy comprises cytarabine administered for 7 days and daunorubicin administered for 3 days. In one embodiment, the induction therapy comprises cytarabine administered for 7 days and idarubicin administered for 3 days.

In one embodiment, in the methods presented in this application, the induction cycle can be repeated no later than 35 days after the previous induction cycle. In one embodiment, in the methods presented in this application, the induction cycle can be

- 33 039805 repeat no earlier than 14 days after bone marrow puncture/biopsy. In one embodiment, in the methods provided herein, the induction cycle can be repeated by administering cytarabine for 5 days and daunorubicin or idarubicin for 2 days, starting no later than 35 days after the previous induction cycle. In one embodiment, in the methods provided herein, the induction cycle can be repeated by administering cytarabine for 5 days and daunorubicin or idarubicin for 2 days, starting no earlier than 14 days after bone marrow puncture/biopsy.

In one embodiment, the consolidation therapy comprises cytarabine administered for 3 days. In one embodiment, the consolidation therapy comprises cytarabine administered on days 1, 3 and 5 of the cycle. In one embodiment, the consolidation therapy comprises mitoxantrone and etoposide given for 5 days. In one embodiment, in the methods presented in this application, the consolidation cycle can be carried out within 28-42.

Examples

Example 1 Phase A Phase 1, multicentre, open-label safety study of Compound 1 and Compound 2 in combination with induction therapy and consolidation therapy in patients with newly diagnosed acute myeloid leukemia with IDH1 and/or IDH2 mutation

Goals

Primary goal:

To determine the safety and tolerability of 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2(trifluoromethyl)pyridin-4-yl]amino}-1,3,5- triazin-2-yl)amino]propan-2-ol (hereinafter referred to as Compound 1) and Compound 2 when administered with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia (AML) with isocitrate dehydrogenase-1 (IDH1) and/ or isocitrate dehydrogenase-2 (IDH2) mutation.

Secondary Goals:

characterize the pharmacokinetics (PK) of Compound 1 and Compound 2 in plasma samples when administered with AML induction therapy and consolidation therapy;

set the recommended phase 2 dose (RP2D) of Compound 1 and Compound 2 when administered with AML induction and consolidation therapy;

assess plasma levels of 2-hydroxyglutarate (2-HG);

evaluate the clinical activity of Compound 1 in combination with AML induction and consolidation therapy.

Performance Criteria Safety Assessments

Security will be assessed based on the following:

dose-limiting toxicities (DLTs);

adverse events (AEs), serious adverse events (SAEs) and AEs leading to discontinuation of treatment;

results of safety laboratory tests, physical examination, vital signs, 12-lead electrocardiograms (ECG), left ventricular ejection fraction (LVEF), and Eastern Cooperative Oncology Group (ECOG) General Status (PS) score;

drug exposure, including dose intensities and dose modifications.

Results of pharmacokinetic (PK) and pharmacodynamic (PD) studies

The PK and PD profile of Compound 1 and Compound 2 will be assessed based on the following: plasma concentrations and PK parameters of Compound 1 and Compound 2 and the major metabolite of Compound 1;

plasma concentrations of 2-HG versus plasma concentrations of Compound 1 and Compound 2 as a function of time.

Criteria for assessing clinical activity

The clinical activity of Compound 1 and Compound 2 in combination with AML induction and consolidation therapy will be evaluated based on the following:

percentage of patients in complete remission (CRR);

percentage of patients with an objective response (ORR), including complete remission (CR), CR with partial hematological recovery - neutrophils and/or platelets (CRi [includes CR with partial platelet recovery (CRp)]), partial remission (PR), and morphologic non-leukemic state (MLFS);

duration of response (DOR) and duration of CR (DOCR);

time to response (TTR) and time to CR (TTCR);

event-free survival (EFS);

overall survival (OS).

Study plan

Compound 1 and Compound 2 are in Phase 1 open multicentre clinical trial

- 34 039805 to evaluate the safety of Compound 1 and Compound 2 in combination with AML induction and consolidation therapy. The trial will evaluate 1-dose levels of Compound 2 in patients with an IDH1 mutation and 2-dose levels of Compound 1 in patients with an IDH2 mutation. Compound 1 or Compound 2 will be administered with 2 types of AML induction therapy (cytarabine with either daunorubicin or idarubicin) and 2 types of AML consolidation therapy (mitoxantrone with etoposide [ME] or cytarabine). For patients who have a double IDH1 and IDH2 mutation, the appointment of Compound 1 or Compound 2 will depend on the decision of the investigator and the medical observer.

Patients will be treated as follows:

all patients will receive induction therapy (7+3 cytarabine, daunorubicin/idarubicin) in combination with Compound 1 or Compound 2;

after 1 cycle of induction therapy, patients may undergo a second induction cycle administered in accordance with institutional practice (i.e. repeat 7+3 or 7+3 at reduced doses or a regimen such as 5+2 cytarabine, daunorubicin/idarubicin). The second induction cycle can be started after day 14 after bone marrow puncture/biopsy (if any) and no later than 35 days after day 1 of the first induction;

patients who do not achieve CR or CRi (including CRp) after a maximum of 2 inductions will be excluded from the study;

patients who achieve CR or CRi (including CRp) at the end of induction therapy will continue to receive consolidation therapy (ME or up to 4 cycles of an intermediate dose of cytarabine) in combination with Compound 1 or Compound 2. Consolidation treatment should begin no later than approximately 2 weeks after hematological recovery in the last induction cycle or no later than 12 weeks after day 1 of the first induction cycle;

patients who have completed consolidation therapy and are in CR or CRi (including CRp) may continue maintenance therapy and receive daily treatment with Compound 1 or Compound 2 until 1 year from day 1 of the first induction cycle or until relapse, development of unacceptable toxicity, or hematopoietic stem transplantation cells (HSCT) based on the decision of the investigator and medical observer.

The answer will be judged by the researcher based on the criteria of the International Working Group (IWG).

The type of induction therapy and/or consolidation therapy each patient receives is based on investigator judgment and/or open cohorts.

Enrollment of patients in each type of induction therapy will be done in parallel for the first cohort of 6 DLT evaluable patients for daunorubicin with cytarabine and idarubicin with cytarabine for the Compound 1 and Compound 2 administration groups. For consolidation therapy, each of the minimum 6 evaluable patients will receive either cytarabine 1-1.5 g/m ² or ME. Patients with low-risk cytogenetics may take 2-3 g/m ² cytarabine; no minimum number of patients has been established for this group.

Determination of dose-limiting toxicity

Dose-limiting toxicity is defined as any of the following Aes that are clinically significant and in the judgment of the investigator are associated with Compound 1 or Compound 2 alone or in combination with daunorubicin, idarubicin, or cytarabine.

Hematologic: Long-term myelosuppression with stage 4 neutropenia or thrombocytopenia lasting >42 days from day 1 of first induction cycle, in the absence of persistent leukemia (based on the National Cancer Institute Common Adverse Event Terminology Criteria [NCI CTCAE], version 4.03, leukemia-specific criteria, ie, bone marrow saturation <5% on day 28 or later from the start of the drug study without evidence of leukemia). A leukemia-specific score should be used for cytopenias (based on percent reduction from baseline: 50-75%=Grade 3, >75%=Grade 4).

Non-hematologic: All > Grade 3 toxicity not due to underlying AML disease or disease complications or myelosuppressive treatment, except >Grade 3 blood bilirubin elevations in subjects with a UGT1A1 mutation taking Compound 1. Because isolated elevations of blood bilirubin have been observed in subjects with UGT1A1 mutation taking Compound 1, an increase in blood bilirubin >5 χ upper limit of normal (ULN) can be considered as DLT in these subjects.

The definition of DLT does not include the expected systemic and infectious complications of treatment with anthracyclines and cytarabine, including but not limited to:

anorexia requiring total parenteral nutrition;

fatigue requiring bed rest;

gastrointestinal infectious complications such as colitis, typhilitis, mucositis, stomatitis;

liver function tests (LFT), laboratory abnormalities of metabolites or electrolytes that return to baseline within 14 days.

- 35 039805

The clinical trial team, including representatives of the sponsor, medical observer, and participating investigators, will also review any emerging toxicity that is not explicitly covered by the DLT criteria to determine if there is any evidence to designate it as DLT.

The severity of toxicity will be assessed according to NCI CTCAE version 4.03. All AEs that cannot be clearly identified as not related to Compound 1 or Compound 2 will be considered relevant for the determination of DLT and will be considered by the clinical research team.

DLT-evaluated patients

DLT-eligible patients for induction therapy are defined as patients who receive all doses of the first cycle of induction chemotherapy and at least 75% of the doses of Compound 1 or Compound 2 in the first 28 days after the first dose of induction therapy or experience DLT during the first 28 days. In addition, patients must take all 3 doses of Compound 1 or Compound 2 on days 1-3 and at least 2 doses of Compound 1 or Compound 2 on days 4-7 of the first induction to be considered DLT-evaluable. A patient diary will be used in outpatient care to record details regarding dosing of Compound 1 and Compound 2.

Safety Assessment for Induction Therapy

This study will use a 6+6 dosing regimen for Compound 1 and Compound 2, similar to the standard 3+3 dosing regimen, but with greater accuracy in determining RP2D as more patients are evaluated at each dose level. Each cohort for dose evaluation is planned to include 6 DLT-evaluated patients starting at Dose Level 1. Decisions to increase or decrease dose will be made independently for each type of induction combination therapy (i.e. cytarabine with either daunorubicin or idarubicin. For For Compound 2, only 1 dose reduction is permitted to Dose Level - 1. For Compound 1, 1 dose increase to Dose Level 2 is permitted and 1 dose reduction to Dose Level - 1 is permitted.

Dose assessment rules for Compound 1:

If 0 or 1 in 6 patients experience DLT at the current dose level, that dose will be considered safe for that induction regimen. At dose level 1, the dose increase will proceed to level 2 if level 1 is also determined to be safe in consolidation (see below). Approximately 6 additional patients will then be included at dose level 1, as needed, to evaluate consolidation at this dose and further evaluate safety.

If 2 out of 6 patients experience DLT, the cohort will be expanded to include 6 additional patients for a total of 12 patients at this dose level.

If 3 or fewer out of 12 patients experience DLT, the current dose level will be considered safe for induction. At dose level 1, the dose increase will proceed to level 2 if level 1 is also determined to be safe in consolidation.

If 4 or more out of 12 patients experience DLT at Dose Level 1: The dose reduction will go up to Dose Level -1. If 4 or more out of 12 patients experience DLT at Dose Level 2: Return to Dose Level 1. If 4 or more out of 12 patients experience DLT at Dose Level -1: This induction regimen will be closed to further enrollment of patients.

If 3 or more out of 6 patients experience DLT at Dose Level 1: Dose reduction will go down to Dose Level -1. If 3 or more out of 6 patients experience DLT at dose level 2: return to Dose level 1. If 3 or more out of 6 patients experience DLT at dose level -1: this induction regimen will be closed to further enrollment of patients.

Dose assessment rules for Compound 2:

No dose increase for Compound 2.

If 0 or 1 in 6 patients experience DLT at dose level 1, that dose level will be considered safe for that induction regimen. Approximately 6 additional patients will be included at this dose level, if necessary, to evaluate consolidation at this dose and further evaluate safety.

If 2 out of 6 patients experience DLT at dose level 1, the cohort will be expanded to include 6 additional patients for a total of 12 patients at that dose level.

If 3 or fewer out of 12 patients experience DLT, dose level 1 will be considered safe for induction.

If 4 or more out of 12 patients experience DLT, the dose reduction will go down to dose level -1.

If 3 or more out of 6 patients experience DLT, the dose reduction will go down to dose level -1.

If the dose is reduced to dose level -1, the evaluation of this dose will proceed as described above. If 3 or more out of 6 patients or 4 or more out of 12 patients experience DLT at dose level -1, this induction regimen will be closed to further patient enrollment.

Safety Assessment for Consolidation Therapy

The safety of consolidation therapy at each dose level will be reviewed regularly and evaluated when 6 patients have completed at least 28 days of consolidation treatment.

- 36 039805 or stop treatment due to toxicity. All safety data obtained will be evaluated to determine whether or not the dose is safe and tolerable.

For Compound 1, escalating to 200 mg requires that the 100 mg dose be determined safe for both induction (either daunorubicin with cytarabine or idarubicin with cytarabine) and consolidation (either cytarabine 1-1.5 g/m ² , or or ME).

Daunorubicin+cytarabine+Compound 1 200mg induction cohort will be opened if daunorubicin+cytarabine+Compound 1 100mg is considered safe and idarubicin+cytarabine+Compound 1 200mg induction cohort will be opened if idarubicin+cytarabine+Compound 1 100mg is considered safe . Cytarabine 1-1.5 g/m ² (and cytarabine 2-3 g/m ² ) + Compound 1 200 mg consolidation cohort will be open if cytarabine 1-1.5 g/m 2 (or cytarabine 2-3 g/m 2 m 2 )+Compound 1 100mg is considered safe, and IU+Compound 1 200mg a consolidation cohort will be opened if IU+Compound 1 100mg is considered safe.

Interim security check

Interim safety reviews will be conducted after the completion of each induction dose in the patient cohort (i.e. all patients in the cohort have determined their DLT intervals) and when the first 6 patients evaluated in consolidation therapy have completed at least 28 days of treatment or discontinued treatment due to toxicity . Security ratings include the following:

observed toxicity, including DLT;

consideration of AEs/SAEs;

PK/PD data;

consideration of the characteristics of cardiac activity and laboratory data;

puncture / biopsy of the bone marrow.

The safety assessment will be performed by the clinical trial team. Dose reductions of Compound 1 or Compound 2 may be made earlier for patient safety or at the discretion of the investigator in discussion with the sponsor.

Investigational drug

A single dose of Compound 1 or Compound 2 will be administered orally starting on Day 1 of induction until administration of daunorubicin/idarubicin and cytarabine, and will be administered daily until treatment is discontinued or the study is completed. Doses of Compound 1 or Compound 2 should be taken within ±4 hours of the scheduled dose at approximately the same time each day. Each daily dose of Compound 1 should be taken after 2 hours of fasting (water is allowed) and food should be avoided for at least 1 hour after Compound 1 is administered. All patients are advised not to consume grapefruit and products containing grapefruit.

The dose of Compound 2 administered to patients with an IDH1 mutation will be 500 mg (unless the dose is reduced to 250 mg due to DLTs). The dose of Compound 1 administered to patients with an IDH2 mutation will depend on what dose level the cohort is open to enrolling patients when the patient is eligible for the study. Dose levels are presented in 7. No individual dose escalation is permitted during the period of induction or consolidation therapy for Compound 1.

Patients who are on maintenance therapy after consolidation may take Compound 1 or Compound 2 daily for up to 1 year from Day 1 of the first induction cycle. Patients taking Compound 2 will continue treatment at the same dose they were taking. Patients receiving Compound 1 100 mg may continue treatment at the same dose, the dose may be increased to 200 mg if that dose has been found safe at induction and consolidation. Individual dose increases to 200 mg during maintenance therapy using Compound 1 must be confirmed by a medical observer.

Alternative dosing schedules for Compound 1 or Compound 2, including administering the same daily dose using different schedules in parallel cohorts, can be used in consultation with the clinical research team.

Table 7 Dose Levels for Compound 1

COMPOUND 1 (IDH2 mutation) Dose level Dose -one 50 mg one 100 mg 2 200 mg

- 37 039805

Table 8. Dose Levels for Compound 2

COMPOUND 2 (IDH1 mutation) Dose level Dose -one 2 50 mg one 50 0 mg

Table 9. Scheme of induction with Compound 1 or Compound 2

Treatment Day 1 Day 2 Day 3 Days 4-7 Days 8-28 ^a,b IV cytarabine 200 mg/m ^{2 s} X X X X i.v. daunorubic in 6 0 mg/m ² ; or IV idarubicin 12 mg/m ^{2 s} X X X orally COMPOUND 1 or COMPOUND 2 X X X X X

a) Patients may undergo a second induction cycle in accordance with institutional practice (i.e. repeat 7+3, or 7+3 at reduced doses or regimen such as 5+2 cytarabine, daunorubicin/idarubicin) starting after Day 14 after puncture / biopsy of the bone marrow (if any) and no later than 35 days after Day 1 of the first induction.

b) Patients must take Compound 1 or Compound 2 on all days of the induction cycle(s) (ie until the last day of the cycle if the induction cycle is greater than 28 days).

c) Dose adjustments may be made for cytarabine, daunorubicin and/or idarubicin as indicated in the package insert.

Table 10. Consolidation scheme with Compound 1 or Compound 2

Treatment Day 1 Day 2 Day 3 Day 4 Day 5 Days 6-28 ^a IV ^cytarabine ; X X X X X or mitoxantrone 10 mg/m ² and etoposide 100 mg/m ^{2 c} ' ^d orally CONNECTION 1 or COMPOUND 2 X X X X X X

a) A window of 28-42 days is allowed for each consolidation cycle. Patients should take Compound 1 or Compound 2 on all days of the consolidation cycle(s) (ie until the last day of the cycle if the consolidation cycle is greater than 28 days).

b) Cytarabine will be administered at or between 1 and 1.5 mg/m ² IV every 12 hours, Days 1-3. Patients with low-risk cytogenetics may take higher doses of cytarabine at or between 2-3 mg/m ² IV every 12 hours, Days 1-3, or Days 1, 3, and 5. Patients may go through up to 4 consolidation cycles with cytarabine.

c) Mitoxantrone 10 mg/m ² and etoposide 100 mg/m ² may be chosen as the consolidation regimen in accordance with institutional practice.

d) Dose adjustments can be made for cytarabine, mitoxantrone and/or etoposide as indicated in the package insert.

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Estimated number of patients

A total of approximately 72 DLT evaluable patients (approximately 12 patients required for each dose level of COMPOUND 1 or COMPOUND 2 per type 7+3 induction therapy) will be enrolled in this study. Given that up to 20% of patients drop out during the DLT evaluation period, a total of up to approximately 90 patients will be enrolled in this study.

Additional patients may be included in the dose level study to replace patients who are not evaluable due to DLT, to fill in consolidation cohorts, or for further safety, PK, PK/PD, or preliminary clinical activity studies.

Inclusion Criteria

Patients are eligible for inclusion in the study if they meet the following criteria:

Age>18 years;

previously untreated AML (de novo or secondary) defined according to WHO criteria, excluding APL [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation, with planned induction therapy, and subsequent consolidation therapy. Secondary AML is defined as AML occurring after myelodysplastic syndromes (MDS) or a prior hematological disorder (AHD), or AML occurring after genotoxic injury, including radiation and/or chemotherapy. Patients may have previously received treatment with hypomethylating agents (HMAs) for MDS;

ECOG PS 0-2;

Satisfactory liver function, as evidenced by:

serum total bilirubin <1.5 x ULN (upper limit of normal), unless considered to be associated with Gilbert's disease, a gene mutation in UGT1A1 (only for patients who will take Compound 1), or a leukemic process after approval by a medical observer;

aspartic aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) < 3.0 x ULN, unless considered to be associated with a leukemic process after approval by a medical examiner;

satisfactory renal function as evidenced by serum creatinine <2.0 x ULN or creatinine clearance >40 ml/min based on Crockforth-Gault glomerular filtration rate (GFR);

consent to serial sampling of blood and bone marrow;

meet any criteria necessary for the safe and correct use of the induction and consolidation aids used in this test;

able to understand and willing to sign the informed consent form. A legal representative may give consent on behalf of a subject who otherwise cannot give informed consent, if this is acceptable and approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC);

female subjects of reproductive potential must agree to undergo a pregnancy test under medical supervision prior to the start of the study. The first pregnancy test will be done at screening (7 days before the first drug administration). A pregnancy test must also be performed on the day of the first administration of investigational medicinal product and must be negative before the start of administration and before administration on Day 1 of all subsequent cycles;

female subjects of reproductive potential must have a negative serological pregnancy test 7 days prior to initiation of therapy. Subjects of reproductive potential are defined as mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion, or who have not been postmenopausal for at least 24 consecutive months. Women of reproductive potential, as well as fertile men and their partners who are women of reproductive potential, must agree to abstain from sexual intercourse or use two highly effective forms of contraception from the time informed consent is provided during the study and for 90 days (women and men) after last dose of Compound 1 or Compound 2. A highly effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, a double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization .

Exclusion Criteria

Patients are excluded from the study if they meet any of the following criteria:

prior chemotherapy for the treatment of AML.

Hydroxyurea is approved for the control of peripheral leukemic blasts in subjects with

- 39 039805 leukocytosis (leukocyte count [WBC] > 30,000/µl);

taking drugs with narrow therapeutic windows, unless they can be switched to other drugs before enrollment in the study or if these drugs could be adequately monitored during the study;

taking known strong inducers or inhibitors of cytochrome P450 (CYP) 3A4;

taking drugs that are P-glycoprotein (P-gp) or breast cancer resistance protein transporter (BCRP)-sensitive substrates, unless they can be transferred to other drugs for> 5 half-lives before the administration of Compound 1 or Compound 2, or if these drugs could be adequately monitored during the study;

pregnancy or breastfeeding;

uncontrolled active infection or uncontrolled invasive fungal infection (positive blood or tissue culture). Infection controlled by approved or well-controlled antibiotic/antifungal treatment is acceptable;

Prior history of malignancies other than MDS or AML, unless the subject has had the disease for > 1 year prior to treatment. However, subjects with the following histories/comorbid conditions are eligible:

basal or squamous cell carcinoma of the skin;

carcinoma in situ of the cervix;

carcinoma in situ of the breast;

accidentally histologically detected prostate cancer;

serious active heart disease within 6 months prior to treatment, including congestive heart failure class III or IV according to the classification of the New York Heart Association (NYHA); myocardial infarction, unstable angina and/or stroke; or LVEF < 40% based on echocardiogram (ECHO) or multi-view radioisotope scan (MUGA) obtained within 28 days prior to treatment;

a corrected QT interval using the Frederick formula (QTcF) >450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT syndrome). Bundle branch block and prolonged QTc interval are allowed with the approval of the medical supervisor;

taking drugs known to prolong the QT interval, unless they can be switched to other drugs for > 5 half-lives before the start of administration (if an equivalent drug treatment is not available, QTc will be carefully monitored);

known infection with human immunodeficiency virus (HIV) or active hepatitis B or C;

dysphagia, short bowel syndrome, gastroparesis, or other conditions that limit the intake or gastrointestinal absorption of orally administered drugs;

clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Cerebrospinal fluid (CSF) assessment at screening is required only if there is clinical suspicion of CNS involvement with leukemia at screening;

directly life-threatening severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or shock and/or disseminated intravascular coagulation;

any other medical or psychological condition that, in the opinion of the investigator, may affect the patient's ability to give informed consent or participate in the study.

Duration of treatment and completion of the study Duration of treatment

Daily treatment with Compound 1 or Compound 2 will begin on the first day of induction therapy. All patients will receive 1 cycle of induction therapy. A second induction cycle is allowed for patients at the discretion of the investigator. After induction therapy, patients who achieve CR or CRi (including CRp) will receive consolidation therapy.

Patients who achieve CR or CRi (including CRp) who are on both induction and consolidation therapy may continue to take Compound 1 or Compound 2 alone after consolidation therapy until relapse, development of unacceptable toxicity, or HSCT, for up to 1 year from Day 1 of the first induction cycle.

HSCT

Subjects who achieve a satisfactory response and are eligible for HSCT (hematopoietic stem cell transplantation) may switch to HSCT upon discontinuation of treatment with Compound 1 or Compound 2. Patients who have HSCT will be withdrawn from the study and will be monitored for survival.

Survival Tracking

After patients stop study treatment, they are contacted approximately every 3 months to collect survival data up to 1 year from the last patient's enrollment.

End of study

The end of the study (last visit of the last patient) is defined as the time by which all patients either completed the 1-year survival tracking period, died, dropped out of the study, were lost to follow-up, or withdrew consent before the end of the 1-year tracking period.

Statistical Methods

Statistical analyzes will be mostly descriptive. Study data will be aggregated to analyze distribution, demographic and baseline characteristics, safety parameters, PK, PD, and clinical activity. Qualitative data will be summarized by population distributions (number and percentage of patients) and current data will be summarized by descriptive statistics (mean, standard deviation, median, minimum and maximum). All data will be presented in individual patient lists. All summaries, lists, numbers and analyzes will be done by dose level/scheme.

Study data will be analyzed and presented in a primary clinical trial report (CSR) based on data from all patients until all patients complete induction therapy and consolidation therapy, if applicable, or stop treatment. Any additional data for patients continuing to receive investigational treatment, or who are being monitored for survival after cessation of data collection for primary CSR, will be reported after all patients terminate the study.

Safety will be assessed by the incidence of AEs, the severity and type of AEs, and by the patient's basic physiological parameters, the general condition of the cancer patient according to the ECOG scale, clinical laboratory results, ECG and LVEF data, exposure and drug modification. Safety data will be summarized using descriptive statistics by dose level/regimen and total amount.

Descriptive statistics will be used to summarize the PK parameters for each dose level and, where appropriate, for the entire population. The relationship between dose and both the maximum concentration (C _max ) and the area under the concentration-time curve (AUC) will be analyzed graphically for dose proportionality.

Descriptive statistics will be used to summarize the PD parameters of 2-HG inhibition for each dose cohort and, where appropriate, for the entire population. The PK/PD ratio for Compound 1 or Compound 2 and 2-HG inhibition will be assessed.

Response to treatment will be assessed by investigators using the IWG criteria for AML. An objective response is defined as including all CR, CRi (includes CRp), PR, and MLFS responses. The responses at each time point and the best response will be recorded by the patient himself; the best overall response rate and ORR will be aggregated and two-tailed 95% confidence intervals (CIs) for the response rate will be calculated. Time to response/remission will also be recorded and summarized as needed.

Time to events, including DOR, EFS and OS, will be estimated using Kaplan-Meier methods, as appropriate. Median, 3-month, 6-month and 1-year evaluations with associated 95% CIs will be performed as needed.

In some AML embodiments, patients receiving Compound 1 and AML induction and consolidation therapy, for example, in accordance with the clinical protocol presented herein, will show a response to treatment. In some embodiments, the response to treatment is a complete response (CR), morphologic leukemia-free state (MLFS), morphological complete remission with partial neutrophil recovery (CRi), morphological complete remission with partial platelet recovery (CRp), or partial remission (PR), according to IWG modified AML response criteria (Cheson, et al. J Clin Oncol 2003;21(24):4642-9). In some embodiments, the response to treatment is a hematological improvement. In some AML embodiments, patients taking Compound 1 and AML induction and consolidation therapy in the methods provided herein will show an improvement in adverse event-free survival (EFS), duration of response (DOR), time to response (TTR), and/or overall survival (OS).

Thus, having described certain aspects of several embodiments, it should be understood that various changes, modifications, and improvements will be apparent to those skilled in the art. Such changes, modifications and improvements are contemplated as part of the present disclosure and are intended to be within the spirit and scope of the invention. Accordingly, the above description and drawings are by way of example only.

CLAIM

Claims (21)

CLAIM 1. Method for the treatment of newly diagnosed acute myeloid leukemia (AML), including - 41 039805 administering to the subject a therapeutically effective amount of an isocitrate dehydrogenase 1 (IDH1) inhibitor, and a) implementing an induction therapy regimen comprising a combination of cytarabine and an anthracycline selected from daunorubicin and idarubicin; b) the implementation of a consolidation regimen, including cytarabine; where the mutant IDH1 inhibitor is (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2- yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 2) having the following formula: or a pharmaceutically acceptable salt, solvate or polymorph thereof, and is administered with both an induction regimen and a consolidation regimen, and wherein newly diagnosed AML is characterized by the presence of a mutant IDH1 allele. 2. The method of claim 1 wherein the dose of cytarabine used as induction therapy is in the range between about 100 and about 500 mg/m ² /day, where the term about means within 10% of the indicated value. 3. The method of claim 2, wherein the dose of cytarabine is in the range between about 150 and about 300 mg/m ² /day, where the term about means within 10% of the indicated value. 4. The method of claim 3 wherein the dose of cytarabine is about 200 mg/m ² /day, wherein the term about means within 10% of the indicated value. 5. The method according to claim 1, wherein the dose of cytarabine used as consolidation therapy is in the range between about 1 and about 10 g/m ² /day, where the term about means within 10% of the indicated value. 6. The method of claim 5, wherein the dose of cytarabine is between about 1 and about 5 g/m ² , where about means within 10% of the indicated value. 7. The method of claim 6 wherein the dose of cytarabine is 1 or 1.5 or 2 or 3 g/m ² /day, where the term about means within 10% of the indicated value. 8. The method of claim 1 wherein the anthracycline is daunorubicin administered at a dose ranging between about 10 and about 300 mg/m ² , where about means within 10% of the indicated value. 9. The method of claim 8, wherein the dose of daunorubicin is between about 30 mg/m ² /day and about 150 mg/m ² /day, where about means within 10% of the indicated value. 10. The method of claim 9, wherein the dose of daunorubicin is about 60 mg/m ² /day, wherein the term about means within 10% of the indicated value. 11. The method of claim 1 wherein the anthracycline is idarubicin administered at a dose ranging between about 1 and about 25 mg/m ² /day, where about means within 10% of the indicated value. 12. The method of claim 11, wherein the dose of idarubicin is between about 3 and about 15 mg/m ² /day, where the term about means within 10% of the indicated value. 13. The method of claim 12 wherein the dose of idarubicin is about 12 mg/m ² , wherein the term about means within 10% of the indicated value. 14. The method of claim 1 wherein the induction regimen comprises daunorubicin and cytarabine, wherein cytarabine is administered for 7 days and daunorubicin is administered for 3 days. 15. The method of claim 1 wherein the induction regimen comprises daunorubicin and cytarabine, wherein cytarabine is administered for 7 days and idarubicin is administered for 3 days. 16. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 20-2000 mg/day, where the term about means within 10% of the indicated value. 17. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 50-500 mg/day, where the term about means within 10% of the indicated value. 18. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 50 mg/day, where the term about means within 10% of the indicated value. 19. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 75 mg/day, where the term about means within 10% of the indicated value. 20. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 100 mg/day, where the term about means within 10% of the indicated value. 21. The method according to any one of claims 1-15, wherein the dose of Compound 2 is about 500 mg/day, where the term about means within 10% of the indicated value.