WO2019088039A1 - Treatment of acute myeloid leukemia - Google Patents

Abstract

This disclosure provides methods for treating AML. In particular, this disclosure provides methods for treating AML including relapsed or refractory AML, comprising twice daily administering to a subject having AML, including relapsed or refractory AML about 30-100 mg of a compound of Formula (I). In some embodiments, the compound of Formula (I) has Formula (II).

Description

TREATMENT OF ACUTE MYELOID LEUKEMIA RELATED APPLICATIONS

CROSS REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Provisional Application No. 62/579,023, filed October 30, 2017, the disclosure of which is incorporated herein by reference in its entirety.

This disclosure provides methods for treating acute myeloid leukemia (AML). In particular, this disclosure provides methods for treating AML, including a relapsed or refractory AML, comprising administering twice daily to a subject having AML, including a relapsed or refractory AML, 30-100 mg of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one.

Spleen tyrosine kinase (SYK) is a 72 kDa non-receptor cytoplasmic tyrosine kinase. SYK has a primary amino acid sequence similar to that of zeta-associated protein-70 (ZAP-70) and is involved in receptor-mediated signal transduction. The N-terminal domain of SYK contains two Src-homology 2 (SH2) domains, which bind to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) found in the cytoplasmic signaling domains of many immunoreceptor complexes. The C-terminus contains the catalytic domain, and includes several catalytic loop autophosphorylation sites that are responsible for receptor-induced SYK activation and subsequent downstream signal propagation. SYK is expressed in many cell types involved in adaptive and innate immunity, including lymphocytes (B cells, T cells, and NK cells), granulocytes (basophils, neutrophils, and eosinophils), monocytes, macrophages, dendritic cells, and mast cells. SYK is expressed in other cell types, including airway epithelium and fibroblasts in the upper respiratory system. See, e.g., TURNER et al., Immunology Today, 21(3):148-54 (2000); and SANDERSON et al., Inflammation & Allergy - Drug Targets, 8:87-95 (2009).

SYK’s role in ITAM-dependent signaling and its expression in many cell types suggest that compounds which inhibit SYK activity may be useful for treating hematological malignancies, such as acute myeloid leukemia (AML), B-cell chronic lymphocytic leukemia, B-cell lymphoma (e.g., mantle cell lymphoma), and T-cell lymphoma (e.g., peripheral or cutaneous T-cell lymphoma); as well as epithelial cancers, such as lung cancer, pancreatic cancer, and colon cancer. See, e.g., HAHN et al., Cancer Cell, 16:281-294 (2009); CHU et al., Immunol. Rev., 165:167-180 (1998); FELDMAN et al., Leukemia, 22:1139-43 (2008); RINALDI et al., Br. J. Haematol., 132:303-316 (2006); STREUBEL et al., Leukemia, 20:313-18 (2006); BUCHNER et al., Cancer Research, 69(13):5424-32 (2009); BAUDOT et al., Oncogene, 28:3261-73 (2009); and SINGH et al., Cancer Cell, 15:489-500 (2009).

SYK has also been shown to directly bind and activate FMS-like tyrosine kinase 3 (FLT-3). FLT-3 is a Class III receptor tyrosine kinase that is normally expressed only in hematopoietic stem and progenitor cells. However, its expression has been found in the blasts of a majority of patients with AML. Activating mutations of FLT-3, are observed in approximately 30% of AML patients. These FLT-3 mutations, associated with early relapse and poor survival, represent a critical prognostic factor for AML. A recently published study suggested that SYK is a critical regulator of FLT-3 in AML. FLT-3 was found to be transactivated by SYK via direct binding. See, e.g., PUISSANT et al., Cancer Cell, 25:226-242 (2014). Highly activated SYK was predominantly found in FLT-3-ITD-positive AML (Activating mutations of FLT-3, include internal tandem duplication ITDs, FLT-3-ITD) and FLT-3-ITD AML cells were more vulnerable to SYK suppression than their FLT-3 wild-type (WT) counterparts. SYK overexpression was also found to promote resistance to FLT-3-ITD-targeted therapy in an in vivo FLT-3-ITD model of AML.

Deregulated tyrosine kinase activity has long been implicated in the molecular pathogenesis of cancer, including leukemia. SYK and FMS-like tyrosine kinase 3 (FLT-3) are among tyrosine kinases that have been identified as causative factors in specific hematologic malignancies. Both SYK and FLT-3 appear to play an important role in the pathogenesis of acute leukemia, particularly AML. AML is an aggressive hematopoietic cancer arising from bone marrow immature myeloid progenitor cells transformed by recurrent genetic alterations that cooperate to induce cell proliferation and survival. These driver genetic events include signaling regulation (e.g., FMS-like tyrosine kinase 3, FLT-3). Among these genes, FLT3 is the one most frequently altered in AML.

6-((1R,2S)-2-Aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one, is a potent and reversible dual inhibitor of SYK and FLT-3, which has demonstrated growth inhibition of cell lines and xenograft tumor models of AML origin, independent of FLT-3 mutation status.

Most patients diagnosed with AML have very poor prognosis. For patients with relapsed disease, no standard non-transplant therapy has demonstrated the capacity for cure. For these patients, AML is often a fatal disease. New approaches to the therapy of AML, including refractory or relapsed AML, are needed.

In certain embodiments, provided herein is a method of treating acute myeloid leukemia (AML), comprising administering twice daily to a subject having an AML about 30-100 mg of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, provided herein is a method of treating relapsed or refractory AML, comprising administering twice daily to a subject having relapsed or refractory AML about 30-100 mg of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, of the compound of formula (I) is a compound of Formula (II):

or a polymorph thereof.

In certain embodiments, the compound of Formula (I) or (II) is administered orally. In certain embodiments, the compound of Formula (I) or (II) is administered as a solid dosage form. In certain embodiments, administration comprises one or more additional therapeutic agents. In certain embodiments, the subject is human.
Examples of embodiments of the present invention are shown below:
1. A method of treating acute myeloid leukemia (AML) in a subject, comprising administering twice daily to the subject having an AML about 30-100 mg of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
2. The method of the preceding item, wherein the compound is of Formula (II):

or a polymorph thereof.
3. The method of any of the preceding items, wherein about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
4. The method of any of the preceding items, wherein about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
5. The method of any of the preceding items, wherein about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
6. The method of any of the preceding items wherein about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
7. The method of any of the preceding items, wherein about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
8. The method of any of the preceding items, wherein about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
9. The method of any of the preceding items, wherein about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
10. The method of any of the preceding items, wherein about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
11. The method of any of the preceding items, wherein the AML is refractory or relapsed.
12. The method of any of the preceding items, wherein the acute myeloid leukemia is refractory.
13. The method of any of the preceding items, wherein the acute myeloid leukemia is relapsed.
14. The method of any of the preceding items, further comprising administration of one or more additional therapeutic agents.
15. The method of any of the preceding items, wherein the compound is administered orally.
16. The method of any of the preceding items, wherein the compound is administered as a solid dosage form.
17. The method of any of the preceding items, wherein the subject is a mammal.
18. The method of any of the preceding items, wherein the subject is a human.
19. A composition for treating acute myeloid leukemia (AML) in a subject, comprising a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, characterized in that about 30-100 mg of the compound is administered twice daily to the subject having an AML.
20. The composition of the preceding item, wherein the compound is of Formula (II):

or a polymorph thereof.
21. The composition of any of the preceding items, characterized in that about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
22. The composition of any of the preceding items, characterized in that about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
23. The composition of any of the preceding items, characterized in that about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
24. The composition of any of the preceding items, characterized in that about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
25. The composition of any of the preceding items, characterized in that about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
26. The composition of any of the preceding items, characterized in that about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
27. The composition of any of the preceding items, characterized in that about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
28. The composition of any of the preceding items, characterized in that about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
29. The composition of any of the preceding items, wherein the AML is refractory or relapsed.
30. The composition of any of the preceding items, wherein the acute myeloid leukemia is refractory.
31. The composition of any of the preceding items, wherein the acute myeloid leukemia is relapsed.
32. The composition of any of the preceding items, characterized in that the composition is administered in combination with one or more additional therapeutic agents.
33. The composition of any of the preceding items, characterized in that the composition is administered orally.
34. The composition of any of the preceding items, characterized in that the composition is administered as a solid dosage form.
35. The composition of any of the preceding items, wherein the subject is a mammal.
36. The composition of any of the preceding items, wherein the subject is a human.
37. A compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for use in a method of treating acute myeloid leukemia (AML) in a subject, characterized in that about 30-100 mg of the compound is administered twice daily to the subject having an AML.
38. The compound for use of the preceding item, wherein the compound is of Formula (II):

or a polymorph thereof.
39. The compound for use of any of the preceding items, characterized in that about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
40. The compound for use of any of the preceding items, characterized in that about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
41. The compound for use of any of the preceding items, characterized in that about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
42. The compound for use of any of the preceding items, characterized in that about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
43. The compound for use of any of the preceding items, characterized in that about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
44. The compound for use of any of the preceding items, characterized in that about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
45. The compound for use of any of the preceding items, characterized in that about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
46. The compound for use of any of the preceding items, characterized in that about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
47. The compound for use of any of the preceding items, wherein the AML is refractory or relapsed.
48. The compound for use of any of the preceding items, wherein the acute myeloid leukemia is refractory.
49. The compound for use of any of the preceding items, wherein the acute myeloid leukemia is relapsed.
50. The compound for use of any of the preceding items, characterized in that the compound is administered in combination with one or more additional therapeutic agents.
51. The compound for use of any of the preceding items, characterized in that the compound is administered orally.
52. The compound for use of any of the preceding items, characterized in that the compound is administered as a solid dosage form.
53. The compound for use of any of the preceding items, wherein the subject is a mammal.
54. The compound for use of any of the preceding items, wherein the subject is a human.
55. Use of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in the manufacture of a medicament for treating acute myeloid leukemia (AML) in a subject, characterized in that about 30-100 mg of the compound is administered twice daily to the subject having an AML.
56. The use of the preceding item, wherein the compound is of Formula (II):

or a polymorph thereof.
57. The use of any of the preceding items, characterized in that about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
58. The use of any of the preceding items, characterized in that about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
59. The use of any of the preceding items, characterized in that about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
60. The use of any of the preceding items, characterized in that about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
61. The use of any of the preceding items, characterized in that about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
62. The use of any of the preceding items, characterized in that about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
63. The use of any of the preceding items, characterized in that about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
64. The use of any of the preceding items, characterized in that about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
65. The use of any of the preceding items, wherein the AML is refractory or relapsed.
66. The use of any of the preceding items, wherein the acute myeloid leukemia is refractory.
67. The use of any of the preceding items, wherein the acute myeloid leukemia is relapsed.
68. The use of any of the preceding items, characterized in that the compound is administered in combination with one or more additional therapeutic agents.
69. The use of any of the preceding items, characterized in that the compound is administered orally.
70. The use of any of the preceding items, characterized in that the compound is administered as a solid dosage form.
71. The use of any of the preceding items, wherein the subject is a mammal.
72. The use of any of the preceding items, wherein the subject is a human.

FIG. 1 depicts simulated concentration of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one, as a function of time, following administration of 80 mg twice daily and 160 mg once daily of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one.

FIG. 2A depicts the maximum inhibition (%) of FLT-3 associated with timepoint at which it was achieved and each corresponding response outcome.

FIG. 2B depicts the maximum bone marrow blast count reduction (%) from baseline for response-evaluable points.

DETAILED DESCRIPTION

Definitions
While embodiments provided herein have been shown and described herein, such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments provided herein can be employed in practicing the same. It is intended that the appended claims define the scope of this disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

The term “about” refers to approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a number or a numerical range, it means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of ±10%.

Unless otherwise specified, the terms “include” and “including” and the like are intended to be non-limiting. For example, “including” means including but not limited to, unless otherwise indicated.

As used herein, and unless otherwise specified, “polymorph” can be used herein to describe a crystalline material, e.g., a crystalline form. Thus, “crystalline form” and “polymorph” are synonymous; the terms distinguish between crystals that have different properties (e.g., different XRPD patterns and/or different DSC scan results). In certain embodiments, “polymorph” as used herein are also meant to include all crystalline and amorphous forms of a compound or a salt thereof, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms of the compounds or a salt thereof, as well as mixtures thereof.

In addition, if a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

“Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space, i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(.±.)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain two or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

The term “mixture” refers to the combined components of the mixture regardless of the phase-state of the combination (e.g., liquid or liquid/ crystalline).

The term “Spleen tyrosine kinase” used herein refers to any member of the Syk family of tyrosine kinases. SYK is a 72 kDa non-receptor cytoplasmic tyrosine kinase.

The term “Spleen tyrosine kinase inhibitor” or “SYK inhibitor” used herein refers to a compound having the ability to interact with Spleen tyrosine kinase and inhibit its enzymatic activity.

As used herein, the terms “treatment,” “treat,” and “treating” are meant to include the full spectrum of intervention for the cancer from which the subject is suffering, such as administration of the combination to alleviate, slow, stop, or reverse one or more symptoms of the cancer or to delay the progression of the cancer even if the cancer is not actually eliminated. Treatment can include, for example, a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse, e.g., the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.

The term “subject”, as used herein, means a mammal, and “mammal” includes, but is not limited to, a human. In certain embodiments, the subject has been treated with an agent, e.g., an immunotherapy agent and/or an SYK inhibitor, prior to initiation of treatment according to the method of the disclosure. In certain embodiments, the subject is at risk of developing or experiencing a recurrence of AML. In certain embodiments, the subject is an AML patient.

As used herein, and unless otherwise specified, the terms “acute myeloid leukemia,” “acute myelogenous leukemia” and “AML” are synonymous and are used interchangeably in the specification.

As used herein, and unless otherwise specified, the term “refractory” refers to a circumstance where a subject or a mammal, even after intensive treatment, has residual leukemia cells in their marrow.

As used herein, and unless otherwise specified, the term “relapsed” refers to a situation where a subject or a mammal, which has had a remission of AML after therapy has a return of leukemia cells in the marrow and a decrease in normal blood cells.

The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids. For reviews of suitable salts, see, e.g., Berge, et al., J. Pharm. Sci. 66:1-19 (1977) and Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000. Non-limiting examples of suitable acid salts includes: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, lactate acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Non-limiting examples of suitable base salts includes: sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

The terms “carrier”, “adjuvant”, or “vehicle” are used interchangeably herein, and include any and all solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.

Unless otherwise stated, compounds described herein include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure.

Unless otherwise stated, compounds described herein include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. In the compounds described herein where relative stereochemistry is defined, the diastereomeric purity of such a compound may be at least 80%, at least 90%, at least 95%, or at least 99%. As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted relative stereochemistry, expressed as a percentage of the total amount of all diastereomers present.
Compounds

In certain embodiments, the compound for use in the compositions and methods provided herein is of Formula I, or 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one:

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, the compound for use in the compositions and methods provided herein is of Formula II, or 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate:

or a polymorph thereof.

The compounds of Formula I and Formula II are described in WO 2011/079051, US 8,440,689, and US 2016/0176869. They may be prepared by methods known to one skilled in the art and/or according to the methods described in WO 2011/079051, US 8,440,689, and US 2016/0176869, each of which is hereby incorporated by reference in its entirety.

The compounds of Formula (I) and (II) for use in the methods provided herein contain two chiral centers, and can exist as a mixture of stereoisomers. This disclosure encompasses the use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the stereoisomers of the compounds of Formula (I) or (II) provided herein can be used in methods and compositions disclosed herein.

In some embodiments, a polymorph of a compound, or a salt, solvate (e.g., hydrate), or solvate of a salt thereof, disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2016/0176869, which is hereby incorporated by reference in its entirety. In one embodiment, the compound is Form 1, a crystalline form of the compound of Formula (II). In one embodiment, the compound is Form 2, an amorphous form of the compound of Formula (II). In one embodiment, the compound is Form 3, a crystalline form of a hydrochloride dihydrate of the compound of Formula (I). In one embodiment, the compound is Form 4, a crystalline form of a hydrochloride salt of the compound of Formula (I). In one embodiment, the compound is Form 5, a crystalline form of a hydrochloride salt of the compound of Formula (I). In one embodiment, the compound is Form 6, an amorphous form of a hydrochloride salt of the compound of Formula (I). In one embodiment, the compound is Form 7, a crystalline form of a hydrochloride salt of the compound of Formula (I). In one embodiment, the compound is Form 8, a crystalline form of a hydrochloride hydrate salt of the compound of Formula (I). In one embodiment, the compound is Form 9, a crystalline form of a hydrochloride hydrate salt of the compound of Formula (I). In one embodiment, the compound is Form 10, a crystalline form of a hydrochloride hydrate salt of the compound of Formula (I). In one embodiment, the compound is Form 11, a crystalline form of a hydrochloride hydrate salt of the compound of Formula (I). In one embodiment, the compound is Form 12, a crystalline form of a free base of the compound of Formula (I). In one embodiment, the compound is Form 13, a crystalline form of a free base of the compound of Formula (I). In one embodiment, the compound is Form 14, a crystalline form of a free base hemihydrate of the compound of Formula (I). In one embodiment, the compound is Form 15, a crystalline form of a free base monohydrate of the compound of Formula (I). In one embodiment, the compound is Form 16, a crystalline form of a free base trihydrate of the compound of Formula (I). In one embodiment, the compound is Form 17, a crystalline form of a free base monohydrate of the compound of Formula (I). In one embodiment, the compound is an amorphous form of compound of Formula (I). In one embodiment, the compound is an amorphous form of compound of Formula (II). In one embodiment, the compound is a mixture of solid forms (e.g., polymorphs and/or amorphous forms) of the compound of Formula (I) or Formula (II), disclosed herein.

Any of the compounds disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.

It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure.
Methods of treatment and/or medical uses

In certain embodiments, provided herein is a method of treating AML in a subject, comprising administering twice daily to the subject having AML about 30-100 mg of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, provided herein is a method of treating relapsed or refractory AML in a subject, comprising administering twice daily to the subject having a relapsed or refractory AML about 30-100 mg of a compound of Formula (I):

or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

In certain embodiments, of the compound of Formula (I) is a compound of Formula (II):

or a polymorph thereof. In such embodiments, the amount in milligrams administered to the subject is adjusted for the difference in molecular weight between the compounds of Formulae (I) and (II). For example, 30-100 mg of the compound of Formula (I) corresponds to 46-156 mg of the compound of Formula (II). Thus, when a certain amount of the compound of Formula (II) is indicated herein, this amount refers to the corresponding amount of the compound of Formula (I).

In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 30-100 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 30 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 35 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 40 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 45 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 50 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 55 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 60 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 65 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 70 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 75 mg. In certain embodiments, the about 80 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 85 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 90 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 95 mg. In certain embodiments, the amount of the compound of Formula (I) used in the compositions and methods provided herein is about 100 mg.

In certain embodiments of the methods provided herein, the compound of Formula (I) or Formula (II) is administered twice daily for 28 days. In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I). In certain embodiments, the compound is a polymorph of the compound of Formula (II).

In certain embodiments, the AML is newly diagnosed AML. In certain embodiments, the AML is refractory AML. In certain embodiments the AML is relapsed AML.

In certain embodiments, the subjects have wild type FLT-3. In certain embodiments, the subjects have mutated FLT-3. In certain embodiments, the FLT-3 mutation is internal tandem duplication FLT-3-ITD mutation within the juxtamembrane region of FLT-3. In certain embodiments, the FLT-3 mutation is a point mutation, e.g., D835Y, in the FLT-3 activation loop. In certain embodiments, the subjects have FLT-3-ITD mutation. In certain embodiments, the subjects have FLT-3 point mutation.

In certain embodiments, provided herein is a method of suppressing relapse of AML in a patient population with refractory or relapsed AML, comprising administering twice daily to the subject having refractory or relapsed AML about 30-100 mg of a compound of Formula (I). In such embodiments, the compound may be of Formula (II).

In certain embodiments, provided herein is a method of suppressing a relapse in a wild type (WT) AML patient population. In certain embodiments, provided herein is a method of suppressing a relapse in a FLT-3 mutated AML patient population. In certain embodiments, the compound is of Formula (I) or Formula (II). In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I). In certain embodiments, the compound is a polymorph of the compound of Formula (II).

In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 10% of patients have a steady-state trough concentration of a compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 20% of patients have a steady-state trough concentration of a compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 30% of patients have a steady-state trough concentration of a compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 40% of patients have a steady-state trough concentration of a compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 50% of patients have a steady-state trough concentration of compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 60% of patients have a steady-state trough concentration of compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 70% of patients have a steady-state trough concentration of compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 80% of patients have a steady-state trough concentration of compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 90% of patients have a steady-state trough concentration of compound of Formula (I) of greater than 100 ng/ml. In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I).

In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 60% pFLT-3 inhibition is observed. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 70% pFLT-3 inhibition is observed. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 80% pFLT-3 inhibition is observed. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 90% pFLT-3 inhibition is observed. In certain embodiments, following the twice daily administration of a dose of about 30-100 mg of a compound of Formula (I), more than 95% pFLT-3 inhibition is observed. In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I).

In certain embodiments, the compound of Formula (I) is administered orally. In certain embodiments, the compound of Formula (I) is administered intravenously. In certain embodiments, the compound of Formula (II) is administered orally. In certain embodiments, the compound of Formula (II) is administered intravenously. In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I). In certain embodiments, the compound is a polymorph of a compound of Formula (II).

It will be understood that, in certain embodiments, about 30-100 mg of a compound of Formula (I) is taken in the morning and about 30-100 mg of a compound of Formula (I) is taken in the evening. It will be understood that the compound of Formula (I) may be taken with or without food. In certain embodiments, about 30-100 mg of a compound of Formula (I) is taken with food. In certain embodiments, about 30-100 mg of a compound of Formula (I) is taken while fasting.
Pharmaceutical Compositions

In certain embodiments, a compound of Formula (I) or Formula (II) is administered orally such as in a solid dosage form or a liquid dosage form. In certain embodiments, a compound of Formula (I) or Formula (II) is administered as a solid dosage form. In certain embodiments, a compound of Formula (I) or Formula (II) is administered as a liquid dosage form. In certain embodiments, the compound is a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I). In certain embodiments, the compound is a polymorph of a compound of Formula (II).

In certain embodiments, solid dosage forms for oral administration are capsules, tablets, pills, powders, and granules. In certain embodiments, in such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as, for example, sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as, for example, glycerol, (d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as, for example, paraffin, (f) absorption accelerators such as, for example, quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as, for example, kaolin and bentonite clay, and (i) lubricants such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In certain embodiments, capsules, tablets, pills, powders, and granules, may also comprise buffering agents such as phosphates or carbonates.

In certain embodiments, the solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also optionally be of a composition that they release the active ingredient(s) only, or in one embodiment, in a certain part of the intestinal tract, optionally, in a delayed manner. In certain embodiments, solid dosage forms may be embedding compositions that may comprise polymeric substances and waxes.

In certain embodiments, liquid dosage forms for oral administration are pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, in addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments, besides inert diluents, the oral compositions can also include adjuvants such as, for example, wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

In certain embodiments, the compounds of Formula (I) or (II) are formulated as disclosed in International Application Publication No. WO2016/097862. In some embodiments, such formulations are the formulations disclosed, for example, in examples 1, 2, 4, 5, and 6 of International Application Publication No. WO2016/097862.
Combination therapies

Also provided herein are combination therapies for treatment of AML in which, in addition to twice daily administration of a compound of Formula (I) or a compound of Formula (II) as provided herein, one or more agents known to modulate other pathways, or the same pathway, may be used. In certain embodiments, such therapies include the combination of a compound of Formula (I), a compound of Formula (II), a stereoisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph of Formula (I), or a polymorph of a compound of Formula (II), with one or more additional therapeutic agents such as anticancer agents, chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide, where desired, a synergistic or additive therapeutic effect. In certain embodiments, pathways that may be targeted by administering another agent include, but are not limited to, spleen tyrosine kinase (SYK), MAP kinase, Raf kinases, Akt, NFkB, WNT, RAS/ RAF/MEK/ERK, JNK/SAPK, p38 MAPK, Src Family Kinases, JAK/STAT and/or PKC signaling pathways. In some embodiments, other agents may target one or more members of one or more signaling pathways. Representative members of the nuclear factor-kappaB (NFkB) pathway include but are not limited to RelA (p65), RelB, c-Rel, p50/p105 (NF-κB 1), p52/p 100 (NF-κB2), IkB, and IkB kinase. Non-limiting examples of receptor tyrosine kinases that are members of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that may be targeted by one or more agents include FLT3, EGFR, IGF-1R, HER2/neu, VEGFR, and PDGFR. Downstream members of the PI3K/AKT pathway that may be targeted by agents according to the methods of the invention include, but are not limited to, forkhead box O transcription factors, Bad, GSK-3β, I-κB, mTOR, MDM-2, and S6 ribosomal subunit.

Example 1: Clinical relapsed or refractory AML study

This study evaluated the safety and efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate, a potent, dual inhibitor of SYK and FLT-3, for the treatment of relapsed or refractory AML. The study was designed during its dose escalation phase to assess the maximal tolerated dose and/or recommended phase 2 dose for 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in a continuous dosing schedule, either once daily or alternatively twice daily. The subsequent dose expansion phase of the study is designed to evaluate the efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in both FLT-3 mutated and FLT-3 WT patient populations. A retrospective analysis was also performed to explore the contribution of FLT-3 and/or SYK inhibition to the level of clinical activity observed.

Simulated PK model results: Patients were included for Population PK analysis using NONMEM 7.3.0. Simulations were conducted using preliminary model to predict PK profile. Simulated results predicted 44% of patients (N=2000) would have a steady-state trough concentration greater than 100 ng/ml upon twice daily exposure to 80 mg dose of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one compared to 30% of patients (N=2000) that would have a steady-state trough concentration greater than 100 ng/ml upon daily exposure to 160 mg dose of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one. See figure 1.

A steady-state trough concentration of >100 ng/ml led to >90% pFLT-3 inhibition using plasma inhibitory activity (PIA) assay. The inhibitory effect of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate treatment on FLT-3-ITD phosphorylation (pFLT-3) was observed using a plasma inhibitory activity (PIA) assay. Thus, twice daily dose of 80 mg of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one led to higher steady state trough exposure, resulting in sustained pFLT-3 inhibition. Therefore, twice daily dose of 80 mg of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one may have clinical efficacy. Levis et al., Blood 108:3477 (2006).

Patients: 31 patients were enrolled in the clinical study over a period of two years. Of the 31 patients, 15 patients were FLT-3-WT, 8 patients had FLT-3-ITD mutation, 5 patients had FLT-3-D835Y mutation, and 3 had concurrent FLT-3-ITD/D835Y mutations. Median age was 67 years. 17 patients (or 55%) were male. 11 patients (or 35%) had ≧ 4 prior lines of therapy.

Drugs used in this study: 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate (dose equivalent of 60 mg QD, 100 mg QD, 120 mg QD, 140 mg QD, 160 mg QD, and 80 mg BID of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one). 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate was administered in 28 day cycles.

Table 1.

¹QD is once daily administration. ²BID is twice daily administration. ³PO is oral administration. ⁴ Formula (I) is 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one. ⁵N is number of patients.

Results: Preliminary plasma PK of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate was characterized by rapid absorption (median t_max, 2 hours), moderate variability in steady-state exposures (38.8% coefficient of variation for C1 d15 dose-normalized AUC_tau), and mean accumulation of 1.9-fold after repeated QD dosing for 15 days.

Ten patients achieved >90% pFLT-3 inhibition. See figure 2A. Early signs of clinical activity were observed in both FLT-3-mutated and WT patients. See figure 2B. Three patients achieved response at higher dose levels: 1 achieved a complete response (CR) (WT/160 mg) and 2 achieved a complete response with incomplete hematologic recovery (Cri) (WT/140 mg; FLT-3 ITD/160 mg). Also, four other patients (2 FLT-3 ITD/100 mg; TKD/120 mg; TKD/160 mg) achieved >50% bone marrow (BM) blast reduction from baseline (BL) without BM recovery. Two more patients (FLT-3 ITD/80mg BID) achieved >50% BM blast reduction from BL (92 to 15% and 81 to 22% respectively) after the data cut. In figure 2A and 2B, CR was observed in the 21st patient (from left side); CRi was observed in the 15th and 22th patients (from left side); SD was observed in the 3rd, 5th, 7-14th, 18-20th and 23-25th patients (from left side); and PD was observed in the 1st, 2nd, 4th, 6th, 16th and 17th patients (from left side). 1st, 3rd, and 6th patients (from left side) had both FLT3-ITD and FLT3-TKD; 8th, 9th, 13th, 18th, 19th, 22th, 24th and 25th patients (from left side) had FLT3-ITD; 12th, 16th, 20th and 23rd patients (from left side) had FLT3-TKD; and the remaining patients (2nd, 4th, 5th, 7th, 10th, 11th, 14th, 15th, 17th and 21st (from left side)) had FLT3-WT.

6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate demonstrated an acceptable safety and PK profile as well as preliminary antitumor activity in patients with refractory or relapsed AML. 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate BID led to higher trough exposure, offering longer duration of >90% pFLT-3 inhibition potentially required for FLT-3-driven efficacy. Early anti-leukemic activity has been observed in both FLT-3 mutant and WT patients at higher doses (140 and 160 mg QD) of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate.

Example 2: Clinical relapsed or refractory AML study design

This study evaluates the safety and efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate, a potent, dual inhibitor of SYK and FLT-3, administered BID for the treatment of relapsed or refractory AML. The study is designed to assess the efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in both FLT-3-ITD and FLT-3 WT patient populations. A retrospective analysis is also performed to explore the contribution of FLT-3 and/or SYK inhibition to the level of clinical activity observed.

Primary Objectives: (1) to determine the safety, tolerability, and maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate administered orally on a BID dosing schedule in patients with relapsed or refractory AML. (2) to evaluate preliminary efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in relapsed or refractory AML as measured by overall response rate (ORR).

Secondary Objectives: (1) To evaluate additional efficacy measures of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate, such as duration of response (DOR), time to progression (TTP), mortality rate at 3 and 6 months, and overall survival (OS). (2) To evaluate differential efficacy of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in patients with or without FLT-3-ITD mutation. (3) To characterize the plasma PK of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in patients with relapsed or refractory AML. (4) To evaluate the PD effects of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate against FLT-3 and SYK signaling in circulating AML blasts.
Subject population:

Patients are males and females age 18 years or older with histopathologically documented primary or secondary AML (excluding acute promyelocytic leukemia) as defined by WHO criteria, for whom no standard therapies are anticipated to result in a durable remission based on the opinion of the investigator, or who refuses standard therapies (phase 1b and 2). For the phase 2 portion of the study, patients must be refractory to or relapsed after no more than 2 prior chemotherapy regimens and must not have prior exposure to any investigational FLT-3 inhibitors. Patients must have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients must not have clinically significant toxicity from prior chemotherapy, hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate, or clinically significant graft-versus-host disease requiring ongoing immunosuppressive therapy.
Number of Subjects:

Approximately 12 to 15 patients are enrolled in the 1b dose finding phase of the study. For the phase 2, expansion phase, up to 66 patients are enrolled in both FLT-3 wild type (WT) and FLT-3-internal tandem duplication (ITD) mutant populations.
Dose level(s):

The starting dose of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate for the phase 1b portion of this study is dose equivalent of 60 mg QD of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one.

A 3 + 3 dose escalation design is used to determine the MTD of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in AML. Each 28-day treatment cycle is composed of 28 consecutive days of QD treatment with 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate. Planned dose escalation follows 20-mg increments of escalation (eg, from dose equivalent of 60 mg to 80 mg QD of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one). A more aggressive dose escalation (more than 20-mg increments but not exceeding 100% escalation), evaluation of alternative regimens, and expansion of an existing dose level up to 12 evaluable patients are all permissible following discussions between the sponsor and the investigators based on evolving safety, tolerability, and PK data of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate.

Dose escalation continues until either MTD is reached or the RP2D (if different from MTD) is determined based on safety, tolerability, PK, PD, and preliminary efficacy data, if available.

At least 6 patients are evaluated at RP2D (either the MTD or at a lower dose as determined) before making a decision to advance to the phase 2 expansion phase. In the process of determining or refining RP2D, expansion of more than 1 dose level to at least 6 patients (up to a maximum of 12 evaluable patients per dose level) is permissible so that pharmacodynamic measures and early signs of clinical activity can be assessed to a greater extent to assist dose selection.

The phase 2 expansion study in relapsed or refractory AML will be conducted using a Simon’s 2- stage design. The objectives of this phase 2 stage of the study are to evaluate longer-term safety and tolerability of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate administered at the RP2D and to detect any efficacy signal that warrants further development of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate in AML. The primary measure of efficacy for the phase 2 portion is the ORR, which includes complete response (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and partial response (PR).

Nine and 15 response-evaluable patients are enrolled initially in the FLT-3 WT and FLT-3 ITD mutant cohorts, respectively, during the first stage. Best response is assessed by the end of Cycle 4 of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate treatment for the purpose of an interim analysis between Stage 1 and Stage 2.

The FLT- 3 WT and FLT-3 ITD mutant cohorts proceed to the second stage if ≧ 2 and ≧ 6 patients, respectively, respond to treatment (ORR). Other efficacy measures, such as DOR, TTP, and mortality rate are also considered in the decision to expand the study to the second stage.

If the FLT-3 WT and/or FLT-3 ITD mutant cohort(s) proceed(s) to the second stage, a further 14 and 17 evaluable patients are assessed in the 2 cohorts, respectively. Best responses from both cohorts are assessed individually and combined in an effort to understand the all-comer response rate.

Retrospective analysis is performed to identify potential patient selection markers either based on levels of baseline activation or post treatment modulation of FLT-3 and SYK, the 2 targets of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate. Analysis for mutations reported for AML is also performed.
Duration of treatment:

Treatment continues until disease progression (PD), unacceptable toxicities, completion of the study, or withdrawal due to other reasons. The estimated treatment duration is 12 months.
Route of administration:

6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate tablets.
Period of evaluation:

All patients, including those patients no longer on treatment, are assessed for survival. Patients who discontinue the study, regardless of reasons for discontinuation, are followed for survival every month until death, loss to follow-up, or withdrawal of consent for further follow-up, for up to 12 months after discontinuation of the study drug.
Criteria for inclusion:

(1) Is a male or female subjects aged 18 years or older.

(2) Must have a histopathologically documented diagnosis of primary or secondary AML (excluding acute promyelocytic leukemia), as defined by WHO criteria (Jaffe et al, 2001), for whom no standard therapies are anticipated to result in a durable remission according to the clinical judgement of the principal investigator, or who refuses standard therapies (phase 1b and 2).

(3) For phase 2 patients must additionally meet the following: (a) must be refractory to or relapsed after no more than 2 prior chemotherapy regimens. Re-induction with the same regimen or stem cell transplant is not considered a separate regimen, and (b) must not have prior exposure to any investigational FLT-3 inhibitors.

(4) Has eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

(5) Female patients who: (a) are postmenopausal for at least 1 year before the screening visit, or (b) are surgically sterile, or (c) if childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or (d) agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subjects. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Male patients, even if surgically sterilized (i.e., status post vasectomy), who: (a) agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or (b) agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subjects. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner) and withdrawal are not acceptable methods of contraception.

(6) Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patients at any time without prejudice to future medical care.

(7) In the absence of rapid progressive disease, the interval from prior systemic anticancer treatment to time of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate administration should be at least 2 weeks for cytotoxic agents (other than hydroxyurea), or at least 5 half-lives for noncytotoxic agents, and patients have to have recovered from acute toxicities of these therapies. Patients who are on hydroxyurea may be included in the study and may continue on hydroxyurea for the first 28 days while participating in this study.

(8) Suitable venous access for the study-required blood sampling, including PK and PD sampling and blood transfusion support.

(9) Clinical laboratory values as specified: (a) Total bilirubin must be ≦ 1.5*the upper limit of normal (ULN). (b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 2.5*ULN. (c) Serum creatinine must be < 1.5 * ULN or creatinine clearance ≧ 50 mL/min either as estimated by the Cockcroft-Gault equation or based on urine collection (12 or 24 hours).
Exclusion criteria:

(1) Has clinically active central nervous system leukemia.

(2) Is a Female patient who is lactating and breastfeeding or has a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.

(3) Has any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the investigator’s opinion, potentially jeopardize the safety of the patient or interfere with the objectives of the study.

(4) Had prior treatment with investigational agents ≦ 21 days or ≦ 5 * their half-lives (whichever is shorter) before the first dose of study treatment. A minimum of 10 days should elapse from prior investigational therapy to initiating protocol therapy.

(5) Has persistent clinically significant toxicity from prior chemotherapy that is Grade 2 or higher by the NCI CTCAE.

(6) Received a hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate; has clinically significant graft-versus-host disease (GVHD) requiring ongoing immunosuppressive therapy post HSCT at the time of screening (use of topical steroids for ongoing skin GVHD is permitted).

(7) Active, systemic infection requiring intravenous antibiotic, antifungal, or antiviral therapy or other serious infection within 14 days before the first dose of study drug.

(8) Major surgery within 14 days before the first dose of study drug and have not recovered fully from any complications from surgery.

(9) Prior radiotherapy less than 2 weeks before the first dose of study treatment or have not recovered from acute toxic effects from radiotherapy.

(10) Known human immunodeficiency virus (HIV) positive (testing not required).

(11) Known hepatitis B surface antigen-positive, known or suspected active hepatitis C infection (testing not required).

(12) Patients with any of the following cardiovascular conditions are excluded: (a) Acute myocardial infarction within 6 months before starting study drug. (b) Current or history of New York Heart Association Class III or IV heart failure. (c) Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. (d) Friderichia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475 msec (women) on a 12-lead electrocardiogram (ECG) during the Screening period. (e) Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant.

(13) Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate including difficulty swallowing tablets; diarrhea >Grade 1 despite supportive therapy.

(14) Use or consumption of any of the following substances: (a) Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) and/or strong reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first dose of study drug. In general the use of inhibitors of P-glycoprotein (P-gp) and/or strong reversible inhibitors of cytochrome P450 (CYP)3A, such as amiodarone, azithromycin, captopril, carvedilol, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, nefazodone, posaconazole, quercetin, quinidine, ranolazine, ticagrelor, verapamil, and voriconazole is not permitted during the study. The list of prohibited strong cytochrome P450 (CYP) 3A reversible inhibitors and/or P-gp inhibitors is not exhaustive and is based on the US FDA draft DDI guidance. (b) Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors, such as clarithromycin, conivaptan, mibefradil, telithromycin, or strong CYP3A inducers and/or P-gp inducers, such as avasimibe, carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, rifampin, St John’s wort, within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is longer), before the first dose of study drug. The use of these agents is not permitted during the study. The list of prohibited strong CYP3A inducers and/or P-gp inducers is not exhaustive and is based on the US FDA draft DDI guidance. (d) Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study.

(15) Patients with white blood cell count > 50,000/μL. Hydroxyurea may be used to control the level of circulating leukemic blast cell counts prior to study entry and, if needed, concomitantly while on 6-((1R,2S)-2-aminocyclohexylamino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,4-c]pyridine-3(2H)-one citrate treatment during the first 28 days of the study. Hydroxyurea can be used up to a maximum dose of 5 g/day.
Main criteria for evaluation and analyses:

Primary endpoints: Dose finding phase: (1) adverse events (AEs). (2) serious adverse events (SAEs). (3) dose- limiting toxicities (DLTs) (Cycle 1). (4) clinical laboratory values. (5) vital sign measurements. Phase 2 dose expansion phase: (1) ORR (which will include complete response [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematologic recovery [Cri], and partial response [PR])

Secondary endpoints: (1) duration of response (DOR). (2) time of progression (TTP). (3) mortality rate at 3 and 6 months. (4) overall survival (OS). (5) ORR, DOR, TTP, mortality rate at 3 and 6 months, and OS in FLT-3-ITD mutant versus WT populations. (6) (7) Plasma PK parameters. Including but not limited to maximum (peak) plasma concentration (C_max), first time to reach maximum (peak) plasma concentration (T_max), area under the plasma concentration versus time curve over the dosing interval (AUC_tau), apparent clearance (CL/F), accumulation ratio (Rac), and peak- trough ratio (PTR). (8) PD effect measured as modulation of expression of pathway markers such as pS6 in peripheral AML blasts.

Statistical considerations: For the dose escalation cohort, statistical analyses is primarily descriptive and graphical in nature. No formal statistical hypothesis testing is performed. For the AML expansion cohort, ORR in the response-evaluable population is tabulated descriptively with 95% exact binomial confidence intervals (CIs). Time-to-event data is analyzed by the Kaplan-Meier method and results are summarized by the 25th, 50th, and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of censored observations, by FLT-3 WT and mutant populations.

Sample size justification: During the dose escalation phase, dose escalation is conducted according to a standard 3+3 dose escalation schema, and approximately 12 to 15 response evaluable patients are enrolled. The MTD/RP2D cohort has at least 6 patients. The sample sizes for the AML expansion cohort are estimated using a one-sided test at a significance level of α = 0.1 with a power of 80%. The FLT-3 WT cohort uses a null hypothesis of response rate ≦ 15%, versus an alternative hypothesis of response rate ≧ 35%. Based on a Simon 2-stage design and a 15% dropout rate, approximately 11 patients are needed if the trial fails in the first stage, or 28 patients are needed if the FLT-3 WT cohort succeeds in going to the second stage. The mutant cohort uses a null hypothesis of response rate ≦ 30%, versus an alternative hypothesis of response rate ≧ 50%. Based on a Simon 2-stage design and a 15% dropout rate, approximately 18 patients are needed if the trial fails in the first stage, or 38 patients are needed if the mutant cohort succeeds in going to the second stage.

The embodiments described herein are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure.

All of the patents, patent applications and publications referred to herein are incorporated herein in their entireties. Citation or identification of any reference in this application is not an admission that such reference is available as prior art to this application. The full scope of the disclosure is better understood with reference to the appended claims.

Claims (54)

1. A compound of Formula (I):
   

   

   or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for use in a method of treating acute myeloid leukemia (AML) in a subject, characterized in that about 30-100 mg of the compound is administered twice daily to the subject having an AML.
2. The compound for use of claim 1, wherein the compound is of Formula (II):
   

   

   or a polymorph thereof.
3. The compound for use of claim 1 or 2, characterized in that about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
4. The compound for use of claim 1 or 2, characterized in that about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
5. The compound for use of claim 1 or 2, characterized in that about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
6. The compound for use of claim 1 or 2, characterized in that about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
7. The compound for use of claim 1 or 2, characterized in that about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
8. The compound for use of claim 1 or 2, characterized in that about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
9. The compound for use of claim 1 or 2, characterized in that about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
10. The compound for use of claim 1 or 2, characterized in that about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
11. The compound for use of any one of claims 1-10, wherein the AML is refractory or relapsed.
12. The compound for use of claim 11, wherein the acute myeloid leukemia is refractory.
13. The compound for use of claim 11, wherein the acute myeloid leukemia is relapsed.
14. The compound for use of any one of claims 1-13, characterized in that the compound is administered in combination with one or more additional therapeutic agents.
15. The compound for use of any one of claims 1-14, characterized in that the compound is administered orally.
16. The compound for use of any of claims 1-15, characterized in that the compound is administered as a solid dosage form.
17. The compound for use of any one of claims 1-16, wherein the subject is a mammal.
18. The compound for use of any one of claims 1-17, wherein the subject is a human.
19. A method of treating acute myeloid leukemia (AML) in a subject, comprising administering twice daily to the subject having an AML about 30-100 mg of a compound of Formula (I):
    

    

    or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
20. The method of claim 19, wherein the compound is of Formula (II):
    

    

    or a polymorph thereof.
21. The method of claim 19 or 20, wherein about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
22. The method of claim 19 or 20, wherein about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
23. The method of claim 19 or 20, wherein about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
24. The method of claim 19 or 20, wherein about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
25. The method of claim 19 or 20, wherein about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
26. The method of claim 19 or 20, wherein about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
27. The method of claim 19 or 20, wherein about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
28. The method of claim 19 or 20, wherein about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
29. The method of any one of claims 19-27, wherein the AML is refractory or relapsed.
30. The method of claim 29, wherein the acute myeloid leukemia is refractory.
31. The method of claim 29, wherein the acute myeloid leukemia is relapsed.
32. The method of any one of claims 19-31, further comprising administration of one or more additional therapeutic agents.
33. The method of any one of claims 19-32, wherein the compound is administered orally.
34. The method of any of claims 19-33, wherein the compound is administered as a solid dosage form.
35. The method of any one of claims 19-34, wherein the subject is a mammal.
36. The method of any one of claims 19-35, wherein the subject is a human.
37. A composition for treating acute myeloid leukemia (AML) in a subject, comprising a compound of Formula (I):
    

    

    or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, characterized in that about 30-100 mg of the compound is administered twice daily to the subject having an AML.
38. The composition of claim 37, wherein the compound is of Formula (II):
    

    

    or a polymorph thereof.
39. The composition of claim 37-38, characterized in that about 30 mg of the compound of Formula (I) or (II) is administered twice daily.
40. The composition of claim 37-38, characterized in that about 40 mg of the compound of Formula (I) or (II) is administered twice daily.
41. The composition of claim 37-38, characterized in that about 50 mg of the compound of Formula (I) or (II) is administered twice daily.
42. The composition of claim 37-38, characterized in that about 60 mg of the compound of Formula (I) or (II) is administered twice daily.
43. The composition of claim 37-38, characterized in that about 70 mg of the compound of Formula (I) or (II) is administered twice daily.
44. The composition of claim 37-38, characterized in that about 80 mg of the compound of Formula (I) or (II) is administered twice daily.
45. The composition of claim 37-38, characterized in that about 90 mg of the compound of Formula (I) or (II) is administered twice daily.
46. The composition of claim 37-38, characterized in that about 100 mg of the compound of Formula (I) or (II) is administered twice daily.
47. The composition of any one of claims 37-46, wherein the AML is refractory or relapsed.
48. The composition of claim 47, wherein the acute myeloid leukemia is refractory.
49. The composition of claim 47, wherein the acute myeloid leukemia is relapsed.
50. The composition of any one of claims 37-49, characterized in that the composition is administered in combination with one or more additional therapeutic agents.
51. The composition of any one of claims 37-50, characterized in that the composition is administered orally.
52. The composition of any of claims 37-51, characterized in that the composition is administered as a solid dosage form.
53. The composition of any one of claims 37-52, wherein the subject is a mammal.
54. The composition of any one of claims 37-53, wherein the subject is a human.

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