Pharmaceutical compositions containing compounds and methods of use thereof

Abstract

This document relates to pharmaceutical compositions comprising compounds and methods of using thereof, and particularly provides pharmaceutical compositions (e.g., oral formulations) containing (S)-2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione or an enantiomer, mixture of enantiomers, tautomers, isotopes or pharmaceutically acceptable salt thereof, and a carrier or diluent. Methods for preparing said pharmaceutical compositions and methods for using said pharmaceutical compositions are also provided herein.

Description

[0001] The applicant filed PCT application PCT / US2020 / 056410 on October 20, 2020, entitled "Pharmaceutical composition comprising (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione and method of use thereof". This PCT application entered the Chinese national phase on June 20, 2022, with application number 202080088915.6. This application is a divisional application of that Chinese application.

[0002] This application claims priority to U.S. Provisional Application No. 62 / 923,927, filed October 21, 2019, which is incorporated herein by reference. 1. Technical Field

[0003] This document provides pharmaceutical compositions comprising (S)-2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione or an enantiomer, mixture of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salt thereof, and a carrier or diluent. This document also provides methods for using said pharmaceutical compositions to treat, prevent, and manage various diseases. 2. Background Technology

[0004] The main characteristic of cancer is an increase in the number of abnormal cells originating from designated normal tissues. These abnormal cells invade adjacent tissues or spread to local lymph nodes and metastasize via lymphatic or hematogenous spread of malignant cells. Clinical data and molecular biological studies indicate that cancer is a multi-step process that begins with subtle precancerous changes that can develop into neoplasmosis under certain conditions. Neoplasmic lesions can undergo clonal evolution and develop an increased ability to invade, grow, metastasize, and heterogeneously, especially when tumor cells evade host immune surveillance. Current cancer treatments may include surgery, chemotherapy, hormone therapy, and / or radiation therapy to eradicate the patient's tumor cells. Recent advances in cancer treatment are discussed by Rajkumar et al. in Nature Reviews Clinical Oncology 11, 628–630 (2014).

[0005] All current cancer treatments come with significant drawbacks for patients. For example, surgery may be contraindicated or unacceptable to the patient due to their health condition. Furthermore, surgery may not completely remove tumor tissue. Radiation therapy is only effective when tumor tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy also frequently causes severe side effects. Hormone therapy is rarely administered as a single drug. While it can be effective, it is often used to prevent or delay cancer recurrence after other treatments have cleared most of the cancer cells.

[0006] Despite the availability of various chemotherapy drugs, chemotherapy has many drawbacks. Almost all chemotherapy drugs are toxic, and chemotherapy causes severe, often dangerous, side effects, including severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even with combined use of chemotherapy drugs, many tumor cells develop or become resistant to them. In fact, cells resistant to a specific chemotherapy drug used in a treatment regimen often prove resistant to other drugs, even those with different mechanisms of action. This phenomenon is called multidirectional resistance or multidrug resistance. Due to resistance, many cancers prove or become refractory to standard chemotherapy regimens.

[0007] Hematological malignancies are cancers originating from 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 lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), and myelodysplastic syndromes (MDS).

[0008] The variety of possible pharmaceutical compositions (e.g., oral formulations containing different excipients) contributes to the potential diversity of physical and chemical properties of a given pharmaceutical compound. The discovery and selection of pharmaceutical compositions are crucial for developing an effective, stable, and commercially viable drug. 3. Summary of the Invention

[0009] This article provides pharmaceutical compositions (e.g., oral formulations) comprising compound 1:

[0010]

[0011] Compound 1 may be an enantiomer, mixture of enantiomers, tautomers, isotopes, or a pharmaceutically acceptable salt thereof, and a carrier or diluent. Compound 1 has the chemical name (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. Methods for preparing pharmaceutical compositions are also provided herein. Compound 1, or its enantiomers, mixtures of enantiomers, tautomers, isotopes, or a pharmaceutically acceptable salt thereof, are also collectively referred to as "Compound A".

[0012] In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, or a mixture thereof. In another embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, a mixture of mannitol and cellulose, or a mixture of mannitol and starch. In yet another embodiment, the carrier or diluent is a mixture of mannitol and starch. In some embodiments, the terms "carrier" or "diluent" may be used interchangeably with the term "adhesive."

[0013] The pharmaceutical compositions provided herein are useful formulations for use in animals or humans. Therefore, embodiments of this document include the use of these pharmaceutical compositions as final pharmaceutical products. Some embodiments provide pharmaceutical compositions for preparing a final dosage form with improved properties, such as powder flowability, compactibility, tablet compressibility, stability, and excipient compatibility, which are necessary for the production, processing, formulation, and / or storage of the final pharmaceutical product.

[0014] Also provided are pharmaceutical compositions formulated for administration via appropriate routes and methods, comprising an effective concentration of compound A (e.g., compound 1 provided herein). In one embodiment, the pharmaceutical composition is an oral formulation. In one embodiment, the pharmaceutical composition is an immediate-release (IR) oral formulation.

[0015] In one embodiment, the pharmaceutical composition delivers an amount effective for treating hematologic malignancies. In one embodiment, the pharmaceutical composition delivers an amount effective for preventing hematologic malignancies. In one embodiment, the pharmaceutical composition delivers an amount effective for improving hematologic malignancies.

[0016] In one implementation scheme, the hematologic malignancy is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), or myelodysplastic syndrome (MDS).

[0017] 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 improving non-Hodgkin's lymphoma.

[0018] This document also provides methods for using the pharmaceutical compositions provided herein, alone or in combination with rituximab, for the treatment, prevention, or management of non-Hodgkin's lymphoma (NHL). In one embodiment, the method is used for the treatment of NHL. In one embodiment, the method is used for the prevention of NHL. In one embodiment, the method is used for the management of NHL.

[0019] In some implementations, NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary central nervous system lymphoma (PCNSL).

[0020] This document also provides methods for using the pharmaceutical compositions provided herein, alone or in combination with atoruzumab, for the treatment, prevention, or management of chronic lymphocytic leukemia (CLL). In one embodiment, the method is used for the treatment of CLL. In one embodiment, the method is used for the prevention of CLL. In one embodiment, the method is used for the management of CLL.

[0021] This document also provides methods for using the pharmaceutical compositions provided herein, alone or in combination with atoruzumab, for the treatment, prevention, or management of small lymphocytic lymphoma (SLL). In one embodiment, the method is used for the treatment of SLL. In one embodiment, the method is used for the prevention of SLL. In one embodiment, the method is used for the management of SLL.

[0022] This article also provides a method of using the pharmaceutical composition provided herein for treating the disease provided herein, wherein the method includes administering a therapeutically effective amount of the pharmaceutical composition to a patient.

[0023] Also provided are pharmaceutical packages or cartons comprising one or more containers filled with one or more components of a pharmaceutical composition. Optionally associated with said container may be a notice in the form of a government agency regulation governing the production, use, or sale of the pharmaceutical or biological product, reflecting approval from the manufacturing institution for sale and use in human use. The package or carton may be labeled with information relating to the method of administration, the order of administration (e.g., alone, sequentially, or simultaneously).

[0024] Furthermore, methods for preparing the pharmaceutical compositions provided herein are provided.

[0025] The above and other aspects of the subject matter described herein will become apparent upon reference to the detailed description below. 4. Brief description of the attached diagram

[0026] Figure 1A , Figure 1B and Figure 1C The chemical stability (total impurities) of the prototype formulation was shown for up to 12 weeks under the conditions of 40°C / 75%RH without desiccant, 40°C / 75%RH with desiccant, and 50°C / 75%RH with desiccant.

[0027] Figure 2A , Figure 2B and Figure 2C The data show the chiral stability of the prototype formulation for up to 12 weeks under the following conditions: 40°C / 75%RH without desiccant, 40°C / 75%RH with desiccant, and 50°C / 75%RH with desiccant.

[0028] Figure 3 Provide a flowchart of the wet granulation process.

[0029] Figure 4 Provide a flowchart of the RC process.

[0030] Figure 5 The dissolution profiles are shown for the roller compaction batch (Cap-5) and the high-shear wet granulation batch (Cap-10).

[0031] Figure 6 The flowchart shows the crushing process for Cap-5 formulation batches.

[0032] Figure 7 Provide a representative XRPD plot of compound 1 hydrochloride in form A.

[0033] 5. Detailed Explanation

[0034] 5.1 Definition

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for terms used herein, the definitions in this section shall prevail unless otherwise stated.

[0036] As used herein, as well as in the specification and appended claims, the indefinite articles “a” and “an” and the definite article “the” include both plural and singular things, unless the context clearly indicates otherwise.

[0037] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be understood to specify the presence of the mentioned features or components, but do not exclude the presence or addition of one or more features or components or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include examples covered by the term “consisting of”. Therefore, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0038] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the said features or components constituting it. In another embodiment, the term "consisting of" excludes any other features or components from any subsequent enumeration, except those features or components that are not essential to the desired technical effect.

[0039] As used herein, the term "or" should be understood as inclusive, meaning any one or any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C". Exceptions to this definition only arise when a combination of elements, functions, steps, or behaviors is inherently mutually exclusive in some way.

[0040] As used herein and unless otherwise specified, when used in conjunction with a dose, amount, or weight percentage of a component of a composition or dosage form, the terms “about” and “approximately” mean a dose, amount, or weight percentage recognized by those skilled in the art as providing a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. In some embodiments, when used in the context, the terms “about” and “approximately” mean a dose, amount, or weight percentage within the range of 30%, 20%, 15%, 10%, or 5% of the specified dose, amount, or weight percentage.

[0041] As used herein and unless otherwise stated, when used in conjunction with numerical values ​​or ranges of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., 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., mass or percentage); or peak position (e.g., by IR or Raman spectroscopy or XRPD analysis), the terms "about" and "approximately" indicate that the value or range of values ​​may deviate to a degree that would be reasonable to a person skilled in the art while still describing the particular solid form. For example, in certain embodiments, when used in the context, the terms "about" and "approximately" indicate that the numerical value or range of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the value or range of values. For example, in some embodiments, the value of the XRPD peak position may vary within a range of up to ±0.2°2θ while still describing the particular XRPD peak. As used in this article, the tilde (i.e., "~") preceding a numerical value or range indicates "about" or "approximately".

[0042] Unless otherwise specified, the terms “X-ray powder diffraction”, “powder X-ray diffraction”, “PXRD” and “XRPD” may be used interchangeably in this application.

[0043] As used herein and unless otherwise stated, the term "solid form" and related terms refer to a physical form that is not primarily in a liquid or gaseous state. As used herein, the term "solid form" includes semi-solids. Solid forms can be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of various forms.

[0044] As used herein and unless otherwise specified, when used to describe a substance, component, product, or form, the term "crystalline" and related terms as used herein mean that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams, and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd edition, 1843-1844 (1995).

[0045] As used herein and unless otherwise specified, the terms "amorphous," "amorphous form," and related terms as used herein mean that the substance, component, or product under discussion is substantially non-crystalline, as determined by X-ray diffraction. Specifically, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long-range crystal order. In some embodiments, the amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In other embodiments, the amorphous form of a substance may comprise less than about 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, or 50 wt% of one or more other amorphous and / or crystalline forms. In some embodiments, the amorphous form of a substance may be physically and / or chemically pure. In some embodiments, the amorphous form of the substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure. In some embodiments, the amorphous form of the substance may include other components or ingredients (e.g., additives, polymers, or excipients that may be used to further stabilize the amorphous form). In some embodiments, the amorphous form may be a solid solution.

[0046] As used herein and unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable, relatively non-toxic acid (including inorganic and organic acids). In some embodiments, suitable acids include, but are not limited to, acetic acid, adipic acid, 4-aminosalicylic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, carbonic acid, citric acid, cyclohexylsulfamic acid, dihydrogen phosphate, 2,5-dihydroxybenzoic acid (gentianic acid), 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, and hydrogen. Iodic acid, isobutyric acid, isothiocyanate, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, monohydrocarbonic acid, monohydrophosphoric acid, monohydrosulfuric acid, mucoic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, nitric acid, oxalic acid, primic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, pyroglutamic acid, salicylic acid, linalic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, etc. (see, for example, SMBerge et al., J. Pharm. Sci., 66: 1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, eds. PHStahl and CGWermuth, (2002), Wiley, Weinheim). In some embodiments, the suitable acid is a strong acid (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, pyridine-sulfonic acid, or other substituted sulfonic acids. Salts of other relatively non-toxic compounds with acidic properties are also included, such as amino acids like aspartic acid, and other compounds like aspirin, ibuprofen, saccharin, etc. Acid addition salts can be obtained by contacting a neutral form of the compound with a sufficient amount of the desired acid (pure acid or in a suitable solvent). As a solid, the salt can exist in crystalline or amorphous form or mixtures thereof. The salt can also exist in polycrystalline form.

[0047] It should be noted that if there is a difference between the drawn structure and its name, the drawn structure should be given more weight.

[0048] As used herein and unless otherwise stated, the term “treatment” means the complete or partial relief of one or more symptoms of a patient, disease, or condition, or related to the patient, disease, or condition, or the slowing or halting of the further progression or worsening of said symptoms, or the reduction or elimination of the cause of the patient, disease, or condition itself.

[0049] As used herein and unless otherwise stated, the term “prevention” means, in whole or in part, delaying and / or preventing the onset, recurrence or spread of a patient, disease or condition; preventing an individual from acquiring a patient, disease or condition; or reducing an individual’s risk of acquiring a patient, disease or condition.

[0050] As used herein and unless otherwise stated, the term “management” includes preventing a specific disease or relapse in a patient with the disease, prolonging the duration of remission in a patient with the disease or condition, reducing patient mortality, and / or maintaining or avoiding the severity of symptoms associated with the managed disease or condition.

[0051] As used herein and unless otherwise stated, the term “effective amount” in relation to a compound means an amount that is sufficient to treat, prevent, or manage a patient, disease, condition, or its symptoms.

[0052] As used herein and unless otherwise stated, the terms “individual” or “patient” include animals, including but not limited to cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals and in another embodiment are humans.

[0053] As used herein and unless otherwise stated, the term "relapse" refers to a patient, disease, or condition that has responded to treatment (e.g., achieved a complete response) and then worsens. Treatment may include one or more therapies. In one embodiment, the patient, disease, or condition has previously been treated with one or more therapies. In another embodiment, the patient, disease, or condition has previously been treated with one, two, three, or four therapies. In some embodiments, the patient, disease, or condition is a hematologic malignancy.

[0054] In one embodiment, "relapsed" DLBCL can refer to DLBCL that has been previously treated with one or more treatment methods. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with one, two, three, or four treatment methods. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with two or more treatment methods.

[0055] In one embodiment, "relapsed" FL can refer to FL previously treated with one or more therapies. In one embodiment, relapsed FL is FL previously treated with one, two, three, or four treatment methods. In one embodiment, relapsed FL is FL previously treated with two or more therapies.

[0056] As used herein and unless otherwise stated, the term "refractory" refers to a patient, disease, or condition that does not respond to prior treatment, which may include one or more therapies. In one embodiment, the patient, disease, or condition has been previously treated with one, two, three, or four therapies. In one embodiment, the patient, disease, or condition has been previously treated with two or more therapies and shows less than a complete response (CR) to the most recent therapy comprising the treatment regimen. In some embodiments, the patient, disease, or condition is a hematologic malignancy.

[0057] In one embodiment, "relapsed or refractory" CLL / SLL may refer to CLL / SLL previously treated with one or more therapies. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL previously treated with one, two, three, or four therapies. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL previously treated with two or more therapies. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL 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.

[0058] For cancers such as hematologic malignancies, inhibition can be evaluated by suppressing disease progression, inhibiting tumor growth, reducing primary tumor size, alleviating tumor-related symptoms, inhibiting tumor-secreting factors, delaying the onset of primary or secondary tumors, slowing the development of primary or secondary tumors, reducing the incidence of primary or secondary tumors, mitigating or reducing the severity of secondary effects of the disease, preventing tumor growth and regression, increasing time to progression (TTP), increasing progression-free survival (PFS), and increasing overall survival (OS). OS as used in this article refers to the time from the start of treatment to death from any cause. TTP as used in this article refers to the time from the start of treatment to tumor progression; TTP does not include death. In one implementation, PFS refers to the time from the start of treatment to tumor progression or death. In one implementation, 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 implementation, the PFS rate is calculated using the Kaplan-Meier evaluation. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, including disease progression, treatment cessation from any cause, or death. In one implementation, the overall response rate (ORR) refers to the percentage of patients who achieve a response. In one implementation, ORR represents the sum of the percentages of patients achieving a complete and partial response. In one implementation, ORR represents the percentage of patients achieving an optimal response ≥ partial response (PR). In one implementation, Duration of Response (DoR) is the time from achieving a response until relapse or disease progression. In one implementation, DoR is the time from achieving a response ≥ partial response (PR) to relapse or disease progression. In one implementation, DoR is the time from the first recorded response to the first recorded disease progression or death. In one implementation, DoR is the time from the first recorded response ≥ partial response (PR) to the first recorded disease progression or death. In one implementation, Time to Response (TTR) refers to the time from the first administration of the compound to the first recorded response. In one implementation, TTR refers to the time from the first administration of the compound to the first recorded response ≥ partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention. In this context, the term "prophylaxis" includes complete prevention of clinically apparent cancer development or prevention of the occurrence of preclinically apparent stages of cancer. This definition is also intended to include prevention of transformation into malignant cells or halting or reversing the progression of preclinical cells to malignant cells. This includes prophylactic treatment for individuals at risk of developing cancer.

[0059] In some implementations, NHL treatment can be evaluated using the Deauville Criteria for fluorodeoxyglucose-positron emission tomography (FDG-PET) scan interpretation (see 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 (“Lugano Criteria”), using the response and endpoint definitions shown in Tables 1-3.

[0060] Table 1. Standards for Relevant Parts

[0061]

[0062]

[0063] CNS = Central Nervous System; CSF = Cerebrospinal Fluid; CT = Computed Tomography; FDG = Fluoride-deoxyglucose; GI = Gastrointestinal Tract; MRI = Magnetic Resonance Imaging; PET = Positron Emission Tomography; N / A = Not Applicable.

[0064] a PET / CT is sufficient to detect bone marrow involvement and is considered highly suggestive of involvement of other extraly lymphatic sites. If necessary, a biopsy of the affected sites may be considered for confirmation.

[0065] Table 2. Lugano response criteria for non-Hodgkin lymphoma.

[0066]

[0067]

[0068]

[0069] CMR = Complete metabolic response; LDi = Longest transverse diameter of the lesion; PPD = Cross product of LDi and vertical diameter; SDi = Shortest axis perpendicular to LDi; SPD = Sum of the products of vertical diameters of multiple lesions; N / A = Not applicable.

[0070] a Bone marrow involvement at baseline, CR requires

[0071] b In the Waldeyer's ring or extranodal sites with high physiological uptake or activation in the spleen or bone marrow (e.g., chemotherapy or myeloid colony-stimulating factor), uptake can be greater than in the normal mediastinum and / or liver. In such cases, if uptake at the initially affected site is not greater than in the surrounding normal tissue, CMR can be inferred.

[0072] c FDG-avid lymphoma should be evaluated for its response via PET-CT. Some diseases can usually be assessed on CT alone (e.g., marginal zone lymphoma).

[0073] d PET should be combined with contrast-enhanced diagnostic CT, and can be performed simultaneously or separately.

[0074] Table 3. PET Five-Point Scale (5-PS).

[0075] 1 No intake above the background. 2 Intake ≤ mediastinum 3 Intake > mediastinum but ≤ liver 4 Moderate intake > Liver 5 Intake significantly higher than liver and / or new lesions X The new uptake area is unlikely to be associated with lymphoma.

[0076] a The Deauville Five-Point Scale (5PS) is an internationally recommended clinical and clinical trial scale used for initial staging and treatment response assessment of Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphoma (NHL) using FDG-PET / CT.

[0077] In one implementation scheme, the treatment response to CLL / SLL can be evaluated using the International Workshop on Chronic Lymphocytic Leukemia criteria (see 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).

[0078] Table 4. Definition of response after treatment in patients with chronic lymphocytic leukemia.

[0079]

[0080]

[0081] CR = Complete remission (all criteria must be met); PD = Disease progression (at least one criterion from either Group A or Group B must be met); PR = Partial remission (for PR, if there were previous abnormalities, at least two parameters in Group A and at least one parameter in Group B need improvement; if there were only one abnormal parameter in Group A and Group B before treatment, only that parameter needs improvement); SD = Stable disease (all criteria must be met; isolated systemic symptoms cannot define PD).

[0082] a The total number of lymph node products (6 or fewer) (assessed by CT scans and physical examinations in clinical trials or physical examinations in general practice).

[0083] b A spleen size <13cm is considered normal. There is no clear international consensus regarding the normal size of the liver; therefore, in clinical trials, liver size should be assessed by imaging and manual palpation and recorded according to the definitions used in the study protocol.

[0084] In one implementation scheme, the treatment response to CLL / SLL can be assessed using the Eastern Cooperative Oncology Group (ECOG) performance status (Table 5).

[0085] Table 5. ECOG performance status.

[0086]

[0087] ECOG = Eastern Cooperative Oncology Group, Robert Comis, MD, Chair of the Cooperative Group.

[0088] Source: Oken M et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 5(6): 649-655 (1982).

[0089] In some implementations, stable disease or absence of disease can be determined by methods known in the art, such as evaluating patient symptoms, physical examination, visualization of already imaged tumors, such as using 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), ophthalmological examination, vitreous fluid sampling, retinal photographs, bone marrow evaluation, and other recognized evaluation methods.

[0090] As used herein and unless otherwise stated, the terms "co-administered" and "in combination with" include the simultaneous, joint, or sequential administration of one or more therapeutic substances (e.g., compounds provided herein and another anticancer substance or supportive care substance) without a specific time limit. In one embodiment, the substances are simultaneously present in cells or the patient's body or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic substances are in the same composition or unit dosage form. In another embodiment, the therapeutic substances are in separate compositions or unit dosage forms.

[0091] The term "supportive care substance" refers to any substance used to treat, prevent, or manage adverse reactions resulting from treatment with other therapeutic substances.

[0092] 5.2 Pharmaceutical compositions comprising compound 1

[0093] In some embodiments, this document provides pharmaceutical compositions (e.g., oral formulations) comprising compound 1:

[0094]

[0095] Compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes or pharmaceutically acceptable salts, as well as carriers or diluents. Compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes or pharmaceutically acceptable salts are also collectively referred to as "Compound A".

[0096] In one embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, or a mixture thereof. In another embodiment, the carrier or diluent is mannitol, lactose, starch, cellulose, a mixture of mannitol and cellulose, or a mixture of mannitol and starch. In yet another embodiment, the carrier or diluent is a mixture of mannitol and starch. In some embodiments, the term "carrier" may be used interchangeably with the term "adhesive."

[0097] In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration to patients. In one embodiment, the pharmaceutical compositions provided herein exhibit advantageous physical and / or pharmacological properties. These properties include, but are not limited to, ease of determination, uniformity of content, flowability of the produced product, 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 under non-refrigerated conditions. In some embodiments, "non-refrigerated" means at a temperature of 20°C or above. In one embodiment, the pharmaceutical compositions provided herein are stored under refrigerated conditions. In one embodiment, the pharmaceutical compositions provided herein, when stored under refrigerated conditions, 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. In one embodiment, the properties of the pharmaceutical compositions provided herein make them suitable for immediate release (IR).

[0098] The pharmaceutical compositions provided herein can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release preparations, or elixirs for oral administration, or sterile solutions or suspensions for ocular or parenteral administration, as well as transdermal patch preparations and dry powder inhalers. Typically, the above 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, 10th edition, 2013). In one embodiment, the pharmaceutical composition provided herein is an oral dosage form. In one embodiment, the oral unit dosage form is a tablet. In one embodiment, the oral unit dosage form is a caplet. In one embodiment, the oral unit dosage form is a capsule. In one embodiment, the pharmaceutical composition provided herein is an immediate-release capsule.

[0099] Tablets, capsules, and pouches typically contain about 50 mg to about 500 mg of a pharmaceutical composition (i.e., the active ingredient and excipients). Capsules can be of any size. Examples of standard sizes include #000, #00, #0, #1, #2, #3, #4, and #5. See, for example, Remington's Pharmaceutical Sciences, pp. 1658-1659 (edited. Alfonso Gennaro, Mack Publishing Company, Easton Pennsylvania, 18th edition, 1990), which is incorporated herein by reference. In some embodiments, the capsules provided herein have a size of #1 or larger, #2 or larger, #3 or larger, or #4 or larger.

[0100] In the composition, one or more compounds or pharmaceutically acceptable salts at effective concentrations are mixed with a suitable drug carrier or solvent. In some embodiments, the concentration of the compounds in the composition is effective for delivering an amount at administration that treats, prevents, or improves one or more symptoms and / or progression of non-Hodgkin's lymphoma.

[0101] (a) Form of compound 1

[0102] Compound 1 has the chemical name (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. The method for preparing compound 1 is described in U.S. Patent Application No. 16 / 390,815, the entirety of which is incorporated herein by reference.

[0103] In one embodiment, compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salts are provided in a solid form in the pharmaceutical composition. 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 an anhydrous compound. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is non-solventized. In one embodiment, the solid form is amorphous.

[0104] The solid form can be characterized using many methods known to those skilled 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), and hot-stage microscopy), dynamic vapor adsorption (DVS), spectroscopy (e.g., infrared, Raman, and nuclear magnetic resonance), and high-performance liquid chromatography (HPLC). The particle size and particle size distribution of the solid forms described herein can be determined using conventional methods such as laser light scattering techniques.

[0105] In one embodiment, the pharmaceutical composition comprises a 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.

[0106] In one embodiment, the pharmaceutical composition comprises a salt of compound 1. In one embodiment, the salt is a hydrochloride, fumarate, toluenesulfonate, maleate, or benzenesulfonate of compound 1. 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.

[0107] In one embodiment, the pharmaceutical composition comprises the hydrochloride salt of compound 1. In one embodiment, the pharmaceutical composition comprises the fumarate salt of compound 1. In one embodiment, the pharmaceutical composition comprises the toluenesulfonate salt of compound 1. In one embodiment, the pharmaceutical composition comprises the maleate salt of compound 1. In one embodiment, the pharmaceutical composition comprises the benzenesulfonate salt of compound 1.

[0108] In one embodiment, the pharmaceutical composition comprises compound 1 hydrochloride in the form of A.

[0109] In one embodiment, form A is a hydrate of the hydrochloride salt of compound 1. In another embodiment, form A is a channel hydrate of the hydrochloride salt of compound 1.

[0110] Figure 7 The image provides a representative XRPD plot of compound 1 in hydrochloride form A.

[0111] In one embodiment, the pharmaceutical composition provided herein comprises a hydrochloride salt of compound 1 in solid form, said solid form being characterized by peaks located at approximately the following positions: 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 or all of the following: 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 of the said peaks. In one embodiment, the solid form is characterized by 5 of the said peaks. In one embodiment, the solid form is characterized by 7 of the said peaks. In one embodiment, the solid form is characterized by 9 of the said peaks. In one embodiment, the solid form is characterized by 11 of the said peaks. In one embodiment, the solid form is characterized by all of the said peaks.

[0112] In one embodiment, the pharmaceutical composition provided herein comprises a hydrochloride salt of compound 1 in solid form, characterized by an XRPD plot including peaks at approximately 15.1, 16.3, and 20.7°2θ. In one embodiment, the XRPD plot further includes peaks at approximately 7.8 and 22.4°2θ. In one embodiment, the XRPD plot further includes peaks at approximately 18.2, 18.9, and 24.8°2θ. In one embodiment, the XRPD plot includes peaks at approximately 7.8, 15.1, 16.3, 17.9, 18.2, 18.9, 19.2, 20.4, 20.7, 21.7, 22.4, and 24.8°2θ.

[0113] In one embodiment, the pharmaceutical composition provided herein comprises a hydrochloride salt of compound 1 in solid form, characterized by an XRPD plot including peaks at approximately 4.2, 7.8, and 11.1°2θ. In one embodiment, the XRPD plot includes peaks at approximately 4.2, 7.8, 11.1, 12.4, and 15.1°2θ. In one embodiment, the XRPD plot includes peaks at approximately 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, and 16.3°2θ. In one embodiment, the XRPD plot includes peaks at approximately 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1, and 17.3°2θ.

[0114] In one embodiment, the pharmaceutical composition provided herein comprises a hydrochloride salt of compound 1 in solid form, characterized by being... Figure 7 The XRPD diagram presented in the image matches the XRPD diagram.

[0115] In one embodiment, XRPD maps are obtained using Cu Kα radiation.

[0116] (b) Mannitol-starch based pharmaceutical compositions

[0117] In one embodiment, the carrier or diluent in the pharmaceutical composition provided herein is a mixture of mannitol and starch.

[0118] In one embodiment, the pharmaceutical composition further includes a disintegrant, a flow aid, a lubricant, or a mixture thereof.

[0119] In one embodiment, this document provides a pharmaceutical composition comprising: 1) a compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotope or pharmaceutically acceptable salt thereof, in an amount of about 0.05% w / w to about 2% w / w; 2) a mixture of mannitol and starch in an amount of about 85% w / w to about 99.7% w / w; 3) a disintegrant in an amount of about 0% w / w to about 6% w / w; 4) a gliding agent in an amount of about 0% w / w to about 2% w / w; and 5) a lubricant in an amount of about 0% w / w to about 10% w / w.

[0120] In one embodiment, compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salts are hydrochloride salts of compound 1. In one embodiment, the hydrochloride salt of compound 1 is a crystalline form of compound 1 hydrochloride. In one embodiment, the hydrochloride salt of compound 1 is characterized by an XRPD plot including peaks at approximately 15.1, 16.3, and 20.7°2θ.

[0121] In one embodiment, the amount of compound 1 or its enantiomers, enantiomer mixtures, tautomers, isotopes, or pharmaceutically acceptable salts is from about 0.05% w / w to about 2% w / w (by the total weight of the pharmaceutical composition). In one embodiment, the amount is from about 0.07% w / w to about 1.5% w / w. In one embodiment, the amount is from about 0.1% w / w to about 1% w / w. In one embodiment, the amount is from about 0.14% w / w to about 0.71% w / w. In one embodiment, the amount is from about 0.1% w / w to about 0.2% w / w. In one embodiment, the amount is from about 0.6% w / w to about 0.8% w / w.

[0122] In one embodiment, the amount of compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salts is about 0.05% w / w, about 0.06% w / w, about 0.08% w / w, about 0.09% w / w, about 0.1% w / w, about 0.11% w / w, about 0.12% w / w, about 0.13% w / w, about 0.14% w / w, about 0.15% w / w, about 0.16% w / w, about 0.17% w / w, about 0.18% w / w, about 0.19% w / w, about 0.2% w / w, about 0.25% w / w, about 0.3% w / w, Approximately 0.35% w / w, approximately 0.4% w / w, approximately 0.45% w / w, approximately 0.5% w / w, approximately 0.6% w / w, approximately 0.65% w / w, approximately 0.7% w / w, approximately 0.75% w / w, approximately 0.8% w / w, approximately 0.85% w / w, approximately 0.9% w / w, approximately 0.95% w / w, approximately 1% w / w, approximately 1.1% w / w, approximately 1.2% w / w, approximately 1.3% w / w, approximately 1.4% w / w, approximately 1.5% w / w, approximately 1.6% w / w, approximately 1.7% w / w, approximately 1.8% w / w, approximately 1.9% w / w, or approximately 2% w / w. In one embodiment, the amount is approximately 0.14% w / w. In one embodiment, the amount is approximately 0.142% w / w. In one embodiment, the amount is approximately 0.71% w / w. In another embodiment, the amount is approximately 0.712% w / w.

[0123] In one embodiment, the starch is partially pregelatinized starch.

[0124] In one embodiment, the amount of the mannitol and starch mixture is from about 85% w / w to about 99.7% w / w (by total weight of the pharmaceutical composition). In one embodiment, the amount of the starch and lactose mixture is from about 87.5% w / w to about 97.5% w / w. In one embodiment, the amount of the starch and lactose mixture is from about 90% w / w to about 95% w / w. In one embodiment, the amount of the starch and lactose mixture is from about 91.5% w / w to about 93% w / w. In one embodiment, the amount of the starch and lactose mixture is from about 92% w / w to about 93% w / w.

[0125] In one embodiment, the amount of mannitol and starch mixture is approximately 85% w / w, approximately 86% w / w, approximately 87% w / w, approximately 88% w / w, approximately 89% w / w, approximately 90% w / w, approximately 90.5% w / w, approximately 91% w / w, approximately 91.5% w / w, approximately 91.6% w / w, approximately 91.7% w / w, approximately 91.8% w / w, approximately 91.9% w / w, approximately 92% w / w, approximately 92.1% w / w, approximately 92.2% w / w, approximately... 92.3% w / w, approximately 92.4% w / w, approximately 92.5% w / w, approximately 92.6% w / w, approximately 92.7% w / w, approximately 92.8% w / w, approximately 92.9% w / w, approximately 93% w / w, approximately 93.5% w / w, approximately 94% w / w, approximately 94.5% w / w, approximately 95% w / w, approximately 96% w / w, approximately 97% w / w, approximately 98% w / w, approximately 99% w / w, approximately 99.5% w / w, or approximately 99.7% w / w. In one embodiment, the amount of the mannitol and starch mixture is approximately 91.9% w / w. In one embodiment, the amount of the mannitol and starch mixture is approximately 92.3% w / w. In one embodiment, the amount of the mannitol and starch mixture is approximately 92.9% w / w. In one embodiment, the amount of the mannitol and starch mixture is approximately 91.86% w / w. In another embodiment, the amount of the mannitol and starch mixture is approximately 92.29% w / w. In yet another embodiment, the amount of the mannitol and starch mixture is approximately 92.86% w / w.

[0126] In one embodiment, the amount of mannitol is from about 67% w / w to about 77.7% w / w, and the amount of starch is from about 18% w / w to about 22% w / w. In another embodiment, the amount of mannitol is from about 69% w / w to about 76% w / w, and the amount of starch is from about 18.5% w / w to about 21.5% w / w. In another embodiment, the amount of mannitol is from about 71% w / w to about 74% w / w, and the amount of starch is from about 19% w / w to about 21% w / w. In another embodiment, the amount of mannitol is from about 71.5% w / w to about 73% w / w, and the amount of starch is about 20% w / w. In yet another embodiment, the amount of mannitol is from about 72% w / w to about 73% w / w, and the amount of starch is about 20% w / w.

[0127] In one embodiment, the amount of mannitol is approximately 67% w / w, approximately 68% w / w, approximately 69% w / w, approximately 70% w / w, approximately 70.5% w / w, approximately 71% w / w, approximately 71.5% w / w, approximately 71.6% w / w, approximately 71.7% w / w, approximately 71.8% w / w, approximately 71.9% w / w, approximately 72% w / w, approximately 72.1% w / w, approximately 72.2% w / w, and approximately 72%. 3% w / w, approximately 72.4% w / w, approximately 72.5% w / w, approximately 72.6% w / w, approximately 72.7% w / w, approximately 72.8% w / w, approximately 72.9% w / w, approximately 73% w / w, approximately 73.5% w / w, approximately 74% w / w, approximately 74.5% w / w, approximately 75% w / w, approximately 76% w / w, approximately 77% w / w, approximately 77.5% w / w, or approximately 77.7% w / w. In one embodiment, the amount of mannitol is approximately 71.9% w / w. In one embodiment, the amount of mannitol is approximately 72.3% w / w. In one embodiment, the amount of mannitol is approximately 72.9% w / w. In one embodiment, the amount of mannitol is approximately 71.86% w / w. In one embodiment, the amount of mannitol is approximately 72.29% w / w. In another embodiment, the amount of mannitol is approximately 72.86% w / w.

[0128] In one embodiment, the amount of starch is approximately 18% w / w, approximately 18.5% w / w, approximately 19% w / w, approximately 19.5% w / w, approximately 20% w / w, approximately 20.5% w / w, approximately 21% w / w, approximately 21.5% w / w, or approximately 22% w / w. In another embodiment, the amount of starch is approximately 20% w / w.

[0129] 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.

[0130] In one embodiment, the disintegrant is cropovidone.

[0131] In one embodiment, the amount of disintegrant is from about 0% w / w to about 6% w / w (by weight of the total pharmaceutical composition). In one embodiment, the amount of disintegrant is from about 1% w / w to about 5% w / w. In one embodiment, the amount of disintegrant is from about 2% w / w to about 4% w / w.

[0132] In one embodiment, the amount of disintegrant is about 0% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, 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).

[0133] In one embodiment, the disintegrant is approximately 3% w / w of cropovidone.

[0134] In one embodiment, the flow aid is silica. In another embodiment, the flow aid is colloidal silica.

[0135] In one embodiment, the flow aid is a hydrophilic flow aid. In one embodiment, the flow aid has a density of approximately 200 μm. 2 / g surface area. In one embodiment, the flow aid is Aerosil 200.

[0136] In one embodiment, the amount of the flow aid is from about 0% w / w to about 2% w / w (by weight of the total pharmaceutical composition). In one embodiment, the amount of the flow aid is from about 0.25% w / w to about 1.75% w / w. In one embodiment, the amount of the flow aid is from about 0.5% w / w to about 1.5% w / w. In one embodiment, the amount of the flow aid is from about 0.75% w / w to about 1.25% w / w.

[0137] In one embodiment, the amount of the glialant is approximately 0% w / w, approximately 0.1% w / w, approximately 0.2% w / w, approximately 0.25% w / w, approximately 0.3% w / w, approximately 0.4% w / w, approximately 0.5% w / w, approximately 0.55% w / w, approximately 0.6% w / w, approximately 0.65% w / w, approximately 0.7% w / w, approximately 0.75% w / w, approximately 0.8% w / w, approximately 0.85% w / w, approximately 0.9% w / w, and approximately 0.95% w / w. / w, approximately 1% w / w, approximately 1.05% w / w, approximately 1.1% w / w, approximately 1.15% w / w, approximately 1.2% w / w, approximately 1.25% w / w, approximately 1.3% w / w, approximately 1.35% w / w, approximately 1.4% w / w, approximately 1.45% w / w, approximately 1.5% w / w, approximately 1.6% w / w, approximately 1.7% w / w, approximately 1.75% w / w, approximately 1.8% w / w, approximately 1.9% w / w, or approximately 2% w / w. In one embodiment, the amount of the flow aid is approximately 1% w / w. In one embodiment, the amount of the flow aid is approximately 0% w / w (i.e., the pharmaceutical composition does not contain a flow aid).

[0138] In one embodiment, the flow aid is approximately 1% w / w of silica.

[0139] In one embodiment, the lubricant is sodium stearate, stearic acid, or magnesium stearate. In one embodiment, the lubricant is sodium stearate. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is magnesium stearate.

[0140] In one embodiment, the amount of lubricant is from about 0% w / w to about 10% w / w (by the total weight of the pharmaceutical composition). In one embodiment, the amount of lubricant is from about 1.5% w / w to about 7.5% w / w. In one embodiment, the amount of lubricant is from about 2% w / w to about 6% w / w. In one embodiment, the amount of lubricant is from about 2% w / w to about 4% w / w. In one embodiment, the amount of lubricant is from about 3% w / w to about 5% w / w. In one embodiment, the amount of lubricant is from about 4% w / w to about 6% w / w.

[0141] In one embodiment, the amount of lubricant is approximately 0% w / w, approximately 0.5% w / w, approximately 1% w / w, approximately 1.5% w / w, approximately 2% w / w, approximately 2.5% w / w, approximately 3% w / w, approximately 3.5% w / w, approximately 4% w / w, approximately 4.5% w / w, approximately 5% w / w, approximately 5.5% w / w, approximately 6% w / w, approximately 6.5% w / w, approximately 7% w / w, approximately 7.5% w / w, approximately 8% w / w, approximately 8.5% w / w, approximately 9% w / w, approximately 9.5% w / w, or approximately 10% w / w. In one embodiment, the amount of lubricant is approximately 3% w / w. In one embodiment, the amount of lubricant is approximately 5% w / w.

[0142] In one embodiment, the lubricant is sodium stearate in an amount of approximately 3% w / w.

[0143] In one embodiment, the lubricant is stearic acid in an amount of approximately 5% w / w.

[0144] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) mannitol in an amount of about 71% w / w to about 74% w / w; and pregelatinized starch in an amount of about 19% w / w to about 21% w / w; 3) crospovidone in an amount of about 2% w / w to about 4% w / w; 4) silica in an amount of about 0.5% w / w to about 1.5% w / w; and 5) sodium stearate fumarate in an amount of about 2% w / w to about 4% w / w. In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a 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) cropovidone in an amount of about 3% w / w; 4) silica in an amount of about 1% w / w; and 5) sodium stearate 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 No. 4 capsule.

[0145] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.6% w / w to about 0.8% w / w; 2) mannitol in an amount of about 71% w / w to about 74% w / w; and pregelatinized starch in an amount of about 19% w / w to about 21% w / w; 3) crospovidone in an amount of about 2% w / w to about 4% w / w; 4) silica in an amount of about 0.5% w / w to about 1.5% w / w; and 5) sodium stearate fumarate in an amount of about 2% w / w to about 4% w / w. In one embodiment, a pharmaceutical composition is provided herein comprising: 1) approximately 0.71% w / w of a hydrochloride salt of compound 1 (e.g., form A); 2) approximately 72.29% w / w of mannitol and approximately 20% w / w of pregelatinized starch; 3) approximately 3% w / w of cropovidone; 4) approximately 1% w / w of silica; and 5) approximately 3% w / w of sodium stearate fumarate. In one embodiment, the pharmaceutical composition has a total weight of approximately 75 mg. In one embodiment, the pharmaceutical composition is contained in capsule No. 4. In one embodiment, the pharmaceutical composition has a total weight of approximately 225 mg. In one embodiment, the pharmaceutical composition is contained in capsule No. 1.

[0146] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) mannitol in an amount of about 71% w / w to about 74% w / w; and pregelatinized starch in an amount of about 19% w / w to about 21% w / w; 3) cropovidone in an amount of about 2% w / w to about 4% w / w; and 4) stearic acid in an amount of about 4% w / w to about 6% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising: 1) a 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) cropovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0147] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) mannitol in an amount of about 74% w / w to about 77% w / w; and pregelatinized starch in an amount of about 19% w / w to about 21% w / w; 3) crospovidone in an amount of about 2% w / w to about 4% w / w; and 4) magnesium stearate in an amount of about 0.5% w / w to about 1.5% w / w. In one embodiment, a pharmaceutical composition is provided herein comprising: 1) about 0.14% w / w of a hydrochloride salt of compound 1 (e.g., form A); 2) about 75.86% w / w of mannitol and about 20% w / w of pregelatinized starch; 3) about 3% w / w of cropovidone; and 4) about 1% w / w of magnesium stearate.

[0148] (c) Mannitol-cellulose based pharmaceutical compositions

[0149] 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 includes a disintegrant, a glidant, a lubricant, or a mixture thereof.

[0150] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) an amount of compound 1 or an enantiomer, enantiomer mixture, tautomer, isotope or pharmaceutically acceptable salt thereof, in an amount of about 0.05% w / w to about 0.2% w / w; 2) an amount of a mixture of mannitol and cellulose in an amount of about 85% w / w to about 99.7% w / w; 3) an amount of a disintegrant in an amount of about 0% w / w to about 6% w / w; and 4) an amount of a lubricant in an amount of about 0% w / w to about 10% w / w.

[0151] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) mannitol in an amount of about 72% w / w to about 75% w / w; and microcrystalline cellulose in an amount of about 19% w / w to about 21% w / w; 3) cropovidone in an amount of about 2% w / w to about 4% w / w; and 4) sodium stearate fumarate in an amount of about 2% w / w to about 4% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising: 1) a 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 73.8% w / w; and microcrystalline cellulose in an amount of about 20% w / w; 3) cropovidone in an amount of about 3% w / w; and 4) sodium stearate fumarate in an amount of about 3% w / w.

[0152] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) mannitol in an amount of about 70% w / w to about 73% w / w; and microcrystalline cellulose in an amount of about 19% w / w to about 21% w / w; 3) cropovidone in an amount of about 2% w / w to about 4% w / w; and 4) stearic acid in an amount of about 4% w / w to about 6% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising: 1) a 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) cropovidone in an amount of about 3% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0153] (d) Cellulose-based pharmaceutical compositions

[0154] In one embodiment, the carrier or diluent in the pharmaceutical composition provided herein is cellulose. In one embodiment, the pharmaceutical composition further includes a disintegrant, a flow aid, a lubricant, or a mixture thereof.

[0155] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) an amount of compound 1 or an enantiomer, enantiomer mixture, tautomer, isotope or pharmaceutically acceptable salt thereof, in an amount of about 0.05% w / w to about 2% w / w; 2) a amount of cellulose, in an amount of about 75% w / w to about 95% w / w; 3) a disintegrant, in an amount of about 0% w / w to about 20% w / w; and 4) a lubricant, in an amount of about 0% w / w to about 10% w / w.

[0156] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.1% w / w to about 0.2% w / w; 2) a microcrystalline cellulose in an amount of about 82% w / w to about 87% w / w; 3) a cropovidone in an amount of about 8% w / w to about 12% w / w; and 4) stearic acid in an amount of about 4% w / w to about 6% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrochloride salt of compound 1 (e.g., form A) in an amount of about 0.14% w / w; 2) a microcrystalline cellulose in an amount of about 84.86% w / w; 3) a cropovidone in an amount of about 10% w / w; and 4) stearic acid in an amount of about 5% w / w.

[0157] (e) Other embodiments of the pharmaceutical composition

[0158] In one embodiment, the pharmaceutical composition provided herein may optionally further comprise one or more other excipients. Other excipients include, but are not limited to, wetting agents, solubilizers, crystallization stabilizers, anti-adhesion agents, and precipitation inhibitors.

[0159] In one embodiment, the pharmaceutical composition provided herein is formulated as a capsule. In one embodiment, the capsule is an HPMC capsule.

[0160] Typically, compositions are formulated for single-dose administration. To formulate a composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a chosen solvent at an effective concentration (to alleviate or improve the condition being treated). Suitable drug carriers or solvents for administering the compounds provided herein include any such carriers known to those skilled in the art as being appropriate for a particular mode of administration.

[0161] Furthermore, the compound can be formulated as the sole pharmaceutically active ingredient in a composition, or in combination with other active ingredients. Liposome suspensions, including tissue-targeting liposomes such as tumor-targeting liposomes, are also suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as known in the art. Briefly, liposomes, such as multilayer vesicles (MLVs), can be formed by drying lecithin and cephalin-serine (7:3 molar ratio) on the inside of a flask. A solution of the compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are rinsed to remove unencapsulated compounds, the precipitate is centrifuged, and then resuspended in PBS.

[0162] The active compound is encapsulated in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect on the patient without undesirable side effects. Therapeuticly effective concentrations can be determined by testing the compound in the in vitro and in vivo systems described herein, from which the dosage for human use can be deduced.

[0163] The concentration of the active compound in a pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, metabolism and excretion rate of the active compound, the physicochemical properties of the compound, the dosage regimen and amount administered, and other factors known to those skilled in the art.

[0164] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may include any of the following components: sterile diluents such as water for injection, saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparaben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and tonic agents such as sodium chloride or glucose. Parenteral preparations may be packaged in ampoules, pens, disposable syringes, or single- or multi-dose vials made of glass, plastic, or other suitable materials.

[0165] When a compound exhibits insufficient solubility, methods for solubilizing the compound can be used. These methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO) and surfactants such as... It can also be dissolved in an aqueous solution of sodium bicarbonate.

[0166] When compounds are mixed or added, the resulting mixture can be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the intended method of administration and the solubility of the compound in the chosen carrier or solvent. The effective concentration is sufficient to improve the symptoms of the disease, ailment, or condition being treated and can be determined empirically.

[0167] Pharmaceutical compositions are provided 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 pharmaceutically acceptable salt, for administration to humans and animals. Therapeutic active pharmaceutical compounds and their salts are formulated and administered in single-dose or multi-dose forms. As used herein, a unit-dose form refers to a physically discrete unit suitable for human and animal individuals, individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, along with the desired drug carrier, solvent, or diluent. Examples of unit-dose forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit-dose forms can be administered in multiple doses or fractions. Multi-dose forms are multiple identical unit dosage forms packaged in a single container and administered in separate unit-dose forms. Examples of multi-dose forms include vials, bottles, pint bottles, or gallon bottles of tablets or capsules. Thus, a multi-dose form is multiple unit doses not separated in the package.

[0168] Dosage forms or compositions containing 0.005% to 100% of the active ingredient can be prepared, with the remainder consisting of a non-toxic carrier. For oral administration, pharmaceutically acceptable non-toxic compositions are formed by incorporating any commonly used excipients, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. The compositions include solutions, suspensions, tablets, capsules, powders, and sustained-release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydride, polyglycolic acid, polyorthoesters, polylactic acid, etc. Methods for preparing the compositions are known to those skilled in the art.

[0169] Active compounds or pharmaceutically acceptable salts can be prepared together with a carrier that protects the compound from rapid excretion from the body, such as a sustained-release formulation or a coating.

[0170] The composition may include other active compounds to achieve the desired combination of properties. The compounds provided herein, or their pharmaceutically acceptable salts, may also be advantageously used in combination with another medicine known in the general art as valuable in treating one or more of the aforementioned diseases or medical conditions (e.g., diseases related to oxidative stress) for therapeutic or preventative purposes. It should be understood that the combined therapies constitute another aspect of the compositions and treatment methods provided herein.

[0171] (d) Methods for preparing dosage forms

[0172] The pharmaceutical compositions (dosage forms) described herein can be prepared by any pharmaceutical method, but all methods include the step of combining the active ingredient with an excipient that constitutes one or more essential components. Typically, the composition is prepared by uniformly mixing (e.g., direct mixing) the active ingredient with a liquid excipient or finely crushed solid excipient, or both, and then, if necessary, shaping the product into the desired appearance (e.g., compaction, such as roller compaction). If desired, tablets can be coated using standard aqueous or anhydrous techniques.

[0173] The dosage forms provided herein can be prepared by compression or molding, optionally containing one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) in a suitable machine, said active ingredient optionally mixed with excipients and / or surfactants or dispersants as described above. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Encapsulation of the dosage forms provided herein can be accomplished using hydroxypropyl methylcellulose, calcium alginate, or gelatin capsules.

[0174] In some implementations, the active ingredient and excipients are directly mixed and filled, for example, into capsules, or directly compressed into tablets.

[0175] In some embodiments, the dosage forms or pharmaceutical compositions provided herein are prepared by a wet granulation method. In one embodiment, the wet granulation method includes the steps of: (i) mixing an active ingredient (e.g., compound 1 or an enantiomer, mixture of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salt thereof) with a first portion of excipient (intragranule excipient) and water to form wet granules; (ii) drying and then grinding (e.g., by coil) the granules; and (iii) mixing the ground granules with the remaining excipient (extragranule excipient) to form a final mixture. In one embodiment, this method is followed by an encapsulation step.

[0176] In one embodiment, the in-particle excipients include a binder (e.g., starch) and a disintegrant (e.g., crospovidone), and the out-of-particle excipients include a diluent (e.g., mannitol) and a lubricant (e.g., stearic acid). In one embodiment, the ratio of in-particle excipients to out-of-particle excipients does not exceed approximately 33:67. In one embodiment, the ratio of in-particle excipients to out-of-particle excipients does not exceed approximately 23:77. In one embodiment, the ratio of in-particle excipients to out-of-particle excipients is approximately 23:77.

[0177] In one embodiment, prior to step (i), the active ingredient is passed through a 60-mesh (250 μm) sieve or a sieve with a smaller pore size.

[0178] In one embodiment, the particle size of the milled particles (e.g., measured by D50) matches (e.g., within ±10%, ±20%, or ±30%) the particle size of the excipient (e.g., a diluent, such as mannitol) as the main component.

[0179] In some embodiments, the dosage forms or pharmaceutical compositions provided herein are prepared by a compaction method. In one embodiment, the compaction method includes the steps of: (i) mixing an active ingredient (e.g., compound 1 or an enantiomer, mixture of enantiomers, tautomers, isotopes, or pharmaceutically acceptable salt thereof) with a first portion of excipients (intragranule excipients) to form an intragranule mixture; (ii) passing the intragranule mixture through a compaction mill to form dry granules; and (iii) mixing the dry granules with the remaining excipients (extragranule excipients) to form a final mixture. In one embodiment, step (i) includes premixing the active ingredient with a small portion of a binder (e.g., starch) and then mixing it with the remaining intragranule excipients. In one embodiment, this method is followed by an encapsulation step.

[0180] In one embodiment, prior to step (i), the active ingredient is passed through a 60-mesh (250 μm) sieve or a sieve with a smaller pore size.

[0181] In one embodiment, the in-particle excipients include binders (e.g., starch), diluents (e.g., mannitol), disintegrants (e.g., cropovidone), flow aids (e.g., silica), and lubricants (e.g., sodium stearate fumarate), while the out-of-particle excipients include flow aids (e.g., silica) and lubricants (e.g., sodium stearate fumarate). In one embodiment, the ratio of in-particle excipients to out-of-particle excipients is not less than approximately 67:33. In one embodiment, the ratio of in-particle excipients to out-of-particle excipients is not less than approximately 98:2. In one embodiment, the ratio of in-particle excipients to out-of-particle excipients is approximately 98:2.

[0182] 5.3 Usage Method

[0183] In one embodiment, this document provides a method for treating hematologic malignancies, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition provided herein.

[0184] In one embodiment, this document provides a method for preventing hematologic malignancies, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition provided herein.

[0185] In one embodiment, this document provides a method for managing hematologic malignancies, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition provided herein.

[0186] In one implementation plan, the hematologic malignancy is leukemia.

[0187] In one embodiment, the hematologic malignancy is acute myeloid leukemia. In another embodiment, the acute myeloid leukemia is B-cell acute myeloid leukemia.

[0188] In one implementation scheme, the hematologic malignancy is acute lymphoblastic leukemia.

[0189] In one implementation scheme, the hematologic malignancy is chronic lymphocytic leukemia / small lymphocytic lymphoma.

[0190] In one implementation scheme, the hematologic malignancy is myeloma.

[0191] In one embodiment, the hematologic malignancy is multiple myeloma. In another embodiment, multiple myeloma is plasma cell leukemia (PCL).

[0192] In one implementation scheme, the hematologic malignancy is lymphoma.

[0193] In one implementation scheme, the hematologic malignancy is non-Hodgkin's lymphoma.

[0194] In one implementation scheme, the hematologic malignancy is diffuse large B-cell lymphoma.

[0195] In one embodiment, the hematologic malignancy is 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.

[0196] In one implementation scheme, the hematologic malignancy is Burkitt lymphoma.

[0197] In one embodiment, the hematologic malignancy is a marginal zone lymphoma. In another embodiment, the marginal zone lymphoma is a splenic marginal zone lymphoma (SMZL).

[0198] In one implementation scheme, the hematologic malignancy is Hodgkin's lymphoma.

[0199] In one implementation scheme, hematologic malignancy is myelodysplastic syndrome.

[0200] In one implementation scheme, the hematologic malignancy is newly diagnosed. In another implementation scheme, the hematologic malignancy is relapsed or refractory.

[0201] In one embodiment, the AML is a newly diagnosed AML. In one embodiment, the AML is relapsed or refractory AML. In one embodiment, the B-cell AML is a newly diagnosed B-cell AML. In one embodiment, the B-cell AML is relapsed or refractory B-cell AML.

[0202] In one implementation scheme, ALL is a newly diagnosed case of ALL. In another implementation scheme, ALL is relapsed or refractory ALL.

[0203] In one embodiment, MM is newly diagnosed MM. In one embodiment, MM is relapsed or refractory MM. In one embodiment, PCL is newly diagnosed PCL. In one embodiment, PCL is relapsed or refractory PCL.

[0204] In one implementation, HL is a newly diagnosed HL. In another implementation, HL is relapsed or refractory HL.

[0205] In one implementation, NHL is a newly diagnosed NHL. In another implementation, NHL is relapsed or refractory NHL.

[0206] In one embodiment, TCL is newly diagnosed TCL. In one embodiment, TCL is relapsed or refractory TCL. In one embodiment, ALCL is newly diagnosed ALCL. In one embodiment, ALCL is relapsed or refractory ALCL. In one embodiment, Sezary syndrome is newly diagnosed Sezary syndrome. In one embodiment, Sezary syndrome is relapsed or refractory Sezary syndrome.

[0207] In one implementation, BL is a newly diagnosed BL. In another implementation, BL is a relapsed or refractory BL.

[0208] In one embodiment, MZL is newly diagnosed MZL. In one embodiment, MZL is relapsed or refractory MZL. In one embodiment, SMZL is newly diagnosed SMZL. In one embodiment, SMZL is relapsed or refractory SMZL.

[0209] In one implementation, the MDS is a newly diagnosed MDS. In another implementation, the MDS is a relapsed or refractory MDS.

[0210] In one embodiment, this document provides a method for achieving a complete response, partial response, or disease stabilization in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for increasing overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for increasing overall survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for increasing progression-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for increasing event-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for increasing time to progression in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, this document provides a method for achieving increased disease-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient suffering from a hematologic malignancy as described herein. In one embodiment, the hematologic malignancy is AML (e.g., B-cell AML). In one embodiment, the hematologic malignancy is ALL. In one embodiment, the hematologic malignancy is CLL / SLL. In one embodiment, the hematologic malignancy is MM. In one embodiment, the hematologic malignancy is PCL. In one embodiment, the hematologic malignancy is NHL. In one embodiment, the hematologic malignancy is DLBCL. In one embodiment, the hematologic malignancy is TCL (e.g., ALCL or Sezary syndrome). In one embodiment, the hematologic malignancy is Burkitt lymphoma. In one embodiment, the hematologic malignancy is HL. In one embodiment, the hematologic malignancy is MZL (e.g., SMZL). In one embodiment, the hematologic malignancy is MDS.

[0211] In one embodiment, this document provides a method for treating AML, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the AML is B-cell AML.

[0212] In one embodiment, this document provides a method for preventing AML, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the AML is B-cell AML.

[0213] In one embodiment, this document provides a method for managing AML, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the AML is B-cell AML.

[0214] In one embodiment, this document provides a method for treating ALL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0215] In one embodiment, this document provides a method for preventing ALL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0216] In one embodiment, this document provides a method for managing ALL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0217] In one embodiment, this document provides a method for treating MM, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0218] In one embodiment, this document provides a method for preventing MM, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0219] In one embodiment, this document provides a method for managing MM, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0220] In one embodiment, this document provides a method for treating PCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0221] In one embodiment, this document provides a method for preventing PCL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0222] In one embodiment, this document provides a method for managing PCL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0223] In one embodiment, this document provides a method for treating TCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, TCL is ALCL. In one embodiment, TCL is Sezary syndrome.

[0224] In one embodiment, this document provides a method for preventing TCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, TCL is ALCL. In one embodiment, TCL is Sezary syndrome.

[0225] In one embodiment, this document provides a method for managing TCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, TCL is ALCL. In one embodiment, TCL is Sezary syndrome.

[0226] In one embodiment, this document provides a method for treating BL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0227] In one embodiment, this document provides a method for preventing BL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0228] In one embodiment, this document provides a method for managing BL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0229] In one embodiment, this document provides a method for treating HL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0230] In one embodiment, this document provides a method for preventing HL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0231] In one embodiment, this document provides a method for managing HL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0232] In one embodiment, this document provides a method for treating MZL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, MZL is SMZL.

[0233] In one embodiment, this document provides a method for preventing MZL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, MZL is SMZL.

[0234] In one embodiment, this document provides a method for administering MZL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the MZL is SMZL.

[0235] In one embodiment, this document provides a method for treating MDS, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0236] In one embodiment, this document provides a method for preventing MDS, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0237] In one embodiment, this document provides a method for managing MDS, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0238] In one embodiment, this document provides a method for using the pharmaceutical composition provided herein, alone or in combination with rituximab, for the treatment, prevention, or management of non-Hodgkin's lymphoma (NHL).

[0239] In one embodiment, this document provides a method for treating NHL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0240] In one embodiment, this document provides a method for preventing NHL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0241] In one embodiment, this document provides a method for managing NHL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0242] In one embodiment, NHL is DLBCL. In one embodiment, DLBCL is primary DLBCL. In one embodiment, DLBCL is activated B-cell-like DLBCL (ABC-DLBCL). In one embodiment, DLBCL is germinal center B-cell-like DLBCL (GCB-DLBCL). In one embodiment, DLBCL is unclassified DLBCL. In one embodiment, DLBCL is primary mediastinal B-cell type DLBCL (PMBL DLBCL). In one embodiment, DLBCL is double-hit DLBCL (DHIT DLBCL), also known as cMyc / Bcl-2 mutant DLBCL. In one embodiment, DLBCL is triple-hit DLBCL (THIT DLBCL), also known as cMyc / Bcl2 / Bcl6 rearranged DLBCL.

[0243] In one implementation, NHL is follicular lymphoma (FL).

[0244] In one implementation, NHL is mantle cell lymphoma (MCL).

[0245] In one implementation, NHL is primary central nervous system lymphoma (PCNSL).

[0246] In one embodiment, NHL is relapsed or refractory NHL. In one embodiment, NHL is relapsed NHL. In one embodiment, NHL is refractory NHL.

[0247] In some implementations, the NHL individual has radiographic evidence of disease progression after achieving a complete response (CR). In other implementations, the NHL individual achieved less than CR with a recent regimen involving systemic therapy and has radiographic evidence of disease activity, progression, or relapse within 12 months of a previous stem cell transplantation (SCT).

[0248] In some implementations, the individual with NHL has failed one or more therapies and is not a candidate for other therapies. In some implementations, the individual has received at least one prior treatment and does not qualify for any therapy other than those described herein. In some implementations, the individual has relapsed or progressed after standard anticancer therapy.

[0249] In some implementations, the individual has failed at least one existing therapy. In some implementations, the individual has failed at least two existing therapies.

[0250] In one implementation, NHL is relapsed or refractory DLBCL. In one implementation, DLBCL is relapsed DLBCL. In one implementation, DLBCL is refractory DLBCL. In one implementation, DLBCL is relapsed / refractory DLBCL. In one implementation, DLBCL is doxorubicin refractory. In one implementation, DLBCL is doxorubicin resistant. In one implementation, DLBCL is refractory to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, gemcitabine, dexamethasone, ifosfamide, polotuxumab, or CAR-T.

[0251] In one implementation, DLBCL is treated with two or more existing therapies.

[0252] In one embodiment, DLBCL is transformed lymphoma. In another embodiment, DLBCL is not a separately designated (NOS) DLBCL.

[0253] In one implementation, NHL is relapsed or refractory FL. In one implementation, FL is relapsed FL. In one implementation, FL is refractory FL.

[0254] In one embodiment, FL is treated with one or more existing therapies. In another embodiment, FL is treated with two or more existing therapies.

[0255] In one embodiment, NHL is relapsed or refractory MCL. In one embodiment, MCL is relapsed MCL. In one embodiment, MCL is refractory MCL.

[0256] In one embodiment, MCL is treated with one or more existing therapies. In another embodiment, MCL is treated with two or more existing therapies.

[0257] In one embodiment, NHL is relapsed or refractory PCNSL. In one embodiment, PCNSL is relapsed PCNSL. In one embodiment, PCNSL is refractory PCNSL.

[0258] In some embodiments, NHL is a newly diagnosed NHL. In some embodiments, NHL is a newly diagnosed diffuse large B-cell lymphoma. In some embodiments, NHL is a newly diagnosed follicular lymphoma. In some embodiments, NHL is a newly diagnosed mantle cell lymphoma. In some embodiments, NHL is a newly diagnosed primary central nervous system lymphoma.

[0259] In some implementations, the method provided herein further includes administering a therapeutically effective amount of rituximab to an individual.

[0260] In one embodiment, the first therapy (e.g., an active agent, such as the pharmaceutical composition provided herein) is administered before the second therapy (e.g., rituximab) is administered to the individual (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 the second therapy (e.g., rituximab) to the individual).

[0261] In one embodiment, a first therapy (e.g., an active agent, such as a pharmaceutical composition provided herein) is administered simultaneously to an individual along with a second therapy (e.g., rituximab).

[0262] In one embodiment, after administering a second therapy (e.g., rituximab) to an individual (e.g., after 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), the first therapy (e.g., an active agent, such as the pharmaceutical composition provided herein) is administered.

[0263] In some embodiments, rituximab is administered according to the locally approved label or pharmacy manual containing information on its preparation, administration, and storage. In some embodiments, rituximab is administered intravenously. In some embodiments, rituximab is administered subcutaneously. In some embodiments, rituximab is administered by IV injection or IV infusion. In some embodiments, rituximab is administered by IV infusion.

[0264] In some implementations, rituximab is administered at a dosage determined by a physician. In some implementations, rituximab is administered once or twice daily. In some implementations, rituximab is administered at a dose of approximately 50 mg / m². 2 Approximately 1000 mg / m 2 Approximately 100 mg / m 2 Approximately 750 mg / m 2 Approximately 250 mg / m 2 Approximately 500 mg / m 2 Or approximately 300 mg / m 2 to about 400 mg / m 2 The dosage is specified. In some embodiments, rituximab is administered at 375 mg / m² daily. 2 The amount applied.

[0265] In one embodiment, this document provides a method for treating DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0266] In one embodiment, this document provides a method for preventing DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0267] In another embodiment, this document provides a method for managing DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0268] In one embodiment, this document provides a method for treating FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0269] In one embodiment, this document provides a method for preventing FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0270] In another embodiment, this document provides a method for managing FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0271] In one embodiment, this document provides a method for treating MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0272] In one embodiment, this document provides a method for preventing MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0273] In another embodiment, this document provides a method for managing MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0274] In one embodiment, this document provides a method for treating PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0275] In one embodiment, this document provides a method for preventing PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0276] In another embodiment, this document provides a method for managing PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0277] In one embodiment, this document provides a method for treating relapsed or refractory DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0278] In one embodiment, this document provides a method for preventing relapsed or refractory DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0279] In another embodiment, this document provides a method for managing relapsed or refractory DLBCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0280] In one embodiment, this document provides a method for treating relapsed or refractory FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0281] In one embodiment, this document provides a method for preventing relapsed or refractory FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0282] In another embodiment, this document provides a method for managing relapsed or refractory FL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0283] In one embodiment, this document provides a method for treating relapsed or refractory MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0284] In one embodiment, this document provides a method for preventing relapsed or refractory MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0285] In another embodiment, this document provides a method for managing relapsed or refractory MCL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0286] In one embodiment, this document provides a method for treating relapsed or refractory PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0287] In one embodiment, this document provides a method for preventing relapsed or refractory PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0288] In another embodiment, this document provides a method for managing relapsed or refractory PCNSL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0289] In another embodiment, this document provides a method for achieving a complete response, partial response, or disease stabilization as determined according to the Lugano response criteria, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for achieving an increase in overall survival, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for achieving an increase in progression-free survival, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for achieving an increase in event-free survival, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for achieving an increase in time to progression, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In another embodiment, this document provides a method for increasing disease-free survival in patients, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with NHL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the individual.

[0290] In one embodiment, this document provides a method for using the pharmaceutical composition provided herein, alone or in combination with atoruzumab, for the treatment, prevention, or management of chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0291] As used herein and unless otherwise stated, “CLL / SLL” or “CLL and / or SLL” means CLL or SLL, or CLL and SLL. In one embodiment, the methods provided herein are used to treat, prevent, or manage CLL. In one embodiment, the methods provided herein are used to treat, prevent, or manage SLL. In one embodiment, the methods provided herein are used to treat, prevent, or manage CLL and SLL.

[0292] In one embodiment, this document provides a method for treating CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0293] In one embodiment, this document provides a method for preventing CLL / SLL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0294] In one embodiment, this document provides a method for managing CLL / SLL, which includes administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it.

[0295] In one embodiment, the individual with CLL / SLL has experienced failure of one or more therapies. In one embodiment, the individual has experienced failure of at least one existing therapy. In one embodiment, the individual has experienced failure of at least two existing therapies. In one embodiment, the individual has previously been treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the individual is relapsed or refractory to BTK inhibitors. 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 teiralutinib.

[0296] In one implementation, CLL / SLL is a newly diagnosed CLL / SLL. In another implementation, CLL / SLL is a relapsed or refractory CLL / SLL (R / R CLL / SLL).

[0297] In one embodiment, CLL is characterized by a mutated IGHV (immunoglobulin heavy chain gene). In another embodiment, CLL is characterized by a non-mutated IGHV.

[0298] In one embodiment, CLL is characterized by one or more mutations in TP53 (tumor protein 53). In another embodiment, CLL is characterized by wild-type TP53.

[0299] In one embodiment, CLL is characterized by one or more cytogenetic abnormalities: for example, 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).

[0300] In one implementation, CLL is characterized by Richter's transformation (also known as Richter's syndrome).

[0301] In one implementation, the method provided herein further includes administering a therapeutically effective amount of atoruzumab to an individual.

[0302] In one embodiment, the first therapy (e.g., an active agent, such as the pharmaceutical composition provided herein) is administered before the second therapy (e.g., atoruzumab) is administered to the individual (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 prior to administration of the second therapy (e.g., atoruzumab) to the individual).

[0303] In one embodiment, a first therapy (e.g., an active agent, such as the pharmaceutical composition provided herein) is simultaneously administered to an individual along with a second therapy (e.g., atoruzumab).

[0304] In one embodiment, after administering a second therapy (e.g., atoruzumab) to an individual (e.g., after 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), the first therapy provided herein (e.g., an active agent, such as the pharmaceutical composition provided herein) is administered.

[0305] In one embodiment, atoruzumab is administered according to the locally approved label or pharmacy manual containing information on its preparation, administration, and storage. In one embodiment, atoruzumab is administered intravenously. In one embodiment, atoruzumab is administered subcutaneously. In one embodiment, atoruzumab is administered via intravenous (IV) injection or IV infusion. In one embodiment, atoruzumab is administered via IV injection. In one embodiment, atoruzumab is administered via IV infusion.

[0306] In one embodiment, atoruzumab is administered at a dosage determined by a physician. In one embodiment, atoruzumab is administered daily. In one embodiment, atoruzumab is administered at a dose of about 75 mg / day to about 1100 mg / day. In one embodiment, atoruzumab is administered at a dose of about 75 mg / day to about 125 mg / day, about 800 mg / day to about 1000 mg / day, or about 900 mg / day to about 1100 mg / day. In one embodiment, atoruzumab is administered at a dose of about 100 mg / day. In one embodiment, atoruzumab is administered at a dose of about 900 mg / day. In one embodiment, atoruzumab is administered at a dose of about 1000 mg / day. In one embodiment, atoruzumab is administered at a dose of approximately 100 mg on day 1 of the first 28-day cycle, at a dose of approximately 900 mg on day 2 of the first 28-day cycle, and at a dose of approximately 1000 mg on days 8 and 15 of the first 28-day cycle, and on day 1 of the second to sixth 28-day cycles. In another embodiment, atoruzumab is administered at a combined dose of approximately 1000 mg on days 1 and 2 of the first 28-day cycle, and at a dose of approximately 1000 mg on days 8 and 15 of the first 28-day cycle, and on day 1 of the second to sixth 28-day cycles. Atoruzumab may be administered for more than six cycles. In one embodiment, atoruzumab is administered in the first 28-day cycle as described herein, and at a dose of approximately 1000 mg on day 1 of the second to twelfth 28-day cycles. In one embodiment, atoruzumab is administered in the first 28-day cycle as described herein, and in approximately 1000 mg on day 1 of the second to 24th 28-day cycles. In another embodiment, atoruzumab is administered in the first 28-day cycle as described herein, and in approximately 1000 mg on day 1 of the subsequent 28-day cycles until disease progression.

[0307] In one embodiment, this document provides a method for treating newly diagnosed CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0308] In one embodiment, this document provides a method for preventing newly diagnosed CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0309] In one embodiment, this document provides a method for managing a newly diagnosed CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0310] In one embodiment, this document provides a method for treating relapsed or refractory CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0311] In one embodiment, this document provides a method for preventing relapsed or refractory CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0312] In one embodiment, this document provides a method for managing relapsed or refractory CLL / SLL, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to an individual in need of it. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0313] In another embodiment, this document provides a method for achieving a complete response, partial response, or disease stabilization in a patient, as determined according to the criteria of the International Symposium on Chronic Lymphocytic Leukemia, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In one embodiment, minimal residual disease (MRD) testing may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimal residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a 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, this document provides a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In another embodiment, this document provides a method for achieving an increase in overall survival in a patient, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In another embodiment, this document provides a method for increasing progression-free survival in patients, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In another embodiment, this document provides a method for increasing event-free survival in patients, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In another embodiment, this document provides a method for increasing time to progression in patients, comprising administering a therapeutically effective amount of the pharmaceutical composition of compound 1 provided herein to a patient with CLL / SLL. In another embodiment, this document provides a method for increasing disease-free survival in patients, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of atoruzumab to the individual.

[0314] The methods described herein include treating patients regardless of their age. In some implementations, the individual is 18 years of age or older. In other implementations, the individual is older than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other implementations, the individual is younger than 65 years of age. In other implementations, the individual is older than 65 years of age.

[0315] This article also provides a pharmaceutical composition for use in a method of treating the disease described herein, wherein the method includes administering a therapeutically effective amount of the pharmaceutical composition to a patient.

[0316] 5.4 Application route

[0317] The pharmaceutical compositions provided herein can be administered orally. In one embodiment, when administered orally, the pharmaceutical compositions provided herein are taken with food and water. In another embodiment, the pharmaceutical compositions provided herein are dispersed in water or fruit juice (e.g., apple juice or orange juice) and administered orally as a solution or suspension.

[0318] The pharmaceutical compositions described herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, or intramucosally, by inhalation, or locally to the ear, nose, eye, or skin. The method of administration is determined by the healthcare professional and may depend in part on the site of the medical condition.

[0319] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. The composition may be formulated into dosage units containing a daily dose or convenient partial daily doses, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt. Typically, all compositions are prepared according to known methods of medicinal chemistry.

[0320] Depending on the state of the disease to be treated and the individual's condition, the pharmaceutical compositions described herein can be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or local (e.g., transdermal or local) routes of administration. The pharmaceutical compositions described herein can be formulated alone or with pharmaceutically acceptable excipients, carriers, adjuvants, and solvents, suitable for each route of administration, in appropriate dosage units.

[0321] In one embodiment, the pharmaceutical composition provided herein is administered orally. In another embodiment, the pharmaceutical composition provided herein is administered parenterally. Still in another embodiment, the pharmaceutical composition provided herein is administered intravenously.

[0322] The pharmaceutical compositions provided herein may be administered as a single dose, such as a single rapid bolus injection or oral capsule, tablet, or pill; or over a period of time, such as over a period of continuous infusion or over a period of divided bolus injections. If necessary, the pharmaceutical compositions provided herein may be repeatedly administered, for example until the patient experiences stable disease or remission, or until the patient experiences disease progression or unacceptable toxicity.

[0323] The pharmaceutical compositions provided herein may be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration may be continuous (i.e., daily, for several consecutive days or days), intermittent (i.e., cyclical, including rest periods of several days, weeks, or months without medication). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as the pharmaceutical compositions provided herein, is administered once or more daily, for a period of time. The term "continuous" means that a therapeutic compound, such as the pharmaceutical compositions provided herein, is administered daily for an uninterrupted period of at least 7 days to 52 weeks. The terms "intermittent" or "intermittently" as used herein mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the pharmaceutical compositions provided herein may be administered 1–6 days per week, cyclically (e.g., daily for 2–8 weeks, followed by a rest period (no administration) for up to one week), or every other day. The term "cyclically" as used herein is intended to mean that a therapeutic compound, such as the pharmaceutical compositions provided herein, is administered daily or continuously, but with a rest period.

[0324] In some embodiments, the frequency of administration ranges from approximately a daily dose to approximately a monthly dose. In some embodiments, administration is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the pharmaceutical composition provided herein is administered once daily. In another embodiment, the pharmaceutical composition provided herein is administered twice daily. Still in another embodiment, the pharmaceutical composition provided herein is administered three times daily. And still in another embodiment, the pharmaceutical composition provided herein is administered four times daily.

[0325] In some embodiments, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein during one or more 7-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-5 of a 7-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-3 of a 7-day cycle.

[0326] In some embodiments, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein over one or more 14-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-7 of a 14-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-10 of a 14-day cycle.

[0327] In some embodiments, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein during one or more 28-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-21 of a 28-day cycle. In another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-10 and 15-24 of a 28-day cycle.

[0328] In one embodiment, the pharmaceutical composition provided herein is administered once daily for 5 days, followed by a 2-day rest period. In another embodiment, the pharmaceutical composition provided herein is administered once daily for 3 days, followed by a 4-day rest period. In another embodiment, the pharmaceutical composition provided herein is administered once daily for 7 days, followed by a 7-day rest period. In another embodiment, the pharmaceutical composition provided herein is administered once daily for 10 days, followed by a 4-day rest period. In yet another embodiment, the pharmaceutical composition provided herein is administered once daily for 21 days, followed by a 7-day rest period.

[0329] In some embodiments, the treatment includes administering a therapeutically effective amount of rituximab over one or more treatment cycles. In one embodiment, rituximab is administered every 7 days. In one embodiment, rituximab is administered every 4 weeks. In one embodiment, rituximab is administered 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 cycles 2-6, and then every 8 weeks.

[0330] In one embodiment, the treatment comprises administering a therapeutically effective amount of atoruzumab over one or more treatment cycles. In one embodiment, atoruzumab is administered twice every 7 days. In one embodiment, atoruzumab is administered once weekly. In one embodiment, atoruzumab is administered once every 4 weeks. In one embodiment, atoruzumab is administered on days 1, 2, 8, and 15 of the first 28-day cycle, and on day 1 of cycles 2-6. In one embodiment, atoruzumab is administered on day 1 of cycles 2-12. In one embodiment, atoruzumab is administered on day 1 of cycles 2-24. In one embodiment, atoruzumab is administered on day 1 of subsequent 28-day cycles until disease progression.

[0331] In one embodiment, atoruzumab is administered at a dose of approximately 100 mg on day 1 of the first 28-day cycle, at a dose of approximately 900 mg on day 2 of the first 28-day cycle, and at a dose of approximately 1000 mg on days 8 and 15 of the first 28-day cycle. In another embodiment, atoruzumab is administered at a combined dose of approximately 1000 mg on days 1 and 2 of the first 28-day cycle, and at a dose of approximately 1000 mg on days 8 and 15 of the first 28-day cycle. In another embodiment, atoruzumab is administered at a dose of approximately 1000 mg on day 1 of cycles 2-6. In another embodiment, atoruzumab is administered at a dose of approximately 1000 mg on day 1 of cycles 2-12. In another embodiment, atoruzumab is administered at a dose of approximately 1000 mg on day 1 of cycles 2-24. In one implementation, atoruzumab is administered at a dose of approximately 1000 mg on day 1 of a subsequent 28-day cycle until disease progression.

[0332] Any treatment cycle described herein may be repeated for at least 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles, 12 cycles, 13 cycles, 14 cycles, 15 cycles, 16 cycles, 17 cycles, 18 cycles, 19 cycles, 20 cycles, 21 cycles, 22 cycles, 23 cycles, 24 cycles, 25 cycles, 26 cycles, 27 cycles, 28 cycles, 29 cycles, 30 cycles, or more. In some cases, the treatment cycle described herein comprises 1 cycle to about 24 cycles, about 2 cycles to about 16 cycles, or about 2 cycles to about 4 cycles. In some embodiments, a therapeutically effective amount of the pharmaceutical composition and / or rituximab provided herein is administered for 1 to 13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutically effective amount of the pharmaceutical composition and / or rituximab provided herein is administered for 1 to 24 cycles of 28 days (e.g., about 2 years). In some embodiments, a therapeutically effective amount of the pharmaceutical composition and / or atoruzumab provided herein is administered for 1 to 13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutically effective amount of the pharmaceutical composition and / or atoruzumab provided herein is administered for 1 to 24 cycles of 28 days (e.g., about 2 years). In some cases, the cycle therapy is not limited to the number of cycles and continues until disease progression. In some cases, the cycle may include variations in the duration of the administration and / or rest periods described herein. 5. Detailed Implementation

[0333] Example

[0334] Some embodiments of the present invention are illustrated by the following non-limiting examples.

[0335] Abbreviations used:

[0336] DCM dichloromethane DIEA N,N-Diisopropylethylamine DMSO Dimethyl sulfoxide ESI Electrospray ionization EtOAc Ethyl acetate LCMS Liquid chromatography-mass spectrometry MeOH methanol MS mass spectrometry NMP N-Methylpyrrolidone NMR Nuclear magnetic resonance

[0337] Synthesis of 6.1(S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (Compound 1)

[0338]

[0339] (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 B... 10 H 14 (4.92 g, 40.3 mmol) was added in small, fractional batches over 5 minutes. The reaction flask was fitted with a diaphragm and a venting needle (pressure), and the mixture was vigorously stirred for 10 minutes. The mixture was allowed to reach ambient temperature and stirred for 3 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (0–10% MeOH-DCM) to provide a yellow solid (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (4.23 g, 56%). LCMS (ESI) m / z 411.8 [M+H] + .

[0340] (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: A dry NMP (6 mL) 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) was cooled to 0 °C, and then 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 reach ambient temperature and stirred for 18 hours. The reaction mixture was slowly added to H2O (60 mL), cooled to 0 °C, and mixed vigorously. The resulting suspension was filtered, and the collected solids were washed with H2O and Et2O. The solid was dissolved in EtOAc, and the solution was dried over MgSO4, filtered, and concentrated to provide a yellow solid of (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.600 g, 79%). LCMS (ESI) m / z 430.0 [M+H] + .

[0341] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoaziridine-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione: To a dry DMSO (1.0 mL) solution of (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (300 mg, 0.698 mmol), 4-(aziridine-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.122 mL, 0.698 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). The solution was purified by chiral reversed-phase chromatography to give (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (89 mg, 24%, 97% ee). LCMS (ESI) m / z 536.2 [M+H] + .

[0342] 6.2 Cell-based assays using compound 1

[0343] The following are examples of cell-based assays that utilize typical non-Hodgkin lymphoma (NHL) cell lines to determine the antiproliferative and apoptotic activities of compound 1.

[0344] Assays for cell proliferation and viability using the SU-DHL-4 cell line: The following exemplary assays utilize DLBCL cell lines, such as the SU-DHL-4 cell line treated for 120 hours (Deutsche sammlon von Mikroorganismen und Zellkulturen GmbH [DSMZ]: catalog number ACC-495). The seeding density of SU-DHL-4 can be optimized to ensure linearity of assays in 1536-well plates.

[0345] Using an acoustic dispenser (EDC ATS-100), compound 1 at increased concentrations (from 0.5 nM to 10 μM) was spotted into empty 1536-well plates in a 20-spot dilution pattern (non-uniformly spaced data points). The DMSO concentration was kept constant, with a final test concentration of 0.1% DMSO. Prior to the assay, SU-DHL-4 cells were grown in RPMI-1640 (Roswell Park Memorial Institute-1640) medium containing 10% FBS (fetal bovine serum: HyClone) and expanded in culture flasks to provide sufficient raw materials. Cells were then diluted to 500 cells per well in 5 μL volumes and added directly to the 1536-well plates containing the added compound. Cells were grown at 37°C and 5% CO2 for 120 hours. When cells begin to be exposed to the compound (t0), according to the manufacturer's (Promega Corporation, Madison, WI) instructions, the luminescence level is quantified by measuring the presence of 5′-adenosine triphosphate (ATP) in living cells at a 1 volume: 2 volume ratio. luminescent cell viability assay (Cell) The Luminescent Cell Viability Assay was used to assess the initial number of viable cells. After 120 hours, the cells were analyzed using Cell... Cell viability was assessed and luminescence was read. All growth inhibition curves were processed and evaluated using Activity Base (IDBS, Alameda, CA). Cell viability IC50 was calculated using a four-parameter logistic model (sigmoidal dose-response model). 50 value:

[0346] y=(A+((BA) / (1+((C / x)^D))))

[0347] in:

[0348] A = Y Min

[0349] B = YMax

[0350] C = EC 50

[0351] D = Hill slope

[0352] IC 50 =When Y = 50% of the DMSO control, the concentration of the compound

[0353] Y = Cell viability, measured in luminescent units, and

[0354] x = concentration of the compound.

[0355] Compound 1 was found to be active in SU-DHL-4 cell proliferation assays, with an IC50 value of 1. 50 <0.2μM.

[0356] Cell proliferation and viability assays using blood cell lines: The exemplary antiproliferative assays described below used the exemplary blood cell lines described below. The in vitro growth inhibitory activity of compound 1 described herein was evaluated using 384-well flow cytometry.

[0357] Table 6. Blood cell lines

[0358]

[0359]

[0360]

[0361]

[0362] ABC = Activated B-cell-like cells; FBS = Fetal bovine serum; GCB = Germinal center B-cells; IMDM = Iscove modified Dulbecco medium; NEAA = Non-essential amino acids; RPMI = RPMI 1640.

[0363] Cell lines were seeded in 384-well plates and evaluated using either compound 1 at concentrations increased from 0.00015 μM to 10 μM or a dimethyl sulfoxide (DMSO) control. The final concentration of DMSO was 0.1% (v / v). After adding compound 1 or DMSO and incubating for 120 hours, cells were analyzed by flow cytometry using Annexin V and the live-cell non-permeable DNA dye DRAQ7. Thermo Fisher Scientific (TFS) analysis was used to determine cell number and cell death. In the early stages of apoptosis, phosphatidylserine translocates from the inner to the outer layer of the cell membrane, and Annexin V binds to exposed phosphatidylserine residues found on the surface of apoptotic cells. Intact live cells exclude the live dye DRAQ7, and the live dye DRAQ7 stains only cells that have died due to apoptosis or necrosis.

[0364] Then, flow cytometry data analysis was performed using FlowJo_v10 software to determine the number of viable cells (Annexin V and DRAQ7 double-negative cells) and the percentage of apoptotic cells (Annexin V positive cells) under each condition. The viable cell counts for each concentration were normalized relative to the DMSO control (as 100%) to calculate the percentage of remaining viable cells after treatment, and plotted using GraphPad Prism 7.03. The IC50 was then calculated by fitting a nonlinear regression curve using log(inhibitor) vs. normalized response-variable slope analysis on GraphPad Prism 7.03. 50 (50% inhibitory concentration) and E max (Maximum potency achieved) value. The area under the curve (AUC) was calculated by performing an AUC analysis on GraphPad Prism 7.03. Similarly, for apoptosis analysis, the percentage of apoptotic cells relative to DMSO in "early" (Annexin V positive and DRAQ7 negative) and "late" (Annexin V and DRAQ7 positive) apoptotic cell gates was plotted using GraphPad Prism 7.03. The AUC and EC50 of the apoptosis curve were calculated by performing an AUC analysis on GraphPad Prism 7.03 and fitting a nonlinear regression curve using log(agonist) vs. standardized response-variable slope analysis. 50 (The concentration of compounds that produce half of the maximum apoptosis response) and Y max (Maximum percentage of apoptosis achieved) value.

[0365] A set of dose-response proliferation curves and nonlinear curve-fit regression of blood cell lines were used to determine the IC50 of the percentage of viable cells. 50 AUC and E max (E of survivability) max The dose-response apoptosis curve was used to determine the percentage of apoptosis (EC5) between 100 at low doses and 0 at high doses (the latter corresponding to inhibition of all viable cells), and the EC5 was used to determine the percentage of apoptosis. 50 AUC and Y max (Y-cell apoptosis) maxThe value varied between 0 at low doses and 100 at high doses (the latter corresponding to the death of all cells). Tumor cells were exposed to serially diluted (0.00015 μM to 10 μM) compounds 1 or a dimethyl sulfoxide (DMSO) control for 5 days. Viability and apoptosis of all cell lines were assessed by Annexin V / 7-aminoactinomycin D (7-AAD) flow cytometry. Compound 1 showed antiproliferative and / or apoptotic activity in almost all tested blood cell lines, as shown in the table below.

[0366] Table 7. Antiproliferative and apoptotic effects of compound 1 in blood cell lines

[0367]

[0368]

[0369]

[0370] AUC = Area under the curve; IC 50 =50% inhibition concentration (μM); E max = The maximum efficacy achieved in eliminating tumor cells, expressed as the percentage of remaining tumor cells; EC 50 = The concentration (μM) of the compound that produces the half-maximal apoptosis response; Y max = Percentage of control calculated at the highest concentration of compound 1.

[0371] 6.3 Excipient compatibility

[0372] Excipient compatibility study design

[0373] The purpose of the excipient compatibility study is to evaluate the effect of each excipient on the stability of compound 1, to classify excipients in each functional category, and to provide a rational basis for the selection of excipients.

[0374] The table below lists the composition of the excipient compatibility blends. Excipients have many functions, including diluents, binders, disintegrants, flow aids, and lubricants. Given the relatively high solubility of compound 1, dissolution may not be a critical issue compared to low doses (as low as 0.1 mg). Therefore, surfactants are not included in this excipient evaluation.

[0375] Due to the low dosage specifications, segregation and content uniformity (CU) variations may be major process challenges. Granulation processes (rolling or high-shear wet granulation) may offer a better option than direct mixing to minimize segregation. Therefore, for each formulation mixture, in addition to powder mixtures, compacted slug samples were prepared to simulate roller pressing conditions, and wet & dry samples were prepared to simulate wet granulation process conditions.

[0376] The mixture was placed under open conditions of 5°C (control), 50°C (dry), and 50°C / 75% RH (humid) for 2 weeks to evaluate the chemical and chiral stability of the samples. Two copies of the sample were prepared for each time point and condition.

[0377] Table 8. Composition of excipient compatibility mixtures

[0378]

[0379]

[0380] Excipient compatibility scheme

[0381] For each mixture in the table, different forms (blend mix, lumps, and wet & dried mix) are used to simulate direct mixing, rolling, and wet pelleting process conditions.

[0382] For each formulation mixture, accurately weigh 120 mg of the HCl salt of compound 1 (form A) and the corresponding excipient. Prepare the mixture by mixing at 32 rpm for 20 minutes on a Turbula mixer. For blister samples, press the mixture into blister packs at 4.4 kN for 100 ms in an RRDI. For wet mixture samples, add 20% water to the mixture powder, magnetically stir for 5 minutes, and then dry in a 50°C oven for 1 hour.

[0383] For chemical and chiral stability, all samples were tested for stability by maintaining them at 5°C, 50°C, and 50°C / 75%RH for 2 weeks. The following two tables show the chemical and chiral analysis data, respectively.

[0384] Chemical stability

[0385] Table 9. Chemical stability data from excipient compatibility studies

[0386]

[0387] N / A = No data obtained

[0388] NT = Untested

[0389] Chiral stability

[0390] Table 10. Chiral stability data from excipient compatibility studies

[0391]

[0392]

[0393] N / A = No data obtained

[0394] NT = Untested

[0395] 6.4 Stability of the prototype formulation

[0396] Prototype formulation design

[0397] Based on the results of excipient compatibility studies, the original capsule formulation was selected, as shown in the table below.

[0398] For direct mixing and rolling processes, both MCC and pregelatinized starch are used as binders in prototype formulations because they exhibit similar stability in terms of excipient compatibility; silica is used as a flow aid; and magnesium stearate and sodium stearate fumarate are used as lubricants.

[0399] For wet granulation processes, MCC and pregelatinized starch are used, although pregelatinized starch shows slightly better performance than MCC in terms of excipient compatibility; silica is not used; stearic acid (not magnesium stearate or sodium stearate fumarate) is used as a lubricant.

[0400] Table 11. Prototype Formulation Combinations

[0401]

[0402] Preparation of prototype formulation

[0403] For direct-mix formulations (Cap-1, Cap-2, Cap-3), first pass the excipients through a 30-mesh / 595μm sieve and the API through a 60-mesh / 250μm sieve. Use geometric dilution to improve the homogeneity of the mixture – first mix the API with a small amount of starch or MCC at 15 rpm for 20 minutes, then mix the compound with the remaining excipients (except magnesium stearate) at 15 rpm for 20 minutes, repeat the compounding, rinse the compound with mannitol, and then finally mix at 15 rpm for 10 minutes. If magnesium stearate is used as a lubricant, add it last and mix at 15 rpm for another 3 minutes.

[0404] For compacted formulations (Cap-4, Cap-5, Cap-6), first pass the excipients through a 30-mesh / 595μm sieve and the API through a 60-mesh / 250μm sieve. Use geometric dilution to improve the uniformity of the mixture – first mix the API with a small amount of starch or MCC at 15 rpm for 20 minutes, then coil (457μm sieve) with the remaining in-granule excipients (except magnesium stearate) at 15 rpm for 20 minutes, coil again (457μm sieve), rinse the coil with mannitol, and then mix at 15 rpm for 10 minutes. If magnesium stearate is used as a lubricant, add the magnesium stearate portion of the granules last and mix at 15 rpm for another 3 minutes. Then, pass the in-granule mixture through a Gerteis Polygran compactor (grooved roller, roller speed 2 rpm, roller gap 2.0 mm, rolling force 4 kN / cm, sieve aperture 1.0 mm, granulator speed 50 rpm). Finally, mix the external lubricant with the dry particles.

[0405] For wet granulation formulations (Cap-7, Cap-8, Cap-9), all excipients (except lubricant) and APIs are first passed through a 30-mesh / 595 μm sieve. They are then mixed for 10 minutes in a Freund Vector high-shear granulator bowl at an impeller speed of 300 rpm and a shredder speed of 3000 rpm. Following this, 20% water is sprayed at 30 g / min using the same impeller speed and shredder speed, followed by 1 minute of wet massing. The wet granules are then passed through a 5-mesh / 4 mm sieve and dried in a Mini Glatt fluidized bed dryer (inlet air temperature 50°C, inlet air flow rate 50 CFM, product temperature NMT 42°C). The dried granules are then passed through a comul (610 μm sieve) and mixed with stearic acid (lubricant) screened at 30 mesh at 15 rpm for 10 minutes.

[0406] The final mixture was encapsulated in a Bosch GKF 702 encapsulator into No. 4 white opaque HPMC capsules with a fill weight of 75 mg.

[0407] The table below shows the preliminary test results for prototype formulation batches under different process conditions. For the same formulation composition, batches using the milling process consistently had smaller AV values ​​(Cap-4 vs Cap-1, Cap-5 vs Cap-2, Cap-6 vs Cap-3) than batches using the direct mixing process; therefore, for the production of HCl salt drug products of Compound 1, the milling process is superior to the direct mixing process for obtaining better content uniformity. Different processes affect chemical stability. Compared with direct mixing, the total chemical degradation after the milling process does not change significantly; however, degradation increases after the wet granulation process, which means that the wet granulation process may have a higher level of chemical stability risk than the milling process. Chiral purity is not affected by different process conditions.

[0408] Table 12. Batch Results of the Prototype Formulation

[0409]

[0410] *AV: Acceptable value

[0411] Stability of the original formulation

[0412] Each formulation was encapsulated in 50 100cc HDPE bottles, induction sealed, with 10 capsules per bottle. 35 bottles contained 2g of desiccant, and 15 bottles did not contain desiccant. Stability was evaluated under accelerated conditions (40°C / 75%RH and 50°C / 75%RH).

[0413] Figure 1A , Figure 1B and Figure 1C The chemical stability (total impurities) of the prototype formulation was demonstrated for up to 12 weeks at 40°C / 75%RH without desiccant, 40°C / 75%RH with desiccant, and 50°C / 75%RH with desiccant.

[0414] At 40°C / 75% RH, the effect of desiccant vs. no desiccant on stability was investigated. Formulations packaged with desiccant showed a significantly slower rate of API impurity growth than those without desiccant packaging. This indicates that humidity control is important for the stability of pharmaceutical products, and hydrolysis is one of the main degradation pathways of the HCl salt of Compound 1. Desiccants are needed to maintain the shelf life of pharmaceutical products containing the HCl salt of Compound 1.

[0415] For the three rolled formulations, at 40°C / 75%RH with desiccant, Cap-5 and Cap-6 formulations showed similar total impurity growth rates, slower than Cap-4. At 50°C / 75%RH with desiccant, the total impurity growth rate was faster than at 40°C, but the order of preference among the formulations remained unchanged. The main compositional difference between Cap-4 and Cap-5 / Cap-6 is that magnesium stearate is used as a lubricant in Cap-4, while sodium stearate fumarate (SSF) is used as a lubricant in Cap-5 / Cap-6. Therefore, SSF is superior to magnesium stearate as a lubricant in rolled formulations. The binder used in Cap-5 is pregelatinized starch, while microcrystalline cellulose is used in Cap-6. Cap-5 and Cap-6 have similar chemical stability.

[0416] For the three wet granulation formulations, at 40°C / 75%RH with a desiccant, Cap-9 exhibited a faster impurity growth rate than Cap-7 and Cap-8. At 50°C / 75%RH with a desiccant, the impurity growth rate was faster than at 40°C, but the order of impurity growth among the formulations remained unchanged; Cap-8 had a slightly faster impurity growth rate than Cap-7.

[0417] Cap-5 and Cap-7 have similar formulation compositions but are produced using different granulation processes. The wet-granulated formulation (Cap-7) has a higher initial impurity content than the rolled-up formulation (Cap-5), which is likely due to the process; however, during the stability period, they have similar rates of total impurity growth.

[0418] Figure 2A , Figure 2B and Figure 2C The data show the chiral stability of the prototype formulation for up to 12 weeks at 40℃ / 75%RH without desiccant, 40℃ / 75%RH with desiccant, and 50℃ / 75%RH with desiccant.

[0419] At 40°C / 75%RH, the effect of desiccant vs. no desiccant on stability showed that formulations packaged with desiccant exhibited a significantly slower chiral isomerization rate than those without desiccant packaging. This implies that humidity control is important for the chiral stability of pharmaceutical products, and that desiccants are necessary to maintain the shelf life of pharmaceutical products.

[0420] For the crushed formulations, at 40°C / 75% RH with desiccant, all three formulations exhibited slow chiral isomerization rates—a decrease in chiral purity of approximately 1% over 12 weeks. The order of chiral stability appeared to be Cap-4 > Cap-5 > Cap-6. At 50°C / 75% RH with desiccant, the chiral isomerization rate was faster than at 40°C, but the order among the formulations remained unchanged. It appears that chiral stability poses a less significant risk to drug shelf life than chemical stability.

[0421] For wet-granulation formulations, at 40°C / 75% RH with desiccant, all three formulations also exhibited slow chiral isomerization rates—with a decrease in chiral purity of less than 1.5% over 12 weeks. The order of chiral stability appeared to be Cap-8 > Cap-7 > Cap-9. At 50°C / 75% RH with desiccant, the chiral isomerization rate was faster than at 40°C, but the order among the formulations remained unchanged.

[0422] Cap-5 and Cap-7 have similar formulation compositions but are processed using different granulation processes. Both formulations initially exhibit the same level of chiral purity; after 12 weeks, the wet-granulated formulation (Cap-7) shows a slightly lower level of chiral purity than the rolled-up formulation (Cap-5). Cap-5 and Cap-7 were selected for further process development.

[0423] 6.5 Process Evaluation and Development

[0424] (a) Evaluation and development of high-shear wet granulation process

[0425] In-particle excipient / out-of-particle excipient ratio

[0426] The recommended clinical dosage of the HCl salt of compound 1 is as low as 0.1 mg, packed into 75 mg capsules, representing a drug loading of approximately 0.14%. Such an extremely low drug loading poses challenges to the process and content uniformity. High-shear wet granulation not only effectively disperses the API with high shear forces during mixing but also forms particles to prevent segregation during bulk storage and packaging. For low-dose formulations with content uniformity issues, high-shear wet granulation may be a good option.

[0427] To improve the content uniformity of Cap-7 batches (CU% RSD 6.1%, AV 16.5), the wet granulation process was optimized. Since the API dosage was fixed, the ratio of in-granule excipients to out-of-granule excipients was reduced (from 95 / 5 to 23 / 77), increasing the drug loading of the in-granule mixture from 0.14% to 0.6%. Figure 3This shows a flowchart of the wet granulation process. In the original process, everything except the lubricant was inside the granules; in the new process, API, pregelatinized starch, and cropovidone are inside the granules, while mannitol and the lubricant are outside the granules.

[0428] Cap-10 was prepared using an in-particle excipient / out-particle excipient ratio of 23:77, while Cap-7 was prepared using an in-particle excipient / out-particle excipient ratio of 95:5. The treatment results for Cap-10 (CU% RSD 2.5%, AV 5.27) indicate that reducing the in-particle excipient / out-particle excipient ratio can improve content uniformity for wet granulation processes. To confirm this conclusion, repeat batches were prepared – Cap-11 was prepared using the same process as Cap-7, with an initial high in-particle excipient / out-particle excipient ratio of 95:5; while Cap-13 was prepared using the same process as Cap-10. The process results in the table below show good batch repeatability – the CU% RSDs for Cap-7 and Cap-11 are comparable (6.1 vs 6.8), but significantly higher than the batch repeatability of Cap-10 and Cap-13 (2.5 vs 3.3). Therefore, it has been confirmed that the novel wet granulation process with a lower ratio of in-particle to out-of-particle excipients will improve the content uniformity of low-dose formulations.

[0429] Table 13. Summary of process results for batches prepared by high-shear wet granulation

[0430] Batch number Specification API screen Excipient screen Content determination (%) CU%RSD AV Cap-7 0.1mg 30 mesh 30 mesh 101.46 6.1 16.51 Cap-10 0.1mg 30 mesh 30 mesh 101.7 2.5 5.27 Cap-11 0.1mg 30 mesh 30 mesh 109.4 6.8 21.5 Cap-12 0.1mg 60 mesh 30 mesh 99.1 3.5 8.5 Cap-13 0.1mg 30 mesh 30 mesh 96.2 3.3 10.3 Cap-14 0.1mg 60 mesh 30 mesh 91 2.0 11.5

[0431] API screen mesh size

[0432] API particle size also affects content uniformity, as smaller API particles disperse better. The HCl salt API crystals of Compound 1 tend to aggregate; although high shear mixing forces can break down the aggregates, it is less efficient than sieving for low-dose formulations. For processes with high in-particle / out-of-particle excipient ratios, batch Cap-12 passed API through a 60-mesh (250 μm) sieve compared to Cap-7 and Cap-11 using a 30-mesh (595 μm) sieve. As a result, the CU% RSD significantly decreased from 6.1% for Cap-7 to 3.5% for Cap-12. This trend also holds true for newer wet granulation processes with lower in-particle / out-of-particle excipient ratios—changing the API sieve mesh size from 30 to 60 reduced the CU% RSD from 2.5% for Cap-10 to 2.0% for Cap-14. Therefore, passing API through smaller sieve openings can improve batch content uniformity.

[0433] Grinding particle size matching

[0434] In a wet granulation process with a low in-particle / out-of-particle excipient ratio (23 / 77), API is mixed with starch, cropovidone, and water to form wet granules, which are then dried and comul-milled. The milled granules are then mixed with mannitol and a lubricant to form the final mixture. Since mannitol powder constitutes the majority of the final mixture (approximately 72% w / w), it is important that the particle size of the milled granules be matched to that of the mannitol to minimize segregation.

[0435] Cap-13 is a repeat batch of Cap-10, using a lower in-particle / out-of-particle excipient ratio. Cap-10 has good CU data, but Cap-13's CU data is not as good (3.3 vs 2.5). The table below lists the particle size distribution of Cap-10, Cap-13, and the mannitol excipient (Pearlitol 200SD). The particle size of the Cap-10 milled particles (D50 145 μm) is very well matched with that of the mannitol (D50 148 μm); however, the particle size of the Cap-13 milled particles (D50 259 μm) is much larger than that of the mannitol (D50 148 μm), which may explain why Cap-13's CU data is not as good as Cap-10's. The particle size of the final mixture of Cap-10 and Cap-13 is similar because mannitol is the major component and dominates the average particle size of the final mixture, rather than the milled particles.

[0436] In another duplicate batch (Cap-14), the particle size of the abrasive particles was monitored and controlled before mixing with mannitol and lubricant. The particle size (D50 139 μm) was matched to that of Cap-10 with the abrasive particles and mannitol, which explains why the CU% RSD (2.0) of Cap-14 was as good as that of Cap-10 (2.5).

[0437] Table 14. Particle size distribution of wet granulation batches and main excipients

[0438] Sample Name D(10)(μm) D(50)(μm) D(90)(μm) Cap-10 abrasive particles 38 145 448 Cap-10 final mixture 73 158 323 Cap-13 abrasive particles 76 259 573 Cap-13 Final Mixture 62 150 301 Cap-14 abrasive particles 33 139 440 Cap-14 Final Mixture NT NT NT Mannitol (Pearlitol 200SD) 85 148 237 Pregelatinized starch (Starch 1500) 18 88 183

[0439] NT: Not tested

[0440] SEM images of the excipients, ground particles, and final mixture (not shown in this paper) were obtained to better understand particle size and surface morphology. SEM images of pregelatinized starch (Starch 1500) and mannitol (Pearlitol 200SD) show that most pregelatinized starch particles are smaller than mannitol particles. SEM images of the Cap-10 ground particles show that the ground particles are primarily aggregates of starch particles, and the particle size is similar to that of mannitol. SEM images of the final Cap-10 mixture show that it consists of mannitol particles.

[0441] In summary, for high-shear wet granulation processes, reducing the ratio of in-granule to out-of-granule excipients, passing the API through a sieve with a smaller aperture, and matching the size of the ground particles with that of mannitol can improve the content uniformity of low-dose formulations.

[0442] Evaluation and development of rolling technology

[0443] In-particle excipient / out-of-particle excipient ratio

[0444] The recommended clinical dosage of the HCl salt of compound 1 is as low as 0.1 mg, packed in 75 mg capsules, representing approximately 0.14% drug loading. Such an extremely low drug loading presents challenges for the manufacturing process and content uniformity. While the compaction process itself does not help to achieve uniform API dispersion, it does help prevent subsequent segregation; to achieve good content uniformity, the API should be well dispersed prior to the compaction step.

[0445] Cap-5 batches were subjected to geometric dilution to improve mixing homogeneity, yielding acceptable content homogeneity results (3.1% RSD, AV 7.4). To further improve content homogeneity, the in-particle drug loading was increased before compaction. Since the amount of API is fixed, the in-particle / out-of-particle excipient ratio needed to be reduced (from 98 / 2 to 14 / 86) to increase the drug loading of the in-particle mixture from 0.14% to 1%. Figure 4 Show the flowchart of the RC process.

[0446] Cap-5 was initially rolled using a 98:2 ratio of in-granule excipients to out-of-granule excipients, while Cap-15 was prepared using a new rolling process with a 14:86 ratio of in-granule excipients to out-of-granule excipients. Since starch alone cannot be successfully rolled, in Cap-15, the excipient ratio in the in-granule portion remains similar to that in the out-of-granule portion.

[0447] In Cap-5 batches, the API is passed through a 60-mesh (250 μm) sieve before mixing; however, since the use of a 60-mesh sieve is not common in mass production, a 30-mesh (595 μm) sieve is used for both the API and excipients in Cap-15 batches. There are no other process changes between Cap-15 and Cap-5.

[0448] The table below summarizes the process results for the rolling development batches. The CU% RSD for Cap-15 is higher than that for Cap-5 (9.0 vs 3.1). Even with additional mixing and co-milling steps, the content uniformity of the repeated batch (Cap-16) did not change significantly (CU% RSD of 8.6). Unlike wet granulation, the new method using a lower in-particle / out-of-particle excipient ratio (14:86) did not improve the content uniformity of low-dose formulations in the rolling process.

[0449] Table 15. Summary of process results for rolling development batches

[0450] Batch number Specification API screen Excipient screen Content determination (%LC) CU%RSD AV Cap-5 0.1mg 60 mesh 30 mesh 98.29 3.1 7.42 Cap-15 0.1mg 30 mesh 30 mesh 103.4 9.0 19.9 Cap-16 0.1mg 30 mesh 30 mesh 95.5 8.6 20.2 Cap-17 0.1mg 30 mesh 30 mesh 103.8 5.8 13.9 Cap-18 0.1mg 60 mesh 30 mesh 92.4 2.9 11.9

[0451] Particle size analysis was performed on the ground particles and the final mixture of the compacted batches, and the results are shown in the table below. For Cap-15 and Cap-16 batches, the D(50) values ​​of the ground particles and the final mixture were similar; however, there was a significant difference in the D(90) values ​​between the ground particles and the final mixture, indicating that the ground particles contained too many large particles, which did not mix well with the excipients when the excipients constituted the majority of the final mixture. Further work is needed to identify suitable process conditions to control the particle size of the ground particles to match the particle size of the excipients in processes with low in-particle / excipient ratios. However, since acceptable CU has already been achieved with conventional high in-particle / excipient ratio processes, further work on a new process is not necessary.

[0452] Table 16. Particle size distribution of compacted batches

[0453] Sample Name D(10)(μm) D(50)(μm) D(90)(μm) Cap-5 Final Mixture 8 110 595 Cap-15 abrasive particles 16 145 568 Cap-15 Final Mixture 18 126 238 Cap-16 abrasive particles 16 154 659 Cap-16 Final Mixture 18 131 279 Cap-17 abrasive particles 15 165 786 Cap-17 Final Mixture 14 146 780 Cap-18 abrasive particles 31 253 864 Cap-18 Final Mixture 17 173 832

[0454] API screen mesh size

[0455] API particle size also affects content uniformity, as smaller API particles tend to disperse better. API crystals of the HCl salt of Compound 1 readily aggregate, and the mixing process is too gentle to break up large aggregates. Therefore, sieving the API powder through a sieve before mixing is an effective method to break up large aggregates.

[0456] For the initial high in-particle / out-of-particle excipient ratio process, batch Cap-5 passed API through a 60-mesh (250 μm) sieve and achieved an acceptable CU% RSD (3.1%); however, when Cap-17 increased the API sieve aperture to 30 mesh (595 μm), the CU% RSD increased to 5.8%. When Cap-18 reduced the API sieve aperture to 60 mesh (250 μm), the CU% RSD recovered to 2.9%. Therefore, passing API through a smaller sieve aperture can improve the content uniformity of the rolled batch.

[0457] In summary, for the rolling process, passing the API through a 60-mesh sieve instead of a 30-mesh sieve is important for the content uniformity of low-dose formulations.

[0458] 6.6 Evaluation and Production of Formulations

[0459] Cap-5 and Cap-7 have similar formulation compositions but are produced using different granulation processes. The wet-granulated formulation (Cap-7) has a 0.7% higher initial total impurity content than the rolled formulation (Cap-5), likely due to increased chemical degradation caused by the wetting and drying processes involved in wet granulation; however, the total impurity growth rates were similar for both batches in stability studies. Both formulations require a desiccant to maintain a suitable shelf life. Overall, the wet granulation process carries a higher risk of chemical instability than the rolled process. For chiral purity, the two formulations are similar.

[0460] Manufacturability was evaluated using content uniformity and content analysis values. Based on process development data, although the content uniformity (CU% RSD) of wet granulation batches was better than that of rolling, the content uniformity of rolling batches was still acceptable. Compared to wet granulation, rolling has a lower risk of API loss (content analysis value) because the rolling process is simpler.

[0461] Because the HCl salt API of compound 1 has relatively high solubility compared to the recommended dose level, the risk of drug product dissolution is low. Figure 5 The performance (dissolution profiles) of the formulations produced by the two granulation processes are shown. Although the wet granulation batch (Cap-10) has a faster dissolution rate, the rolled batch (Cap-5) still has a sufficiently good dissolution rate.

[0462] The crushed and Cap-5 formulations were selected for further evaluation. The following three tables list the formulation composition for different dosage strengths. Hydroxypropyl methylcellulose (HPMC) was chosen instead of gelatin as the capsule shell material due to the need for a desiccant, as gelatin capsules would break during storage in the presence of a desiccant.

[0463] Table 17. Capsule composition, 0.1mg specification

[0464]

[0465]

[0466] 1 Approximate capsule weight based on 38.0mg capsule weight.

[0467] Table 18. Capsule composition, 0.5mg specification

[0468]

[0469] 1 Approximate capsule weight based on 38.0mg capsule weight.

[0470] Table 19. Capsule composition, 1.5mg specification

[0471]

[0472]

[0473] 1 Approximate capsule weight based on 75.0mg capsule weight.

[0474] Figure 6 The rolling process flow chart for the above batch is shown. The production process of the HCl salt capsules of compound 1 is described as follows: (i) the HCl salt of compound 1 is premixed with a small portion of pregelatinized starch, and then mixed with the remaining in-granule excipients (pregelatinized starch, mannitol, crospovidone, silica, sodium stearate); (ii) the in-granule mixture is passed through a rolling mill; (iii) the out-of-granule silica and sodium stearate are sieved and added to the granules and mixed; and (iv) capsules of appropriate size are filled to the specified weight.

[0475] Three batches (Cap-19, Cap-20, and Cap-21, in 0.1 mg, 0.5 mg, and 1.5 mg dosage strengths, respectively) were produced and packaged in 3 kg quantities. The stability results for each batch are listed in the table below. The capsules were packaged in 100cc opaque high-density polyethylene (HDPE) bottles with inductive seals and tamper-evident, child-proof polypropylene caps. Each bottle contained 21 capsules and 2g of desiccant.

[0476] Table 20. Batch Results

[0477] batch# Dosage specifications Content determination (%LC) CU%RSD AV Cap-19 0.1mg 96.1％ 2.43％ 8.4 Cap-20 0.5mg 97.2％ 1.61％ 3.8 Cap-21 1.5mg 96.2％ 1.89％ 5.5

[0478] The embodiments provided herein are not limited to the specific embodiments shown in the examples, which are intended to illustrate some aspects of the provided embodiments, and any functionally equivalent embodiments are included in this disclosure. In fact, various modifications to the embodiments provided herein, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0479] Many references have been cited, and their entirety is included in the text for reference.

Claims

1. A pharmaceutical composition comprising compound 1: Or an enantiomer, a mixture of enantiomers, a tautomer, an isotope, or a pharmaceutically 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. The pharmaceutical composition of claim 1, wherein the carrier or diluent is a mixture of mannitol and starch.

3. The pharmaceutical composition of claim 2, comprising: 1) compound 1 or an enantiomer, mixture of enantiomers, tautomers, isotopes or pharmaceutically acceptable salt thereof, in an amount of 0.05% w / w to 2% w / w; 2) a mixture of mannitol and starch in an amount of 85% w / w to 99.7% w / w; 3) a disintegrant in an amount of 0% w / w to 6% w / w; 4) A gliding agent, in an amount of 0% w / w to 2% w / w; 5) Lubricant, in an amount of 0% w / w to 10% w / w.

4. The pharmaceutical composition of claim 3, wherein compound 1 or its enantiomers, mixtures of enantiomers, tautomers, isotopes or pharmaceutically acceptable salts are hydrochloride salts of compound 1.

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

6. The pharmaceutical composition of claim 4, wherein the hydrochloride of compound 1 is characterized by its XRPD plot including peaks at 15.1, 16.3, and 20.7°2θ ± 0.2°2θ.

7. The pharmaceutical composition of claim 3, wherein the amount of compound 1 or its enantiomers, enantiomer mixtures, tautomers, isotopes or pharmaceutically acceptable salts is from 0.1% w / w to 1% w / w.

8. The pharmaceutical composition of claim 7, wherein the amount of compound 1 or its enantiomers, enantiomer mixtures, tautomers, isotopes or pharmaceutically acceptable salts is from 0.14% w / w to 0.71% w / w.

9. The pharmaceutical composition of claim 3, wherein the starch is pregelatinized starch.

10. The pharmaceutical composition of claim 3, wherein the amount of mannitol is 67% w / w to 77% w / w, and the amount of starch is 18% w / w to 22% w / w.

11. The pharmaceutical composition of claim 3, wherein the amount of the mannitol and starch mixture is 90% w / w to 95% w / w.

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

13. The pharmaceutical composition of claim 3, wherein the amount of the mannitol and starch mixture is from 91.5% w / w to 93% w / w.

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

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

4.

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

6.

17. The pharmaceutical composition of claim 3, wherein the disintegrant is cropovidone.

18. The pharmaceutical composition of claim 3, wherein the amount of disintegrant is from 1% w / w to 5% w / w.

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

20. The pharmaceutical composition of claim 3, wherein the gliding agent is silica.

21. The pharmaceutical composition of claim 3, wherein the amount of the gliding agent is from 0.5% w / w to 1.5% w / w.

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

23. The pharmaceutical composition of claim 3, wherein the lubricant is sodium stearate fumarate, stearic acid, or magnesium stearate.

24. The pharmaceutical composition of claim 3, wherein the amount of lubricant is from 1.5% w / w to 7.5% w / w.

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

26. The pharmaceutical composition of claim 3, comprising: 1) 0.14% w / w of compound 1 hydrochloride; 2) 72.86% w / w of mannitol and 20% w / w of pregelatinized starch; 3) 3% w / w of cropovidone; 4) 1% w / w of silica; and 5) 3% w / w of sodium stearate fumarate.

27. The pharmaceutical composition of claim 26, having a total weight of 75 mg.

28. The pharmaceutical composition of claim 27, wherein it is contained in capsule No.

4.

29. The pharmaceutical composition of claim 3, comprising: 1) 0.71% w / w of compound 1 hydrochloride; 2) 72.29% w / w of mannitol and 20% w / w of pregelatinized starch; 3) 3% w / w of cropovidone; 4) 1% w / w of silica; and 5) 3% w / w of sodium stearate fumarate.

30. The pharmaceutical composition of claim 29, having a total weight of 75 mg.

31. The pharmaceutical composition of claim 30, wherein it is contained in capsule No.

4.

32. The pharmaceutical composition of claim 29, having a total weight of 225 mg.

33. The pharmaceutical composition of claim 32, wherein it is contained in capsule No.

1.

34. The pharmaceutical composition of claim 3, comprising: 1) 0.14% w / w of compound 1 hydrochloride; 2) 71.86% w / w of mannitol and 20% w / w of pregelatinized starch; 3) 3% w / w of cropovidone; and 4) 5% w / w of stearic acid.

35. The pharmaceutical composition of claim 3, comprising: 1) 0.14% w / w of compound 1 hydrochloride; 2) 75.86% w / w of mannitol; and 20% w / w of pregelatinized starch; 3) 3% w / w of cropovidone; and 4) 1% w / w of magnesium stearate.

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

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

38. The pharmaceutical composition of claim 37, comprising: 1) 0.14% w / w of compound 1 hydrochloride; 2) 73.86% w / w of mannitol and 20% w / w of microcrystalline cellulose; 3) 3% w / w of cropovidone; and 4) 3% w / w of sodium stearate fumarate.

39. The pharmaceutical composition of claim 37, comprising: 1) 0.14% w / w of compound 1 hydrochloride; 2) 71.86% w / w of mannitol and 20% w / w of microcrystalline cellulose; 3) 3% w / w of cropovidone; and 4) 5% w / w of stearic acid.

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

41. The pharmaceutical composition of claim 40, comprising: 1) compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotope or pharmaceutically acceptable salt thereof, in an amount of 0.05% w / w to 2% w / w; 2) Cellulose, in amounts ranging from 75% w / w to 95% w / w; 3) Disintegrant, in an amount of 0% w / w to 20% w / w; 4) Lubricant, in an amount of 0% w / w to 10% w / w.

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

43. Use of the pharmaceutical composition of any one of claims 1-42 in the preparation of a medicament for treating hematologic malignancies.

44. The use of claim 43, wherein the hematologic malignancy is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or myelodysplastic syndrome (MDS).

45. The use of claim 43, wherein the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) or marginal zone lymphoma (MZL).

46. ​​A method for preparing a pharmaceutical composition according to any one of claims 1-42, comprising the steps of: (i) mixing compound 1 or an enantiomer, mixture of enantiomers, tautomers, isotopes or pharmaceutically acceptable salt thereof with a first excipient and water to form wet granules; (ii) Dry, then grind into particles; (iii) The ground particles are mixed with the remaining excipients to form the final mixture.

47. The method of claim 46, wherein the ratio of the first portion of the excipient to the remaining excipient is 23:

77.

48. The method of claim 46 or 47, wherein prior to step (i), compound 1 or its enantiomers, enantiomer mixtures, tautomers, isotopes or pharmaceutically acceptable salts are passed through a 60-mesh sieve or a sieve with a smaller aperture.

49. The method of claim 46 or 47, wherein the particle size of the abrasive particles matches the particle size of the main component of the remaining excipient.

50. A method for preparing a pharmaceutical composition according to any one of claims 1-42, comprising the steps of: (i) mixing compound 1 or an enantiomer, a mixture of enantiomers, a tautomer, an isotope or a pharmaceutically acceptable salt thereof with a first portion of excipient to form an intragranular mixture; (ii) passing the intragranular mixture through a milling machine to form dry granules; and (iii) mixing the dry granules with the remaining excipient to form a final mixture.

51. The method of claim 50, wherein prior to step (i), compound 1 or its enantiomers, enantiomer mixtures, tautomers, isotopes or pharmaceutically acceptable salts are passed through a 60-mesh sieve or a sieve with a smaller aperture.

52. The method of claim 51, wherein the ratio of the first portion of excipient to the remaining excipient is 98:2.

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