Formulations and dosages for administering compounds that inhibit the MCL1 protein

Abstract

Formulations of compounds of Formula I are provided, as are doses and administration regimens useful in methods of treating cancer, including hematological malignancies such as, for example, acute myeloid leukemia, multiple myeloma, and non-Hodgkin's lymphoma. TIFF2022542379000038.tif79170

Description

[Technical Field]

[0001] The present invention relates to novel formulations comprising compounds of formula I and / or salts thereof, and to methods for treating cancers, including hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma, in patients having such malignancies. The present invention further relates to dosages and administration schedules for treating such diseases. [Background technology]

[0002] Programmed cell death, or apoptosis, is regulated by a complex network of protein-protein interactions between pro-apoptotic and anti-apoptotic subgroups that form the B-cell lymphoma / leukemia 2 (BCL2) protein family (Czabotar et al, Nat'l Rev Mol Cell Biol. 15:49-63 (2014); Strasser et al, EMBO J. 30:2667-3683 (2011); Kozopas et al, Proc Nat'l Acad Sci USA 90:3516-3520 (1993)). Myelocyte leukemia 1 (MCL1) is a member of this family that promotes cell survival. In contrast, pro-apoptotic family members such as the mitochondrial pore-forming factor BCL2 alloantigonist / killer (BAK) and BCL2-binding X (BAX), or BCL2 homology 3 (BH3)-only protein family members such as the BCL2 interaction mediator of cell death (BIM) and the p53 upregulatory modulator of apoptosis (PUMA), are crucial effectors for inducing apoptosis. Upon induction of apoptotic stimulation, pro-apoptotic BH3-only proteins bind to MCL1 and other pro-survivability BCL2 family members, disrupting the interaction between MCL1 and the pro-apoptotic effector proteins BAK and BAX. This disruption leads to activation and oligomerization of BAK and BAX; permeabilization of other outer membranes of mitochondria (MOMP); release of cytochrome C; caspase activation; and cell death (Czabotar et al (2014); Strasser et al, (2011)).

[0003] Myelocellular leukemia 1 is expressed in a range of human and mouse tissues. In mice, for example, conditional gene knockout studies have demonstrated that MCL1 is important for the survival of numerous cell types, including lymphocytes, hematopoietic stem cells, neutrophils, and cardiomyocytes (Thomas et al, Genes Dev 27:1365-1377 (2014); Wang et al, Genes Dev 27:1351-1364 (2013); Strasser et al, (2011)). MCL1 overexpression has been linked to the development of numerous solid tumors and hematopoietic malignancies (Ashkenazi et al. Nature Rev 15:273-284 (2017); Merino et al, Sci Transl Med 9:1-10 (2017); Kotschy et al, Nature 538:477-482 (2016); Glaser et al, Genes Dev. 26:120-125 (2012)).

[0004] The compound of formula I and its salt are compounds that inhibit the MCL1 protein. The structure of the compound of formula I is shown below. [ka] Compounds of formula I and their salts, as well as methods for synthesizing these compounds, are described in International Publication No. 2016 / 033486 and U.S. Patent No. 9,562,061. These references are incorporated herein by reference as a whole, as if they were explicitly stated in detail. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2016 / 033486 Brochure [Patent Document 2] U.S. Patent No. 9,562,061 [Non-patent literature]

[0006] [Non-Patent Document 1] Czabotar et al, Nat'l Rev Mol Cell Biol.15:49-63(2014) [Non-Patent Document 2] Strasser et al,EMBO J.30:2667-3683(2011) [Non-Patent Document 3] Kozopas et al,Proc Nat'l Acad Sci USA 90:3516-3520(1993) [Non-Patent Document 4] Thomas et al,Genes Dev 27:1365-1377(2014) [Non-Patent Document 5] Wang et al,Genes Dev 27:1351-1364(2013) [Non-Patent Document 6] Ashkenazi et al.Nature Rev 15:273-284(2017) [Non-Patent Document 7] Merino et al, Sci Transl Med 9:1-10(2017) [Non-Patent Document 8] Kotschy et al,Nature 538:477-482(2016) [Non-Patent Document 9] Glaser et al,Genes Dev.26:120-125(2012) [Overview of the project] [Problems that the invention aims to solve]

[0007] There is a need for suitable formulations, doses, and administration schedules containing compounds that inhibit the MCL1 protein, such as compounds of formula I and / or salts of compounds of formula I. Furthermore, there is a need for formulations and quantities of such formulations that are useful for treating cancer and hematological malignancies, among many others, such as acute myeloid leukemia (AML), multiple myeloma (MM), and especially non-Hodgkin lymphoma (NHL). [Means for solving the problem]

[0008] In one embodiment, the present invention relates to a pharmaceutical formulation, the formulation being: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The present invention provides a pharmaceutical formulation in which the concentration of the compound of formula I or its salt ranges from 15 mg / mL to 30 mg / mL, and the pH of the formulation ranges from 8.7 to 9.9.

[0009] In another embodiment, the present invention relates to an aqueous solution of a therapeutic agent, wherein the solution is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water, The present invention provides an aqueous therapeutic agent in which the amount of compound I or a salt of compound I in the solution ranges from 25 mg to 400 mg.

[0010] In yet another aspect, the present invention provides a method for preparing an aqueous solution suitable for intravenous injection into a patient, comprising the step of combining any one of the pharmaceutical formulations of Embodiments 1 to 36 with physiological saline.

[0011] In yet another embodiment, the present invention relates to a method for treating a cancer patient, the method comprising the steps of: administering to the patient an aqueous solution containing a compound of formula I or a salt of a compound of formula I, wherein the compound of formula I has the following structure: [ka] It has, Furthermore, the compound of formula I or a salt of the compound of formula I may be present at a dose of 25 mg / m². 2 ~960mg / m 2 This provides a method that exists in quantities spanning a range.

[0012] In yet another embodiment, the present invention relates to an aqueous solution of a therapeutic agent, wherein the solution is a compound of formula I or a salt thereof, and the compound of formula I has the following structure: [ka] It contains a compound of formula I having or a salt thereof, The compound of formula I or a salt of the compound of formula I is 25 mg / m². 2 ~960mg / m 2 We provide an aqueous solution present in an amount ranging from [a certain range].

[0013] Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following description and claims. [Brief explanation of the drawing]

[0014] [Figure 1] This graph shows the disruption of MCL1-BAK interactions by AMG176 within a Matrigel™ plug containing human HEK293M MCL1(1-327)-Luc / BAK-Luc cells implanted in female thymus-deficient nude mice. [Figure 2] This graph shows BAK activation in OPM2-Luc tumor xenografts treated with AMG176. [Figure 3] This graph shows the induction of cleavage caspase 3 in OPM2-Luc tumor xenografts treated with AMG176. [Figure 4] This graph shows the inhibition of tumor growth in OPM2-Luc xenografts receiving AMG176 once daily. [Figure 5]This graph shows the inhibition of tumor growth in OPM2-Luc xenografts receiving intermittent administration of AMG176. [Figure 6] This graph shows the effect of AMG176 treatment on tumor size in female thymus-deficient nude mice. [Figure 7] This figure shows the effect of AMG176 treatment on tumor tissue volume, as measured by whole-body bioluminescence imaging in NOD / SCID IL2rg (NSG) mice. [Figure 8] This graph shows the effect of AMG176 + carfilzomib combination treatment on tumor tissue volume, as measured by whole-body bioluminescence imaging in NOD / SCID IL2rg (NSG) mice. [Modes for carrying out the invention]

[0015] Unless otherwise indicated, all figures used in this specification and the claims, representing quantities of components, reaction conditions, etc., should be understood in all cases to be modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters described in the following specification and the attached claims are approximations that may vary depending on the standard deviation found in each of their test measurements. Typically, such numerical quantities will not deviate by more than 5% from the given values.

[0016] The term "comprising" is open-ended, meaning it encompasses but does not limit everything. This term may be used herein as synonymous with "having" or "including." "Comprising" is intended to include any indicated or enumerated component or element, but not exclude any other components or elements. For example, if a composition is stated to include A and B, it means that the composition has A and B, but may also include C or C, D, E, and even other further components.

[0017] Compounds for use in the present invention include, but are not limited to, those of formula I. For example, pharmaceutically acceptable salts may also be used. The term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Examples of such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, and methanesulfonic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, or dicyclohexylamine.

[0018] A buffer is a solution or substance that can be used to create a solution containing either a weak acid and its salt or a weak base and its salt. Buffers are resistant to changes in pH. Typically, a buffer is an aqueous solution of either a weak acid and its conjugate base or a weak base and its conjugate acid. Buffers are typically used to maintain a stable pH in a solution so that they can neutralize small amounts of additional acid or base. For any given buffer, there is a working pH range and a certain amount of acid or base that can be neutralized before the pH changes. The amount of acid or base that can be added to the buffer before its pH changes is called its buffering capacity. Some examples of buffers include, but are not limited to, citric acid, acetic acid, KH2PO4, borates, and glycine. Glycine is a preferred buffer in embodiments of the present invention. Any safe, non-toxic, and non-reactive buffer suitable for providing a stable pH of about 9 may be used in accordance with the present invention.

[0019] The term "cyclodextrin" refers to a member of the family of compounds containing cyclic oligosaccharides that include a macrocyclic ring of glucose subunits linked by α-1,4-glycosidic bonds. Cyclodextrins are typically produced from starch by enzymatic conversion. They are used in the food, pharmaceutical, drug delivery, and chemical industries, as well as in agriculture and environmental engineering. Cyclodextrins contain five or more linked α-D-glucopyranoside units. Typically, cyclodextrins contain 6 to 8 glucose monomers. However, cyclodextrins containing 32 or more 1,4-anhydroglucopyranoside units are known. In some embodiments, the cyclodextrin compound is hydroxypropyl-β-cyclodextrin, which is commercially available from numerous suppliers, including Sigma Aldrich (Saint Louis, Missouri). Generally, any cyclodextrin that dissolves the compound of formula I or a salt of the compound of formula I may be used according to the present invention, provided that it is non-toxic and suitable for administration to humans. Natural cyclodextrins tend to have poor solubility. However, chemical substitution at 2, 3, and 6 hydroxyl sites significantly increases solubility.

[0020] Preferably, the cyclodextrin compound is hydroxypropyl-β-cyclodextrin.

[0021] The embodiments of this disclosure are described in detail below. While specific embodiments of this disclosure are described, it will be understood that the embodiments of this disclosure are not intended to be limited to those described embodiments. On the contrary, references to embodiments of this disclosure are intended to include alternative forms, modifications and equivalents that may be included within the scope of the embodiments of this disclosure as defined by the appended claims.

[0022] Embodiment The embodiments listed below are numbered for convenience, to facilitate and clarify references when referring to multiple embodiments. This disclosure constitutes a disclosure of any combination of technically compatible embodiments (including those listed below), whether those embodiments are not explicitly disclosed in combination with each other or even when they are explicitly combined with each other.

[0023] In the first aspect and embodiment, the present invention relates to a pharmaceutical formulation, the formulation being: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The present invention provides a pharmaceutical formulation in which the concentration of the compound of formula I or its salt ranges from 15 mg / mL to 30 mg / mL, and the pH of the formulation ranges from 8.7 to 9.9. 2. The pharmaceutical formulation of Embodiment 1, wherein the buffering agent is glycine. 3. The cyclodextrin compound is hydroxypropyl-β-cyclodextrin in the pharmaceutical formulation of Embodiment 1 or Embodiment 2. 4. A pharmaceutical formulation according to any one of Embodiments 1 to 3, wherein the pH of the formulation is 8.8 to 9.8. 5. The pharmaceutical formulation of Embodiment 4, wherein the pH ranges from 8.9 to 9.5. 6. The pharmaceutical formulation of Embodiment 4, wherein the pH of the formulation is in the range of 8.9 to 9.2. 7. The pharmaceutical formulation according to claim 4, wherein the pH of the formulation is 9. 8. Any one of Embodiments 1 to 7, wherein the concentration of the compound of formula I or its salt in the formulation is in the range of 20 to 30 mg / mL. 9. The pharmaceutical formulation of Embodiment 8, wherein the concentration of the compound of formula I or its salt in the formulation is in the range of 22 to 28 mg / mL. 10. The pharmaceutical formulation of Embodiment 8, wherein the concentration of the compound of formula I or its salt in the formulation is in the range of 24 to 26 mg / mL. 11. The pharmaceutical formulation of Embodiment 8, wherein the concentration of the compound of formula I or its salt in the formulation is 25 mg / mL. 12. Any one of Embodiments 1 to 11, wherein the amount of cyclodextrin compound in the formulation is in the range of 7.5 to 13% by weight. 13. The pharmaceutical formulation of Embodiment 12, wherein the amount of cyclodextrin compound in the formulation is in the range of 8 to 12% by weight. 14. The pharmaceutical formulation of Embodiment 12, wherein the amount of cyclodextrin compound in the formulation is in the range of 9 to 11% by weight. 15. The pharmaceutical formulation of Embodiment 12, wherein the amount of cyclodextrin compound in the formulation is 10% by weight. 16. The preparation is buffered with glycine, and the buffer used to buffer the preparation is any one of the pharmaceutical preparations of Embodiments 1 to 15, containing glycine in a concentration ranging from 80 mM to 120 mM. 17. The pharmaceutical formulation of Embodiment 16, wherein the formulation is buffered with glycine, and the buffering agent used to buffer the formulation contains glycine in a concentration ranging from 90 mM to 110 mM. 18. The pharmaceutical formulation of Embodiment 16, wherein the formulation is buffered with glycine, and the buffering agent used to buffer the formulation contains glycine in a concentration ranging from 95 mM to 105 mM. 19. The pharmaceutical formulation of Embodiment 16, wherein the formulation is buffered with glycine, and the buffer used to buffer the formulation contains glycine at a concentration of 100 mM. 20. A pharmaceutical formulation having a volume ranging from 5 mL to 25 mL, one of any one of Embodiments 1 to 19. 21. A pharmaceutical formulation of Embodiment 20, wherein the volume of the formulation ranges from 8 mL to 20 mL. 22. A pharmaceutical formulation of Embodiment 20, wherein the volume of the formulation ranges from 9 mL to 15 mL. 23. The pharmaceutical formulation of Embodiment 20, wherein the volume of the formulation is 10 mL. 24. The pharmaceutical formulation of Embodiment 20, wherein the volume of the formulation is in the range of 14 mL to 15 mL. 25. The pharmaceutical formulation of Embodiment 20, wherein the volume of the formulation is 14.4 mL. 26. The pharmaceutical formulation of Embodiment 1 is an aqueous formulation comprising 20 mg / mL to 30 mg / mL of the compound of formula I and 8% to 12% by weight of hydroxypropyl-β-cyclodextrin, and buffered to a pH of 8.8 to 9.2 with 90 mM to 110 mM glycine. 27. The pharmaceutical formulation of Embodiment 1, wherein the formulation is an aqueous formulation containing 25 mg / mL of the compound of formula I and 10% by weight of hydroxypropyl-β-cyclodextrin buffered to pH 9 with 100 mM glycine. 28. The pharmaceutical formulation of Embodiment 26 or Embodiment 27, wherein the amount of the formulation is in the range of 9 mL to 15 mL. 29. The pharmaceutical formulation of Embodiment 26 or Embodiment 27, wherein the amount of the formulation is 10 mL. 30. The pharmaceutical formulation of Embodiment 26 or Embodiment 27, wherein the amount of the formulation is 14.4 mL. 31. The preparation is one of the pharmaceutical preparations of Embodiments 1 to 30 contained in a vial. 32. The pharmaceutical formulation of Embodiment 31, wherein the vial is a 20 mL borosilicate glass vial or a 20 mL aluminosilicate glass vial, and the vial is equipped with an aluminum seal with a stopper and a flip-off cover.

[0024] 33. In the second and third embodiments, the present invention relates to an aqueous solution of a therapeutic agent, wherein the solution is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water, The amount of compound I or a salt of compound I in the solution ranges from 25 mg to 400 mg, providing an aqueous solution. 34. The buffering agent is glycine, an aqueous solution of Embodiment 33. 35. The aqueous solution of Embodiment 33 or Embodiment 34, wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin. 36. An aqueous solution of any one of Embodiments 33 to 35, wherein the amount of compound I or a salt of compound I in the solution is in the range of 200 mg to 360 mg. 37. The solution is an aqueous solution of any one of embodiments 33 to 36 contained in an IV bag.

[0025] 38. In the third aspect and the 38th embodiment, the present invention provides a method for preparing an aqueous solution suitable for intravenous infusion to a patient, comprising the step of combining any one of the pharmaceutical formulations of Embodiments 1 to 32 with physiological saline. In some such embodiments, the method for preparing an aqueous solution suitable for intravenous infusion to a patient comprises the step of transferring any one of the pharmaceutical formulations of Embodiments 1 to 32 to physiological saline. In some such embodiments, the physiological saline is contained in an IV bag. 39. The method of Embodiment 38, wherein the physiological saline solution before binding the pharmaceutical preparation with physiological saline solution contains sodium chloride in an amount ranging from 8 g / L to 10 g / L. 40. The method of Embodiment 38, wherein the physiological saline solution before binding the pharmaceutical preparation with physiological saline solution contains sodium chloride in an amount of 9 g / L.

[0026] 41. In the fourth aspect and the forty-first embodiment, the present invention relates to a method for treating a cancer patient, the method comprising the steps of: administering to the patient an aqueous solution containing a compound of formula I or a salt of a compound of formula I, wherein the compound of formula I has the following structure: [ka] Having; Furthermore, the compound of formula I or a salt of the compound of formula I may be present at a dose of 25 mg / m². 2 ~960mg / m 2 A method that exists in quantities that extend over a certain range. 42. The method of Embodiment 41, wherein cancer is a hematological malignancy. 43. The method of embodiment 42, wherein the hematological malignancy is acute myeloid leukemia, multiple myeloma or non-Hodgkin lymphoma. 44. The method of embodiment 42, wherein the hematological malignancy is acute myeloid leukemia. 45. The method of embodiment 44, wherein the patient has relapsed or refractory acute myeloid leukemia. 46. The method of embodiment 42, wherein the hematological malignancy is multiple myeloma. 47. The method of embodiment 46, wherein the patient has relapsed or refractory multiple myeloma. 48. The method of embodiment 42, wherein the hematological malignancy is acute myeloid leukemia, multiple myeloma or non-Hodgkin lymphoma. 49. The method of embodiment 41, wherein the cancer is selected from breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, renal cancer, lung cancer, non-small cell lung cancer, non-Hodgkin lymphoma, multiple myeloma or acute myeloid leukemia. 50. The compound of formula I or a salt of the compound of formula I is present in an amount ranging from 50 mg / m 2 to 250 mg / m 2 in the method of embodiment 41. 51. The compound of formula I or a salt of the compound of formula I is present in an amount ranging from 50 mg / m 2 to 200 mg / m 2 in the method of embodiment 50. 52. The compound of formula I or a salt of the compound of formula I is present in an amount ranging from 60 mg / m 2 to 180 mg / m 2 in the method of embodiment 50. 53. The compound of formula I or a salt of the compound of formula I is present in an amount of 60 mg / m 2 in the method of embodiment 50. 54. The compound of formula I or a salt of the compound of formula I is present in an amount of 120 mg / m 2 in the method of embodiment 50. 55. The compound of formula I or a salt of the compound of formula I is present in an amount of 180 mg / m 2 in the method of embodiment 50. 56. Any one of Embodiments 41 to 55, further comprising the step of administering to a patient at least twice a week an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I. 57. An aqueous solution containing the compound of formula I or a salt of the compound of formula I is: a) Cyclodextrin compounds; b) Buffering agent; and c) Any one of embodiments 41 to 55, further comprising sodium chloride. 58. The method of Embodiment 57, wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin. 59. The buffering agent is glycine, as in the method of Embodiment 57 or Embodiment 58. 60. A method comprising administering to a patient once or twice a week for at least 1 to 6 weeks any one of Embodiments 41 to 56. 61. The method of Embodiment 60, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered to a patient for at least 6 weeks. 62. The method of Embodiment 60, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered to the patient for at least 5 weeks. 63. The method of Embodiment 60, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered to the patient for at least four weeks. 64. The method of Embodiment 60, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered to the patient for at least three weeks. 65. The method of Embodiment 60, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered to the patient for at least two weeks. 66. Any one of Embodiments 41 to 65, further comprising the step of administering to a patient once or twice a day an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I. 67. An aqueous solution containing the compound of formula I or a salt of the compound of formula I is administered for at least two consecutive days, according to any one of embodiments 41 to 66. 68. An aqueous solution containing the compound of formula I or a salt of the compound of formula I is administered intravenously by any one of embodiments 41 to 67. 69. The method of Embodiment 68, wherein an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I is administered intravenously over a period of at least two hours.

[0027] 70. In the fifth aspect and the seventieth embodiment, the present invention relates to an aqueous solution of a therapeutic agent, wherein the solution is: a compound of formula I or a salt thereof, and the compound of formula I has the following structure: [ka] It comprises a compound of formula I having or a salt thereof; The compound of formula I or a salt of the compound of formula I is 25 mg / m². 2 ~960mg / m 2 We provide an aqueous solution present in an amount ranging from [a certain range]. 71. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 25 mg / m². 2 ~250 mg / m² 2 An aqueous solution of Embodiment 70, present in an amount that extends over the range of [a certain range]. 72. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 50 mg / m². 2 ~200mg / m 2 An aqueous solution of Embodiment 70, present in an amount that extends over the range of [a certain range]. 73. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 60 mg / m². 2 ~180mg / m 2 An aqueous solution of Embodiment 70, present in doses ranging from . 74. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 60 mg / m². 2 An aqueous solution of Embodiment 70, present in the following dosage. 75. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 120 mg / m². 2 An aqueous solution of Embodiment 70, present in the following dosage. 76. The compound of formula I or a salt of the compound of formula I may be administered at a dose of 180 mg / m². 2 An aqueous solution of Embodiment 70, present in the following dosage. 77. An aqueous solution containing the compound of formula I or a salt of the compound of formula I is: a) Cyclodextrin compounds; b) Buffering agent; and c) Any one aqueous solution of Embodiments 70 to 76, further comprising sodium chloride. 78. The aqueous solution of Embodiment 77, wherein the buffering agent is glycine. 79. The aqueous solution of Embodiment 77 or Embodiment 78, wherein the cyclodextrin compound is hydroxypropyl-β-cyclodextrin. 80. An aqueous solution for use in a method of treating cancer in a patient, wherein the aqueous solution contains a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] Having; The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 An aqueous solution, which includes a step of administering an amount within a range. 81. Cancer is a hematological malignant tumor, an aqueous solution for use according to Embodiment 80. 82. An aqueous solution for use according to Embodiment 81, wherein the hematological malignancy is acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. 83. A hematological malignancy is acute myeloid leukemia, an aqueous solution for use according to Embodiment 81. 84. An aqueous solution for use according to Embodiment 83, wherein the patient has relapsed or refractory acute myeloid leukemia. 85. A hematological malignancy is multiple myeloma, an aqueous solution for use according to Embodiment 81. 86. An aqueous solution for use according to Embodiment 85, wherein the patient has relapsed or refractory multiple myeloma. 87. An aqueous solution for use according to Embodiment 81, wherein the hematological malignancy is acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. 88. An aqueous solution for use according to Embodiment 80, selected from cancers such as breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, lung cancer, non-small cell lung cancer, non-Hodgkin lymphoma, multiple myeloma, or acute myeloid leukemia. 89. The method involves administering 50 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~250 mg / m² 2 An aqueous solution for use according to any one of embodiments 80 to 88, comprising the step of administering an amount within the range of [amount]. 90. The method involves administering 50 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~200mg / m 2 An aqueous solution for use according to Embodiment 89, comprising the step of administering in an amount that falls within the range of [a certain range]. 91. The method involves administering 60 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~180mg / m 2 An aqueous solution for use according to Embodiment 89, comprising the step of administering in an amount that falls within the range of [a certain range]. 92. The method involves administering 60 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 An aqueous solution for use according to Embodiment 89, which includes the step of administering in an amount. 93. The method involves administering 120 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 An aqueous solution for use according to Embodiment 89, which includes the step of administering in an amount. 94. The method involves administering 180 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 An aqueous solution for use according to Embodiment 89, which includes the step of administering in an amount. 95. A method for use according to any one of Embodiments 80 to 94, comprising the step of administering to a patient at least twice a week an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I. 96. An aqueous solution containing the compound of formula I or a salt of the compound of formula I is: a) Cyclodextrin compounds; b) Buffering agent; and c) An aqueous solution for use according to embodiments 80-95, further comprising sodium chloride. 97. The cyclodextrin compound is hydroxypropyl-β-cyclodextrin, an aqueous solution for use according to Embodiment 96. 98. The buffer is glycine, an aqueous solution for use according to Embodiment 96 or Embodiment 97. 99. An aqueous solution for use according to any one of Embodiments 80 to 95, comprising the step of administering an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I to a patient once or twice a week for at least one week. 100. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 99, administered to a patient for at least 6 weeks. 101. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 99, administered to a patient for at least 5 weeks. 102. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 99, administered to a patient for at least four weeks. 103. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 99, administered to a patient for at least three weeks. 104. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 99, administered to a patient for at least two weeks. 105. An aqueous solution for use according to any one of Embodiments 80 to 104, further comprising the step of administering an aqueous solution containing the compound of Formula I or a salt of the compound of Formula I to a patient once or twice a day. 106. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to any one of embodiments 80 to 105, administered for at least two consecutive days. 107. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to any one of embodiments 80 to 106, to be administered intravenously. 108. An aqueous solution containing the compound of formula I or a salt of the compound of formula I, for use according to Embodiment 107, which is administered intravenously over a period of at least two hours.

[0028] In some embodiments, the compound of formula I or a salt thereof may be administered together with at least one second therapeutic agent. In some such embodiments, the second therapeutic agent is administered before the administration of the compound of formula I or a salt thereof. In some such embodiments, the second therapeutic agent is administered after the compound of formula I or a salt thereof has been administered to the patient. In yet another such embodiment, the second therapeutic agent is administered simultaneously with the administration of the compound of formula I or a salt thereof to the patient. Various second therapeutic agents that may be used include, but are not limited to, venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0029] The aqueous formulations provided herein, comprising the compound of Formula I and / or a salt thereof, may be used to treat multiple myeloma. Typically, doses for treating multiple myeloma, administered once daily for two consecutive days followed by a five-day no-treatment period (QD2), include, for example, 30, 40, 50, 60, 120, 180, 240, 360, 480, 600, 720, 840, and 960 mg / m². 2 (IV;QD2) QD2 dose including 30-960 mg / m² 2 Doses ranging from these are typical. Typically, doses for treating multiple myeloma once weekly (QW) include, for example, 180, 240, 360, 480, 600, 720, 840, and 960 mg / m². 2 QW doses including 180-960 mg / m² 2 Doses ranging from [a certain range] are available. The formulation is typically administered intravenously.

[0030] The aqueous formulations provided herein, comprising the compound of Formula I and / or a salt thereof, may further be used to treat acute myeloid leukemia. Typically, doses for treating acute myeloid leukemia, administered once daily for two consecutive days followed by a five-day no-treatment period (QD2), include, for example, 60, 120, 180, 240, 360, 480, 600, 720, 840, and 960 mg / m². 2 (IV;QD2) QD2 dose including 30-960 mg / m² 2Doses ranging from these are typical. Typically, for treating acute myeloid leukemia once weekly (QW), doses such as 180, 240, 360, 480, 600, 720, 840, and 960 mg / m² are used. 2 QW doses including 180-960 mg / m² 2 Doses ranging from [a certain range] are available. The formulation is typically administered intravenously.

[0031] The present invention relates to a compound of formula I or a salt thereof, wherein the compound of formula I has the following structure for use in a therapeutic method: [ka] The present invention provides a compound of formula I having or a salt thereof. Preferably, the method comprises the step of administering a solution intravenously. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Optionally, the method may comprise the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0032] The present invention relates to a compound of formula I or a salt thereof, wherein the compound of formula I has the following structure for use in a method for treating multiple myeloma: [ka] The present invention provides a compound of formula I having or a salt thereof. Preferably, the method comprises the step of administering a solution intravenously. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Optionally, the method may comprise the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0033] The present invention relates to a compound of formula I or a salt thereof, wherein the compound of formula I has the following structure for use in a method for treating acute myeloid leukemia: [ka] The present invention provides a compound of formula I having or a salt thereof. Preferably, the method comprises the step of administering a solution intravenously. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Optionally, the method may comprise the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0034] The present invention relates to a compound of formula I or a salt thereof, wherein the compound of formula I has the following structure for use in a method for treating non-Hodgkin lymphoma: [ka] The present invention provides a compound of formula I having or a salt thereof. Preferably, the method comprises the step of administering a solution intravenously. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Optionally, the method may comprise the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0035] The present invention relates to an aqueous solution of a therapeutic agent, wherein the solution is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water, The present invention provides an aqueous therapeutic agent in which the amount of compound I or a salt of compound I in the solution ranges from 25 mg to 400 mg; the concentration of compound I or a salt of compound I in the solution ranges from 15 mg / mL to 30 mg / mL; and the pH of the formulation ranges from 8.7 to 9.9. The present invention further provides an aqueous aqueous solution for use in a method of treating cancer in a patient, preferably the aqueous solution selected from the list consisting of hematological malignancies, most preferably acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma. Preferably the method comprises the step of intravenously administering the aqueous solution, and preferably the method comprises, for example, the step of diluting the solution in a bag containing physiological saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0036] The present invention relates to an aqueous solution of a therapeutic agent for use in a therapeutic method, wherein the solution is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water, The present invention provides an aqueous therapeutic agent in which the amount of compound I or a salt of compound I in the solution ranges from 25 mg to 400 mg. Preferably, the method comprises the step of administering the solution intravenously, and preferably, the method comprises the step of diluting the solution in a bag containing physiological saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0037] The present invention relates to a pharmaceutical formulation for use in a therapeutic method, wherein the formulation is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The present invention provides a pharmaceutical formulation in which the concentration of the compound of formula I or a salt thereof ranges from 15 mg / mL to 30 mg / mL, and the pH of the formulation ranges from 8.7 to 9.9. Preferably, the method comprises the step of intravenous administration of the formulation, and preferably, the method comprises the step of diluting the formulation in a bag containing physiological saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0038] The present invention relates to an aqueous solution for use in a method of treating cancer in a patient, wherein the aqueous solution is: a) A compound of formula I or a salt of a compound of formula I, wherein the compound of formula I has the following structure: [ka] A compound of formula I having or a salt of a compound of formula I; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water; The amount of compound I or a salt of compound I in the solution is provided in an aqueous solution ranging from 25 mg to 400 mg. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from the list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Preferably, the method comprises the step of administering the solution intravenously, and preferably, the method comprises the step of diluting it, for example, in a bag containing physiological saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0039] The present invention relates to an aqueous solution for use in a method of treating cancer, wherein the aqueous solution is: a) A compound of formula I or a salt of a compound of formula I, wherein the compound of formula I has the following structure: [ka] A compound of formula I having or a salt of a compound of formula I; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water; The amount of compound I or a salt of compound I in the solution ranges from 25 mg to 400 mg; The method is 25 mg / m² 2 ~960mg / m 2 The present invention provides an aqueous solution comprising the step of administering a compound of formula I or a salt of a compound of formula I in an amount relating to the range of [amount]. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from the list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Preferably, the method comprises the step of administering the solution intravenously, and preferably, the method comprises the step of diluting it, for example, in a bag containing saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0040] The present invention relates to a pharmaceutical formulation for use in a method of treating cancer, wherein the pharmaceutical formulation is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The present invention provides a pharmaceutical formulation in which the concentration of the compound of formula I or a salt thereof ranges from 15 mg / mL to 30 mg / mL, and the pH of the formulation ranges from 8.7 to 9.9. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from a list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Preferably, the method comprises the step of intravenous administration of the formulation, and preferably, the method comprises, for example, the step of diluting the formulation in a bag containing physiological saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from a list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0041] The present invention relates to a pharmaceutical formulation for use in a method of treating cancer, wherein the pharmaceutical formulation is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: [ka] Compounds of formula I having or salts thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The present invention provides a pharmaceutical preparation in which the concentration of the compound of formula I or its salt ranges from 15 mg / mL to 30 mg / mL, and the pH of the preparation ranges from 8.7 to 9.9. The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m2 The present invention provides a pharmaceutical formulation comprising the step of administering an amount within a range. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from a list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Preferably, the method comprises the step of intravenous administration of the formulation, and preferably, the method comprises, for example, the step of diluting the formulation in a bag containing saline before intravenous administration. The method may optionally further comprise the step of administering a second therapeutic agent selected from a list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0042] The present invention relates to an aqueous solution for use in a method of treating cancer in a patient, wherein the aqueous solution comprises a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The process includes administering an amount that falls within a certain range; The method provides an aqueous solution further comprising the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from the list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Optionally, the method may include the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0043] The present invention relates to an aqueous solution for use in a method for treating acute myeloid leukemia in a patient, wherein the aqueous solution comprises a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The present invention provides an aqueous solution comprising the step of administering an amount within a range. Preferably, the method comprises the step of intravenous administration of the aqueous solution. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0044] The present invention relates to an aqueous solution for use in a method for treating multiple myeloma in a patient, wherein the aqueous solution comprises a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The present invention provides an aqueous solution comprising the step of administering an amount within a range. Preferably, the method comprises the step of intravenous administration of the aqueous solution. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0045] The present invention relates to an aqueous solution for use in a method of treating non-Hodgkin lymphoma in a patient, wherein the aqueous solution comprises a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The present invention provides an aqueous solution comprising the step of administering an amount within a range. Preferably, the method comprises the step of intravenous administration of the aqueous solution. The method may optionally further comprise the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0046] The present invention relates to an aqueous solution for use in a method for treating multiple myeloma, wherein the aqueous solution comprises a compound of formula I or a salt of a compound of formula I, and the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The process includes administering an amount that falls within a certain range; The method provides an aqueous solution further comprising the step of administering carfilzomib as a second therapeutic agent. Preferably, the method includes the step of administering the solution intravenously.

[0047] The present invention relates to a therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone for use in a method of treating cancer in a patient: The method comprises the steps of administering the therapeutic agent to the patient, and further comprising the step of administering an aqueous solution containing a compound of formula I or a salt of a compound of formula I, wherein the compound of formula I has the following structure: [ka] It has, The method involves administering 25 mg / m² of the compound of formula I or a salt of the compound of formula I. 2 ~960mg / m 2 The present invention provides a therapeutic agent comprising the step of administering an amount within a range. Preferably, the cancer is a hematological malignancy, and most preferably, the cancer is selected from the list consisting of acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma. Preferably, the method comprises the step of administering a solution intravenously. Optionally, the method may comprise the step of administering any one pharmaceutical formulation of Embodiments 1 to 30 or any one aqueous solution of Embodiments 33 to 36.

[0048] The present invention provides any one of the formulations disclosed herein for use in a method of treating cancer in a patient. Needless to say, the patient is preferably a human, and preferably the cancer to which the present invention is directed is a human cancer. Preferably, the method includes the step of administering the formulation intravenously.

[0049] The present invention further provides any of the formulations disclosed herein for use in a method of treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma in a patient.

[0050] The present invention further provides the pharmaceutical composition of Embodiment 1 described above for use in a method for treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma.

[0051] The present invention further provides an aqueous solution of the above embodiment 33 for use in a method for treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma.

[0052] The present invention provides a formulation for use in a method of treating cancer in a patient, the method further comprising the step of administering a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Preferably, the formulation comprising a compound of formula I or a salt thereof is administered intravenously.

[0053] The present invention further provides one of the formulations disclosed herein for use in a method of treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma, comprising the step of administering one of the formulations disclosed herein and a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone.

[0054] The present invention provides a pharmaceutical composition of Embodiment 1 for use in a method for treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma in a patient, further comprising the step of administering to the patient the pharmaceutical composition of Embodiment 1 and a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Preferably, the pharmaceutical composition is administered intravenously. Optionally, the method involves administering 25 mg / m² of the compound of Formula I or a salt of the compound of Formula I. 2 ~960mg / m 2 This includes the step of administering an amount that falls within a certain range.

[0055] The present invention further provides a pharmaceutical composition of Embodiment 1 for use in a method for treating multiple myeloma in a patient, comprising the step of administering to the patient the pharmaceutical composition of Embodiment 1 and carfilzomib as a second therapeutic agent. Preferably, the pharmaceutical composition is administered intravenously. Optionally, the method involves administering 25 mg / m² of the compound of Formula I or a salt of the compound of Formula I. 2 ~960mg / m 2 This includes the step of administering an amount that falls within a certain range.

[0056] The present invention further provides an aqueous solution of Embodiment 33 for use in a method of treating acute myeloid leukemia, multiple myeloma, or non-Hodgkin lymphoma in a patient, comprising the step of administering to the patient an aqueous solution of Embodiment 33 and a second therapeutic agent selected from the list consisting of venetoclax, carfilzomib, azacitidine, and dexamethasone. Preferably, the aqueous solution is administered intravenously. Optionally, the method may involve administering a compound of Formula I or a salt of a compound of Formula I at a dose of 25 mg / m². 2 ~960mg / m 2 This includes the step of administering an amount that falls within a certain range.

[0057] The present invention further provides the aqueous solution of Embodiment 33 for use in a method for treating multiple myeloma in a patient, comprising the step of administering to the patient the aqueous solution of Embodiment 33 and carfilzomib as a second therapeutic agent. Preferably, the aqueous solution is administered intravenously. Optionally, the method involves administering 25 mg / m² of the compound of Formula I or a salt of the compound of Formula I. 2 ~960mg / m 2 This includes the step of administering an amount that falls within a certain range.

[0058] The present invention provides a vial containing any one of the pharmaceutical formulations described in Embodiments 1 to 30 above.

[0059] The present invention further provides a vial containing any one of the pharmaceutical formulations of Embodiments 1 to 30 above, wherein the vial is a 20 mL borosilicate glass vial or a 20 mL aluminosilicate glass vial, and the vial is equipped with an aluminum seal with a stopper and a flip-off cover.

[0060] The present invention further provides a vial containing an aqueous solution of any one of the embodiments 33 to 36 described above.

[0061] The present invention further provides an IV bag containing an aqueous solution of any one of the embodiments 33 to 36 described above.

[0062] The present invention further provides an IV bag containing any one of the pharmaceutical formulations of Embodiments 1 to 30 described above. In a preferred embodiment, the solution in the IV bag is diluted compared to the formulation being transferred to the IV bag, for example, by adding saline solution that is not present in the formulation being transferred to the IV bag.

[0063] In one embodiment, the medical use or therapeutic method disclosed herein is as follows: • At least 1000 times, preferably 2000 times, more preferably 3000 times, and most preferably 4000 times, the selectivity of MCL1 compared to BCL2 and / or BCL-XL; and • To produce one or more of the following: stable disease, and more preferably partial remission, and most preferably complete remission. The second of these points is preferably applicable in relation to the treatment of AML - see the examples below.

[0064] The combination therapies disclosed herein may be administered in any order, simultaneously, individually, and sequentially. Therefore, purely as an example, the present invention relates to venetoclax, carfilzomib, azacitidine, and / or dexamethasone for use in a method of treating cancer when administered in combination with any one of the AMG176 embodiments (solutions and formulations, etc.) disclosed herein. In alternative embodiments, the present invention relates to any one of the AMG176 embodiments (solutions and formulations, etc.) for use in a method of treating cancer when administered in combination with venetoclax, carfilzomib, azacitidine, and / or dexamethasone. Preferably, any such combination therapy exceeds the effect achieved by one of the constituent monoagents administered alone (or, if the combination therapy comprises three or more agents, preferably, the combination exceeds the effect achieved using one of the constituent monoagents administered alone and any one of the constituent subcombinations constituting the combination therapy).

[0065] The present invention will be further described with reference to the following embodiments. These embodiments are intended to illustrate the claimed invention, but are not intended to limit it in any way. [Examples]

[0066] The compound of formula I is a selective small molecule inhibitor of the protein-protein interaction between the MCL1 member and the pro-apoptotic member of the BCL2 family, which is being studied in the treatment of patients with cancer and, in particular, patients with hematological malignancies including but not limited to multiple myeloma and acute myeloid leukemia (Caenepeel et al, Cancer Discov 8:1582-1597 (2018)).

[0067] The compound of formula I and its salt are compounds that inhibit the MCL1 protein. The structure of the compound of formula I is shown below. [ka] The compound of Formula 1 is also known as AMG176. The compounds of Formula 1 and their salts, as well as methods for synthesizing the compounds, are described in International Publication No. 2016 / 033486 and U.S. Patent No. 9,562,061. These references are incorporated herein by reference as a whole, as if they were explicitly stated in detail.

[0068] Non-clinical trials - pharmacology The compound of formula I selectively disrupts the human MCL1-BIM interaction in vitro in time-resolved fluorescence resonance energy transition-based assays, reaching an average 50% inhibitory concentration of 0.241 nM (IC). 50 This induces (Table 1). Furthermore, the compound is highly selective for MCL1, demonstrating a selectivity of over 4000 times compared to the pro-survival BCL2 family members, BCL2, and B-cell lymphoma / super-large cell leukemia (BCL-XL). In cell assays, the compound of formula I produced an average IC50 of 30.8 nM. 50 This disrupts the interaction between MCL1 and BAK. In cell viability studies conducted in a group of tumor cell lines derived from multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma, this compound showed less than 1 μM IC2 in 12 of the 23 cell lines tested. 50 Along with the value, ICs in the range of 14nM to over 20μM50 The value was shown.

[0069] [Table 1]

[0070] Treatment with the compound of formula I resulted in dose-dependent inhibition of the interaction between human MCL1 and human BAK in vivo. Treatment with the compound also induced dose-dependent induction of multiple markers of apoptosis, including BAK activation and caspase-3 cleavage, in tumor xenografts (OPM2-Luc) derived from a stable, transduced human MCL1-dependent multiple myeloma cell line using the luciferase gene. In the OPM2-Luc xenograft efficacy model, treatment with the compound of formula I significantly inhibited the growth of settled tumors, and tumor regression was observed at two doses: 30 mg / kg and 60 mg / kg once daily. Additional studies to test the efficacy of the compound of formula I were conducted in the OPM2-Luc tumor xenograft model using an intermittent dosing schedule. The compound of formula I significantly inhibited the growth of settled tumors at doses of 30 mg / kg and 60 mg / kg in schedules of 2 days of administration / 5 days of rest and 5 days of administration / 2 days of rest. Weekly oral administration of AMG176 at doses of 50 and 100 mg / kg resulted in tumor growth inhibition rates (TGI) of 97% and 70%, respectively. The efficacy of the compound of formula I was further evaluated in an orthotopic model of acute myeloid leukemia in which MOLM13 tumor cells were transplanted into mouse bone marrow cells with MOLM13 luciferase. In this model, oral administration of the compound at 30 mg / kg or 60 mg / kg on a 2-day dose / 5-day rest (QD2) schedule resulted in significant dose-dependent inhibition of tumor tissue volume as assessed by systemic luminescence (28% and 69% TGI, respectively), and oral administration of the compound once daily at 100 mg / kg resulted in an 86% TGI. The therapeutic capacity of the combination of the compound of formula I and the protease inhibitor carfilzomib was tested in an orthotopic OPM2-Luc model. In mice treated once daily with the compound (20 mg / kg) and twice weekly with carfilzomib (3 mg / kg), this combination achieved significant inhibition of tumor tissue volume (99% TGI), surpassing the effects achieved with either monotherapy alone (86% TGI with the compound of formula I and 82% TGI with carfilzomib).

[0071] In a study using HEK293M cells transiently transfected with MCL1 and BAK, AMG176 showed an average IC50 of 30.8 nM in serum-free growth medium. 50 It inhibited the interaction between MCL1 and BAK. AMG176 dose-dependently inhibited the viability of tumor cell lines in OPM2 multiple myeloma, and IC176 was found at 15.5 nM (serum-free growth medium), 235.7 nM (growth medium containing 10% fetal bovine serum [FBS]), and 703.4 nM (growth medium containing 5% human serum). 50 This resulted in a value. In an additional tumor cell viability test conducted in growth medium containing 10% FBS, AMG176 showed an IC50 of less than 1 μM in 12 out of 23 tumor cell lines derived from multiple myeloma, AML, and NHL. 50 The values ​​are shown (Table 2).

[0072] [Table 2]

[0073] Inhibition of MCL1-BAK protein-protein interaction by AMG176 in the HEK293M Matrigel® plug model Inhibition of the MCL1-BAK protein-protein interaction was used as a pharmacodynamic (PD) assay in HEK293M cells stably transfected to express the N-terminal fragment of human MCL1 encoding amino acids 1-327 and full-length human BAK, respectively, linked to the N-terminal and C-terminal fragments of firefly luciferase (the interaction between MCL1[1-327] and BAK results in complementarity between the C-terminus and N-terminal fragments of luciferase and the formation of active luciferase). The effect of AMG176 on the MCL1-BAK protein-protein interaction as a function of both dose and time was evaluated in Matrigel® plugs containing human HEK293M MCL1(1-327)Luc / BAK-Luc cells implanted in female thymus-deficient nude mice; AMG176 significantly inhibited the MCL1-BAK protein-protein interaction as measured by luciferase activity (Figure 1). Statistically significant inhibition was observed using 3 mg / kg AMG176 (at 2, 8, 12, and 24 hours), 10 mg / kg AMG176 (at 2, 4, 8, and 12 hours), and 30 mg / kg AMG176 (at 2, 4, 8, 12, and 24 hours) compared to the vehicle control group (p<0.0025, (Figure 1)).

[0074] Induction of multiple hallmarks of apoptosis by AMG176, including BAK activation of caspase-3 cleavage, in OPM2-Luc tumor xenografts. Activation of the pro-apoptotic pore-forming protein BAK and proteolytic cleavage of cysteine-aspartate protease caspase 3 (a hallmark of apoptosis induction) in MCL1-dependent OPM2-Luc multiple myeloma tumor cells functioned as a PD assay. In female thymus-deficient nude mice, 5 × 10 cells in 0.1 mL were used. 6 The individual was injected subcutaneously (SC). The tumor was approximately 400-600 mm. 3When the volume reached a range, AMG176 was administered orally at doses of 10, 20, 30, or 60 mg / kg. Mice were anesthetized 2, 4, 8, 12, and 24 hours after administration (n=3 / group), terminal plasma samples were collected for PK analysis, tumors were halved, and rapidly frozen in liquid nitrogen for PK and molecular analysis. Tumor lysates were prepared to evaluate BAK activation and caspase 3 cleavage using electrochemiluminescence immunoassay. Tumors treated with a vehicle (25% HPβCD, pH 8) served as negative controls and showed baseline levels of apoptosis. Statistically significant BAK activation was observed at doses of 30 mg / kg (at 2, 4, and 8 hours) and 60 mg / kg (at 2, 4, 8, and 12 hours) compared to the vehicle control group (p<0.05 [Figure 2]). At 4 hours post-administration, the 60 mg / kg group showed maximum BAK activation corresponding to the peak AMG176 plasma concentration. Figure 3 shows the induction of caspase-3 cleavage in plasma and tumors and the corresponding concentrations of AMG176. Compared to the vehicle control group, statistically significant induction of caspase-3 cleavage was observed at doses of 20 mg / kg (at 4, 8, and 12 hours post-administration), 30 mg / kg (at 2, 4, 8, 8, and 12 hours post-administration), and 60 mg / kg (at 2, 4, 8, 12, and 24 hours post-administration) (p<0.05 [Figure 2]). At 2 hours post-administration, approximately 7.5 times induction of cleaved caspase-3 was observed in the 60 mg / kg group, and this persisted until 12 hours post-administration. By 24 hours post-administration, cleaved caspase levels had decreased to more than 5 times that of the control, corresponding to the decrease in AMG176 plasma concentration.

[0075] AMG176 inhibited the growth of OPM2-Luc tumor xenografts as a monotherapy. The ability of AMG176 to inhibit tumor growth in an MCL1-dependent OPM2 multiple myeloma xenograft model was evaluated. OPM2-Luc cells (5 × 10⁶ 6The ) was implanted subcutaneously in female thymus-deficient nude mice. Treatment with AMG176 at 10, 20, 30, or 60 mg / kg once daily via vehicle or oral supplementation resulted in a tumor volume of approximately 150 mm. 3 The study was initiated on day 14, when n=10 / group was reached. Dose-dependent TGI was observed, and AMG176 statistically significantly inhibited the growth of OPM2-Luc tumors at doses of 20, 30, and 60 mg / kg (p<0.001 compared to the vehicle control group) (Figure 4). The 20 mg / kg group showed a 63% TGI (p<0.001 compared to the vehicle control group). The 30 and 60 mg / kg groups showed statistically significant tumor regression compared to the vehicle control group (50% regression and 100% regression, respectively; p<0.001 and p<0.0001, respectively). Three out of 10 animals in the 30 mg / kg group and all 10 out of 10 animals in the 60 mg / kg group were tumor-free on day 24. There was no evidence of AMG176-related changes in body weight and physical score assessments; however, it should be noted that AMG176 is less potent against mouse MCL1 than against human MCL1.

[0076] In a separate study, the ability of AMG176 to inhibit tumor growth was tested in OPM2-Luc multiple myeloma xenograft models using various intermittent dosing schedules. OPM2-Luc cells (5 × 10⁶ 6 The tumor was implanted subcutaneously into female thymus-deficient nude mice. The tumor volume was approximately 150 mm². 3At the point when the target was reached, treatment was initiated on day 14 with oral supplementation once daily with a vehicle or a dose of 30 or 60 mg / kg (QD) in a 5-day dose / 2-day rest period (5x / week, QD5) or a 2-day dose / 5-day rest period (2x / week, QD2) (n=10 / group). Dose-dependent TGI was observed along with the total doses and schedules tested (Figure 5). At the 30 mg / kg dose, 84% of TGI was observed with once-daily administration (p<0.001 compared to the vehicle control group), 85% of TGI was observed with a 5-day dose / 2-day rest period (p<0.001), and 54% of TGI was observed with a 2-day dose / 5-day rest period (p<0.001). At a dose of 60 mg / kg, 100% tumor regression was observed with once-daily administration, 87% with 5 days of treatment / 2 days of rest, and 21% with 2 days of treatment / 5 days of rest (p<0.001). Six out of 10 animals in the 5-day treatment / 2-day rest group at 60 mg / kg and all 10 animals in the once-daily administration group were tumor-free on day 26. No evidence of overt toxicity was observed in the AMG176 treatment groups, as determined by changes in body weight and physical score assessments; however, as mentioned above, AMG176 is less potent against mouse MCL1 than against human MCL1.

[0077] The effect of once-weekly administration of AMG176 on tumor growth in OPM2-Luc xenografts in female thymus-deficient nude mice. The ability of AMG176 to inhibit tumor growth in an OPM2 multiple myeloma xenograft model was tested using a once-weekly administration schedule. Female thymus-deficient nude mice were given 5 × 10⁶ doses. 6 Human OPM2-Luc multiple myeloma tumor cells were subcutaneously injected. The average tumor volume was 120-206 mm². 3Treatment was initiated on day 15 using a vehicle or weekly oral doses of 50 or 100 mg / kg and weekly intraperitoneal administration of 50 mg / kg. Tumor volume and body weight were measured twice weekly until day 26. AMG176 significantly inhibited the growth of OPM2-Luc tumors. In the 50 mg / kg oral group, a 97% TGI (p<0.0001) was observed; in the 100 mg / kg group, a 70% regression was observed (p<0.0001). In the 50 mg / kg intraperitoneal administration group, a 98% regression was observed (p<0.0001) (Figure 6). Five out of ten animals in the 100 mg / kg group were tumor-free on day 26. No evidence of apparent toxicity was observed in the AMG176 treatment groups, as determined by changes in body weight.

[0078] In vivo activity of AMG176 in a MOLM13-Luc orthotopic model of acute myeloid leukemia in female NSG mice AMG176 was evaluated to investigate its ability to inhibit the growth of orthotopic Molm13-Luc tumors established in female NOD / SCID IL2rg (NSG) mice. On day 0, 70 female NSG mice were given 5 × 10⁶ doses. 4 Human Molm13-Luc AML tumor cells were intravenously injected. After randomization to four groups (n=10 / group), oral treatment with AMG176 initiated on day 7 resulted in significant TGI of orthotopic Molm13-Lu tumors. In the QD2 treatment schedule, 30 mg / kg of AMG176 resulted in a 28% TGI compared to the vehicle control group (p<0.0001), and 60 mg / kg of AMG176 resulted in a 69% TGI (p<0.0001); treatment with AMG176 at 100 mg / kg QD resulted in an 86% TGI (p<0.0001) (Figure 7). No evidence of apparent toxicity was observed in the AMG176 treatment groups, as determined by changes in body weight.

[0079] In vivo activity of AMG176 + carfilzomib in an orthotopic model of OPM2-Luc multiple myeloma AMG176 previously demonstrated the ability to induce statistically significant TGI as a monotherapy in an OPM2-Luc multiple myeloma model. This study investigated the potential of the combination of AMG176 and carfilzomib to inhibit tumor growth in an OPM2-Luc orthotopic model. On day 0, female NSG mice were transfected with the firefly luciferase gene (1 × 10⁶). 6 Human OPM2-Luc multiple myeloma tumor cells were intravenously injected with OPM2-Luc. After randomization to four groups (n=10 / group), mice were treated orally once daily with either a vehicle or AMG176 at 20 mg / kg, and intravenously with either a vehicle or carfilzomib at 3 mg / kg twice weekly from day 4 to day 20. In mice treated once daily with AMG176 (20 mg / kg) and twice weekly with carfilzomib (3 mg / kg), this combination achieved a statistically significant inhibition of tumor tissue volume (99% TGI compared to carfilzomib alone, p<0.0001), surpassing the effects achieved with either monotherapy (86% and 82% TGI with AMG176 or carfilzomib, respectively) (Figure 8). Unexpected deaths were observed in both the carfilzomib monotherapy and combination therapy groups, indicating a lack of tolerability of IV carfilzomib in NSG mice.

[0080] Non-clinical trials - pharmacokinetics The pharmacokinetics (PK) of the compound of formula I after single intravenous (IV) or oral administration were characterized in male CD1 mice, female thymus-deficient nude mice, male Nu / Nu mice, male Sprague Dawley rats, male beagle dogs, and male cynomolgus monkeys. The clearance (CL) of this compound was lower in mice, rats, dogs, and monkeys compared to their hepatic blood flow. The steady-state volume of distribution (V) in mice, rats, dogs, and monkeys was also determined. ss ) was variable across species. The mean peripheral discharge half-life (t) in mice, rats, dogs and monkeys. 1 / 2,zThe values ​​were 13.8, 19.5, 10.8, and 1.66 hours, respectively. The compound of formula I was highly plasma-protein bound in vitro and did not preferentially disperse in blood cells.

[0081] Non-clinical trials - toxicology Nonclinical safety studies for the compound of formula I consisted of a preliminary 14-day canine IV toxicology study, a Good Laboratory Practice (GLP) 28-day rat and canine IV toxicology study, and an in vitro preliminary genotoxicity study (GLP human delayed-rectifying potassium ion channel gene (hERG) and non-GLP isolated rabbit heart) to characterize potential cardiovascular effects. The doses selected for the 28-day IV rat and canine toxicology study were intended to characterize the toxicity of the compound of formula I and provide data supporting the starting dose in the human first-in-heart (FIH) study. The IV administration route and the 2-day dosing / 5-day rest schedule were used to support the expected clinical route and dosing schedule. In the 28-day GLP rat IV injection toxicology study, a highly toxic dose (STD) was observed in 10% of the animals. 10 The effective dose was 60 mg / kg based on mortality in a 120 mg / kg study, and in a 28-day GLP IV toxicology study in dogs, the maximum dose without serious toxicity (HNSTD) was 10 mg / kg based on mortality at 20 mg / kg. In both rats and dogs, morbidity and mortality were associated with mucosal epithelial degeneration in the small and large intestines. The compound of formula I was neither mutagenic nor chromosomal aberration-inducing in in vitro genotoxicity studies. The compound was also not phototoxic in in vivo phototoxicity studies. In a vehicle containing hydroxypropyl-β-cyclodextrin, the compound of formula I exhibited hemolysis (in vitro) in rat blood at concentrations of 0.048, 0.12, 0.24, 1.2, and 2.4 mg / mL and in dog blood at concentrations of 0.1 and 1.0 mg / mL, but was not hemolytic in human blood at the highest concentration tested, 0.25 mg / mL.

[0082] Effect in humans The compound of formula I has been investigated and has been investigated in a Phase 1 FIH multi-center joint non-randomized open-label dose-escalation study in subjects with relapsed / refractory multiple myeloma and subjects with relapsed / refractory acute myeloid leukemia. Preliminary data were available for 32 subjects with multiple myeloma and 10 subjects with AML.

[0083] Multiple myeloma A total of 32 subjects were enrolled and received at least 1 dose of the compound of formula I: 26 subjects in Part 1a (once daily for 2 consecutive days followed by a 5-day drug holiday [QD2]) and 6 subjects in Part 1b (once weekly [QW]). In Part 1a, subjects were enrolled across 8 cohorts with dose ranges of 30 - 240 mg / m 2 [QD2]. In Part 1b, subjects were enrolled across 2 cohorts with dose ranges of 120 / 180 mg / m 2 or ~120 / 240 mg / m 2 .

[0084] Preliminary PK data were available from 25 subjects in Part 1a and 6 subjects in Part 1b. The exposure of AMG176 (maximum observed drug concentration [C max ) and area under the concentration-time curve [AUC]) generally increased with increasing dose across the tested dose range.

[0085] In Part 1a, adverse events during treatment were reported in 25 subjects (96%); the most frequently reported events (≥20% of subjects) were nausea (35%), neutropenia and diarrhea (31% each), and fatigue and anemia (27% each). Grade 3 adverse events occurred in 17 subjects (65%), and grade 4 adverse events occurred in 8 subjects (31%); grade 3 or higher adverse events reported in two or more subjects were neutropenia (31%), anemia (15%), and leukopenia, hypertension and neutropenia (8% each). Serious adverse events were reported in 8 subjects (31%); however, by preferred terminology, no serious adverse events occurred in two or more subjects. There were no adverse events leading to discontinuation of the investigational drug. Two fatal adverse events occurred. The fatal event of hepatic failure occurred at 50 mg / m² 2 This event occurred in subjects within the cohort; it occurred during an exacerbation and was considered unrelated to AMG176 by the investigator. The fatal event of tumor lysis syndrome occurred at 240 mg / m². 2 This event occurred in one subject within the cohort; this was the only dose-limiting toxicity (DLT) that was considered by the investigator to be related to AMG176 and subsequently reported. Adverse events considered by the investigator to be related to AMG176 treatment were reported in 18 subjects (69%); by preferred terminology, the most frequently reported events (≥15% of subjects) were neutropenia (23%), nausea (23%), and diarrhea (19%).

[0086] In Part 1b, adverse events were reported in 5 subjects (83%); the most frequently reported events (occurring in 2 or more subjects) were neutropenia (67%), nausea (50%), and diarrhea, fatigue, and hypertension (each 33%). Grade 3 adverse events occurred in 5 subjects (83%), and Grade 4 adverse events occurred in 1 subject (17%); Grade 3 or higher adverse events reported in 2 or more subjects were neutropenia (67%) and hypertension (33%). Serious adverse events were not reported, there were no adverse events that led to discontinuation of the investigational drug, and no fatal adverse events occurred. Adverse events considered by the study physicians to be related to AMG176 treatment were reported in 5 subjects (83%); by preferred terms, the most frequently reported events (≥30%) were

[0087] acute myeloid leukemia In Part 3, a total of 10 subjects were enrolled across 2 cohorts, and the doses were 60 mg / m 2 or ~120 mg / m 2 respectively.

[0088] Preliminary PK data were available from 10 subjects with AML. The exposure (C max and AUC) of AMG176 generally increased with increasing dose across the tested dose range.

[0089] Adverse events were reported in 8 subjects (80%); the most frequently reported events (occurring in 2 or more subjects) were hypokalemia, peripheral edema, and nausea (30% each), and elevated blood bilirubin levels, hypomagnesemia, anemia, fever, and vomiting (20% each). Grade 3 adverse events occurred in 7 subjects (70%), and grade 4 adverse events occurred in 2 subjects (20%); the most common grade 3 or higher adverse event reported in 2 or more subjects in both linked cohorts was anemia (20%). Serious adverse events were reported in 6 subjects (60%); no serious adverse events occurred in 2 or more subjects according to basic terminology. Adverse events led to discontinuation of the investigational drug in 2 subjects (20%); superior vena cava syndrome and febrile neutropenia were reported in 10% of subjects according to basic terminology. No fatal adverse events occurred. Adverse events considered by the investigators to be related to AMG176 treatment were reported in 4 subjects (40%); by preferred terminology, the most frequently reported events (occurring in 2 or more subjects) were nausea (20%) and elevated blood bilirubin levels (20%).

[0090] Logical justification for conducting clinical trials using AMG176 Apoptosis is a well-established survival mechanism used by numerous types of cancer cells (Fouad and Aanei, Am J Can Res 7:1016-1036 (2017); Hanahan and Weinberg, Vell 144:646-674 (2011)). Malignant transformation induces cellular stress from various pro-apoptotic episodes, giving tumors a strong selective advantage in evolving mechanisms that ultimately lead to apoptosis avoidance, including hypoxia and gain-of-function mutations in oncogenes.

[0091] Apoptosis is regulated by a complex network of protein-protein interactions between pro-apoptotic and anti-apoptotic subgroups that form the BCL2 protein family (Czabotar et al, 2014; Strasser et al, 2011; Kozopas et al, 1993). Myelocyte leukemia 1 is a member of this family that promotes cell survival. In contrast, pro-apoptotic family members such as BAK and BAX, which are mitochondrial pore-forming factors, or BH3-only protein family members such as BIM and PUMA, are crucial effectors for inducing apoptosis. When apoptotic stimulation is induced, pro-apoptotic BH3-only proteins bind to MCL1 and other pro-survival BCL2 family members, disrupting the interaction between MCL1 and the pro-apoptotic effector proteins BAK and BAX. This disruption leads to activation and oligomerization of BAK and BAX; MOMP; release of cytochrome C; caspase activation; and cell death (Czabotar et al (2014); Strasser et al (2011)). Myelocyte leukemia 1 is expressed in a range of human and mouse tissues. In mice, for example, conditional gene knockout studies have demonstrated that MCL1 is important for the survival of numerous cell types, including lymphocytes, hematopoietic stem cells, neutrophils, and cardiomyocytes (Thomas et al, 2013; Wang et al, 2013; Strasser et al, 2011).

[0092] MCL1 overexpression has been associated with the development of numerous solid tumors and human hematopoietic malignancies (Ashkenazi et al 2017; Merino et al 2017; Kotschy et al 2016; Glaser et al 2012), as well as resistance to chemotherapy and BCL2 / BCL-XL inhibitors (Wertz et al, Nature 471:119-114 (2011); van Delft et al, Cancer Cell 10:389-399 (2006)). Localized amplification of the MCL1 gene has been observed in up to 10% of cancers originating from multiple histological types, including lung and breast cancer (Beroukhim et al, Nature 463:899-905 (2010)). These findings suggest that inhibition of MCL1 represents a novel and compelling therapeutic strategy for cancer treatment.

[0093] AMG176 is a small molecule potent and selective inhibitor of protein-protein interactions between MCL1 and pro-apoptotic members of the BCL2 family, developed with the intention of treating patients with hematological malignancies, including multiple myeloma and AML. In vitro, AMG176 induced dose-dependent inhibition of the interaction between MCL1 and the pro-apoptotic effector protein BAK, and treatment with AMG176 resulted in rapid induction of apoptosis in hematological cancer cell lines. In vivo, treatment with AMG176 significantly inhibited the growth of xenograft models of multiple myeloma and AML tumors.

[0094] All human trials were conducted in accordance with the guidelines of the appropriate regulatory bodies.

[0095] Pharmaceutical preparations The compound of formula I (AMG176) used is an anhydrous crystalline material, a white to light brown powder. The compound of formula I is prepared as a sterile concentrate for injection. This concentrate is diluted in an IV bag containing physiological saline (0.9% sodium chloride (9 g / L)) and then administered intravenously.

[0096] Dosage form AMG176 can be synthesized using the procedures specified in International Publication No. 2016 / 033486 and U.S. Patent No. 9,562,061. AMG176 was prepared as a sterile concentrate for injection solution at a concentration of 25 mg / mL with 10 wt / w% hydroxypropyl-β-cyclodextrin (HPβCD) (high molar substitution grade Cavitron® W7 HP7 PHARMA (commercially available from Ashland Inc. (Covington, KY)) and buffered to pH 9 with 100 mM glycine (commercially available from Sigma Aldrich (St. Louis, MO) and EMD Millipore (Burlington, MA)). Thus, AMG176 was supplied as a sterile, preservative-free solution for IV injection in a disposable vial containing 10 mL of 25 mg / mL of AMG176. Disposable vials containing 14.4 mL of 25 mg / mL of AMG176 were also prepared and found to be useful.

[0097] For a 10 mL concentrated solution, the primary container closure system was a 20 mL borosilicate glass vial with an aluminum seal, a 20 mm elastomer stopper, and a flip-off dust cover. For a 14.4 mL concentrated solution, a 30R borosilicate glass vial with an aluminum seal, a 20 mm elastomer stopper, and a flip-off dust cover was used.

[0098] The AMG176 sterile concentrate vial was prepared by a solution formulation and sterile filling process. First, approximately 70% to 75% by weight of water for injection (WFI) of the total batch weight was loaded into the formulation container. Next, mixing was started, and HPβCD was loaded into the container and mixed until the cyclodextrin was dissolved. Next, sodium hydroxide was added to the container and the resulting mixture was mixed until the NaOH was dissolved. The resulting mixture was then heated to 45°C. AMG176 was then added to the container while maintaining the temperature at 45°C and the resulting mixture was mixed until the AMG176 was dissolved. The resulting solution was cooled to 25°C, and then glycine was added to the container. The resulting mixture was mixed until all the glycine was dissolved. Hydrochloric acid (1M) was gradually added to the container while mixing until the pH of the solution reached 9.1. The container was then filled to a sufficient (QS) level with WFI to approximately 95% of the total batch weight. The pH of the solution was measured, and if necessary, 1M HCl was added until the target pH of 9.1 was achieved. Next, WFI was added in sufficient quantities to provide 100% of the total batch weight. Then the pH and concentration of AMG176 were determined. Filtration of the bulk drug product was performed using a 0.2 μm polyethersulfone (PES) filter, transferring the contents from the compounding container to the appropriate holding container. Integrity testing before and after filtration was performed on the filtration device. The holding container was kept closed at a temperature below 30°C until sterile filtration and filling were initiated. Next, the sample solution was filtered through a single in-line PES 0.2 μM sterile filter into a second sterile container, and then filling and filter integrity testing was performed before and after filtration. Next, vials were filled to the target volume using the filtered mixture, then the vials were capped, the filling weight was checked, and then they were sealed. The sealed vials were stored below 25°C and protected from light. Next, a visual inspection was performed, and the vials were pulled for specification testing.

[0099] Adult patients with relapsed or refractory AML received intravenous AMG176 (infused over at least 2 hours) on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle as part of a dose escalation study. The dose escalation was 60 mg / m². 2 It started with 180 mg / m². 2For the above dose levels, 120 mg / m² 2 The lead-in dose was implanted during week 1. The primary objectives included safety, tolerability, and pharmacokinetic evaluation. A secondary objective was a preliminary evaluation of efficacy, assessed using the ELN criteria. The preliminary endpoint included pharmacodynamic evaluation of MCL-1 inhibition within circulating AML blasts.

[0100] On the data cutoff date (May 17, 2019), 11 patients (median age [range] = 74 [36-81] years) received AMG176 (60 mg / m²). 2 n=5; 120 mg / m² 2 n=5; 180 mg / m² 2 Patients received median (range) 2 (1-5) prior therapies, and 7 patients had received prior venetoclax. Patients were treated with AMG176 for median (range) 1 (1-6) cycles. Ten out of 11 patients discontinued treatment. The reasons for discontinuation were disease progression (n=5), adverse events (n=3), and patient request (n=2). Triadically adverse events (TEAEs) of any grade occurred in 10 patients (91%), and TEAEs of grade ≥3 occurred in 8 patients (73%) (Table 3). Common TEAEs of any grade (occurring in ≥3 patients) were peripheral edema (n=4, 36%) and nausea (n=4, 36%). The most common grade ≥3 TEAE (occurring in ≥2 patients) was nausea (n=2, 18%). Treatment-related AEs occurred in 5 patients (46%); treatment-related AEs of grade ≥3 occurred in 2 patients (18%). No fatal adverse events were reported.

[0101] The peak plasma concentration of AMG176 was observed, as expected, near the end of intravenous infusion, and AMG176 plasma exposure increased in a dose-dependent manner. Four out of eleven patients had post-baseline response assessments at the data cutoff, with the best overall response being incomplete hematological recovery (CRi; n=1, 60 mg / m²). 2 Complete remission with dose (n=1, 60 mg / m²) or partial remission (n=1, 60 mg / m²)2 The dose was stable (n=2). In patients who achieved CRi, evidence of pharmacodynamic impact was observed through the release of the pro-apoptotic protein Bax and activation of effector caspase 3 in peripheral blood AML blasts 3 hours after infusion. At the data cutoff date, the maximum tolerable dose of AMG176 had not yet been reached.

[0102] At the evaluated dose levels, AMG176 administered as monotherapy exhibits an acceptable safety, tolerability, and pharmacokinetic profile. Preliminary evidence of intended pro-apoptotic activity has been observed in vivo, and clinical efficacy has been observed in two patients to date. Detailed safety and efficacy studies of AMG176 in patients with AML are currently underway.

[0103] [Table 3]

[0104] All publications and patent applications cited herein are incorporated herein by reference in whole for all purposes, as if each individual publication or patent application were specifically and individually incorporated by reference, and as if each reference were fully contained within it. The above invention has been described in some detail by illustrations and examples for the purpose of clarifying the understanding, but it will be readily apparent to those skilled in the art that certain changes and modifications can be made thereto without departing from the scope of the appended claims in light of the teachings of the invention.

Claims

1. A pharmaceutical preparation for intravenous administration for use in the treatment of hematological malignancies, wherein the preparation is: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: 【Chemistry 1】 The compound of formula I having or the salt thereof; b) Cyclodextrin compounds; c) Buffering agent; and d) Contains water, The concentration of the compound of formula I or its salt in the formulation is in the range of 20 mg / mL to 30 mg / mL, and the pH of the formulation is in the range of 8.7 to 9.

8. The cyclodextrin compound is hydroxypropyl-β-cyclodextrin, and the amount of the cyclodextrin compound in the formulation is in the range of 7.5 to 13% by weight, and A pharmaceutical preparation in which the buffer is glycine and the concentration of the glycine is in the range of 80 mM to 120 mM.

2. The pharmaceutical formulation according to claim 1, wherein the pH of the formulation is in the range of 8.9 to 9.

2.

3. The pharmaceutical preparation according to claim 1, wherein the concentration of the compound of formula I or the salt thereof in the preparation is in the range of 24 to 26 mg / mL.

4. The pharmaceutical preparation according to claim 1, wherein the amount of the cyclodextrin compound in the preparation is in the range of 9 to 11% by weight.

5. The pharmaceutical formulation according to claim 1, wherein the formulation is buffered with glycine, and the buffer used to buffer the formulation contains glycine in a concentration ranging from 95 mM to 105 mM.

6. The pharmaceutical formulation according to claim 1, wherein the volume of the formulation is in the range of 5 mL to 25 mL.

7. The pharmaceutical preparation according to claim 6, wherein the volume of the preparation is in the range of 9 mL to 15 mL.

8. The pharmaceutical preparation according to claim 7, wherein the volume of the preparation is in the range of 14 mL to 15 mL.

9. The pharmaceutical formulation according to claim 1, wherein the formulation is an aqueous formulation comprising 20 mg / mL to 30 mg / mL of the compound of formula I and 8% to 12% by weight of hydroxypropyl-β-cyclodextrin, and is buffered to a pH of 8.8 to 9.2 with 90 mM to 110 mM glycine.

10. The pharmaceutical formulation according to claim 1, wherein the formulation is an aqueous formulation comprising 25 mg / mL of the compound of formula I and 10% by weight of hydroxypropyl-β-cyclodextrin buffered to pH 9 with 100 mM glycine.

11. The pharmaceutical formulation according to claim 9, wherein the volume of the formulation is in the range of 9 mL to 15 mL.

12. The pharmaceutical preparation according to claim 9, wherein the preparation is contained in a vial.

13. The pharmaceutical formulation according to claim 12, wherein the vial is a 20 mL borosilicate glass vial or a 20 mL aluminosilicate glass vial, and the vial is equipped with a stopper and an aluminum seal with a flip-off cover.

14. A therapeutic aqueous solution for intravenous administration for use in the treatment of hematological malignancies, wherein the solution comprises: a) A compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: 【Chemistry 2】 The compound of formula I having or the salt thereof; b) Cyclodextrin compounds; c) Buffering agent; d) Sodium chloride; and e) Contains water, The amount of the compound of formula I or the salt of the compound of formula I in the solution is in the range of 200 mg to 360 mg. The cyclodextrin compound is hydroxypropyl-β-cyclodextrin, and An aqueous solution in which the buffering agent is glycine.

15. The solution is the aqueous solution according to claim 14, contained in an IV bag.

16. A method for preparing an aqueous solution suitable for intravenous injection into a patient, comprising the step of mixing the pharmaceutical preparation according to claim 1 with physiological saline.

17. The method according to claim 16, wherein the physiological saline contains sodium chloride in an amount ranging from 8 g / L to 10 g / L before the step of mixing the pharmaceutical preparation with the physiological saline.

18. A therapeutic aqueous solution for intravenous administration, for use in the treatment of hematological malignancies, The solution contains a compound of formula I or a salt thereof, wherein the compound of formula I has the following structure: 【Transformation 3】 It has, The compound of formula I or the salt of the compound of formula I is 25 mg / m³ ２ ~250 mg / m² ２ This is a dosage that falls within a certain range. The aqueous solution further comprises a cyclodextrin compound and a buffering agent. The cyclodextrin compound is hydroxypropyl-β-cyclodextrin, An aqueous solution in which the buffering agent is glycine.

19. The compound of formula I or the salt of the compound of formula I may be 60 mg / m³ ２ ~180 mg / m² ２ The aqueous solution according to claim 18, wherein the dose is within the range of the specified range.

20. The aqueous solution according to claim 18, wherein the aqueous solution containing the compound of formula I or the salt of the compound of formula I further contains sodium chloride.

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