Pharmaceutical Compositions Comprising (S)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione and Methods of Use Thereof

Abstract

Provided herein are pharmaceutical compositions (e.g., oral dosage formulations) comprising (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitution, or pharmaceutically acceptable salt thereof, and a carrier or diluent. Also provided herein are methods of making and using the pharmaceutical compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 923,927, filed October 21, 2019, which is hereby incorporated by reference in its entirety. [Technical field]

[0002] 1.Technical Field Provided herein is a pharmaceutical composition (the present composition) comprising (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopically substituted or a pharma- ceutically acceptable salt thereof, and a carrier or diluent. Methods of using the pharmaceutical composition for the treatment, prevention and management of various disorders are also provided herein. [Background technology]

[0003] 2.Background technology Cancer is primarily characterized by an increase in the number of abnormal cells arising from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or hematogenous spread and metastasis of malignant cells to regional lymph nodes. Clinical data and molecular biological studies have shown that cancer is a multi-step process that begins with minor preneoplastic changes and may progress to neoplasia under certain conditions. In particular, under circumstances in which tumor cells escape the host's immune surveillance mechanisms, tumor lesions may undergo clonal evolution and develop increased capacities for invasion, growth, metastasis, and heterogeneity. Current cancer treatments include surgery, chemotherapy, hormonal therapy, and / or radiation therapy, which are capable of eradicating tumor cells in patients. Recent advances in cancer treatment are discussed in Rajkumar et al. in Nature Reviews Clinical Oncology 11, 628-630 (2014).

[0004] All current cancer treatment approaches have significant drawbacks for the patient. For example, surgery may be contraindicated for the patient's health or may be unacceptable to the patient. Furthermore, surgery may not completely remove the new tissue. Radiation therapy is effective only if the tumor tissue is more sensitive to radiation than normal tissue. Radiation therapy often causes severe side effects. Hormonal therapy is rarely administered as a single agent. Although hormonal therapy is effective, it is often used to prevent or delay the recurrence of cancer after other treatments have removed the majority of the cancer cells.

[0005] Despite the availability of a wide variety of chemotherapy agents, chemotherapy has many drawbacks. Almost all chemotherapy agents are toxic, and chemotherapy often causes severe and dangerous side effects (e.g., severe nausea, bone marrow suppression, and immunosuppression). Furthermore, many tumor cells become resistant or resistant to chemotherapy agents, even when administered in combination. In fact, cells that are resistant to a particular chemotherapy agent used in a treatment protocol often also become resistant to other agents, even if the other agents act by a different mechanism than the agent used in the particular treatment. This phenomenon is called multidrug resistance. Such drug resistance causes many cancers to become resistant or refractory to standard chemotherapy treatment protocols.

[0006] Hematological malignancies are cancers that start in hematopoietic tissues such as bone marrow or immune system cells.Examples of hematological malignancies are leukemia, lymphoma and myeloma.More specific examples of hematological malignancies include, but are not limited to, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL) and myelodysplastic syndrome (MDS).

[0007] The variety of possible pharmaceutical compositions (e.g., oral dosage forms containing various excipients) creates a diversity in the physical and chemical properties of the pharmaceutical compounds of interest. The discovery and selection of pharmaceutical compositions is of great importance in the development of effective, stable, and marketable pharmaceutical products.

[0008] 3. Abstract The present specification relates to Compound 1: [ka] A pharmaceutical composition (e.g., an oral dosage formulation) is provided, comprising: Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, and a carrier or diluent. Compound 1 has the compound name: (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. Also provided herein is a method for preparing said pharmaceutical composition. Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, is collectively referred to as "Compound A".

[0009] In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, or a mixture thereof. In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, a mixture of mannitol and cellulose, or a mixture of mannitol and starch. In one embodiment, the carrier or diluent is a mixture of mannitol and starch. In some embodiments, the term "carrier" or "diluent" is used interchangeably with the term "binder."

[0010] The pharmaceutical compositions provided herein are useful formulations for use in animals or humans.Thus, embodiments of the present invention encompass the use of these pharmaceutical compositions as final pharmaceutical products.Certain embodiments provide pharmaceutical compositions useful in producing final dosage forms with improved properties required for the manufacture, processing, formulation and / or storage of final pharmaceutical products, such as powder flow properties, compression properties, tableting properties, stability properties and excipient compatibility.

[0011] Also provided is a pharmaceutical composition that contains an effective concentration of Compound A (e.g., Compound 1) provided herein and is formulated for administration by a suitable route and means. In one embodiment, the pharmaceutical composition is an oral dosage formulation. In one embodiment, the pharmaceutical composition is an oral dosage formulation for immediate release (IR).

[0012] In one embodiment, the pharmaceutical composition delivers an amount effective for the treatment of a hematological malignancy. In one embodiment, the pharmaceutical composition delivers an amount effective for the prevention of a hematological malignancy. In one embodiment, the pharmaceutical composition delivers an amount effective for the amelioration of a hematological malignancy.

[0013] In one embodiment, the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL) or myelodysplastic syndrome (MDS).

[0014] In one embodiment, the pharmaceutical composition delivers an amount effective for treating non-Hodgkin's lymphoma. In one embodiment, the pharmaceutical composition delivers an amount effective for preventing non-Hodgkin's lymphoma. In one embodiment, the pharmaceutical composition delivers an amount effective for ameliorating non-Hodgkin's lymphoma.

[0015] Also provided herein is a method of using the pharmaceutical composition provided herein, alone or in combination with rituximab, for treating, preventing or managing non-Hodgkin's lymphoma (NHL). In one embodiment, the method is for treating NHL. In one embodiment, the method is for preventing NHL. In one embodiment, the method is for managing NHL.

[0016] In certain embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) or primary central nervous system lymphoma (PCNSL).

[0017] Also provided herein is a method of using the pharmaceutical composition provided herein, alone or in combination with obinutuzumab, for treating, preventing or managing chronic lymphocytic leukemia (CLL).In one embodiment, the method is for treating CLL.In one embodiment, the method is for preventing CLL.In one embodiment, the method is for managing CLL.

[0018] Also provided herein is a method of using the pharmaceutical composition provided herein, alone or in combination with obinutuzumab, for treating, preventing or managing small lymphocytic lymphoma (SLL). In one embodiment, the method is for treating SLL. In one embodiment, the method is for preventing SLL. In one embodiment, the method is for managing SLL.

[0019] Provided herein is a pharmaceutical composition for use in a method of treating a disease as described herein, the method comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition.

[0020] Further provided are pharmaceutical packs or kits comprising one or more containers holding one or more of the components of the pharmaceutical compositions. The containers may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, which notice may represent approval by the government agency for the manufacture, use, or sale for administration to humans. The packs or kits may be labeled with information regarding the mode of administration, the order in which the agents are to be administered (e.g., separately, sequentially, or simultaneously), and the like.

[0021] Further provided are methods for producing the pharmaceutical compositions provided herein.

[0022] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. [Brief description of the drawings]

[0023] [Figure 1] Figures 1A, 1B and 1C show the chemical stability (total impurities) for the prototype formulations up to 12 weeks at 40°C / 75% RH without desiccant, 40°C / 75% RH with desiccant and 50°C / 75% RH with desiccant, respectively. [Diagram 2] Figures 2A, 2B, and 2C show chiral stability data for the prototype formulations up to 12 weeks at 40°C / 75% RH without desiccant, 40°C / 75% RH with desiccant, and 50°C / 75% RH with desiccant, respectively. [Diagram 3] FIG. 3 provides a process map for the wet granulation process. [Figure 4] FIG. 4 provides a process map for the RC method. [Diagram 5] FIG. 5 shows the dissolution profiles of the roller compacted batch (Cap-5) and the high shear wet granulation batch (Cap-10). [Figure 6] FIG. 6 shows the roller compaction process map for a batch of Cap-5 formulation. [Figure 7]FIG. 7 shows a representative XRPD pattern of Form A of Compound 1 hydrochloride. Detailed Description of the Invention

[0024] 5. Detailed Description of the Invention 5.1.Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the present specification, if there are multiple definitions of a term, the definition in this section shall prevail unless otherwise specified.

[0025] As used in this specification and the claims appended hereto, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless the context clearly dictates otherwise.

[0026] As used herein, the terms "comprise" and "comprise" can be used interchangeably. The terms "comprise" and "comprise" are intended to specify the presence of the features or components described as referenced, but do not exclude the presence or addition of one or more features or components, or groups thereof. Furthermore, the terms "comprise" and "comprise" are intended to include examples encompassed by the term "consisting of". As a result, the term "consisting of" can be used in place of the terms "comprise" and "comprise" to provide more specific embodiments of the present invention.

[0027] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98% or 99% of the recited features or components which they comprise. In another embodiment, the term "consisting of" excludes from the scope of any succeeding description any other feature or component, excepting those that are not essential to the technical effect to be achieved.

[0028] As used herein, the term "or" is to be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C." Exceptions to this definition occur only when combinations of elements, features, steps or acts are inherently mutually exclusive in some way.

[0029] As used herein, and unless otherwise indicated, the terms "about" and "approximately" when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that is recognized by those of skill in the art to provide a pharmacological effect equivalent to that obtained from the given dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately" when used in this context contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of the given dose, amount, or weight percentage.

[0030] As used herein, and unless otherwise indicated, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​given to characterize a particular solid form (e.g., a particular temperature or temperature range, such as describing melting, dehydration, desolvation, or glass transition temperature; mass change, e.g., mass change as a function of temperature or humidity; solvent or water content, e.g., content expressed by mass or percent; or peak position, e.g., in an analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​still describes the particular solid form, but may deviate to an extent that would be considered reasonable by a person skilled in the art. For example, in certain embodiments, the terms "about" and "and," when used in this context, indicate that the numerical value or range of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 2%, 1%, 0.5%, or 0.25% of the stated numerical value or range of values. For example, in some embodiments, values ​​of XRPD peak positions are descriptive of particular XRPD peaks, but may vary by up to ±0.2 degrees 2θ. As used herein, a tilde (i.e., "~") before a numerical value or range of values ​​indicates "about" or "approximately."

[0031] Unless otherwise stated, the terms "X-ray powder diffraction," "X-ray powder diffraction," "PXRD," and "XRPD" are used interchangeably herein.

[0032] As used herein, and unless otherwise specified, the term "solid form" and related terms refer to a physical form that is not predominantly in a liquid or gaseous state. As used herein, the term "solid form" includes semi-solids. A solid form may be crystalline, amorphous, partially crystalline, partially amorphous, or a mixture of multiple forms.

[0033] As used herein, and unless otherwise specified, "crystalline" and related terms, when used to describe a substance, component, product, or form, means that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23 rd See, for example, the American Journal of Physics, Vol. 1, No. 1, 1843-1844 (1995).

[0034] As used herein, and unless otherwise indicated, "amorphous," "amorphous form," and related terms as used herein mean that a given substance, component, or product is substantially not crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" refers to a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other amorphous and / or crystalline forms. In certain embodiments, an amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, the amorphous form of the substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physical and / or chemical purity. In certain embodiments, the amorphous form of the substance may include additional components or constituents (e.g., additives, polymers or excipients that may function to further stabilize the amorphous form). In certain embodiments, the amorphous form may be a solid solution.

[0035] As used herein, and unless otherwise stated, the term "pharmaceutical acceptable salts" refers to salts made from pharmaceutical acceptable relatively non-toxic acids, including inorganic and organic acids. In certain embodiments, suitable acids include acetic acid, adipic acid, 4-aminosalicylic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, carbonic acid, citric acid, cyclamic acid, dihydrogen phosphate, 2,5-dihydroxybenzoic acid (gentisic acid), 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, galactanoic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, Glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isobutyric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, monohydrogen carbonate, monohydrogen phosphate, monohydrogen sulfate, mucic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, pyroglutamic acid, salicylic acid, suberic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, and the like (see, e.g., SM Berge et al., J. Pharm. Sci., 66:1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and CG Wermuth, Eds., (2002), Wiley, Weinheim). In certain embodiments, suitable acids are strong acids (e.g., pKa less than about 1), including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, pyridinesulfonic acid or other substituted sulfonic acids. Also included are salts of relatively non-toxic compounds that exhibit acidity (e.g., amino acids such as aspartic acid) and other compounds (e.g., aspirin, ibuprofen, saccharin, etc.). Acid addition salts can be obtained by contacting a neutral compound with a sufficient amount of the desired acid, either neat or in a solvent.Salts can exist as solids, crystalline or amorphous, or as a mixture thereof. Salts can also exist in polymorphic forms.

[0036] Please note that if there is a discrepancy between a depicted structure and its structure name, the depicted structure takes precedence.

[0037] As used herein, and unless otherwise specified, the term "treat" means to alleviate all or part of a disorder, disease or condition or one or more symptoms associated with a disorder, disease or condition, to attenuate or halt the further progression or worsening of those symptoms, or to alleviate or eradicate the cause of the disorder, disease or condition.

[0038] As used herein, and unless otherwise specified, the term "prevent" means a method of delaying and / or preventing the onset, recurrence or spread of all or part of a disorder, disease or condition; a method of eliminating a subject from developing a disorder, disease or condition; or a method of reducing a subject's risk of developing a disorder, disease or condition.

[0039] As used herein, and unless otherwise specified, the term "managing" includes preventing recurrence in a patient suffering from a particular disease or disorder, increasing the amount of time a patient suffering from a disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0040] As used herein, and unless otherwise specified, the term "effective amount" in reference to a compound means an amount capable of treating, preventing or managing a disorder, disease or condition, or a symptom thereof.

[0041] As used herein, and unless otherwise indicated, the term "subject" or "patient" refers to animals, such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and includes, but is not limited to, animals, including, in one embodiment, mammals, and in another embodiment, humans.

[0042] As used herein, and unless otherwise indicated, the term "relapse" refers to a disorder, disease, or condition that has progressed after responding to treatment (e.g., achieving a complete response). Treatment can include one or more courses of treatment. In one embodiment, the disorder, disease, or condition has been previously treated with one or more courses of treatment. In another embodiment, the disorder, disease, or condition has been previously treated with one course of treatment, two courses of treatment, three courses of treatment, or four courses of treatment. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0043] In one embodiment, "relapsed" DLBCL may refer to DLBCL that has been previously treated with one or more lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with one line of therapy, two lines of therapy, three lines of therapy, or four lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with two or more lines of therapy.

[0044] In one embodiment, a "relapsed" FL may refer to a FL previously treated with one or more courses of treatment. In one embodiment, a relapsed FL is a FL previously treated with one course of treatment, two courses of treatment, three courses of treatment, or four courses of treatment. In one embodiment, a relapsed FL is a FL previously treated with two or more courses of treatment.

[0045] As used herein, and unless otherwise stated, the term "refractory" refers to a disorder, disease, or condition that has not responded to prior therapy, which may include one or more lines of therapy. In one embodiment, the disorder, disease, or condition has been previously treated with one line of therapy, two lines of therapy, three lines of therapy, or four lines of therapy. In one embodiment, the disorder, disease, or condition has been previously treated with two or more lines of therapy and has less than a complete response (CR) to a regimen, including the most recent systemic therapy. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0046] In one embodiment, "relapsed or refractory" CLL / SLL may refer to CLL / SLL that has been previously treated with one line of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with one line of therapy, two lines of therapy, three lines of therapy, or four lines of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with two or more lines of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, relapsed or refractory CLL / SLL is relapsed or refractory to a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0047] In the context of cancer, e.g., hematological malignancies, inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, delay of occurrence of primary or secondary tumors. Delay of occurrence of primary or secondary tumors, reduction of occurrence of primary or secondary tumors, delay or reduction of severity of secondary effects of disease, arrest of tumor growth and tumor regression, increase in time to progression (TTP), increase in progression-free survival (PFS), increase in overall survival (OS), etc. As used herein, OS refers to the time from the start of treatment to death from any cause. As used herein, TTP refers to the time from the start of treatment to tumor progression, TTP does not include death. In one embodiment, PFS refers to the time from the start of treatment to tumor progression or death. In one embodiment, PFS refers to the time from the first administration of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using Kaplan-Meier estimates. Progression-free survival (EFS) refers to the time from initiation of treatment to any failure of treatment, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment, overall response rate (ORR) refers to the % of patients who achieve a response. In one embodiment, ORR refers to the sum of the % of patients who achieve a complete response and a partial response. In one embodiment, ORR refers to the % of patients whose best response is >= partial response (PR). In one embodiment, duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one embodiment, DoR is the time from achieving a response >= partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from first documented response to first documented progressive disease or death. In one embodiment, DoR is the time from first documented response >= partial response (PR) to first documented progressive disease or death. In one embodiment, time to response (TTR) refers to the time from first administration of a compound to first documented response. In one embodiment, TTR refers to the time from the first administration of a compound to the first documented response >= partial response (PR). At the extreme, complete inhibition is referred to herein as prevention or chemoprevention.In this context, the term "prevention" includes either completely preventing the onset of a clinically evident stage of cancer or preventing the onset of a preclinically evident stage of cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or arresting or reversing the progression of premalignant cells to malignant cells. This also includes prophylactic treatment of subjects at risk of developing cancer.

[0048] In certain embodiments, treatment of NHL uses the International Workshop Criteria for Malignant Lymphoma (Cheson et al., J. Clin. Oncol., 2014, 32(27):3059-3068) and the Deauville Criteria for Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Scan Interpretation (Itti et al., Eur. J. Nucl. Med. Mol. Imaging, 2013, 40(9):1312-20; Meignan et al., Leuk Lymphoma, 2014, 55(1):31-37) (the "Lugano Criteria"), with the response and endpoint definitions set forth in Tables 1-3. [Table 1]

[0049] [Table 2] [Table 3] [Table 4]

[0050] In one embodiment, treatment response for CLL / SLL is determined according to the International Workshop on Chronic Lymphocytic Leukemia criteria (Hallek, M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood, 131(25), 2745-2760 (2018)) (Table 4). [Table 5]

[0051] In one embodiment, treatment response to CLL / SLL may be assessed by Eastern Cooperative Oncology Group (ECOG) performance status (Table 5). [Table 6]

[0052] In certain embodiments, stable or non-stable can be determined by methods known in the art, such as, for example, evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged, for example, with FDG-PET (fluorodeoxyglucose positron emission tomography), PET / CT (positron emission tomography / computed tomography) scans, MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmic examination, vitreous fluid sampling, retinal photography, bone marrow evaluation and other commonly recognized modalities of evaluation.

[0053] As used herein, and unless otherwise specified, the terms "co-administration" and "combination" include any simultaneous, concurrent, or sequential administration of one or more therapeutic agents (e.g., a compound provided herein and another anti-cancer or supportive care agent) without time limitations. In one embodiment, the agents are present in a cell or in a patient's body at the same time or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form.

[0054] The term "supportive care agent" refers to any substance that treats, prevents, or manages side effects from treatment with another therapeutic agent.

[0055] 5.2. Pharmaceutical Compositions Containing Compound 1 In certain embodiments, provided herein is Compound 1: [ka] or a pharmaceutical composition (e.g., an oral dosage form) comprising an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, and a carrier or diluent. Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, is also collectively referred to as "Compound A."

[0056] In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose or a mixture thereof. In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, a mixture of mannitol and cellulose or a mixture of mannitol and starch. In one embodiment, the carrier or diluent is a mixture of mannitol and starch. In some embodiments, the term "carrier" is used interchangeably with the term "binder."

[0057] In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration to a patient. In one embodiment, the pharmaceutical compositions provided herein exhibit advantageous physical and / or pharmacological properties. Such properties include, but are not limited to, ease of assay, uniformity of ingredients, flow properties for manufacture, dissolution and bioavailability and stability. In one embodiment, the pharmaceutical compositions provided herein have a shelf life of at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months without refrigeration. In certain embodiments, "without refrigeration" refers to a temperature of 20° C. or higher. In one embodiment, the pharmaceutical compositions provided herein are stored under refrigerated conditions. In one embodiment, the pharmaceutical compositions provided herein have a shelf life of at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months when stored under refrigerated conditions. In one embodiment, the properties of the pharmaceutical compositions provided herein make them suitable for immediate release (IR).

[0058] The pharmaceutical compositions provided herein can be formulated into suitable pharmaceutical preparations for oral administration (e.g., solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release preparations, or elixirs, etc.) or sterile solutions or suspensions for ocular or parenteral administration, as well as transdermal patch formulations and dry powder inhalers. Typically, the compounds are formulated into pharmaceutical compositions using techniques and methods well known in the art (see, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Tenth Edition 2013). In one embodiment, the pharmaceutical compositions provided herein are oral dosage forms. In one embodiment, the oral dosage unit form is a tablet. In one embodiment, the oral dosage unit form is a caplet. In one embodiment, the oral dosage unit form is a capsule. In one embodiment, the pharmaceutical compositions provided herein are immediate release capsules.

[0059] Tablets, caplets and capsules typically contain about 50 mg to about 500 mg of pharmaceutical composition (i.e., active ingredient and excipients). Capsules can be any size. Examples of standard sizes include #000, #00, #0, #1, #2, #3, #4 and #5. See, for example, Remington's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack Publishing Company, Easton Pennsylvania, 18th ed., 1990), which are incorporated by reference herein. In some embodiments, the capsules provided herein are size #1 or larger, #2 or larger, #3 or larger or #4 or larger.

[0060] In the composition, an effective concentration of one or more compounds or pharma- ceutically acceptable salts are mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective to deliver an amount that, upon administration, treats, prevents, or alleviates one or more symptoms and / or progression of non-Hodgkin's lymphoma.

[0061] (a) Form of Compound 1 Compound 1 has the chemical name (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. Methods for producing Compound 1 are described in U.S. Application Serial No. 16 / 390,815, the entirety of which is incorporated herein by reference.

[0062] In one embodiment, Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, is provided in a pharmaceutical composition in a solid form. In one embodiment, the solid form is amorphous. In one embodiment, the solid form is crystalline. In one embodiment, the solid form is a hydrate. In one embodiment, the solid form is anhydrous. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is a non-solvate.

[0063] The solid forms can be characterized using many methods known to those of skill in the art, including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (PXRD), microscopy (e.g., optical microscopy, scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy), dynamic vapor sorption (DVS), spectroscopy (e.g., infrared, Raman, nuclear magnetic resonance), high performance liquid chromatography (HPLC), etc. The particle size and particle size distribution of the solid forms provided herein can be determined by conventional methods, such as laser light scattering.

[0064] In one embodiment, the pharmaceutical composition comprises the free base of Compound 1. In one embodiment, the free base of Compound 1 is amorphous. In one embodiment, the free base of Compound 1 is crystalline. In one embodiment, the free base of Compound 1 is a mixture of one or more amorphous and crystalline forms.

[0065] In one embodiment, the pharmaceutical composition comprises a salt of Compound 1. In one embodiment, the salt is a hydrochloride, fumarate, tosylate, maleate, or besylate salt of Compound 1, and in one embodiment, the salt of Compound 1 is amorphous. In one embodiment, the salt of Compound 1 is crystalline. In one embodiment, the salt of Compound 1 is a mixture of one or more amorphous and crystalline forms.

[0066] In one embodiment, the pharmaceutical composition comprises a hydrochloride salt of Compound 1. In one embodiment, the pharmaceutical composition comprises a fumarate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises a tosylate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises a maleate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises a besylate salt of Compound 1.

[0067] In one embodiment, the pharmaceutical composition comprises Form A of the hydrochloride salt of Compound 1.

[0068] In one embodiment, Form A is a hydrate of the hydrochloride salt of Compound 1. In one embodiment, Form A is a channel hydrate of the hydrochloride salt of Compound 1.

[0069] A representative XRPD pattern of Form A of the hydrochloride salt of Compound 1 is shown in FIG.

[0070] In one embodiment, the pharmaceutical compositions provided herein comprise a hydrochloride salt of Compound 1, which is located at about the following positions: 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1, 17.3, 17.9, 18.2, 18.9, 19.2, 20.1, 20.4, 20.7, 21.7, 22.4, 23.0 , 24.4, 24.8, 25.7, 27.5, 28.1, 29.1, 29.8, 30.2 and 30.8 °2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form is characterized by 5 peaks. In one embodiment, the solid form is characterized by 7 peaks. In one embodiment, the solid form is characterized by 9 peaks. In one embodiment, the solid form is characterized by 11 peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0071] In one embodiment, the pharmaceutical compositions provided herein include a hydrochloride salt of Compound 1, which is in a solid form characterized by an XRPD pattern including peaks at about 15.1, about 16.3, and about 20.7 °2θ. In one embodiment, the XRPD pattern further includes peaks at about 7.8 and about 22.4 °2θ. In one embodiment, the XRPD pattern further includes peaks at about 18.2, about 18.9, and about 24.8 °2θ. In one embodiment, the XRPD pattern includes peaks at about 7.8, about 15.1, about 16.3, about 17.9, about 18.2, about 18.9, about 19.2, about 20.4, about 20.7, about 21.7, about 22.4, and about 24.8 °2θ.

[0072] In one embodiment, the pharmaceutical compositions provided herein include a hydrochloride salt of Compound 1, which is in a solid form characterized by an XRPD pattern consisting of peaks at about 4.2, 7.8, and 11.1 °2θ. In one embodiment, the XRPD pattern includes peaks at about 4.2, 7.8, 11.1, 12.4, and 15.1 °2θ. In one embodiment, the XRPD pattern includes peaks at about 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, and 16.3 °2θ. In one embodiment, the XRPD pattern includes peaks at about 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1, and 17.3 °2θ.

[0073] In one embodiment, the pharmaceutical compositions provided herein comprise the hydrochloride salt of Compound 1, which is in a solid form characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 7.

[0074] In one embodiment, the XRPD pattern is obtained using CuKα radiation.

[0075] (b) Mannitol-starch based pharmaceutical composition In one embodiment, the carrier or diluent in the pharmaceutical compositions provided herein is a mixture of mannitol and starch.

[0076] In one embodiment, the pharmaceutical composition further comprises a disintegrant, a glidant, a glidant or a mixture thereof.

[0077] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitution, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05 to about 2% w / w; 2) a mixture of mannitol and starch in an amount of about 85 to about 99.7% w / w; 3) a disintegrant in an amount of about 0 to about 6% w / w; 4) a lubricant in an amount of about 0 to about 2% w / w; and 5) a lubricant in an amount of about 0 to about 10% w / w.

[0078] In one embodiment, compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitution, or pharma- ceutically acceptable salt thereof, is the hydrochloride salt of compound 1. In one embodiment, the hydrochloride salt of compound 1 is a crystalline hydrochloride salt of compound 1. In one embodiment, the hydrochloride salt of compound 1 is characterized by an XRPD pattern comprising peaks at about 15.1, 16.3, and 20.7 degrees 2θ.

[0079] In one embodiment, the amount of Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitute, or a pharma- ceutically acceptable salt thereof is about 0.05 to about 2% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount is about 0.07 to about 1.5% w / w. In one embodiment, the amount is about 0.1 to about 1% w / w. In one embodiment, the amount is about 0.14 to about 0.71% w / w. In one embodiment, the amount is about 0.1 to about 0.2% w / w. In one embodiment, the amount is about 0.6 to about 0.8% w / w.

[0080] In one embodiment, the amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitute, or a pharma- ceutically acceptable salt thereof, is about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9 or about 2% w / w. In one embodiment, the amount is about 0.14% w / w. In one embodiment, the amount is about 0.142% w / w. In one embodiment, the amount is about 0.71% w / w. In one embodiment, the amount is about 0.712% w / w.

[0081] In one embodiment the starch is a partially pregelatinized starch, hi one embodiment the starch is a pregelatinized starch.

[0082] In one embodiment, the mixture of mannitol and starch is present in an amount of about 85 to about 99.7% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the mixture of starch and lactose is present in an amount of about 87.5 to about 97.5% w / w. In one embodiment, the mixture of starch and lactose is present in an amount of about 90 to about 95% w / w. In one embodiment, the mixture of starch and lactose is present in an amount of about 91.5 to about 93% w / w. In one embodiment, the mixture of starch and lactose is present in an amount of about 92 to about 93% w / w.

[0083] In one embodiment, the amount of the mixture of mannitol and starch is about 85, about 86, about 87, about 88, about 89, about 90, about 90.5, about 91, about 91.5, about 91.6, about 91.7, about 91.8, about 91.9, about 92, about 92.1, about 92.2, about 92.3, about 92.4, about 92.5, about 92.6, about 92.7, about 92.8, about 92.9, about 93, about 93.5, about 94, about 94.5, about 95, about 96, about 97, about 98, about 99, about 99.5 or about 99.7% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 91.9% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 92.3% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 92.9% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 91.86% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 92.29% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 92.86% w / w.

[0084] In one embodiment, the amount of mannitol is about 67 to about 77.7% w / w, and the amount of starch is about 18 to about 22% w / w. In one embodiment, the amount of mannitol is about 69 to about 76% w / w, and the amount of starch is about 18.5 to about 21.5% w / w. In one embodiment, the amount of mannitol is about 71 to about 74% w / w, and the amount of starch is about 19 to about 21% w / w. In one embodiment, the amount of mannitol is about 71.5 to about 73% w / w, and the amount of starch is about 20% w / w. In one embodiment, the amount of mannitol is about 72 to about 73% w / w, and the amount of starch is about 20% w / w.

[0085] In one embodiment, the amount of mannitol is about 67, about 68, about 69, about 70, about 70.5, about 71, about 71.5, about 71.6, about 71.7, about 71.8, about 71.9, about 72, about 72.1, about 72.2, about 72.3, about 72.4, about 72.5, about 72.6, about 72.7, about 72.8, about 72.9, about 73, about 73.5, about 74, about 74.5, about 75, about 76, about 77, about 77.5 or about 77.7% w / w. In one embodiment, the amount of mannitol is about 71.9% w / w. In one embodiment, the amount of mannitol is about 72.3% w / w. In one embodiment, the amount of mannitol is about 72.9% w / w. In one embodiment, the amount of mannitol is about 71.86% w / w. In one embodiment, the amount of mannitol is about 72.29% w / w. In one embodiment, the amount of mannitol is about 72.86% w / w.

[0086] In one embodiment, the amount of starch is about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5 or about 22% w / w. In one embodiment, the amount of starch is about 20% w / w.

[0087] In one embodiment, the weight ratio of starch to mannitol is about 1:3 to about 1:4. In one embodiment, the weight ratio of starch to mannitol is about 1:3, about 1:3.1, about 1:3.2, about 1:3.3, about 1:3.4, about 1:3.5, about 1:3.6, about 1:3.7, about 1:3.8, about 1:3.9 or about 1:4. In one embodiment, the weight ratio of starch to mannitol is about 1:3.6.

[0088] In one embodiment, the disintegrant is crospovidone.

[0089] In one embodiment, the amount of disintegrant is about 0 to about 6% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of disintegrant is about 1 to about 5% w / w. In one embodiment, the amount of disintegrant is about 2 to about 4% w / w.

[0090] In one embodiment, the amount of disintegrant is about 0, about 1, about 2, about 3, about 4, about 5 or about 6% w / w. In one embodiment, the amount of disintegrant is about 3% w / w. In one embodiment, the amount of disintegrant is about 0% w / w (i.e., the pharmaceutical composition does not contain a disintegrant).

[0091] In one embodiment, the disintegrant is crospovidone in an amount of about 3% w / w.

[0092] In one embodiment, the lubricant is silicon dioxide.In one embodiment, the lubricant is colloidal silicon dioxide.

[0093] In one embodiment, the lubricant is a hydrophilic lubricant. In one embodiment, the lubricant is about 200 ml 2 / g of surface area. In one embodiment, the lubricant is Aerosil 200.

[0094] In one embodiment, the amount of lubricant is about 0 to about 2% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of lubricant is about 0.25 to about 1.75% w / w. In one embodiment, the amount of lubricant is about 0.5 to about 1.5% w / w. In one embodiment, the amount of lubricant is about 0.75 to about 1.25% w / w.

[0095] In one embodiment, the amount of lubricant is about 0, about 0.1, about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, about 1, about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3, about 1.35, about 1.4, about 1.45, about 1.5, about 1.6, about 1.7, about 1.75, about 1.8, about 1.9 or about 2% w / w. In one embodiment, the amount of lubricant is about 1% w / w. In one embodiment, the amount of lubricant is about 0% w / w (i.e., the pharmaceutical composition does not include a lubricant).

[0096] In one embodiment, the lubricant is silicon dioxide in an amount of about 1% w / w.

[0097] In one embodiment, the lubricant is sodium stearyl fumarate, stearic acid or magnesium stearate. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is magnesium stearate.

[0098] In one embodiment, the amount of lubricant is about 0 to about 10% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of lubricant is about 1.5 to about 7.5% w / w. In one embodiment, the amount of lubricant is about 2 to about 6% w / w. In one embodiment, the amount of lubricant is about 2 to about 4% w / w. In one embodiment, the amount of lubricant is about 3 to about 5% w / w. In one embodiment, the amount of lubricant is about 4 to about 6% w / w.

[0099] In one embodiment, the amount of lubricant is about 0, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10% w / w. In one embodiment, the amount of lubricant is about 3% w / w. In one embodiment, the amount of lubricant is about 5% w / w.

[0100] In one embodiment, the lubricant is sodium stearyl fumarate in an amount of about 3% w / w.

[0101] In one embodiment, the lubricant is stearic acid in an amount of about 5% w / w.

[0102] In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 71 to about 74% w / w and pregelatinized starch in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; 4) silicon dioxide in an amount of about 0.5 to about 1.5% w / w; and 5) sodium stearyl fumarate in an amount of about 2 to about 4% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) hydrochloride salt of compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) mannitol in an amount of about 72.86% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; 4) silicon dioxide in an amount of about 1% w / w; and 5) sodium stearyl fumarate in an amount of about 3% w / w. In one embodiment, the pharmaceutical composition has a total weight of about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule.

[0103] In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.6 to about 0.8% w / w; 2) mannitol in an amount of about 71 to about 74% w / w and pregelatinized starch in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; 4) silicon dioxide in an amount of about 0.5 to about 1.5% w / w; and 5) sodium stearyl fumarate in an amount of about 2 to about 4% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.71% w / w; 2) mannitol in an amount of about 72.29% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; 4) silicon dioxide in an amount of about 1% w / w; and 5) sodium stearyl fumarate in an amount of about 3% w / w. In one embodiment, the pharmaceutical composition has a total weight of about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of about 225 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0104] In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 71 to about 74% w / w and pregelatinized starch in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; and 4) stearic acid in an amount of about 4 to about 6% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) mannitol in an amount of about 71.86% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0105] In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 74 to about 77% w / w and pregelatinized starch in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; and 4) magnesium stearate in an amount of about 0.5 to about 1.5% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) mannitol in an amount of about 75.86% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) magnesium stearate in an amount of about 1% w / w.

[0106] (c) Mannitol-Cellulose-Based Pharmaceutical Compositions In one embodiment, the carrier or diluent in the pharmaceutical composition provided herein is a mixture of mannitol and cellulose. In one embodiment, the pharmaceutical composition further comprises a disintegrant, glidant, lubricant or a mixture thereof.

[0107] In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitution, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05 to about 2% w / w; 2) a mixture of mannitol and cellulose in an amount of about 85 to about 99.7% w / w; 3) a disintegrant in an amount of about 0 to about 6% w / w; and 4) a lubricant in an amount of about 0 to about 10% w / w.

[0108] In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 72 to about 75% w / w and microcrystalline cellulose in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; and 4) sodium stearyl fumarate in an amount of about 2 to about 4% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) mannitol in an amount of about 73.86% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) sodium stearyl fumarate in an amount of about 3% w / w.

[0109] In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 70 to about 73% w / w and microcrystalline cellulose in an amount of about 19 to about 21% w / w; 3) crospovidone in an amount of about 2 to about 4% w / w; and 4) stearic acid in an amount of about 4 to about 6% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) mannitol in an amount of about 71.86% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0110] (d) Cellulosic pharmaceutical compositions In one embodiment, the carrier or diluent in the pharmaceutical composition provided herein is cellulose. In one embodiment, the pharmaceutical composition further comprises a disintegrant, a lubricant, or a mixture thereof.

[0111] In one embodiment, provided herein is a pharmaceutical composition comprising the following components: 1) Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05 to about 2% w / w; 2) cellulose in an amount of about 75 to about 95% w / w; 3) a disintegrant in an amount of about 0 to about 20% w / w; and 4) a lubricant in an amount of about 0 to 10% w / w.

[0112] In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) microcrystalline cellulose in an amount of about 82 to about 87% w / w; 3) crospovidone in an amount of about 8 to about 12% w / w; and 4) stearic acid in an amount of about 4 to about 6% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising the following ingredients: 1) the hydrochloride salt of Compound 1 (e.g., Form A) in an amount of about 0.14% w / w; 2) microcrystalline cellulose in an amount of about 84.86% w / w; 3) crospovidone in an amount of about 10% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0113] (e) Additional Pharmaceutical Composition Embodiments In one embodiment, the pharmaceutical compositions provided herein can optionally further comprise one or more additional excipients, including but not limited to wetting agents, solubilizing agents, crystallization stabilizers, anti-adherents and suspending agents.

[0114] In one embodiment, the pharmaceutical compositions provided herein are formulated in a capsule. In one embodiment, the capsule is an HPMC capsule.

[0115] Usually, the composition is formulated for single administration.To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or mixed in the selected vehicle at an effective concentration so that the symptoms to be treated are relieved or improved.The pharmaceutical carrier or vehicle suitable for administering the compound provided herein includes any carrier known to those skilled in the art to be suitable for a particular mode of administration.

[0116] Furthermore, the compound may be formulated as the only pharma- ceutically active ingredient in the composition or may be combined with another active ingredient. Liposomal suspensions, e.g., tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharma-ceutically acceptable carriers. They may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared according to methods known to those skilled in the art. Briefly, liposomes such as multilamellar vesicles (MLVs) may be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) in a flask. A divalent cation-free phosphate buffered saline (PBS) solution of the compound provided herein is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0117] The active compound is contained in a pharma- ceutically acceptable carrier in an amount sufficient to exert a therapeutically effective effect without undesirable side effects on the patient being treated. The therapeutically effective concentration can be empirically determined by testing the compound in the in vitro and in vivo systems described herein, and then extrapolated to the dosage for humans.

[0118] The concentration of active compound in a pharmaceutical composition will vary depending on absorption, tissue distribution, inactivation, metabolism, and excretion rates of the active compound, the physicochemical properties of the compound, the administration schedule and dosage, as well as other factors known to those of skill in the art.

[0119] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can contain any of the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, dimethylacetamide or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid, sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, phosphates, and agents for adjusting tonicity such as sodium chloride, dextrose, etc. Parenteral preparations can be enclosed in ampoules, pens, disposable syringes, or single- or multiple-dose vials made of glass, plastic, or other suitable material.

[0120] In cases where a compound exhibits insufficient solubility, methods can be used to solubilize the compound. Such methods are known to those skilled in the art and include the use of cosolvents such as dimethylsulfoxide (DMSO), TWEEN (登録商標) These include, but are not limited to, the use of surfactants such as tetrahydrofuran or tetrahydrofuran, or elution in aqueous sodium bicarbonate.

[0121] Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will vary depending on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is a concentration sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated, and can be empirically determined.

[0122] Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions and oil-water emulsions, containing an appropriate amount of the compound or its pharma- ceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms, as used herein, refer to physically separate units suitable for human and animal subjects, packaged individually as known in the art. Each unit dosage contains a predetermined amount of therapeutically active compound sufficient to produce a desired therapeutic effect, in association with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dosage form may be administered in a portion or multiple thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses that are not segregated in packaging.

[0123] Dosage forms or compositions containing active ingredients in the range of 0.005% to 100%, the remainder being composed of non-toxic carriers, can be prepared. For oral administration, pharma-ceutically acceptable non-toxic compositions can be formed by incorporating any of the commonly used excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include, but are not limited to, solutions, suspensions, tablets, capsules, powders, and sustained release formulations (e.g., implants and microencapsulated delivery systems), biodegradable and biocompatible polymers (e.g., collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and others). Methods for preparing these compositions are known to those skilled in the art.

[0124] The active compounds or pharma- ceutically acceptable salts can be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings.

[0125] The composition may contain another active compound to obtain a combination of desired properties. The compounds provided herein, or pharma- ceutically acceptable salts thereof described herein, may also be advantageously administered for therapeutic or prophylactic purposes with another pharmacological agent known in the general art to be effective in treating one or more of the diseases or conditions referred to herein (e.g., oxidative stress-related diseases, etc.). It will be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

[0126] (f) Manufacturing method of the dosage form The pharmaceutical compositions (dosage forms) provided herein can be prepared by any method of pharmacy, but all methods include a step of combining the active ingredient with an excipient that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly blending (e.g., direct mixing) the active ingredient with a liquid excipient or finely divided solid excipient or both, and then, if necessary, shaping the product into the desired shape (e.g., by compression, such as roller compaction). If desired, tablets can be coated using standard aqueous or nonaqueous techniques.

[0127] The dosage forms provided herein can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be produced by compressing the active ingredient in a free-flowing form, such as powder or granules, mixed with excipients and / or surfactants or dispersants as described above, in a suitable machine. Molded tablets can be produced by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The dosage forms provided herein can be encapsulated using capsules of hydroxypropylmethylcellulose, calcium alginate, or gelatin.

[0128] In some embodiments, the active ingredient and excipients are directly mixed and, for example, loaded into a capsule or compressed directly into a tablet.

[0129] In some embodiments, the dosage form or pharmaceutical composition provided herein is prepared by wet granulation.In one embodiment, the wet granulation method comprises the steps of: (i) mixing the active ingredient (e.g., Compound 1, or its enantiomer, enantiomeric mixture, tautomer, isotopic substitution or pharma- ceutically acceptable salt) with a first amount of excipient(s) (intragranular excipients) and water to form wet granules; (ii) drying the granules, followed by milling; and (iii) mixing the milled granules with the remaining excipient(s) (extragranular excipients) to form a final mixture.In one embodiment, the method is followed by an encapsulation step.

[0130] In one embodiment, the intragranular excipients include a binder (e.g., starch) and a disintegrant (e.g., crospovidone), and the extragranular excipients include a diluent (e.g., mannitol) and a lubricant (e.g., stearic acid). In one embodiment, the intragranular / extragranular excipient ratio is about 33:67 or less. In one embodiment, the intragranular / extragranular excipient ratio is about 23:77 or less. In one embodiment, the intragranular / extragranular excipient ratio is about 23:77.

[0131] In one embodiment, the active ingredient is passed through a 60 mesh (250 μm) screen or a screen having a smaller aperture size prior to step (i).

[0132] In one embodiment, the particle size of the milled granules (e.g., as measured by D50) matches (e.g., within ±10%, ±20%, or ±30%) the particle size of the major component of the extragranular excipient (e.g., a diluent, e.g., mannitol).

[0133] In some embodiments, the dosage form or pharmaceutical composition provided herein is manufactured by roller compaction. In one embodiment, the roller compaction method includes the following steps: (i) mixing the active ingredient (e.g., Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof) with a first amount of excipient(s) (intraglans) to form an intragranular mixture; (ii) passing the intragranular mixture through a roller compactor to form a dry granule; and (iii) mixing the dry granule with the remaining excipient(s) (extragranular excipients) to form a final mixture. In one embodiment, step (i) includes premixing the active ingredient with a small amount of a binder (e.g., starch) and then mixing with the remaining intragranular excipients. In one embodiment, this step is followed by an encapsulation step.

[0134] In one embodiment, the active ingredient is passed through a 60 mesh (250 μm) screen or a screen having a smaller aperture size prior to step (i).

[0135] In one embodiment, the intragranular excipients include a binder (e.g., starch), a diluent (e.g., mannitol), a disintegrant (e.g., crospovidone), a glidant (e.g., silicon dioxide), and a lubricant (e.g., sodium stearyl fumarate), and the extragranular excipients include a glidant (e.g., silicon dioxide) and a lubricant (e.g., sodium stearyl fumarate). In one embodiment, the intragranular / extragranular excipient ratio is about 67:33 or less. In one embodiment, the intragranular / extragranular excipient ratio is about 98:2 or less. In one embodiment, the intragranular / extragranular excipient ratio is about 98:2.

[0136] 5.3. How to use In one embodiment, provided herein is a method of treating a hematological malignancy, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein.

[0137] In one embodiment, provided herein is a method for preventing hematological malignancies, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein.

[0138] In one embodiment, provided herein is a method for managing a hematological malignancy, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein.

[0139] In one embodiment, the hematological malignancy is leukemia.

[0140] In one embodiment, the hematological malignancy is acute myeloid leukemia. In one embodiment, the acute myeloid leukemia is B-cell acute myeloid leukemia.

[0141] In one embodiment, the hematological malignancy is acute lymphoblastic leukemia.

[0142] In one embodiment, the hematological malignancy is chronic lymphocytic leukemia / small lymphocytic lymphoma.

[0143] In one embodiment, the hematological malignancy is myeloma.

[0144] In one embodiment, the hematological malignancy is multiple myeloma. In one embodiment, the multiple myeloma is plasma cell leukemia (PCL).

[0145] In one embodiment, the hematological malignancy is lymphoma.

[0146] In one embodiment, the hematological malignancy is non-Hodgkin's lymphoma.

[0147] In one embodiment, the hematological malignancy is diffuse large B-cell lymphoma.

[0148] In one embodiment, the hematological malignancy is a T-cell lymphoma. In one embodiment, the T-cell lymphoma is anaplastic large cell lymphoma (ALCL). In one embodiment, the T-cell lymphoma is Sezary syndrome.

[0149] In one embodiment, the hematological malignancy is Burkitt's lymphoma.

[0150] In one embodiment, the hematological malignancy is marginal zone lymphoma. In one embodiment, the marginal zone lymphoma is splenic marginal zone lymphoma (SMZL).

[0151] In one embodiment, the hematological malignancy is Hodgkin's lymphoma.

[0152] In one embodiment, the hematological malignancy is a myelodysplastic syndrome.

[0153] In one embodiment, the hematological malignancy is newly diagnosed. In one embodiment, the hematological malignancy is relapsed or refractory.

[0154] In one embodiment, the AML is newly diagnosed AML. In one embodiment, the AML is relapsed or refractory AML. In one embodiment, the B cell AML is newly diagnosed B cell AML. In one embodiment, the B cell AML is relapsed or refractory B cell AML.

[0155] In one embodiment, the ALL is newly diagnosed ALL. In one embodiment, the ALL is relapsed or refractory ALL.

[0156] In one embodiment, the MM is newly diagnosed MM. In one embodiment, the MM is relapsed or refractory MM. In one embodiment, the PCL is newly diagnosed PCL. In one embodiment, the PCL is relapsed or refractory PCL.

[0157] In one embodiment, the HL is newly diagnosed HL. In one embodiment, the HL is relapsed or refractory HL.

[0158] In one embodiment, the NHL is newly diagnosed NHL. In one embodiment, the NHL is relapsed or refractory NHL.

[0159] In one embodiment, the TCL is newly diagnosed TCL. In one embodiment, the TCL is relapsed or refractory TCL. In one embodiment, the ALCL is newly diagnosed ALCL. In one embodiment, the ALCL is relapsed or refractory ALCL. In one embodiment, the Sézary syndrome is newly diagnosed Sézary syndrome. In one embodiment, the Sézary syndrome is relapsed or refractory Sézary syndrome.

[0160] In one embodiment, the BL is newly diagnosed BL. In one embodiment, the BL is relapsed or refractory BL.

[0161] In one embodiment, the MZL is newly diagnosed MZL. In one embodiment, the MZL is relapsed or refractory MZL. In one embodiment, the SMZL is newly diagnosed SMZL. In one embodiment, the SMZL is relapsed or refractory SMZL.

[0162] In one embodiment, the MDS is newly diagnosed MDS. In one embodiment, the MDS is relapsed or refractory MDS.

[0163] In one embodiment, provided herein is a method for achieving a complete response, partial response, or stable disease in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient having a hematological malignancy. In one embodiment, provided herein is a method for achieving overall survival, progression-free survival, event-free survival, progression-free or disease-free survival in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient having a hematological malignancy. In one embodiment, provided herein is a method for achieving extended overall survival in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient having a hematological malignancy. In one embodiment, provided herein is a method for achieving extended progression-free survival in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient having a hematological malignancy provided herein. In one embodiment, provided herein is a method for achieving increased event-free survival in a patient, comprising administering to the patient having a hematological malignancy provided herein a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, provided herein is a method for achieving an increased time to progression in a patient, comprising administering to the patient having a hematological malignancy provided herein a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, provided herein is a method for achieving an increased disease-free survival in a patient, comprising administering to the patient having a hematological malignancy provided herein a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL.In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sezary syndrome). In one embodiment, the hematological malignancy is Burkitt's lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0164] In one embodiment, provided herein is a method of treating AML, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the AML is B-cell AML.

[0165] In one embodiment, provided herein is a method of preventing AML, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the AML is B-cell AML.

[0166] In one embodiment, provided herein is a method of managing AML, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the AML is B-cell AML.

[0167] In one embodiment, provided herein is a method of treating ALL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0168] In one embodiment, provided herein is a method of preventing ALL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0169] In one embodiment, provided herein is a method of managing ALL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0170] In one embodiment, provided herein is a method of treating MM, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0171] In one embodiment, provided herein is a method for preventing MM, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0172] In one embodiment, provided herein is a method of managing MM, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0173] In one embodiment, provided herein is a method of treating PCL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0174] In one embodiment, provided herein is a method for preventing PCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0175] In one embodiment, provided herein is a method for managing PCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0176] In one embodiment, provided herein is a method of treating TCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the TCL is ALCL. In one embodiment, the TCL is Sézary syndrome.

[0177] In one embodiment, provided herein is a method for preventing TCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the TCL is ALCL. In one embodiment, the TCL is Sezary syndrome.

[0178] In one embodiment, provided herein is a method of managing TCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the TCL is ALCL. In one embodiment, the TCL is Sezary syndrome.

[0179] In one embodiment, provided herein is a method of treating BL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0180] In one embodiment, provided herein is a method for preventing BL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0181] In one embodiment, provided herein is a method of managing BL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0182] In one embodiment, provided herein is a method of treating HL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0183] In one embodiment, provided herein is a method for preventing HL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0184] In one embodiment, provided herein is a method of managing HL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0185] In one embodiment, provided herein is a method of treating MZL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the MZL is SMZL.

[0186] In one embodiment, provided herein is a method of preventing MZL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the MZL is SMZL.

[0187] In one embodiment, provided herein is a method of managing MZL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the MZL is SMZL.

[0188] In one embodiment, provided herein is a method of treating MDS, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0189] In one embodiment, provided herein is a method of preventing MDS, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0190] In one embodiment, provided herein is a method of managing MDS, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0191] In one embodiment, the description provides methods of using the pharmaceutical compositions provided herein, alone or in combination with rituximab, to treat, prevent, or manage non-Hodgkin's lymphoma (NHL).

[0192] In one embodiment, provided herein is a method of treating NHL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0193] In one embodiment, provided herein is a method for preventing NHL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0194] In one embodiment, provided herein is a method of managing NHL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0195] In one embodiment, the NHL is DLBCL. In one embodiment, the DLBCL is primary DLBCL. In one embodiment, the DLBCL is activated B-cell-like DLBCL (ABC-DLBCL). In one embodiment, the DLBCL is germinal center B-cell-like DLBCL (GCB-DLBCL). In one embodiment, the DLBCL is unclassified DLBCL. In one embodiment, the DLBCL is primary mediastinal B-cell DLBCL (PMBL DLBCL). In one embodiment, the DLBCL is double-hit DLBCL (DHIT DLBCL), also known as cMyc / Bcl-2-mutated DLBCL. In one embodiment, the DLBCL is triple-hit DLBCL (THIT DLBCL), also known as cMyc / Bcl2 / Bcl6-rearranged DLBCL.

[0196] In one embodiment, the NHL is follicular lymphoma (FL).

[0197] In one embodiment, the NHL is mantle cell lymphoma (MCL).

[0198] In one embodiment, the NHL is primary central nervous system lymphoma (PCNSL).

[0199] In certain embodiments, the NHL is relapsed or refractory NHL. In one embodiment, the NHL is relapsed NHL. In one embodiment, the NHL is refractory NHL.

[0200] In certain embodiments, the NHL subject has radiological evidence of progression after achieving a complete response (CR). In certain embodiments, the NHL subject has achieved less than a CR to a regimen that includes the most recent systemic therapy and has radiological evidence of active disease or disease progression or recurrence within 12 months of a previous stem cell transplant (SCT).

[0201] In certain embodiments, the NHL subject has failed one or more lines of treatment and is not a candidate for other treatments.In certain embodiments, the subject has received at least one prior therapy and is not eligible for therapy other than the treatment methods described herein.In certain embodiments, the subject relapses after standard anticancer drug treatment or progresses during standard anticancer drug treatment.

[0202] In certain embodiments, the subject has failed at least one prior therapy, hi certain embodiments, the subject has failed at least two prior therapies.

[0203] In one embodiment, the NHL is relapsed or refractory DLBCL. In one embodiment, the DLBCL is relapsed DLBCL. In one embodiment, the DLBCL is refractory DLBCL. In one embodiment, the DLBCL is relapsed / refractory DLBCL. In one embodiment, the DLBCL is refractory to doxorubicin. In one embodiment, the DLBCL is refractory to doxorubicin. In one embodiment, the DLBCL is refractory to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, gemcitabine, dexamethasone, ifosfamide, polatuxuab, or CAR-T.

[0204] In one embodiment, the DLBCL is treated with two or more preceding therapeutic regimens.

[0205] In one embodiment, the DLBCL is transformed lymphoma. In another embodiment, the DLBCL is DLBCL not otherwise specified (NOS).

[0206] In one embodiment, the NHL is relapsed or refractory FL. In one embodiment, the FL is relapsed FL. In one embodiment, the FL is refractory FL.

[0207] In one embodiment, the FL has been treated with one or more prior therapeutic regimens. In one embodiment, the FL has been treated with two or more prior therapeutic regimens.

[0208] In one embodiment, the NHL is relapsed or refractory MCL. In one embodiment, the MCL is relapsed MCL. In one embodiment, the MCL is refractory MCL.

[0209] In one embodiment, the MCL has been treated with one or more prior therapeutic regimens. In one embodiment, the MCL has been treated with two or more prior therapeutic regimens.

[0210] In one embodiment, the NHL is relapsed or refractory PCNSL. In one embodiment, the PCNSL is relapsed PCNSL. In one embodiment, the PCNSL is refractory PCNSL.

[0211] In certain embodiments, the NHL is a newly diagnosed NHL. In certain embodiments, the NHL is a newly diagnosed diffuse large B-cell lymphoma. In certain embodiments, the NHL is a newly diagnosed follicular lymphoma. In certain embodiments, the NHL is a newly diagnosed mantle cell lymphoma. In certain embodiments, the NHL is a newly diagnosed primary central nervous system lymphoma.

[0212] In certain embodiments, the methods provided herein are further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0213] In one embodiment, a first therapy provided herein (e.g., an agent such as a pharmaceutical composition provided herein) is administered to a subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) administration of a second therapy (e.g., rituximab).

[0214] In one embodiment, a first therapy provided herein (e.g., an agent, such as a pharmaceutical composition provided herein) is administered to a subject simultaneously with administration of a second therapy (e.g., rituximab).

[0215] In one embodiment, a first therapy provided herein (e.g., an agent such as a pharmaceutical composition provided herein) is administered to a subject (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) after administration of a second therapy (e.g., rituximab).

[0216] In certain embodiments, rituximab is administered according to the locally approved label or pharmacy manual for manufacturing, administration and storage information. In certain embodiments, rituximab is administered intravenously. In certain embodiments, rituximab is administered subcutaneously. In certain embodiments, rituximab is administered by intravenous injection or intravenous infusion. In certain embodiments, rituximab is administered by intravenous infusion.

[0217] In certain embodiments, rituximab is administered in an amount according to the discretion of a physician. In certain embodiments, rituximab is administered once or twice daily. In certain embodiments, rituximab is administered at a dose of about 50 to about 1000 mg / m 2 , about 100 to about 750mg / m 2 , about 250~500mg / m 2 , or about 300 to about 400 mg / m 2 In certain embodiments, rituximab is administered at a dose of 375 mg / m per day. 2 is administered in an amount of

[0218] In one embodiment, provided herein is a method of treating DLBCL comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein, in one embodiment, the method further comprising administering to the subject a therapeutically effective amount of rituximab.

[0219] In one embodiment, provided herein is a method of preventing DLBCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0220] In another embodiment, provided herein is a method of managing DLBCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0221] In one embodiment, provided herein is a method of treating FL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of rituximab.

[0222] In one embodiment, provided herein is a method of preventing FL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of rituximab.

[0223] In another embodiment, provided herein is a method of managing FL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0224] In one embodiment, provided herein is a method of treating MCL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0225] In one embodiment, provided herein is a method of preventing MCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0226] In another embodiment, provided herein is a method of managing MCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0227] In one embodiment, provided herein is a method of treating PCNSL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0228] In one embodiment, provided herein is a method of preventing PCNSL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0229] In another embodiment, provided herein is a method of managing PCNSL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0230] In one embodiment, provided herein is a method of treating relapsed or refractory DLBCL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0231] In one embodiment, provided herein is a method of preventing relapsed or refractory DLBCL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0232] In another embodiment, provided herein is a method of managing relapsed or refractory DLBCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0233] In one embodiment, provided herein is a method of treating relapsed or refractory FL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of rituximab.

[0234] In one embodiment, provided herein is a method for preventing recurrent or refractory FL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of rituximab.

[0235] In another embodiment, provided herein is a method of managing relapsed or refractory FL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0236] In one embodiment, provided herein is a method of treating relapsed or refractory MCL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0237] In one embodiment, provided herein is a method of preventing relapsed or refractory MCL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0238] In another embodiment, provided herein is a method of managing relapsed or refractory MCL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0239] In one embodiment, provided herein is a method of treating relapsed or refractory PCNSL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0240] In one embodiment, provided herein is a method of preventing relapsed or refractory PCNSL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0241] In another embodiment, provided herein is a method of managing relapsed or refractory PCNSL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0242] In another embodiment, provided herein is a method for achieving a complete response, partial response, or stable disease in a patient with NHL, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an extension of overall survival, progression-free survival, event-free survival, progression-free time, or disease-free survival in a patient, comprising administering to the patient with NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an extension of overall survival in a patient, comprising administering to the patient with NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an extension of progression-free survival in a patient, comprising administering to the patient with NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an extension of event-free survival in a patient, comprising administering to the patient with NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an increased progression-free survival in a patient, comprising administering to a patient having NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an increased disease-free survival in a patient, comprising administering to a patient having NHL a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of rituximab.

[0243] In one embodiment, methods of using the pharmaceutical compositions provided herein, alone or in combination with obinutuzumab, to treat, prevent, or manage chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) are described herein.

[0244] As used herein, and unless otherwise indicated, "CLL / SLL" or "CLL and / or SLL" means CLL or SLL, or CLL and SLL. In one embodiment, the method provided herein is a method for treating, preventing, or managing CLL. In one embodiment, the method provided herein is a method for treating, preventing, or managing SLL. In one embodiment, the method provided herein is a method for treating, preventing, or managing CLL and SLL.

[0245] In one embodiment, the method provided herein is a method of treating CLL / SLL, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein.

[0246] In one embodiment, provided herein is a method for preventing CLL / SLL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein.

[0247] In one embodiment, provided herein is a method of managing CLL / SLL, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein.

[0248] In one embodiment, the CLL / SLL subject has failed one or more lines of therapy. In one embodiment, the subject has failed at least one prior therapy. In one embodiment, the subject has failed at least two prior therapies. In one embodiment, the subject has been previously treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the subject is relapsed or refractory to a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0249] In one embodiment, the CLL / SLL is newly diagnosed CLL / SLL. In one embodiment, the CLL / SLL is relapsed or refractory CLL / SLL (R / R CLL / SLL).

[0250] In one embodiment, the CLL is characterized by a mutated IGHV (immunoglobulin heavy chain gene). In one embodiment, the CLL is characterized by a non-mutated IGHV.

[0251] In one embodiment, CLL is characterized by one or more mutations in TP53 (tumor protein 53). In one embodiment, CLL is characterized by wild-type TP53.

[0252] In one embodiment, CLL is characterized by one or more cytogenetic abnormalities, such as del(13q), del(11q), del(17p), tri12, t(6;17), del(11q22.3), t(11;14), del(18q) and t(14;19). In one embodiment, CLL is characterized by del(17p).

[0253] In one embodiment, the CLL is characterized by Richter's transformation (also known as Richter's syndrome).

[0254] In one embodiment, the methods provided herein further comprise administering to the subject a therapeutically effective amount of obinutuzumab.

[0255] In one embodiment, a first therapy provided herein (e.g., an agent such as a pharmaceutical composition provided herein) is administered to a subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) administration of a second therapy (e.g., obinutuzumab).

[0256] In one embodiment, a first therapy provided herein (e.g., an agent, such as a pharmaceutical composition provided herein) is administered to a subject simultaneously with administration of a second therapy (e.g., obinutuzumab).

[0257] In one embodiment, a first therapy provided herein (e.g., an agent such as a pharmaceutical composition provided herein) is administered (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) after administration of a second therapy (e.g., obinutuzumab) to a subject.

[0258] In one embodiment, obinutuzumab is administered according to the locally approved label or pharmacy manual for manufacturing, administration and storage information. In one embodiment, obinutuzumab is administered intravenously. In one embodiment, obinutuzumab is administered subcutaneously. In one embodiment, obinutuzumab is administered by intravenous (IV) injection or IV infusion. In one embodiment, obinutuzumab is administered by intravenous injection. In one embodiment, obinutuzumab is administered by intravenous infusion.

[0259] In one embodiment, obinutuzumab is administered in an amount according to the physician's judgment. In one embodiment, obinutuzumab is administered per day. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 1100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 125 mg per day, about 800 mg to about 1000 mg per day, or about 900 mg to about 1100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 900 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on each of days 8 and 15 of the first 28-day cycle and day 1 of the second through sixth 28-day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg in combination on days 1 and 2 of the first 28-day cycle, and at a dose of about 1000 mg each on days 8 and 15 of the first 28-day cycle and day 1 of the second through sixth 28-day cycles. Obinutuzumab can be administered for more than six cycles. In one embodiment, obinutuzumab is administered in the first 28-day cycle described herein and at about 1000 mg on day 1 of the second through twelfth 28-day cycles. In one embodiment, obinutuzumab is administered in a first 28 day cycle described herein and is administered at about 1000 mg on day 1 of 28 day cycles 2 through 24. In one embodiment, obinutuzumab is administered in a first 28 day cycle described herein and is administered at about 1000 mg on day 1 of each subsequent 28 day cycle until disease progression.

[0260] In one embodiment, provided herein is a method of treating newly diagnosed CLL / SLL comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein, hi one embodiment, the method further comprises administering to the subject a therapeutically effective amount of obinutuzumab.

[0261] In one embodiment, provided herein is a method of preventing newly diagnosed CLL / SLL comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein, in one embodiment, the method further comprising administering to the subject a therapeutically effective amount of obinutuzumab.

[0262] In another embodiment, provided herein is a method of managing newly diagnosed CLL / SLL comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of obinutuzumab.

[0263] In one embodiment, provided herein is a method of treating relapsed or refractory CLL / SLL comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of obinutuzumab.

[0264] In one embodiment, provided herein is a method of preventing relapsed or refractory CLL / SLL, comprising administering to a subject in need of prevention a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of obinutuzumab.

[0265] In another embodiment, provided herein is a method of managing relapsed or refractory CLL / SLL comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of obinutuzumab.

[0266] In another embodiment, provided herein is a method for achieving a complete response, partial response, or stable disease in a patient as determined by the International Workshop Criteria for Chronic Lymphocytic Leukemia, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient with CLL / SLL. In one embodiment, detection of minimal residual disease (MRD) may be performed in subjects undergoing bone marrow evaluation to confirm complete response (CR). In one embodiment, provided herein is a method for achieving minimal residual disease (MRD) negativity in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient with CLL / SLL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, provided herein is a method for achieving an increased overall survival, progression-free survival, event-free survival, progression-free time, or disease-free survival in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to the patient with CLL / SLL. In another embodiment, provided herein is a method for achieving an increase in overall survival in a patient, comprising administering to the patient having CLL / SLL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an increase in progression-free survival in a patient, comprising administering to the patient having CLL / SLL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an increase in event-free survival in a patient, comprising administering to the patient having CLL / SLL a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein is a method for achieving an increase in progression-free time in a patient, comprising administering to the patient having CLL / SLL a therapeutically effective amount of a pharmaceutical composition provided herein.In another embodiment, provided herein is a method of achieving prolonged disease-free survival in a patient, comprising administering to the patient having CLL / SLL a therapeutically effective amount of a pharmaceutical composition provided herein. In one embodiment, the method is further characterized by administering to the subject a therapeutically effective amount of obinutuzumab.

[0267] The methods provided herein encompass treating patients regardless of their age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age or older. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is 65 years of age or older.

[0268] Also provided herein is a pharmaceutical composition provided herein for use in a method of treating a disease provided herein, the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein.

[0269] 5.4 Route of Administration The pharmaceutical compositions provided herein can be administered orally.In one embodiment, when administered orally, the pharmaceutical compositions provided herein are administered with food and water.In another embodiment, the pharmaceutical compositions provided herein are dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a solution or suspension.

[0270] The pharmaceutical compositions provided herein can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye or skin. The mode of administration is left to the discretion of the health care practitioner and may depend in part on the site of the medical condition.

[0271] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, etc. The composition may be formulated to contain a daily dose or a convenient sub-dose of a daily dose in a dosage unit, which may be a single tablet or capsule or liquid. In one embodiment, the solution is prepared from a water-soluble salt. In general, all of the compositions are prepared according to known methods in medicinal chemistry.

[0272] Depending on the disease state to be treated and the symptoms of the subject, the pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) routes of administration. The pharmaceutical compositions provided herein can be formulated alone or in suitable dosage units with pharma- ceutically acceptable excipients, carriers, adjuvants and vehicles appropriate for each route of administration.

[0273] In one embodiment, the pharmaceutical compositions provided herein are administered orally. In another embodiment, the pharmaceutical compositions provided herein are administered parenterally. In yet another embodiment, the pharmaceutical compositions provided herein are administered intravenously.

[0274] The pharmaceutical compositions provided herein can be delivered as a single dose, for example, a single bolus injection or oral capsule, tablet or pill; or as a periodic administration, for example, a continuous infusion over time or a divided bolus administration over time.The pharmaceutical compositions provided herein can be administered repeatedly as needed, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.

[0275] The pharmaceutical compositions provided herein can be administered once a day (QD) or in multiple divided daily doses (e.g., twice a day (BID), three times a day (TID) and four times a day (QID)). Furthermore, administration can be continuous (i.e., daily or every day), intermittent, e.g., cyclical (i.e., including drug-free days, weeks or months of rest). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as a pharmaceutical composition provided herein, is administered for a period of time, e.g., once or more than once each day. The term "continuously" is intended to mean that a therapeutic compound, such as a pharmaceutical composition provided herein, is administered every day for an uninterrupted period of at least 7 days to 52 weeks. As used herein, the term "intermittent" or "intermittent" is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the pharmaceutical compositions provided herein can be administration for 1-6 days per week, administration in multiple cycles (e.g., daily administration for 2-8 consecutive weeks followed by a drug holiday of up to 1 week) or administration on alternate days. As used herein, the term "cycle" is intended to mean that a therapeutic compound, such as a pharmaceutical composition provided herein, is administered daily or continuously, but with a drug holiday.

[0276] In some embodiments, the dosing frequency ranges from about daily dosing to about monthly dosing. In certain embodiments, dosing is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the pharmaceutical compositions provided herein are administered once a day. In another embodiment, the pharmaceutical compositions provided herein are administered twice a day. In yet another embodiment, the pharmaceutical compositions provided herein are administered three times a day. In yet another embodiment, the pharmaceutical compositions provided herein are administered four times a day.

[0277] In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein in one or more seven day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-5 of a seven day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-3 of a seven day cycle.

[0278] In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein in one or more 14 day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-7 of a 14 day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-10 of a 14 day cycle.

[0279] In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein in one or more 28 day treatment cycles. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-21 of a 28 day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-5, 8-12, 15-19, and 22-26 of a 28 day cycle. In another embodiment, the methods provided herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1-10 and 15-24 of a 28 day cycle.

[0280] In one embodiment, the pharmaceutical compositions provided herein are administered once daily for 5 days followed by 2 days off. In one embodiment, the pharmaceutical compositions provided herein are administered once daily for 3 days followed by 4 days off. In one embodiment, the pharmaceutical compositions provided herein are administered once daily for 7 days followed by 7 days off. In one embodiment, the pharmaceutical compositions provided herein are administered once daily for 10 days followed by 4 days off. In one embodiment, the pharmaceutical compositions provided herein are administered once daily for 21 days followed by 7 days off.

[0281] In certain embodiments, the treatment comprises administering a therapeutically effective amount of rituximab in one or more treatment cycles. In one embodiment, rituximab is administered once every 7 days. In one embodiment, rituximab is administered once every 4 weeks. In one embodiment, rituximab is administered once every 8 weeks. In one embodiment, rituximab is administered on days 1, 8, 15, and 22 of the first 28 day cycle, on day 1 of the second through sixth 28 day cycles, and once every 8 weeks thereafter.

[0282] In one embodiment, the treatment is characterized by administering a therapeutically effective amount of obinutuzumab in one or more treatment cycles. In one embodiment, obinutuzumab is administered twice every 7 days. In one embodiment, obinutuzumab is administered once every week. In one embodiment, obinutuzumab is administered once every 4 weeks. In one embodiment, obinutuzumab is administered on days 1, 2, 8 and 15 of a first 28 day cycle and on day 1 of the second through sixth 28 day cycles. In one embodiment, obinutuzumab is administered on day 1 of the second through twelfth 28 day cycles. In one embodiment, obinutuzumab is administered on day 1 of the second through twenty-fourth 28 day cycles. In one embodiment, obinutuzumab is administered on day 1 of subsequent 28 day cycles until disease progression.

[0283] In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1 of the first 28 day cycle, about 900 mg on day 2 of the first 28 day cycle, and about 1000 mg on each of days 8 and 15 of the first 28 day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on combined days 1 and 2 of the first 28 day cycle, and about 1000 mg on each of days 8 and 15 of the first 28 day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 of the second through sixth 28 day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 of the second through twelfth 28 day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 of the second through twelfth 28 day cycles. In one embodiment, obinutuzumab is administered at about 1000 mg on day 1 of the second through 24th 28 day cycles. In one embodiment, obinutuzumab is administered at about 1000 mg on day 1 of subsequent 28 day cycles until disease progression.

[0284] Any of the treatment cycles described herein can be repeated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more cycles. In certain embodiments, the treatment cycles described herein include 1 to about 24 cycles, about 2 to about 16 cycles, or about 2 to about 4 cycles. In certain embodiments, the treatment cycles as described herein include 1 to about 4 cycles. In certain embodiments, the therapeutically effective amount of the pharmaceutical composition and / or rituximab provided herein is administered for 1 to 13 cycles of 28 days (e.g., for about 1 year). In certain embodiments, the therapeutically effective amount of the pharmaceutical composition and / or rituximab provided herein is administered for 1 to 24 cycles of 28 days (e.g., for about 2 years). In some embodiments, a therapeutically effective amount of a pharmaceutical composition provided herein and / or obinutuzumab is administered for 1-13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutically effective amount of a pharmaceutical composition provided herein and / or obinutuzumab is administered for 1-24 cycles of 28 days (e.g., about 2 years). In certain embodiments, cycle therapy is not limited to the number of cycles and is continued until disease progression. Cycles may, in certain embodiments, include varying the duration of administration and / or rest periods described herein. EXAMPLES

[0285] 6. Working Example Certain aspects of the present invention are illustrated by the following non-limiting examples. [Table 7]

[0286] 6.1. Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (Compound 1) [ka] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione: A suspension of (S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.00 g, 18.3 mmol) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18.30 mmol) in 2:1 dioxane-MeOH (75 mL) was cooled to 0° C. and mixed with B 10 H 14 (4.92 g, 40.3 mmol) was added in portions over 5 min. The reaction flask was fitted with a septum and needle vent (pressure) and stirred vigorously for 10 min. The mixture was allowed to warm to ambient temperature and stirred for 3 h. The mixture was concentrated and the residue was purified by silica gel chromatography (0-10% MeOH-DCM) to give (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione as a yellow solid (4.23 g, 56%). LCMS (ESI) m / z 411.8[M+H] +

[0287] (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: A solution of (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (0.727 g, 1.77 mmol) in dry NMP (6 mL) was cooled to 0° C. and methanesulfonyl chloride (0.275 mL, 3.35 mmol) and DIEA (0.617 mL, 3.53 mmol) were added sequentially. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was added slowly to HO (60 mL) cooled to 0° C. with vigorous stirring. The resulting suspension was filtered and the collected solid was washed with HO and EtO. The solid was dissolved in EtOAc and the solution was dried over MgSO4, filtered and concentrated to give (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (0.600 g, 79%). LCMS (ESI) m / z 430.0 [M+H] + .

[0288] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione: To a solution of (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (300 mg, 0.698 mmol) in dry DMSO (1.0 mL) was added 4-(azetidin-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.122 mL, 0.698 mmol). The reaction mixture was stirred at ambient temperature for 18 h and diluted with DMSO (1 mL). The solution was purified by chiral reverse phase chromatography to give (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (89 mg, 24%, 97% ee). LCMS (ESI) m / z 536.2 [M+H] +

[0289] 6.2. Cell-Based Assays with Compound 1 Below are examples of cell-based assays that can be used to measure the growth inhibitory activity and apoptotic effects of Compound 1 using illustrative non-Hodgkin's lymphoma (NHL) cell lines.

[0290] Cell proliferation and viability assays using the SU-DHL-4 cell line: The following exemplary assay uses a DLBCL cell line, e.g., SU-DHL-4 cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ]: Catalog No. ACC-495) 120 hours after treatment. The seeding density for SU-DHL-4 can be optimized to make the assay linear in 1536-well plates.

[0291] Increasing concentrations of compound 1 (0.5 nM-10 μM) were each spotted in a 20-point dilution format (unequally spaced data points) into an empty 1536-well plate by an acoustic dispenser (EDC ATS-100). The DMSO concentration was kept constant so that the final assay concentration was 0.1% DMSO. Prior to testing, SU-DHL-4 cells were cultured in RPMI-1640 (Roswell Park Memorial Institute-1640) medium containing 10% FBS (fetal bovine serum: HyClone) and grown in culture flasks to obtain sufficient starting material. Cells were then diluted to 500 cells per well in a volume of 5 μL and added directly to the compound-containing 1536-well plate. Cells were grown for 120 hours at 37°C with 5% CO2. At the time when the cells started to be exposed to the compounds (t0), the initial number of viable cells was assessed by quantifying the level of luminescence generated by adenosine 5'-triphosphate (ATP) present in viable cells via the Cell Titer-Glo® Luminescent Cell Viability Assay (Promega Corporation, Madison, WI) in a 1:2 volume ratio according to the manufacturer's instructions. After 120 hours, the viability of the treated cells was assessed by Cell Titer-Glo® luminescence readout. All growth inhibition curves were processed and evaluated using Activity Base (IDBS, Alameda, CA). IC of cell viability 50 Values ​​were calculated using a four parameter logistic model (sigmoidal dose-response model): y=(A+((BA) / (1+((C / x)^D)))) During the ceremony: A=Y Min B=Y Max C=EC 50 D=Hill slope I C 50 = Compound concentration when Y=50% of DMSO control Y = cell viability measured as luminescence units x = concentration of compound

[0292] Compound 1 showed an IC 50 It was confirmed to exhibit activity of <0.2 μM.

[0293] Cell proliferation and survival assays using hematopoietic cell lines: The following exemplary growth inhibition assay uses hematopoietic cell lines as examples: The in vitro growth inhibition activity of compound 1 described herein was evaluated using a 384-well flow cytometry assay. [Table 8] [Table 9]

[0294] Cell lines were seeded into 384-well flat-bottom plates and evaluated with increasing concentrations of compounds ranging from 0.00015 to 10 μM or a dimethyl sulfoxide (DMSO) control. The final concentration of DMSO was 0.1% (v / v). After 120 h of incubation with compound 1 or DMSO, the cells were analyzed by flow cytometry (Attune) using Annexin V and the live cell membrane-impermeant DNA dye DRAQ7. (登録商標) Cell count and cell death were analyzed using a 3D CT scanner (ThermoFisher). Phosphatidylserine is translocated from the inner to the outer membrane during early apoptosis, and annexin V binds to exposed phosphatidylserine on the surface of apoptotic cells. The vital dye DRAQ7 is excluded from intact, viable cells and stains only cells that have died by apoptosis or necrosis.

[0295] Flow cytometry data analysis was then performed using FlowJo_v10 software to measure the number of viable cells (double negative stained cells for Annexin V and DRAQ7) and the percentage of apoptotic cells (Annexin V positive cells) for each condition. The number of viable cells at each concentration was normalized to the DMSO control (considered as 100%), and the percentage of viable cells remaining after treatment was calculated and graphed using GraphPadPrism 7.03. The IC 50 (50% inhibitory concentration) and E max (maximum efficacy achieved) values ​​were calculated by nonlinear regression curve fitting using log(inhibitor) vs normalized response-variable slope analysis in GraphPadPrism 7.03. Area under the curve (AUC) was calculated by area under the curve analysis in GraphPadPrism 7.03. Similarly, for apoptosis analysis, the percentage of apoptosis for the combined "early" (Annexin V positive and DRAQ7 negative) and "late" apoptotic (Annexin V and DRAQ7 positive) cell gates versus DMSO was graphed using GraphPadPrism 7.03. AUC, EC 50 (the compound concentration that produces half the maximal apoptotic response) and Y max (Maximal percentage of apoptosis achieved) values ​​were calculated using area under the curve analysis and nonlinear regression curve fitting using log(agonist) vs normalized response-variable slope analysis performed in GraphPadPrism 7.03.

[0296] Dose-response growth curves of a panel of hematopoietic cell lines and nonlinear curve fitting were used to determine IC for % viable cells. 50 , AUC and E max (E for viability max The EC50 (which varies between 100 (at low doses) and 0 (at high doses), corresponding to inhibition of total viable cells) was determined and a dose-response apoptosis curve was used to calculate the EC50 for % apoptosis. 50 , AUC and Y max The Y of apoptosis was calculated. max(varying between 0 (at low doses) and 100 (at high doses), corresponding to total cell death). Tumor cells were exposed to serial dilutions (0.00015-10 μM) of compound 1 or dimethyl sulfoxide (DMSO) for 5 days. Viability and apoptosis of all cell lines were determined by Annexin V / 7-aminoactinomycin D (7-AAD) flow cytometry. Compound 1 was found to have growth inhibitory and / or apoptotic activity in almost all hematopoietic cell lines tested, as shown in the table below.

[0297] [Table 10] [Table 11]

[0298] 6.3 Excipient Compatibility Excipient compatibility study design The objective of the excipient compatibility study was to evaluate the effect of each excipient on the stability of Compound 1, rank the excipients within each functional category, and provide a rationale for excipient selection.

[0299] The following table lists the composition of the excipient compatibility mixture. The excipients covered many functions including diluents, binders, disintegrants, glidants and lubricants. Considering the relatively high solubility of Compound 1, compared to low doses (around 0.1 mg), dissolution is likely not a significant issue, so surfactants were not included in the excipient evaluation.

[0300] Due to the low dose active ingredient content, segregation and variability in content uniformity (CU) can be major process challenges. Granulation process (roller compaction or high shear wet granulation) can be a better option than direct blending to minimize segregation. Therefore, for each formulation blend, in addition to the powder blend, a compacted slug sample was prepared to mimic roller compaction conditions and a wet & dried sample to mimic wet granulation process conditions.

[0301] The samples were exposed to open conditions of 5°C (control), 50°C (dry), and 50°C / 75%RH (humidified) for 2 weeks to evaluate both chemical and chiral stability. Duplicate samples were prepared for each time point and condition.

[0302] [Table 12]

[0303] Excipient Compatibility Protocol For each mix in the table, various forms (blended mix, slug and wet & dry mix) were used to mimic direct mixing, roller compaction and wet granulation process conditions.

[0304] For each formulation mixture, 120 mg of Compound 1 HCl salt (Form A) and the corresponding excipients were accurately weighed. The mixtures were prepared by mixing in a Turbula mixer at 32 rpm for 20 minutes. For slug samples, the mixtures were compressed into slugs in an RRDI at 4.4 KN for 100 ms. For wet blend samples, 20% water was added to the powder mixture, stirred with a magnetic stirrer for 5 minutes, and then placed in a 50°C oven for 1 hour.

[0305] For both chemical and chiral stability, all samples were placed at 5° C., 50° C. ambient, and 50° C. / 75% RH for 2 weeks. The following two tables show the chemical and chiral assay data, respectively. chemical stability [Table 13]

[0306] Chiral Stability [Table 14]

[0307] 6.4 Stability of Prototype Formulations Prototype formulation design A prototype capsule formulation was selected based on the results of excipient compatibility testing, as shown in the table below.

[0308] In the direct blend and roller compaction methods, MCC and pregelatinized starch showed comparable performance in terms of excipient compatibility stability, so in the prototype formulation, both were used as binders, silicon dioxide was used as a lubricant, and magnesium stearate and sodium stearyl fumarate were used as lubricants.

[0309] In the wet granulation process, both MCC and pregelatinized starch were used, but pregelatinized starch performed slightly better than MCC in excipient compatibility; silicon dioxide was not used; and stearic acid, rather than magnesium stearate or sodium fumarate, was used as the lubricant. [Table 15]

[0310] Prototype drug production For direct blend formulations (Cap-1, Cap-2, Cap-3), excipients were passed through a 30 mesh / 595 μm screen and API was passed through a 60 mesh / 250 μm screen first; geometric dilution was used to improve the uniformity of the blended ingredients-API was first blended with a small amount of starch or MCC for 20 minutes at 15 rpm, then blended again with the remaining excipients (except magnesium stearate) in a Comyl for 20 minutes at 15 rpm, and the Comyl was washed with mannitol before a final blend at 15 rpm for 10 minutes. If magnesium stearate was used as a lubricant, it was added last and blended for an additional 3 minutes at 15 rpm.

[0311] For roller compacted formulations (Cap-4, Cap-5, Cap-6), excipients were passed through a 30 mesh / 595 μm screen and API was passed through a 60 mesh / 250 μm screen first; geometric dilution was used to improve the homogeneity of the blended ingredients - API was first blended with a small amount of starch or MCC at 15 rpm for 20 minutes, then the remaining intragranular excipients (except magnesium stearate) were blended again through a Comil (457 μm screen) at 15 rpm for 20 minutes, and the Comil was washed with mannitol before blending for 10 minutes at 15 rpm. If magnesium stearate was used as a lubricant, intragranular magnesium stearate was added at the end of a further 3 minutes of blending at 5 rpm. The intragranular blend was then passed through a GerteisPolygran roller compactor (continuous roll, roll speed 2 rpm, roll gap 2.0 mm, roll force 4 kN / cm, screen opening 1.0 mm, granulator speed 50 rpm). Finally, an extragranular lubricant was blended into the dry granulation.

[0312] For wet granulation formulations (Cap-7, Cap-8, Cap-9), all excipients (except lubricants) and API were first passed through a 30 mesh / 595 μm screen and then mixed in the bowl of a Freund Vector high shear granulator at 300 rpm impeller speed and 3000 rpm high shear rate for 10 minutes, then sprayed with 20% water at 30 g / min at the same 3000 rpm impeller speed and 3000 rpm shear rate, followed by wet granulation for 1 minute. The wet granules were passed through a 5 mesh / 4 mm screen and then dried in a Mini Glatt fluid bed dryer (inlet air temperature 50° C., inlet air flow rate 50 CFM, product temperature NMT 42° C.). The dried granules were passed through a Comil (610 μm screen) and mixed with 30 mesh screened stearic acid (lubricant) at 15 rpm for 10 minutes.

[0313] All final blends were encapsulated into size 4 white opaque HPMC capsules with a fill weight of 75 mg in a Bosch GKF 702 capsule making machine.

[0314] The following table shows the first test results of prototype formulation batches under various process conditions. For the same formulation composition, the batches using roller compaction method always had smaller AV values ​​than those using direct blending method (Cap-4 vs. Cap-1, Cap-5 vs. Cap-2, Cap-6 vs. Cap-3); therefore, roller compaction is preferred over direct blending method for drug product manufacturing of Compound 1 HCl salt due to better homogeneity of ingredients. The difference in the methods affected the chemical stability. The total amount of chemical degradants did not change significantly after roller compaction compared to direct blending method; however, the degradants increased after wet granulation method, suggesting that wet granulation method may have a higher risk level for chemical stability than roller compaction method. Chiral purity was not affected by the difference in the conditions of the various methods. [Table 16]

[0315] Stability of prototype formulations Capsules of each formulation were packed into 50 induction-sealed 100 CC HDPE bottles with 10 counts per bottle; 35 with desiccant (2 g) and 15 without desiccant. Stability was evaluated at accelerated conditions (40°C / 75% RH and 50°C / 75% RH).

[0316] Figures 1A, 1B and 1C show the chemical stability (total impurities) of the prototype formulations up to 12 weeks at 40°C / 75% RH without desiccant, 40°C / 75% RH with desiccant and 50°C / 75% RH with desiccant, respectively.

[0317] Regarding the effect of the presence or absence of a desiccant on stability at 40°C / 75% RH, formulations packaged with a desiccant had a significantly slower rate of API impurity formation than formulations packaged without a desiccant. This suggests that humidity control is important for drug product stability and that one of the major degradation pathways for Compound 1 hydrochloride is hydrolysis. A desiccant is necessary to maintain the drug product shelf life of Compound 1 hydrochloride.

[0318] For the three roller compaction formulations, at 40°C / 75%RH with desiccant, Cap-5 and Cap-6 formulations showed similar total impurity formation rates, slower than Cap-4. At 50°C / 75%RH with desiccant, the total impurity formation rates were faster than at 40°C, but the order did not change between the formulations. The main compositional difference between Cap-4 and Cap-5 / Cap-6 is that Cap-4 used magnesium stearate as a lubricant, whereas Cap-5 / Cap-6 used sodium stearyl fumarate (SSF) as a lubricant. Therefore, SSF is preferred over magnesium stearate as a lubricant in RC formulations. The binder used in Cap-5 was pregelatinized starch, and the binder in Cap-6 was microcrystalline cellulose. Cap-5 and Cap-6 showed similar chemical stability profiles.

[0319] For the three wet granulation formulations, Cap-9 showed a much faster impurity formation rate than Cap-7 and Cap-8 at 40°C / 75%RH with a desiccant. In addition, at 50°C / 75%RH, the impurity formation rate was faster than at 40°C in the presence of a desiccant, but there was no change in the ranking between the formulations, and Cap-8 showed a slightly faster impurity formation rate than Cap-7.

[0320] Cap-5 and Cap-7 have similar formulations but different granulation methods. The wet granulation formulation (Cap-7) had higher initial impurity levels than the roller compaction formulation (Cap-5), possibly due to the method, but the total impurity formation rates at steady state were similar for both.

[0321] Figures 2A, 2B, and 2C show chiral stability data for the prototype formulations up to 12 weeks at 40°C / 75% RH without desiccant, 40°C / 75% RH with desiccant, and 50°C / 75% RH with desiccant, respectively.

[0322] Regarding the effect of the presence or absence of a desiccant on stability at 40°C / 75% RH, the formulation packaged with a desiccant had a significantly slower rate of chiral isomerization of the API than the formulation packaged without a desiccant, suggesting that humidity control is important for the chiral stability of the drug product and that a desiccant is necessary to maintain the shelf life of the drug product.

[0323] For the roller compacted formulations, all three formulations showed slow chiral isomerization rates at 40°C / 75%RH with desiccant, with chiral purity decreasing by about 1% within 12 weeks. The order of chiral stability appeared to be Cap-4>Cap-5>Cap-6. When desiccant was used at 50°C / 75%RH, the chiral isomerization rate was faster than at 40°C, but the ranking among the formulations did not change. This suggests that chiral stability poses less risk to drug shelf life than chemical stability.

[0324] In the case of wet granulation formulations, at 40°C / 75% RH using a desiccant, the chiral isomerization rate was slow for all three formulations, and the decrease in chiral purity within 12 weeks was less than 1.5%. The order of chiral stability appears to be Cap-8>Cap-7>Cap-9. At 50°C / 75% RH using a desiccant, the chiral isomerization rate was faster than at 40°C, but the ranking between the formulations did not change.

[0325] Cap-5 and Cap-7 have similar formulation compositions but are made by different granulation methods. The two formulations started with the same chiral purity level, but the wet granulation formulation (Cap-7) had a slightly lower chiral purity level than the roller compaction formulation (Cap-5) after 12 weeks. Cap-5 and Cap-7 were selected for process development.

[0326] 6.5 Process Evaluation and Development (a) Evaluation and development of high shear wet granulation methods Intragranular / extragranular excipient ratio The active ingredient content of the clinical dose of Compound 1 hydrochloride formulation was as low as 0.1 mg fill in a 75 mg capsule, with a drug content of approximately 0.14%. Such extremely low drug content poses challenges to process and content uniformity. High shear wet granulation can not only disperse the API sufficiently by high shear forces during mixing, but also form granules that do not segregate during bulk storage and encapsulation. High shear wet granulation can be a good choice for low dose formulations where content uniformity is a concern.

[0327] The wet granulation process was optimized to improve the content uniformity (CU%RSD 6.1%, AV 16.5) of the Cap-7 batch. Since the API drug amount was fixed, the intragranular / extragranular excipient ratio was decreased (95 / 5 to 23 / 77) and the intragranular mixed drug content was increased from 0.14% to 0.6%. Figure 3 shows the process map of the wet granulation process. In the first method, everything except the lubricant was in the intragranular portion, but in the new method, the API, pregelatinized starch and crospovidone are in the intragranular portion, and mannitol and lubricant are in the extragranular portion.

[0328] Cap-10 was manufactured with an intragranular / extragranular excipient ratio of 23:77, while Cap-7 was manufactured with an intragranular / extragranular excipient ratio of 95:5. The results of the Cap-10 method (CU%RSD 2.5%, AV 5.27) showed that the content uniformity can be improved by lowering the intragranular / extragranular excipient ratio for wet granulation. To confirm this conclusion, replicate batches were performed: Cap-11 repeated the Cap-7 method with the initial high intragranular / extragranular excipient ratio of 95:5, and Cap-13 repeated the Cap-10 method. The CU%RSDs of Cap-7 and Cap-11 were shown to be comparable (6.1 vs. 6.8) but significantly higher than the CU%RSDs of Cap-10 and Cap-13 (2.5 vs. 3.3). Therefore, the novel wet granulation process with a low intragranular / extragranular excipient ratio was confirmed to improve the uniformity of the ingredients in low dose formulations. [Table 17]

[0329] The API particle size may also affect the content uniformity, since smaller API particles disperse better. Compound 1 hydrochloride API crystals tend to aggregate, but high shear mixing forces can break up the aggregates, but for low dose formulations, passing through a mesh screen is not as effective. For the method with a high intragranular / extragranular excipient ratio, batch Cap-12 passed the API through a 60 mesh (250 μm) screen, while Cap-7 and Cap-11 used a 30 mesh (595 μm) screen. As a result, the CU%RSD decreased significantly from 6.1% for Cap-7 to 3.5% for Cap-12. This trend was also observed in the new wet granulation method with a low intragranular / extragranular excipient ratio, and when the screen mesh number of the API was changed from 30 to 60, the CU%RSD decreased to 2.5% for Cap-10 and 2.0% for Cap-14. Therefore, passing the API through a smaller screen hole size could improve batch composition uniformity.

[0330] Compatibility of ground granule size For the wet granulation method with a low intragranular / extragranular excipient ratio (23 / 77), the API was mixed with starch, crospovidone, and water to form a wet granule, which was then dried and milled through a Comil; the milled granules were then mixed with mannitol and lubricant to form the final blend. Mannitol powder made up the majority of the final blend (~72% w / w), so it was important to match the particle size of the milled granules to that of mannitol to minimize segregation.

[0331] Cap-13 was a repeat batch of Cap-10 using a lower intragranular / extragranular excipient ratio. Cap-10 showed good CU data, but the CU of Cap-13 was not as good (3.3 vs. 2.5). The table below lists the particle size distribution of Cap-10, Cap-13 and mannitol excipient (Pearlitol 200SD). The particle size of the milled granules of Cap-10 (D50 145 μm) matches well with the particle size of mannitol (D50 148 μm). However, the particle size of the milled granules of Cap-13 (D50 259 μm) is much larger than that of mannitol (D50 148 μm), which may be the reason why the CU data of Cap-13 is not as good as that of Cap-10. The particle size of the final blends of Cap-10 and Cap-13 was similar because mannitol was the major component and dominated the average particle size of the final blends rather than the milled granules.

[0332] In another replicate batch (Cap-14), the particle size of the milled granules was monitored and controlled before mixing with mannitol and lubricant. The particle size of the milled granules (D50 139 μm) was consistent with the particle size of Cap-10 milled granules and mannitol, which may be the reason why the CU%RSD of Cap-14 (2.0) was as good as the CU%RSD of Cap-10 (2.5).

[0333] [Table 18]

[0334] To better understand the particle size and surface morphology, SEM images (not shown here) were taken from the excipients, milled granules, and final blend. SEM images of pregelatinized starch (Starch 1500) and mannitol (Pearlitol 200SD) showed that most of the pregelatinized starch particles were smaller than the mannitol particles. SEM images of Cap-10 milled granules showed that most of the milled granule particles were agglomerates of starch particles, and the size of the granules was similar to that of mannitol. SEM images of Cap-10 final blend showed that it was composed of mannitol particles.

[0335] In conclusion, it was found that in high shear wet granulation, the uniformity of the ingredients in low dose formulations can be improved by decreasing the intragranular / extragranular excipient ratio, passing the API through a screen with smaller pore size, and matching the size of the milled granules to that of mannitol.

[0336] (b) Evaluation and development of roller compaction methods Intragranular / extragranular excipient ratio The clinical dose of the pharmaceutical formulation of the HCl salt of compound 1 was as low as 0.1 mg in a 75 mg capsule, which was about 0.14% of the active ingredient. Such a very low amount of active ingredient poses challenges for process and ingredient uniformity. Roller compaction itself cannot uniformly disperse the API, but it helps prevent subsequent segregation. To achieve good ingredient uniformity, the API needs to be thoroughly dispersed before roller compaction.

[0337] For the Cap-5 batch, geometric dilution was utilized to improve blend uniformity, with acceptable content uniformity results (3.1% RSD, AV 7.4). To further improve content uniformity, increasing intragranular API loads were tested prior to roller compaction. Since the API load was fixed, it was necessary to decrease the intragranular / extragranular excipient ratio (98 / 2 to 14 / 86) to increase the API content of the intragranular blend from 0.14% to 1%. Figure 4 shows the process map for the RC method.

[0338] Whereas Cap-5 used an initial roller compaction process with an intragranular / extragranular excipient ratio of 98:2, the Cap-15 batch was produced using a new roller compaction process with an intragranular / extragranular excipient ratio of 14:86. Since starch alone does not roller compact well, the intragranular excipient ratio was kept similar to the extragranular excipient ratio in Cap-15.

[0339] In the Cap-5 batch, the API was passed through a 60 mesh (250 μm) screen before blending, but in the Cap-15 batch, a 30 mesh (595 μm) screen was used with the API and excipients, since it is not common to use a 60 mesh screen in the manufacture of scale-up batches. There were no other process changes between Cap-15 and Cap-5.

[0340] The table below lists the results of the primary methods for the roller compaction development batches. The CU%RSD of Cap-15 was higher than that of Cap-5 (9.0 vs. 3.1). The replicate batch (Cap-16) with the addition of overmixing and comilling steps did not show any significant change in content uniformity (CU%RSD of 8.6). Unlike wet granulation, the new approach of low intragranular / extragranular excipient ratio (14:86) did not improve content uniformity of the low dose formulation with roller compaction. [Table 19]

[0341] Particle size analysis was performed on the milled granules and the final blend of the roller compacted batches, and the results are shown in the table below. For the Cap-15 and Cap-16 batches, the D(50) values ​​of the milled granules and the final blend were similar, but there was a large difference in the D(90) values ​​of the milled granules and the final blend, which indicated that the milled granules contained too many large particles that could not be well mixed with the extragranular excipients when the latter constituted a large part of the final blend. The low intragranular / extragranular excipient ratio method required additional processing to find the appropriate process conditions to control the particle size of the milled granules to match the particle size of the extragranular excipients. However, it was determined that no new process efforts were necessary since the conventional high intragranular / extragranular excipient ratio method had already achieved acceptable CU. [Table 20]

[0342] API Screen Hole Size The API particle size can also affect the uniformity of the ingredients, since smaller particles tend to disperse better. The API crystals of compound 1HCl salt tended to agglomerate, and the mixing process was too gentle to break up the larger agglomerates, so passing the API powder through a mesh screen before mixing was an effective way to break up the larger agglomerates.

[0343] In the first high intragranular / extragranular excipient ratio method, batch Cap-5 passed the API through a 60 mesh (250 μm) screen and obtained an acceptable CU%RSD (3.1%). However, when Cap-17 increased the API screen pore size to 30 mesh (595 μm), the CU%RSD increased to 5.8%. In Cap-18, the API screen pore size was returned to 60 mesh (250 μm), and the CU%RSD returned to 2.9%. Thus, passing the API through a smaller screen pore size could improve the content uniformity of the roller compacted batches.

[0344] In summary, passing the API through a 60 mesh screen rather than a 30 mesh screen during roller compaction was found to be important for consistency of content in low dose formulations.

[0345] 6.6 Drug Product Evaluation and Manufacturing Cap-5 and Cap-7 are similarly formulated compositions but underwent different granulation methods. The wet granulation formulation (Cap-7) had an initial total impurity level 0.7% higher than the roller compaction formulation (Cap-5), possibly due to the humidification and drying of the wet granulation process inducing more chemical degradants, whereas the total impurity generation rates of the two batches during stability testing were similar. Both formulations required desiccant to maintain an adequate shelf life. Overall, the chemical stability showed a higher risk for the wet granulation method than the roller compaction method. The chiral purity of the two formulations was similar.

[0346] Manufacturability was evaluated for content uniformity and assay values. Based on method development data, wet granulation batches showed better content uniformity (CU%RSD) than roller compaction, but roller compacted batch content uniformity was still within acceptable limits. Roller compaction had a lower risk of API loss (assay values) than wet granulation due to the simplicity of the roller compaction method.

[0347] The solubility of Compound 1 hydrochloride API was relatively high compared to the proposed dose, so there was low risk to drug product dissolution. Figure 5 shows the formulation performance (dissolution profile) of the two granulation methods. The wet granulation batch (Cap-10) had a higher dissolution rate, while the roller compaction batch (Cap-5) still showed a satisfactory dissolution rate.

[0348] The roller compacted and Cap-5 formulations were selected for further evaluation. The following three tables list the formulation compositions for different active ingredient strengths. Because a desiccant was required, hydroxypropyl methylcellulose (HPMC) was selected as the capsule shell material rather than gelatin, since gelatin capsules will crack during storage in the presence of a desiccant. [Table 21] [Table 22] [Table 23]

[0349] The roller compaction process map for the above batch is shown in Figure 6. The process for manufacturing Compound 1 hydrochloride capsules includes the following steps: (i) pre-blending Compound 1 HCl salt with a small amount of pregelatinized starch and then blending with the remaining intragranular excipients (pregelatinized starch, mannitol, crospovidone, silicon dioxide, and sodium stearyl fumarate); (ii) passing the intragranular blend through a roller compactor; (iii) passing the extragranular silicon dioxide and sodium stearyl fumarate through a screen and adding to the granules and blending; and (iv) filling appropriately sized capsules to a specified weight.

[0350] Three batches (Cap-19, Cap-20, and Cap-21, with active ingredient strengths of 0.1 mg, 0.5 mg, and 1.5 mg, respectively) at 3 kg scale were manufactured and packaged. The stability batch results are shown in the table below: The capsules were packaged in 100 cc opaque High Density Polyethylene (HDPE) bottles with induction seal and tamper-evident child-resistant polypropylene caps. Each bottle contained 21 capsules and 2 g of desiccant. [Table 24]

[0351] The embodiments provided herein are not intended to be limited in scope by the specific embodiments shown in the examples, which are intended as illustrations of some aspects of the embodiments provided, and all embodiments that are functionally equivalent are intended to be encompassed by the present invention. Indeed, various modifications of the embodiments shown and described herein will be apparent to those skilled in the art and are intended to be within the scope of the appended claims.

[0352] A number of publications are cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. Compound 1: 【Chemistry 1】 or an enantiomer, a mixture of enantiomers, tautomer, isotopic substitution or a pharma- ceutically acceptable salt thereof, and a carrier or diluent, wherein the carrier or diluent is a mixture of mannitol and starch, a mixture of mannitol and cellulose, or cellulose.

2. 2. The pharmaceutical composition of claim 1, wherein the carrier or diluent is a mixture of mannitol and starch.

3. 3) a mixture of mannitol and starch in an amount of about 85 to about 99.7% w / w; 4) a disintegrant in an amount of about 0 to about 6% w / w; 5) a lubricant in an amount of about 0 to about 2% w / w; and 6) a lubricant in an amount of about 0 to about 10% w / w.

4. 4. The pharmaceutical composition of claim 3, wherein compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitution, or pharma- ceutically acceptable salt thereof, is the hydrochloride salt of compound 1.

5. The pharmaceutical composition according to claim 4 , wherein the hydrochloride of compound 1 is a crystalline form of the hydrochloride of compound 1.

6. 5. The pharmaceutical composition of claim 4, wherein the hydrochloride salt of Compound 1 is characterized by an XRPD pattern comprising peaks at about 15.1, 16.3, and 20.7 degrees 2θ.

7. 7. The pharmaceutical composition of any one of claims 3 to 6, wherein the amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitute, or pharma- ceutically acceptable salt thereof is from about 0.1 to about 1% w / w.

8. 8. The pharmaceutical composition of claim 7, wherein the amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopic substitute, or a pharma- ceutically acceptable salt thereof is from about 0.14 to about 0.71% w / w.

9. The pharmaceutical composition according to any one of claims 3 to 8, wherein the starch is pregelatinized starch.

10. 10. The pharmaceutical composition according to any one of claims 3 to 9, wherein the amount of mannitol is from about 67 to about 77.7% w / w and the amount of starch is from about 18 to about 22% w / w.

11. A pharmaceutical composition according to any one of claims 3 to 9, wherein the amount of the mixture of mannitol and starch is from about 90 to about 95% w / w.

12. 12. The pharmaceutical composition of claim 11, wherein the amount of mannitol is from about 71 to about 74% w / w and the amount of starch is from about 19 to about 21% w / w.

13. A pharmaceutical composition according to any one of claims 3 to 9, wherein the amount of the mixture of mannitol and starch is from about 91.5 to about 93% w / w.

14. 14. The pharmaceutical composition of claim 13, wherein the amount of mannitol is about 71.5 to about 73% w / w and the amount of starch is about 20% w / w.

15. The pharmaceutical composition according to any one of claims 3 to 9, wherein the weight ratio of starch and mannitol is from about 1:3 to about 1:

4.

16. 16. The pharmaceutical composition of claim 15, wherein the weight ratio of starch and mannitol is about 1:3.

6.

17. The pharmaceutical composition according to any one of claims 3 to 16, wherein the disintegrant is crospovidone.

18. The pharmaceutical composition according to any one of claims 3 to 17, wherein the amount of disintegrant is from about 1 to about 5% w / w.

19. 20. The pharmaceutical composition of claim 18, wherein the amount of disintegrant is about 3% w / w.

20. The pharmaceutical composition according to any one of claims 3 to 19, wherein the lubricant is silicon dioxide.

21. A pharmaceutical composition according to any one of claims 3 to 20, wherein the amount of lubricant is from about 0.5 to about 1.5% w / w.

22. 22. The pharmaceutical composition of claim 21, wherein the amount of lubricant is about 1% w / w.

23. The pharmaceutical composition according to any one of claims 3 to 22, wherein the lubricant is sodium stearyl fumarate, stearic acid or magnesium stearate.

24. 24. The pharmaceutical composition according to any one of claims 3 to 23, wherein the amount of lubricant is from about 1.5 to about 7.5% w / w.

25. 25. The pharmaceutical composition of claim 24, wherein the amount of lubricant is from about 3 to about 5% w / w.

26. 4) silicon dioxide in an amount of about 1% w / w; and 5) sodium stearyl fumarate in an amount of about 3% w / w.

27. 27. The pharmaceutical composition of claim 26, wherein the total weight is about 75 mg.

28. 28. The pharmaceutical composition of claim 27, contained in a size 4 capsule.

29. 4) silicon dioxide in an amount of about 1% w / w; and 5) sodium stearyl fumarate in an amount of about 3% w / w.

30. 30. The pharmaceutical composition of claim 29, wherein the total weight is about 75 mg.

31. 31. The pharmaceutical composition of claim 30, contained in a size 4 capsule.

32. 30. The pharmaceutical composition of claim 29, wherein the total weight is about 225 mg.

33. 33. The pharmaceutical composition of claim 32, contained in a size 1 capsule.

34. 4. The pharmaceutical composition of claim 3, comprising: 1) the hydrochloride salt of compound 1 in an amount of about 0.14% w / w; 2) mannitol in an amount of about 71.86% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

35. 4. The pharmaceutical composition of claim 3, comprising: 1) the hydrochloride salt of compound 1 in an amount of about 0.14% w / w; 2) mannitol in an amount of about 75.86% w / w and pregelatinized starch in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) magnesium stearate in an amount of about 1% w / w.

36. 2. The pharmaceutical composition of claim 1, wherein the carrier or diluent is a mixture of mannitol and cellulose.

37. 37. The pharmaceutical composition of claim 36, comprising: 1) compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05 to about 2% w / w; 2) a mixture of mannitol and cellulose in an amount of about 85 to about 99.7% w / w; 3) a disintegrant in an amount of about 0 to about 6% w / w; and 4) a lubricant in an amount of about 0 to about 10% w / w.

38. 38. The pharmaceutical composition of claim 37, comprising: 1) the hydrochloride salt of compound 1 in an amount of about 0.14% w / w; 2) mannitol in an amount of about 73.86% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) sodium stearyl fumarate in an amount of about 3% w / w.

39. 38. The pharmaceutical composition of claim 37, comprising: 1) the hydrochloride salt of compound 1 in an amount of about 0.14% w / w; 2) mannitol in an amount of about 71.86% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) crospovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

40. 2. The pharmaceutical composition of claim 1, wherein the carrier or diluent is cellulose.

41. 41. The pharmaceutical composition of claim 40, comprising: 1) compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, in an amount of about 0.05 to about 2% w / w; 2) cellulose in an amount of about 75 to about 95% w / w; and 3) a disintegrant in an amount of about 0 to about 20% w / w; and 4) a lubricant in an amount of about 0 to about 10% w / w.

42. 42. The pharmaceutical composition of claim 41, comprising: 1) about 0.14% w / w of the hydrochloride salt of compound 1; 2) about 84.86% w / w of microcrystalline cellulose; 3) about 10% w / w of crospovidone; and 4) about 5% w / w of stearic acid.

43. A pharmaceutical composition according to any one of claims 1 to 42 for treating hematological malignancies.

44. 44. The pharmaceutical composition of claim 43, wherein the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL) or myelodysplastic syndrome (MDS).

45. 43. A method for preparing the pharmaceutical composition of any one of claims 1 to 42, comprising the steps of: (i) mixing Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, with a first amount of an excipient(s) (intraglan- tic excipients) and water to form a wet granule; (ii) drying the granule, and then milling the granule; and (iii) mixing the milled granule with the remaining excipient(s) (extragranular excipients) to form a final mixture.

46. 46. ​​The method of claim 45, wherein the intragranular / extragranular excipient ratio is about 23:

77.

47. 47. The method of claim 45 or 46, wherein compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, is passed through a 60 mesh screen or a screen having a smaller pore size prior to step (i).

48. A method according to any one of claims 45 to 47, wherein the particle size of the milled granules corresponds to the particle size of the main component of the extragranular excipient.

49. 43. A method for producing the pharmaceutical composition of any one of claims 1 to 42, comprising the steps of: (i) mixing Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, with a first amount of an excipient(s) (intraglan- tic excipients) to form an intragranular mixture; (ii) passing the intragranular mixture through a roller compactor to form a dry granulation; and (iii) mixing the dry granulation with the remaining excipients (extragranular excipients) to form a final mixture.

50. 50. The method of claim 49, wherein compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic substitution, or a pharma- ceutically acceptable salt thereof, is passed through a 60 mesh screen or a screen having a smaller pore size prior to step (i).

51. 51. The method of claim 50, wherein the intragranular / extragranular excipient ratio is about 98:2.

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