Pharmaceutical composition containing (S)-4-(4-(4-((((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)-3-fluorobenzonitrile and method of using the same

Abstract

Provided herein are pharmaceutical compositions (e.g., oral administration formulations) comprising (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a carrier or diluent. Also provided herein are methods of preparing and using the pharmaceutical compositions. JPEG2023533314000040.jpg155133 JPEG2023533314000041.jpg146134

Description

Technical Field

[0001] 1. Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 048,998, filed Jul. 7, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] Provided herein is a pharmaceutical composition comprising (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof and a carrier or diluent. Also provided herein is a method of using such pharmaceutical compositions for the treatment, prevention and management of various disorders.

Background Art

[0003] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play an important role in immune function. However, the uncontrolled growth of these cells results in bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common hematologic malignancy, but the exact cause of multiple myeloma remains unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, such as, but not limited to, M protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin, except for some patients (estimated 1% - 5%) in whom myeloma cells do not secrete those proteins (referred to as non-secretory myeloma). M protein is an abbreviation for monoclonal protein and is also known as paraprotein, a particularly abnormal protein produced by myeloma plasma cells, and can be found in the blood or urine of almost all patients with multiple myeloma, except for patients with non-secretory myeloma or patients in whom myeloma cells produce immunoglobulin light chains with heavy chains.

[0004] Skeletal symptoms, such as bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast-stimulating factors (including IL-1, IL-6, and TNF), which cause calcium to leach from the bone, leading to eluting lesions; hypercalcemia is another symptom. Osteoclast-stimulating factors, also called cytokines, can interfere with apoptosis or death of myeloma cells. Fifty percent of patients have myeloma-associated bone lesions detectable by radiography at the time of diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal failure.

[0005] Current treatments for multiple myeloma may include one or more of the following: surgery to eradicate multiple myeloma cells in the patient, stem cell transplantation, chemotherapy, immunotherapy, and / or radiation therapy. All current treatment approaches present significant drawbacks for the patient.

[0006] Over the past decade, novel therapeutic agents, particularly immunomodulatory agents such as lenalidomide and pomalidomide, have significantly increased response rates in patients with multiple myeloma, extending progression-free survival (PFS) and overall survival (OS). However, in many patients with multiple myeloma, even after achieving complete response (CR), persistent levels of residual disease remain below the sensitivity of bone marrow (BM) morphology, immunofixation-assisted protein electrophoresis, and light chain quantification, ultimately leading to disease relapse. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is being considered as a surrogate trial endpoint to improve the identification of effective treatments, particularly for frontline trials requiring 5–10 years of follow-up to identify differences in survival. Therefore, monitoring minimal residual disease (MRD) in patients with multiple myeloma provides prognostic value for predicting PFS and OS, as well as for treatment decisions. In myeloma, minimal residual disease (MRD) can be detected using a 0.01% threshold (10⁻⁴ cells) after treatment; that is, multiple myeloma cells with 10⁻⁴ or fewer cells as a percentage of total bone marrow mononuclear cells are considered MRD-negative, and those with 10⁻⁴ or more cells are considered MRD-positive. While the 10⁻⁴ MRD threshold is originally based on technical capability, quantitative MRD detection is currently possible at 10⁻⁵ cells by flow cytometry and 10⁻⁶ cells by high-throughput sequencing (Non-Patent Literature 1). Methods for measuring MRD include DNA sequencing of VDJs, polymerase chain reaction (PCR) (including allele-specific PCR and ASO PCR), and multi-parameter flow cytometry (MPF). For example, an assay for MRD based on chronotype profile measurement is described in Faham et al.'s Patent Literature 1, which is incorporated herein by reference.

[0007] For example, there is a significant need for safe and effective compounds and methods to treat, prevent, and manage multiple myeloma in patients who have recently been diagnosed with multiple myeloma or who are refractory to standard treatments, while reducing or avoiding the toxicity and / or side effects associated with conventional treatments.

[0008] Various possible pharmaceutical compositions (e.g., oral formulations containing different excipients) create potential diversity in the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of pharmaceutical compositions are crucial in the development of effective, stable, and marketable pharmaceutical products. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 8,628,927 [Non-patent literature]

[0010] [Non-Patent Document 1] Rawstron et al.,Blood 2015;125(12):1932-1935 [Overview of the Initiative] [Means for solving the problem]

[0011] Several pharmaceutical compositions containing compound 1 have already been described in U.S. Patent Application Publication No. 16 / 737,721, which is incorporated herein by reference in its entirety.

[0012] In this specification, 1) Compound 1: [ka] A pharmaceutical composition (e.g., an oral formulation) is provided, comprising: 1) hydrobromide, 2) a mixture of mannitol and cellulose or a mixture of mannitol and starch, 3) hydroxypropyl methylcellulose (HPMC), 4) sodium starch glycolate (SSG), and 5) stearic acid.

[0013] In this specification, 1) Compound 1: [ka] Also provided are pharmaceutical compositions (e.g., oral formulations) comprising: 2) a mixture of mannitol and starch; 3) sodium stearyl fumarate; and 4) optionally fumaric acid.

[0014] Compound 1 has the chemical name (S)-4-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)-3-fluorobenzonitrile. Methods for preparing pharmaceutical compositions are also provided herein.

[0015] The pharmaceutical compositions provided herein are formulations (or combinations) useful for use in animals or humans. Accordingly, the embodiments herein encompass the use of these pharmaceutical compositions as final drug products. Some embodiments provide pharmaceutical compositions useful in producing final dosage forms having improved properties required for the manufacture, processing, formulation and / or storage of the final drug product, such as, in particular, powder flow properties, compressibility properties, tablet properties, stability properties and excipient compatibility properties.

[0016] Pharmaceutical compositions are also provided that contain compound 1 provided herein at an effective concentration and are formulated for administration by appropriate routes and means. In one embodiment, the pharmaceutical composition is an oral administration formulation. In one embodiment, the pharmaceutical composition is an immediate-release (IR) oral administration formulation.

[0017] In one embodiment, the pharmaceutical composition delivers an effective amount for treating multiple myeloma. In one embodiment, the pharmaceutical composition delivers an effective amount for preventing multiple myeloma. In one embodiment, the pharmaceutical composition delivers an effective amount for improving multiple myeloma.

[0018] In one embodiment, provided herein is a method of treating multiple myeloma, the method comprising administering the pharmaceutical composition provided herein. Also provided herein is a combination therapy using the pharmaceutical composition provided herein in combination with a treatment method, for example, another pharmaceutical agent having activity against multiple myeloma or its symptoms. Examples of treatment methods within the scope of the method include, but are not limited to, surgery, chemotherapy, radiotherapy, biotherapy, stem cell transplantation, cell therapy, and combinations thereof.

[0019] Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the components of the pharmaceutical composition. Optionally, such containers may be accompanied by a label in a form specified by a government agency that regulates the manufacture, use or sale of pharmaceuticals or biological products, the label indicating approval by that agency for manufacture, sale and use for human administration. The pack or kit can be labeled with information regarding the mode of administration or the order of drug administration (e.g., separately, sequentially or simultaneously).

[0020] These and other aspects of the subject matter described herein will become apparent by reference to the following detailed description.

Brief Description of the Drawings

[0021] [Figure 1] Figures 1A and 1B respectively show the total chemical impurity and chiral impurity levels from the excipient compatibility test. [Figure 2] Figures 2A and 2B respectively show the total chemical impurity and chiral impurity levels for the prototype formulations prepared from the RC process. [Figure 3] Figures 3A, 3B and 3C respectively show the hydrolyzate number 1, hydrolyzate number 2 and chiral impurity levels for the prototype formulations prepared by the RC process. [Figure 4] Figures 4A and 4B respectively show the total chemical impurity and chiral impurity levels for the prototype formulations prepared by the HSWG process. [Figure 5] Figures 5A, 5B, and 5C show the hydrolysis product number 1, hydrolysis product number 2, and chiral impurity levels, respectively, for the prototype formulation prepared by the HSWG process. [Figure 6] Figures 6A and 6B show the effects of stearic acid on chemical and chiral purity based on open-dish storage and under storage conditions, respectively. [Figure 7] The dissolution profile of the prototype formulation prepared by the HSWG process is shown. [Figure 8] This shows the elution release profile of the excipient range DoE batch at pH 4.5 and T=0. [Figure 9] This shows the effect of SSG on dissolution performance using a prototype formulation. [Figure 10] Figure 10A shows the comparative stability (chiral / chemical) profiles of DP produced using various manufacturing processes (comparison of DB, RC, and HSWG); Figure 10B shows the comparative elution profiles. [Figure 11] This shows the elution and release profile of an excipient range DoE batch (T=0) at pH 2.0. [Figure 12] Figures 12A and 12B show the relevant hydrolytic impurity and chiral impurity levels for excipient range DoE batches, respectively. [Figure 13] The multi-media elution profiles of comparative DB free base formulations and HSWG free base formulations with 3% FA at pH 1.2, 2.0, 4.5, and 6.8 using a dose strength of 2 mg are shown. [Figure 14] This document presents a two-step dissolution test to evaluate the impact on drug precipitation risk using DB free base formulations and HSWG free base formulations with 3% FA at a dose intensity of 0.5 mg. [Figure 15] This shows the dissolution performance of comparative DB free base formulations and HSWG free base formulations with 3% FA at pH 4.5 using a dose strength of 2 mg (containing no fumaric acid, 1% FA, and 3% FA). [Figure 16]The average monkey PK data using 2.0 mg DB free base formulations and HSWG free base formulations with 3% FA is shown. [Figure 17] This shows the in vitro elution performance of DB free base formulations with 3% FA at pH 4.5, HSWG free base formulations with and without fumaric acid, and formulations containing HBr salts. [Figure 18] The average monkey PK data using 0.5 mg DB free base formulations and HSWG free base formulations with 3% FA is shown. [Figure 19] This provides a typical X-ray powder diffraction (XRPD) pattern of form K of the free base of compound 1. [Figure 20] This provides a representative XRPD pattern of the free base morphology K' of compound 1. [Figure 21] This provides a representative XRPD pattern of morphology A of the hydrobromide salt of compound 1. [Modes for carrying out the invention]

[0022] 6.1 Definition As used herein and in the appended claims, the indefinite articles “a” and “an” and the definite article “it” include plural and single referents unless the context specifically indicates otherwise.

[0023] As used herein, the terms “include” and “inclusive” can be used synonymously. The terms “include” and “inclusive” should be interpreted as specifying the existence of the described feature or component as referred to, but not as excluding the existence or addition of one or more features or components or groups thereof. In addition, the terms “include” and “inclusive” include examples encompassed by the term “consisting of.” Consequently, the term “consisting of” can be used in place of the terms “include” and “inclusive” to provide more specific embodiments of the present invention.

[0024] The term "consisting of" means that the subject has at least 90%, 95%, 97%, 98%, or 99% of the described features or components that constitute it. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent enumeration, except for features or components that are not essential to the technical effect to be achieved.

[0025] As used herein, the term “or” should be interpreted as an inclusive “or” meaning any one or any combination thereof. Thus, “A, B or C” means any of “A; B; C; A and B; A and C; B and C; A, B and C.” This definition has no exceptions except where the combination of elements, functions, steps, or actions are mutually exclusive in any way.

[0026] When used herein, unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, a dose, volume, or weight percentage that would be recognized by those skilled in the art as providing a pharmacological effect equivalent to that obtained from a specified dose, volume, or weight percentage. In some embodiments, when used in relation thereto, the terms “about” and “approximately” mean a dose, volume, or weight percentage within 30%, 20%, 15%, 10%, or 5% of a specified dose, volume, or weight percentage.

[0027] When used herein, unless otherwise specified, the terms “about” and “approximately” mean a range of numerical values ​​or values ​​provided to characterize a particular solid form, such as a specified temperature or temperature range, such as a specified temperature or temperature range that describes a melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as a change in mass depending on temperature or humidity; a unit of mass or percentage of solvent or water content, such as; or a peak position, such as a peak position in analysis by IR, Raman spectroscopy, or XRPD; indicating that the value or range of values ​​may deviate to an extent that would be reasonable to a person skilled in the art, but still describe a particular solid form. For example, in a particular embodiment, when used in connection therewith, the terms “about” and “approximately” mean 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 given value or range of values. For example, in some embodiments, the XRPD peak position value may vary by up to ±0.2 degrees 2θ, while still describing a particular XRPD peak. When used herein, a tilde (i.e., "~") preceding a number or range of values ​​indicates "about" or "approximately".

[0028] Unless otherwise specified, the terms "X-ray powder diffraction," "powder X-ray diffraction," "PXRD," and "XRPD" are used interchangeably in this application.

[0029] As used herein, unless otherwise specified, the term “solid form” and related terms refer primarily to a physical form that is neither liquid nor gaseous. As used herein, one or more terms “solid form” encompass semi-solids. A solid form may be crystalline, amorphous, partially crystalline, partially amorphous, or a mixture of forms.

[0030] As used herein, unless otherwise specified, the term “crystalline” and related terms, when used to describe a substance, component, product, or form, mean that the substance, component, product, or form is substantially crystalline, as determined, for example, 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).

[0031] When used herein, unless otherwise specified, the terms “amorphous,” “amorphous form,” and related terms as used herein mean that the substance, component, or product in question is substantially not crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In some embodiments, the amorphous form of a substance may substantially contain no other amorphous and / or crystalline forms. In other embodiments, the amorphous form of a substance may contain less than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other amorphous and / or crystalline forms. In some embodiments, the amorphous form of a substance may be physically and / or chemically pure. In some embodiments, the amorphous form of a 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 a substance may contain additional components or ingredients (e.g., additives, polymers, or excipients that may function to further stabilize the amorphous form). In some embodiments, the amorphous form may be a solid solution.

[0032] As used herein, unless otherwise specified, the term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, relatively non-toxic acid, such as an inorganic acid or an organic acid. In one embodiment, suitable acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, citric acid, dihydrogen phosphate, ethensulfonic acid, fumaric acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isobutyric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, monohydrogen carbonate, monohydrogen phosphate, monohydrogen sulfuric acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, suberic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, etc. (e.g., SMBerge et al., J. Pharm. Sci., 66:1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and See CG Wermuth, Eds., (2002), Wiley, Weinheim. In some embodiments, suitable acids are strong acids (e.g., having a pKa of less than about 1), including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, pyridinesulfonic acid, or other substituted sulfonic acids. Other relatively non-toxic compounds with acidic properties are also included, for example, amino acids such as aspartic acid and salts of other compounds such as aspirin, ibuprofen, and saccharin. Acid addition salts can be obtained by contacting a neutral form of the compound with a sufficient amount of the desired acid, either undiluted or in a suitable solvent. As a solid, the salt may exist in crystalline or amorphous form or a mixture thereof. The salt may also exist in crystalline polymorphism.

[0033] As used herein, “multiple myeloma” refers to a hematological condition characterized by malignant plasma cells, including: monoclonal gammaglobulinemia of unspecified significance (MGUS); low-risk, intermediate-risk, and high-risk multiple myeloma; newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk, and high-risk multiple myeloma); transplant-eligible and ineligible multiple myeloma; smoldering (low-grade) multiple myeloma (including low-risk, intermediate-risk, and high-risk smoldering multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; nonsecretory myeloma Immunoglobulin D myeloma; and immunoglobulin E myeloma; and multiple myeloma characterized by genetic abnormalities, such as cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (e.g., t(4;14)(p16;q32)); MAF translocations (e.g., t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (e.g., deletion of chromosome 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploid and amplified (1q)).

[0034] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to alleviating or reducing the severity of the disease or condition being treated, for example, the symptoms associated with multiple myeloma.

[0035] The term "prevention" includes inhibiting the symptoms of a specific disease or disorder, such as multiple myeloma. In some embodiments, patients with a family history of multiple myeloma are candidates for a preventive regimen. Generally, the term "preventing" refers to administering medication to patients at risk of multiple myeloma, particularly before the onset of symptoms.

[0036] As used herein, unless otherwise specified, the term “manage” includes preventing relapses of a particular disease or disorder, such as multiple myeloma, in a patient affected therewith; extending the time a patient affected by the disease or disorder remains in remission; reducing patient mortality; and / or maintaining a reduced or avoidance of the severity of symptoms associated with the managed disease or condition.

[0037] As used herein, “subject” or “patient” means an animal, typically a mammal, and, for example, a human, e.g., a human patient.

[0038] The term "relapsed" refers to a condition in which a patient who has achieved remission of multiple myeloma after treatment has myeloma cells restored and / or reduced normal cells in the bone marrow.

[0039] The term "refractory or resistant" refers to a situation in which, even after intensive treatment, the patient has residual myeloma cells and / or reduced normal cells in the bone marrow.

[0040] As used herein, “induction therapy” refers to the initial treatment performed for a disease or the initial treatment performed with the aim of inducing complete remission of a disease, such as cancer. When used on its own, induction therapy is an acceptable therapy as the best available treatment. If residual cancer is detected, the patient is treated with another treatment referred to as reinduction. If the patient is in complete remission after induction therapy, additional consolidation and / or maintenance therapy is performed to prolong remission or potentially cure the patient.

[0041] As used herein, “consolidation therapy” refers to treatment performed on a disease after remission has been initially achieved. For example, consolidation therapy for cancer is treatment performed after the cancer has disappeared following initial treatment. Examples of consolidation therapy include radiation therapy, stem cell transplantation, or cancer drug therapy. Consolidation therapy is also referred to as intensification therapy or post-remission therapy.

[0042] As used herein, “maintenance therapy” refers to treatment of a disease to prevent or delay relapse after remission or the best possible outcome has been achieved. Examples of maintenance therapy include chemotherapy, hormone therapy, or targeted therapy.

[0043] As used herein, “remission” refers to a reduction or disappearance of the signs and symptoms of cancer, such as multiple myeloma. In partial remission, some, but not all, of the signs and symptoms of the cancer have disappeared. In complete remission, cancer may still be present in the body, but all signs and symptoms of the cancer have disappeared.

[0044] As used herein, “transplantation” refers to high-dose therapy with stem cell rescue. Hematopoietic (blood) or bone marrow stem cells are used not as a procedure, but to rescue a patient after high-dose therapy, such as high-dose chemotherapy and / or radiotherapy. Transplantation includes “autologous” stem cell transplantation (ASCT), which refers to the use of the patient’s own stem cells collected and used as surrogate cells. In some embodiments, transplantation also includes tandem transplantation or multiple transplantation.

[0045] As used herein, unless otherwise specified, the terms “therapeutic dose” and “effective dose” of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, such as multiple myeloma, or to delay or minimize one or more symptoms associated with a disease or disorder to be treated. The terms “therapeutic dose” and “effective dose” may also include an amount that improves the overall treatment, reduces or avoids the symptoms or etiology of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0046] The terms “simultaneous administration” and “in combination with” include administering one or more therapeutic agents (e.g., the compounds provided herein and another anti-multiple myeloma agent, anticancer agent, or supportive care agent) in parallel, simultaneously, or sequentially without specified time limitations. In one embodiment, the agents are simultaneously present in cells or in the patient’s body or simultaneously impart their biological or therapeutic effects. In one embodiment, the therapeutic agents are present in the same composition or unit dosage form. In another embodiment, the therapeutic agents are present in separate compositions or unit dosage forms.

[0047] The term "supportive care agent" refers to any substance that treats, prevents or controls adverse effects from treatment with Compound 1 or its enantiomer or mixture of enantiomers, tautomers, isotopologs or pharmaceutically acceptable salts.

[0048] The term "biotherapeutic therapy" refers to the administration of biopharmaceuticals, such as umbilical cord blood, stem cells, and growth factors.

[0049] With respect to cancer, such as multiple myeloma, inhibition can be evaluated, among other things, by inhibiting disease progression, inhibiting tumor growth, reducing primary tumors, alleviating tumor-related symptoms, inhibiting tumor secretory factors, delaying the appearance of primary or secondary tumors, slowing the development of primary or secondary tumors, reducing the occurrence of primary or secondary tumors, slowing or reducing the severity of secondary effects of the disease, cessation of tumor growth and tumor regression, increasing time to progression (TTP), increasing progression-free survival (PFS), and increasing overall survival (OS). As used herein, OS means the time from the start of treatment to death from any cause. When used herein, TTP means the time from the start of treatment to tumor progression; TTP does not include death. In one embodiment, PFS means the time from the start of treatment to tumor progression or death. In one embodiment, PFS means the time from the first administration of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using the Kaplan-Meier estimator. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, e.g., disease progression, discontinuation of treatment for any reason, or death. In one embodiment, overall response rate (ORR) refers to the proportion of patients who achieve a response. In one embodiment, ORR refers to the sum of the proportions of patients who achieve complete and partial responses. In one embodiment, ORR refers to the proportion of patients whose best response ≥ partial response (PR) according to the IMWG Uniform Response Criteria. In one embodiment, duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one embodiment, DoR is the time from achieving response ≥ partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from the first recorded response to the first recorded progression or death. In one embodiment, DoR is the time from the first recorded response ≥ partial response (PR) to the first recorded progression or death. In one embodiment, time to response (TTR) refers to the time from the first administration of the compound to the first recorded response. In one embodiment, 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 prevention or chemoprevention.In this regard, the term "prevention" includes either completely preventing the development of clinically apparent cancer or preventing the development of cancer at a preclinically apparent stage. This definition is also intended to encompass the prevention of transformation into malignant cells or the cessation or improvement of progression from pre-malignant cells to malignant cells. This includes preventive measures for individuals at risk of developing cancer.

[0050] In one embodiment, treatment for multiple myeloma can be evaluated using the International Uniform Response Criteria for Multiple Myeloma (IURC) with the response and endpoint definitions shown below (see Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10)10:1-7).

[0051] [Table 1]

[0052] As used herein, ECOG status refers to Eastern Cooperative Oncology Group (ECOG) Performance Status (Oken M, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655), as set forth below.

[0053] [Table 2]

[0054] Unless otherwise specified, in the event of any discrepancy between the chemical structure shown for a compound provided herein and the chemical name of the compound provided herein, the chemical structure shall prevail.

[0055] 6.2 Pharmaceutical composition containing compound 1 In one embodiment, as specified herein, compound 1: [ka] Alternatively, a pharmaceutical composition (e.g., an oral formulation) comprising the enantiomer, a mixture of enantiomers, a tautomer, an isotopolog, or a pharmaceutically acceptable salt and a carrier or diluent is provided.

[0056] 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. Such properties include, but are not limited to, ease of assay, content uniformity, flow properties for manufacture, elution and bioavailability, and stability. In one embodiment, the pharmaceutical compositions provided herein have a shelf life of at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months without refrigeration. In some embodiments, "without refrigeration" refers to a temperature of 20°C or higher. In one embodiment, the pharmaceutical compositions provided herein are stored under refrigerated conditions. In one embodiment, when stored under refrigerated conditions, 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. In one embodiment, the properties of the pharmaceutical compositions provided herein make them suitable for immediate release (IR).

[0057] The pharmaceutical compositions provided herein can be incorporated into suitable pharmaceutical formulations for oral administration, such as liquids, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations or elixirs, or into sterile liquids or suspensions for ophthalmic or parenteral administration, as well as into transdermal patch formulations and dry powder inhalers. Typically, the above compounds are incorporated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). In one embodiment, the pharmaceutical composition provided herein is an oral dosage form. In one embodiment, the oral dosage unit form is a tablet. In one embodiment, the oral dosage unit form is a caplet. In one embodiment, the oral dosage unit form is a capsule. In one embodiment, the pharmaceutical composition provided herein is an immediate-release capsule. In one embodiment, the pharmaceutical composition provided herein is an immediate-release (IR) blend-in capsule (BIC).

[0058] Tablets, caplets, and capsules typically contain about 50 mg to about 500 mg of the pharmaceutical composition (i.e., 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, pages 1658-1659 (Alfonso Gennaro ed., Mack Publishing Company, Easton Pennsylvania, 18th ed., 1990), incorporated by reference. In some embodiments, the capsules provided herein are of size #1 or larger, #2 or larger, #3 or larger, or #4 or larger.

[0059] In the composition, one or more compounds or pharmaceutically acceptable salts in an effective concentration are mixed with a suitable pharmaceutical carrier or vehicle. In one embodiment, the concentration of the compounds in the composition is effective in delivering an amount at the time of administration that treats, prevents or improves one or more symptoms and / or progression of multiple myeloma.

[0060] (a) Form of compound 1 Compound 1 has the compound name (S)-4-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)-3-fluorobenzonitrile. A method for preparing Compound 1 is described in U.S. Patent No. 10,357,489, which is incorporated herein by reference in whole.

[0061] In one embodiment, compound 1 or its enantiomer, mixture of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable salts are provided in solid form in a pharmaceutical composition. The solid form of compound 1 or its enantiomer, mixture of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable salts is described in U.S. Patent Application Publication No. 16 / 737,739, which is incorporated herein by reference in whole.

[0062] 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. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is a non-solvate.

[0063] The solid form can be characterized using numerous 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 water vapor adsorption (DVS), spectroscopy (e.g., infrared, Raman, and nuclear magnetic resonance), and high-performance liquid chromatography (HPLC). The particle size and size distribution of the solid form provided herein can be determined by conventional methods, such as laser light scattering techniques.

[0064] In one embodiment, the pharmaceutical composition comprises compound 1 (i.e., as a free base). When used herein, unless otherwise specified, "compound 1" and "free base of compound 1" are used interchangeably. In one embodiment, the free base of compound 1 is amorphous. In one embodiment, the free base of compound 1 is crystalline. In one embodiment, the free base of compound 1 is a mixture of one or more amorphous and crystalline forms.

[0065] In one embodiment, the pharmaceutical composition contains a salt of compound 1. In one embodiment, the salt is hydrochloride, mesylate, hydrobromide, besylate, glycolate, L-malate, napadisylate, sulfate, tosylate, oxalate, isethionate, maleate, phosphate, malonate, gentisinate, L-tartrate, fumarate, citrate, R-mandelate, L-ascorbate, succinate, nitrate, salicylate, edisylate, cyclamate, esylate, D-glucuronate, 4-aminosalicylate, caproate, cinnamate, caprylate, camphorate, D-aspartate, or D-glutamate. In one embodiment, the salt of compound 1 is amorphous. In one embodiment, the salt of compound 1 is crystalline. In one embodiment, the salt of compound 1 is a mixture of one or more amorphous and crystalline forms.

[0066] In one embodiment, the pharmaceutical composition contains the hydrochloride salt of compound 1. In one embodiment, the pharmaceutical composition contains the mesylate salt of compound 1. In one embodiment, the pharmaceutical composition contains the hydrobromide salt of compound 1. In one embodiment, the pharmaceutical composition contains the besylate salt of compound 1. In one embodiment, the pharmaceutical composition contains the glycolate salt of compound 1. In one embodiment, the pharmaceutical composition contains the L-malate salt of compound 1.

[0067] In one embodiment, the pharmaceutical composition comprises form K of the free base of compound 1, form K' of the free base of compound 1, an intermediate form between form K and form K', or a mixture thereof.

[0068] In one embodiment, form K is the channel hydrate of the free base of compound 1. In one embodiment, form K is the monohydrate of the free base of compound 1. In one embodiment, form K' is the dehydrated hydrate of form K. In one embodiment, although not limited by any particular logic, form K' is converted to form K as humidity increases, and form K is converted to form K' as humidity decreases. Therefore, intermediate forms between form K and form K' exist depending on the degree of humidity. In one embodiment, when the water activity is about 0.11 or less, form K is converted to form K'. In one embodiment, when the water activity is about 0.17 or more, form K' is converted to form K.

[0069] In one embodiment, the pharmaceutical composition provided herein comprises form K, form K', or an intermediate form between form K and form K', or a mixture thereof, of the free base of compound 1, characterized by an XRPD pattern having peaks at approximately 14.6, 18.2, and 18.3°2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 22.3 and 23.1°2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern comprises peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, and 23.1°2θ. In one embodiment, the pharmaceutical composition provided herein comprises form K of the free base of compound 1, characterized by an XRPD pattern further comprising at least peaks at approximately 14.2, 18.6, or 20.3°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a form K' of the free base of compound 1, characterized by an XRPD pattern further including at least one peak at approximately 18.0 or 18.8°2θ.

[0070] A typical XRPD pattern of morphology K is provided in Figure 19.

[0071] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized in that peaks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, or all of them, are located at approximately the following positions: 8.6, 10.8, 14.2, 14.3, 14.6, 16.6, 17.3, 17.5, 18.2, 18.3, 18.6, 20.3, 20.5, 20.9, 21.8, 22.3, 22.5, 23.1, 24.5, 25.1, 25.7, 26.0, 27.4, 27.9, and 31.4°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, where peaks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or all of them are located approximately at the following positions: 8.59, 10.78, 14.21, 14.32, The solid form is characterized by being located at 14.60, 16.55, 17.26, 17.45, 18.21, 18.34, 18.62, 20.25, 20.47, 20.87, 21.79, 22.28, 22.45, 23.05, 24.54, 25.05, 25.67, 26.01, 27.43, 27.89 and 31.44°2θ. In one embodiment, the solid form is characterized by having 3 peaks. In one embodiment, the solid form is characterized by having 5 peaks. In one embodiment, the solid form is characterized by having 7 peaks. In one embodiment, the solid form is characterized by having 9 peaks. In one embodiment, the solid form is characterized by having 11 peaks. In one embodiment, the solid form is characterized by having all of the peaks.

[0072] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern containing peaks at approximately 14.2, 14.6, 18.2, and 18.3°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 22.3, 23.1, and 24.5°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern contains peaks at approximately 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.8°2θ.

[0073] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.2, 14.6, 18.2, and 18.3°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1, and 24.5°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.04°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.21, 14.60, 18.21 and 18.34°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.04°2θ.

[0074] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.2, 14.6, 18.2, and 18.3°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1, and 24.5°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.02°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.02°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.21, 14.60, 18.21 and 18.34°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.02°2θ.

[0075] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.2, 14.6, 18.2, and 18.3°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1, and 24.5°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.21, 14.60, 18.21, and 18.34°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.28, 23.05, and 24.54°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.47 and 20.87°2θ. In one embodiment, the XRPD pattern has peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75°2θ.

[0076] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern containing peaks at approximately 14.6, 18.2, 18.3, and 18.6°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 22.3, 23.1, and 24.5°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern contains peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.8°2θ.

[0077] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3 and 18.6°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1 and 24.5°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.04°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.04°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 18.62°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.04°2θ.

[0078] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3, and 18.6°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1, and 24.5°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.02°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23.1, 24.5, and 26.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.02°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 18.62°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.02°2θ.

[0079] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3 and 18.6°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1 and 24.5°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.60, 18.21, 18.34, and 18.62°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.28, 23.05, and 24.54°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.47 and 20.87°2θ. In one embodiment, the XRPD pattern has peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75°2θ.

[0080] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern containing peaks at approximately 14.6, 18.2, 18.3 and 20.3°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 22.3, 23.1 and 24.5°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern contains peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.8°2θ.

[0081] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3 and 20.3°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1 and 24.5°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.04°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.04°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 20.25°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.04°2θ.

[0082] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3 and 20.3°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1 and 24.5°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ±0.02°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ±0.02°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 20.25°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 22.28, 23.05 and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23.05, 24.54, and 26.01°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.02°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.75°2θ±0.02°2θ.

[0083] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.2, 18.3 and 20.3°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.3, 23.1 and 24.5°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.5 and 20.9°2θ. In one embodiment, the XRPD pattern has peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.0°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.8°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.60, 18.21, 18.34 and 20.25°2θ. In one embodiment, the XRPD pattern further includes peaks at 22.28, 23.05 and 24.54°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.47 and 20.87°2θ. In one embodiment, the XRPD pattern has peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23.05, 24.54 and 26.01°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75°2θ.

[0084] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern matching the XRPD pattern presented in Figure 19.

[0085] A typical XRPD pattern for morphology K' is provided in Figure 20.

[0086] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized in that peaks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25, or all of them, are located at approximately the following positions: 8.7, 10.8, 14.4, 14.6, 16.6, 17.4, 17.5, 18.0, 18.3, 18.4, 18.8, 20.5, 20.9, 21.8, 22.4, 22.6, 23.2, 24.7, 25.2, 25.8, 26.2, 26.4, 27.5, 28.1, 31.7, and 38.4°2θ. In one embodiment, the pharmaceutical composition provided herein contains a free base of compound 1, where peaks 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 or all of them are located approximately at the following positions: 8.65, 10.79, 14.36, 14.63, 1 The solid form is characterized by being located at 6.55, 17.35, 17.53, 18.02, 18.25, 18.40, 18.75, 20.52, 20.92, 21.81, 22.36, 22.64, 23.19, 24.68, 25.20, 25.82, 26.17, 26.39, 27.54, 28.08, 31.69, and 38.41°2θ. In one embodiment, the solid form is characterized by having 3 peaks. In one embodiment, the solid form is characterized by having 5 peaks. In one embodiment, the solid form is characterized by having 7 peaks. In one embodiment, the solid form is characterized by having 9 peaks. In one embodiment, the solid form is characterized by having 11 peaks. In one embodiment, the solid form is characterized by having all of the peaks.

[0087] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern containing peaks at approximately 14.6, 18.0, 18.3, and 18.4°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 20.9, 22.4, and 23.2°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 16.6 and 20.5°2θ. In one embodiment, the XRPD pattern contains peaks at approximately 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 14.2°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.6°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 20.3°2θ.

[0088] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.0, 18.3, and 18.4°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ±0.04°2θ. In one embodiment, the XRPD pattern has peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ±0.04°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.02, 18.25 and 18.40°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23.19, and 24.68°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 14.21°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.62°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 20.25°2θ±0.04°2θ.

[0089] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern having peaks at 14.6, 18.0, 18.3, and 18.4°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ±0.02°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.02, 18.25 and 18.40°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23.19, and 24.68°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 14.21°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.62°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 20.25°2θ±0.02°2θ.

[0090] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.0, 18.3, and 18.4°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ. In one embodiment, the XRPD pattern has peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.02, 18.25 and 18.40°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ. In one embodiment, the XRPD pattern contains peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23.19 and 24.68°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.21°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25°2θ.

[0091] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern containing peaks at approximately 14.6, 18.3, 18.4, and 18.8°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 20.9, 22.4, and 23.2°2θ. In one embodiment, the XRPD pattern further contains peaks at approximately 16.6 and 20.5°2θ. In one embodiment, the XRPD pattern contains peaks at approximately 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 14.2°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 18.6°2θ. In one embodiment, the XRPD pattern does not contain a peak at approximately 20.3°2θ.

[0092] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.3, 18.4, and 18.8°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ±0.04°2θ. In one embodiment, the XRPD pattern has peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ±0.04°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.25, 18.40 and 18.75°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ±0.04°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ±0.04°2θ. In one embodiment, the XRPD pattern includes peaks at 8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23.19 and 24.68°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 14.21°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.62°2θ±0.04°2θ. In one embodiment, the XRPD pattern does not include a peak at 20.25°2θ±0.04°2θ.

[0093] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.3, 18.4, and 18.8°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ±0.02°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ±0.02°2θ. In one embodiment, the XRPD pattern has peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ±0.02°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.25, 18.40 and 18.75°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ±0.02°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ±0.02°2θ. In one embodiment, the XRPD pattern includes peaks at 8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23.19 and 24.68°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 14.21°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 18.62°2θ±0.02°2θ. In one embodiment, the XRPD pattern does not include a peak at 20.25°2θ±0.02°2θ.

[0094] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at 14.6, 18.3, 18.4, and 18.8°2θ. In one embodiment, the XRPD pattern further includes peaks at 20.9, 22.4, and 23.2°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.6 and 20.5°2θ. In one embodiment, the XRPD pattern has peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23.2, and 24.7°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.2°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.6°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.3°2θ. In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is a solid form characterized by an XRPD pattern containing peaks at 14.63, 18.25, 18.40 and 18.75°2θ. In one embodiment, the XRPD pattern further contains peaks at 20.92, 22.36 and 23.19°2θ. In one embodiment, the XRPD pattern further contains peaks at 16.55 and 20.52°2θ. In one embodiment, the XRPD pattern contains peaks at 8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23.19 and 24.68°2θ. In one embodiment, the XRPD pattern does not contain a peak at 14.21°2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62°2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25°2θ.

[0095] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, which is in a solid form characterized by an XRPD pattern matching the XRPD pattern shown in Figure 20.

[0096] In one embodiment, without being limited to any particular theory, the XRPD peaks of morphology K' are slightly shifted to higher °2θ values ​​compared to morphology K, suggesting that morphology K' has a slightly contracted lattice.

[0097] In one embodiment, the pharmaceutical composition provided herein comprises form A of the hydrobromide salt of compound 1.

[0098] In one embodiment, the molar ratio of compound 1 to hydrobromide of form A is approximately 1:1. In one embodiment, form A is the monohydrobromide of compound 1. In one embodiment, form A is the non-solvated form of hydrobromide of compound 1. In one embodiment, form A is the anhydride of hydrobromide of compound 1.

[0099] A typical XRPD pattern of morphology A of the hydrobromide salt of compound 1 is provided in Figure 21.

[0100] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of compound 1, which is a solid form characterized in that peaks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or all thereof are located at approximately the following positions: 4.3, 10.3, 11.9, 12.8, 14.4, 15.6, 15.9, 17.1, 17.6, 18.8, 19.3, 20.2, 20.7, 22.4, 22.8, 23.3, 24.0, 26.0, 26.4, 26.9, 27.7, 28.5, 29.6 and 31.1°2θ. In one embodiment, the solid form is characterized by having three peaks. In one embodiment, the solid form is characterized by 5 peaks. In one embodiment, the solid form is characterized by 7 peaks. In one embodiment, the solid form is characterized by 9 peaks. In one embodiment, the solid form is characterized by 11 peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0101] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of compound 1, which is in a solid form characterized by having peaks 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 or all of the following positions: 4.3, 10.3, 11.9, 12.8, 15.7, 15.9, 17.1, 17.2, 17.7, 18.8, 19.3, 19.5, 19.6, 20.2, 20.3, 20.7, 22.5, 22.8, 23.3, 23.9, 24.1, 26.0, 26.3, 26.8, 27.7 and 31.2°2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form is characterized by 5 peaks. In one embodiment, the solid form is characterized by 7 peaks. In one embodiment, the solid form is characterized by 9 peaks. In one embodiment, the solid form is characterized by 11 peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0102] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of compound 1, which is in a solid form characterized by an XRPD pattern having peaks at approximately 10.3, 19.3 and 24.0°2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 17.1 and 20.7°2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 12.8 and 15.6°2θ. In one embodiment, the XRPD pattern has peaks at approximately 10.3, 12.8, 15.6, 15.9, 17.1, 17.6, 19.3, 20.7, 24.0 and 26.0°2θ.

[0103] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of compound 1, which is in a solid form characterized by an XRPD pattern matching the XRPD pattern presented in Figure 21.

[0104] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0105] (b) Pharmaceutical composition of hydrobromide of compound 1 In one embodiment, as described herein, 1) Compound 1: [ka] A pharmaceutical composition is provided comprising: 1) hydrobromide, 2) a mixture of mannitol and cellulose or a mixture of mannitol and starch, 3) hydroxypropyl methylcellulose (HPMC), 4) sodium starch glycolate (SSG), and 5) stearic acid.

[0106] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrobromide of compound 1 in an amount of about 0.05 to about 3% w / w; 2) a carrier or diluent in an amount of about 70 to about 98% w / w; 3) HPMC in an amount of about 0.5 to about 10% w / w; 4) SSG in an amount of about 0.5 to about 10% w / w; and 5) stearic acid in an amount of about 0.5 to about 8% w / w, wherein the carrier or diluent is a mixture of mannitol and cellulose or a mixture of mannitol and starch.

[0107] In one embodiment, the hydrobromide of compound 1 is the crystalline hydrobromide of compound 1. In one embodiment, the hydrobromide of compound 1 is characterized by an XRPD pattern containing peaks at approximately 10.3, 19.3 and 24.0°²θ.

[0108] In one embodiment, the amount of hydrobromide of compound 1 is about 0.05 to about 3% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of hydrobromide of compound 1 is about 0.1 to about 1.5% w / w. In one embodiment, the amount of hydrobromide of compound 1 is about 0.16 to about 0.65% w / w.

[0109] In one embodiment, the amount of hydrobromide in compound 1 is about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0. The amounts are approximately 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3% w / w. In one embodiment, the amount is approximately 0.16% w / w. In one embodiment, the amount is approximately 0.65% w / w.

[0110] In one embodiment, component 2) is a mixture of mannitol and cellulose. In one embodiment, the cellulose is microcrystalline cellulose (MCC).

[0111] In one embodiment, component 2) is a mixture of mannitol and starch. In one embodiment, the starch is partially pregelatinized starch.

[0112] In one embodiment, the amount of the mixture of mannitol and cellulose or the mixture of mannitol and starch is about 70 to about 98% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of the mixture of mannitol and cellulose or the mixture of mannitol and starch is about 80 to about 90% w / w. In one embodiment, the amount of the mixture of mannitol and cellulose or the mixture of mannitol and starch is about 85 to about 86% w / w.

[0113] In one embodiment, the amount of the mixture of mannitol and cellulose or the mixture of mannitol and starch is about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 80.5, about 81, about 81.5, about 82, about 82.5, about 83, about 83.5, about 84, about 84.5, about 85, about 85.5, about 86, about 86.5, about 87, about 87.5, about 88, about 88.5, about 89, about 89.5, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, or about 98% w / w. In one embodiment, the amount is about 85% w / w. In one embodiment, the amount is about 86% w / w. In one embodiment, the amount is approximately 85.35% w / w. In another embodiment, the amount is approximately 85.84% w / w.

[0114] In one embodiment, the amount of mannitol is approximately 35 to 93% w / w, and the amount of cellulose or starch is approximately 5 to 35% w / w. In one embodiment, the amount of mannitol is approximately 50 to 80% w / w, and the amount of cellulose or starch is approximately 10 to 30% w / w. In one embodiment, the amount of mannitol is approximately 65 to 66% w / w, and the amount of cellulose or starch is approximately 20% w / w.

[0115] In one embodiment, the amount of mannitol is approximately 35, 40, 45, 50, 55, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, or 93% w / w. In one embodiment, the amount is approximately 65.35% w / w. In one embodiment, the amount is approximately 65.84% w / w.

[0116] In one embodiment, the amount of cellulose is about 5, about 10, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 30, or about 35% w / w. In one embodiment, the amount is about 20% w / w.

[0117] In one embodiment, the amount of starch is approximately 5, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, or 35% w / w. In one embodiment, the amount is approximately 20% w / w.

[0118] In one embodiment, the weight ratio of cellulose or starch to mannitol is approximately 1:1 to approximately 1:20. In one embodiment, the weight ratio of cellulose or starch to mannitol is approximately 1:1.3 to approximately 1:15. In one embodiment, the weight ratio of cellulose or starch to mannitol is approximately 1:1.7 to approximately 1:8. In one embodiment, the weight ratio of cellulose or starch to mannitol is approximately 1:2 to approximately 1:4. In one embodiment, the weight ratio of cellulose or starch to mannitol is approximately 1:3.3.

[0119] In one embodiment, the HPMC is HPMC E5.

[0120] In one embodiment, the amount of HPMC is about 0.5 to about 10% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of HPMC is about 1 to about 9% w / w. In one embodiment, the amount of HPMC is about 2 to about 8% w / w. In one embodiment, the amount of HPMC is about 3 to about 7% w / w. In one embodiment, the amount of HPMC is about 4 to about 6% w / w.

[0121] In one embodiment, the amount of HPMC is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10% w / w. In one embodiment, the amount of HPMC is about 5% w / w.

[0122] In one embodiment, the SSG is a low pH SSG.

[0123] In one embodiment, the amount of SSG is approximately 0.5 to approximately 10% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of SSG is approximately 1 to approximately 9% w / w. In one embodiment, the amount of SSG is approximately 2 to approximately 8% w / w. In one embodiment, the amount of SSG is approximately 3 to approximately 7% w / w. In one embodiment, the amount of SSG is approximately 4 to approximately 6% w / w.

[0124] In one embodiment, the amount of SSG is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10% w / w. In one embodiment, the amount of SSG is about 5% w / w.

[0125] In one embodiment, the pharmaceutical composition has a pH of about 4.2 to about 5.8 (e.g., slurry pH). In one embodiment, the pH is about 4.4 to about 4.8. In one embodiment, the pH is about 4.5 to about 4.7. In one embodiment, the pH is about 4.5. In one embodiment, the pH is about 4.6. In one embodiment, the pH is about 4.7.

[0126] In one embodiment, the amount of stearic acid is about 0.5 to about 8% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of stearic acid is about 1 to about 7% w / w. In one embodiment, the amount of stearic acid is about 2 to about 6% w / w. In one embodiment, the amount of stearic acid is about 3 to about 5% w / w.

[0127] In one embodiment, the amount of stearic acid is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8% w / w. In one embodiment, the amount of stearic acid is about 4% w / w.

[0128] In one embodiment, the pharmaceutical composition has an average particle size of about 100 to about 250 μM. In one embodiment, the pharmaceutical composition has a D10 of about 15 to about 100 μM. In one embodiment, the pharmaceutical composition has a D10 of about 30 to about 100 μM. In one embodiment, the pharmaceutical composition has a D50 of about 80 to about 250 μM. In one embodiment, the pharmaceutical composition has a D50 of about 100 to about 250 μM. In one embodiment, the pharmaceutical composition has a D90 of about 180 to about 650 μM. In one embodiment, the pharmaceutical composition has a D90 of about 280 to about 650 μM.

[0129] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrobromide of compound 1 (e.g., form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 64 to about 67% w / w and microcrystalline cellulose in an amount of about 19 to about 21% w / w; 3) HPMC E5 in an amount of about 4 to about 6% w / w; 4) low pH SSG in an amount of about 4 to about 6% w / w; and 5) stearic acid in an amount of about 3 to about 5% w / w. In one embodiment, a pharmaceutical composition is provided herein comprising: 1) about 0.16% w / w of hydrobromide of compound 1 (e.g., form A); 2) about 65.84% w / w of mannitol and about 20% w / w of microcrystalline cellulose; 3) about 5% w / w of HPMC E5; 4) about 5% w / w of low pH SSG; and 5) about 4% w / w of stearic acid. In one embodiment, the pharmaceutical composition has a total weight of about 70 to about 280 mg and provides an equal dose strength with about 0.1 to about 0.4 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 70 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of about 140 mg. In one embodiment, the pharmaceutical composition is contained in a size 2 capsule. In one embodiment, the pharmaceutical composition has a total weight of about 210 mg. In one embodiment, the pharmaceutical composition has a total weight of about 280 mg.

[0130] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) a hydrobromide of compound 1 (e.g., form A) in an amount of about 0.6 to about 0.7% w / w; 2) mannitol in an amount of about 64 to about 67% w / w and microcrystalline cellulose in an amount of about 19 to about 21% w / w; 3) HPMC E5 in an amount of about 4 to about 6% w / w; 4) low pH SSG in an amount of about 4 to about 6% w / w; and 5) stearic acid in an amount of about 3 to about 5% w / w. In one embodiment, a pharmaceutical composition is provided herein comprising: 1) about 0.65% w / w of hydrobromide of compound 1 (e.g., form A); 2) about 65.35% w / w of mannitol and about 20% w / w of microcrystalline cellulose; 3) about 5% w / w of HPMC E5; 4) about 5% w / w of low pH SSG; and 5) about 4% w / w of stearic acid. In one embodiment, the pharmaceutical composition has a total weight of about 70 to about 280 mg and provides an equal dose strength with about 0.4 to about 1.6 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 70 mg. In one embodiment, the pharmaceutical composition is contained in a size 3 capsule. In one embodiment, the pharmaceutical composition has a total weight of about 140 mg. In one embodiment, the pharmaceutical composition has a total weight of about 210 mg. In one embodiment, the pharmaceutical composition has a total weight of about 280 mg.

[0131] (c) Pharmaceutical composition of the free base of compound 1 In one embodiment, as described herein, 1) Compound 1: [ka] A pharmaceutical composition is provided comprising: 2) a mixture of mannitol and starch; 3) sodium stearyl fumarate; and 4) optionally fumaric acid.

[0132] In one embodiment, a pharmaceutical composition is provided herein comprising: 1) compound 1 in an amount of about 0.05 to about 4% w / w; 2) a mixture of mannitol and starch in an amount of about 90 to about 99.5% w / w; 3) sodium stearyl fumarate in an amount of about 0.1 to about 5% w / w; and 4) fumaric acid in an amount of about 0 to about 10% w / w.

[0133] In one embodiment, compound 1 is a crystalline compound 1. In one embodiment, compound 1 is characterized by an XRPD pattern containing peaks at approximately 14.6, 18.2 and 18.3°2θ.

[0134] In one embodiment, the amount of compound 1 is about 0.05 to about 4% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of compound 1 is about 0.1 to about 2% w / w. In one embodiment, the amount of compound 1 is about 0.13 to about 1.33% w / w. In one embodiment, the amount of compound 1 is about 0.13 to about 0.27% w / w. In one embodiment, the amount of compound 1 is about 0.27 to about 0.5% w / w. In one embodiment, the amount of compound 1 is about 0.5 to about 0.67% w / w. In one embodiment, the amount of compound 1 is about 0.67 to about 1.33% w / w. In one embodiment, the amount of compound 1 is about 1.33 to about 2.67% w / w.

[0135] In one embodiment, the amount of compound 1 is approximately 0.05, approximately 0.06, approximately 0.07, approximately 0.08, approximately 0.09, approximately 0.1, approximately 0.11, approximately 0.12, approximately 0.13, approximately 0.14, approximately 0.15, approximately 0.16, approximately 0.17, approximately 0.18, approximately 0.19, approximately 0.2, approximately 0.25, approximately 0.3, approximately 0.35, approximately 0.4, approximately 0.45, approximately 0.5, approximately 0.55, approximately 0.6, approximately 0.65, approximately 0.7, approximately 0.75, approximately 0. The amounts are approximately 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4% w / w. In one embodiment, the amount is approximately 0.13% w / w. In one embodiment, the amount is approximately 0.27% w / w. In one embodiment, the amount is approximately 0.5% w / w. In one embodiment, the amount is approximately 0.67% w / w. In one embodiment, the amount is approximately 1.33% w / w. In another embodiment, the amount is approximately 2.67% w / w.

[0136] In one embodiment, the starch is partially pregelatinized starch.

[0137] In one embodiment, the amount of the mannitol and starch mixture is about 90 to about 99.5% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of the mannitol and starch mixture is about 95 to about 99% w / w. In one embodiment, the amount of the mannitol and starch mixture is about 97 to about 99% w / w.

[0138] In one embodiment, the amount of the mannitol and starch mixture is about 90, about 90.5, about 91, about 91.5, about 92, about 92.5, about 93, about 93.5, about 94, about 94.5, about 95, about 95.5, about 96, about 96.5, about 97, about 97.5, about 97.6, about 97.7, about 97.8, about 97.9, about 98, about 98.1, about 98.2, about 98.3, about 98.4, about 98.5, about 98.6, about 98.7, about 98.8, about 98.9, about 99, or about 99.5% w / w. In one embodiment, the amount is about 98% w / w. In one embodiment, the amount is about 99% w / w. In one embodiment, the amount is about 97.67% w / w. In one embodiment, the amount is approximately 98.5% w / w. In one embodiment, the amount is approximately 98.73% w / w. In one embodiment, the amount is approximately 98.87% w / w.

[0139] In one embodiment, the amount of mannitol is approximately 60-89% w / w, and the amount of starch is approximately 10-30% w / w. In another embodiment, the amount of mannitol is approximately 77-79% w / w, and the amount of starch is approximately 20% w / w.

[0140] In one embodiment, the amount of mannitol is approximately 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 89% w / w. In one embodiment, the amount is approximately 78% w / w. In one embodiment, the amount is approximately 79% w / w. In one embodiment, the amount is approximately 77.67% w / w. In one embodiment, the amount is approximately 78.5% w / w. In one embodiment, the amount is approximately 78.73% w / w. In one embodiment, the amount is approximately 78.87% w / w.

[0141] In one embodiment, the amount of starch is approximately 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30% w / w. In one embodiment, the amount is approximately 20% w / w.

[0142] In one embodiment, the weight ratio of starch to mannitol is approximately 1:2 to approximately 1:9. In one embodiment, the weight ratio of starch to mannitol is approximately 1:2.5 to approximately 1:6. In one embodiment, the weight ratio of starch to mannitol is approximately 1:3 to approximately 1:4.5. In one embodiment, the weight ratio of starch to mannitol is approximately 1:3.9.

[0143] In one embodiment, the amount of sodium stearyl fumarate is about 0.1 to about 5% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of sodium stearyl fumarate is about 0.1 to about 3% w / w. In one embodiment, the amount of sodium stearyl fumarate is about 0.5 to about 2% w / w.

[0144] In one embodiment, the amount of sodium stearyl fumarate is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.5, about 4, about 4.5, or about 5% w / w. In one embodiment, the amount of sodium stearyl fumarate is about 1% w / w.

[0145] In one embodiment, the pharmaceutical composition does not contain fumaric acid.

[0146] In one embodiment, the amount of fumaric acid is about 0.1 to about 10% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of fumaric acid is about 0.1 to about 6% w / w. In one embodiment, the amount of fumaric acid is about 0.5 to about 4% w / w. In one embodiment, the amount of fumaric acid is about 1 to about 3% w / w.

[0147] In one embodiment, the amount of fumaric acid is about 0.1, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10% w / w. In one embodiment, the amount of fumaric acid is about 1% w / w. In one embodiment, the amount of fumaric acid is about 3% w / w.

[0148] In one embodiment, the pharmaceutical composition has a pH of about 2.1 to about 8.7 (e.g., slurry pH). In one embodiment, the pH is about 4.4 to about 4.8. In one embodiment, the pH is about 4.5 to about 4.7. In one embodiment, the pH is about 4.5. In one embodiment, the pH is about 4.6. In one embodiment, the pH is about 4.7.

[0149] In one embodiment, the pharmaceutical composition has an average particle size of about 70 to about 250 μM. In one embodiment, the pharmaceutical composition has an average particle size of about 120 to about 200 μM. In one embodiment, the pharmaceutical composition has a D10 of about 30 to about 100 μM. In one embodiment, the pharmaceutical composition has a D10 of about 60 to about 90 μM. In one embodiment, the pharmaceutical composition has a D50 of about 110 to about 280 μM. In one embodiment, the pharmaceutical composition has a D50 of about 130 to about 250 μM. In one embodiment, the pharmaceutical composition has a D90 of about 240 to about 580 μM. In one embodiment, the pharmaceutical composition has a D90 of about 350 to about 560 μM.

[0150] In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.1 to about 0.2% w / w of compound 1 (e.g., form K); 2) about 78 to about 79% w / w of mannitol and about 19 to about 21% w / w of partially pregelatinized starch; and 3) about 0.5 to about 1.5% w / w of sodium stearyl fumarate. In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.13% w / w of compound 1 (e.g., form K); 2) about 78.87% w / w of mannitol and about 20% w / w of partially pregelatinized starch; and 3) about 1% w / w of sodium stearyl fumarate. In one embodiment, the pharmaceutical composition has a total weight of about 75 to about 300 mg and provides a dose strength of about 0.1 to about 0.4 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of approximately 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0151] In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.2 to about 0.3% w / w of compound 1 (e.g., form K); 2) about 78 to about 79% w / w of mannitol and about 19 to about 21% w / w of partially pregelatinized starch; and 3) about 0.5 to about 1.5% w / w of sodium stearyl fumarate. In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.27% w / w of compound 1 (e.g., form K); 2) about 78.73% w / w of mannitol and about 20% w / w of partially pregelatinized starch; and 3) about 1% w / w of sodium stearyl fumarate. In one embodiment, the pharmaceutical composition has a total weight of about 75 to about 300 mg and provides a dose strength of about 0.2 to about 0.8 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of approximately 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0152] In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.4 to about 0.6% w / w of compound 1 (e.g., form K); 2) about 78 to about 79% w / w of mannitol and about 19 to about 21% w / w of partially pregelatinized starch; and 3) about 0.5 to about 1.5% w / w of sodium stearyl fumarate. In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 0.5% w / w of compound 1 (e.g., form K); 2) about 78.5% w / w of mannitol and about 20% w / w of partially pregelatinized starch; and 3) about 1% w / w of sodium stearyl fumarate. In one embodiment, the pharmaceutical composition has a total weight of about 80 to about 300 mg and provides a dose strength of about 0.4 to about 1.5 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 80 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of approximately 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0153] In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 1.2 to about 1.4% w / w of compound 1 (e.g., form K); 2) about 77 to about 78% w / w of mannitol and about 19 to about 21% w / w of partially pregelatinized starch; and 3) about 0.5 to about 1.5% w / w of sodium stearyl fumarate. In one embodiment, a pharmaceutical composition is provided herein comprising 1) about 1.33% w / w of compound 1 (e.g., form K); 2) about 77.67% w / w of mannitol and about 20% w / w of partially pregelatinized starch; and 3) about 1% w / w of sodium stearyl fumarate. In one embodiment, the pharmaceutical composition has a total weight of about 75 to about 300 mg and provides a dose strength of about 1 to about 4 mg of compound 1 (free base). In one embodiment, the pharmaceutical composition has a total weight of about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the pharmaceutical composition has a total weight of approximately 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0154] In one embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 0.4 to about 0.6% w / w; 2) mannitol in an amount of about 75 to about 76% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w; and 4) fumaric acid in an amount of about 2.5 to about 3.5% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 0.5% w / w; 2) mannitol in an amount of about 75.5% w / w and partially pregelatinized starch in an amount of about 20% w / w; 3) sodium stearyl fumarate in an amount of about 1% w / w; and 4) fumaric acid in an amount of about 3% w / w.

[0155] In one embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 1.2 to about 1.4% w / w; 2) mannitol in an amount of about 76 to about 77% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w; and 4) fumaric acid in an amount of about 0.5 to about 1.5% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 1.33% w / w; 2) mannitol in an amount of about 76.67% w / w and partially pregelatinized starch in an amount of about 20% w / w; 3) sodium stearyl fumarate in an amount of about 1% w / w; and 4) fumaric acid in an amount of about 1% w / w.

[0156] In one embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 1.2 to about 1.4% w / w; 2) mannitol in an amount of about 74 to about 75% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w; and 4) fumaric acid in an amount of about 2.5 to about 3.5% w / w. In another embodiment, a pharmaceutical composition is provided herein comprising 1) compound 1 (e.g., form K) in an amount of about 1.33% w / w; 2) mannitol in an amount of about 74.67% w / w and partially pregelatinized starch in an amount of about 20% w / w; 3) sodium stearyl fumarate in an amount of about 1% w / w; and 4) fumaric acid in an amount of about 3% w / w.

[0157] (d) Additional embodiments of pharmaceutical compositions In one embodiment, the pharmaceutical composition provided herein may optionally further comprise one or more additional excipients. These additional excipients include, but are not limited to, wetting agents, solubilizers, crystallization stabilizers, flow aids, and precipitation inhibitors.

[0158] In one embodiment, the pharmaceutical compositions provided herein optionally further comprise one or more of the following: polysorbate (e.g., Tween 80), poloxamer (e.g., poloxamer 188), sodium lauryl sulfate (SLS), HPBCD, VitE-TPGS, HPMCAS (e.g., HPMCAS-LF), HPMC (e.g., HPMC E3), PVP (e.g., PVP VA64 or PVP K30), HPC (e.g., HPC EXF), and talc.

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

[0160] Typically, the compositions are formulated for single-dose administration. To formulate the compositions, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration such that the symptom being treated is alleviated or improved. Suitable pharmaceutical carriers or vehicles for administering the compounds provided herein include any such carriers known to those skilled in the art as being suitable for a particular administration method.

[0161] Furthermore, the compounds can be formulated as the sole pharmaceutically active ingredient in a composition or in combination with other active ingredients. Liposome suspensions, such as tissue-targeted liposomes, e.g., tumor-targeted liposomes, may also be 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 according to methods known to those skilled in the art. Briefly, liposomes, e.g., multilayer vesicles (MLVs), can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (in a molar ratio of 7:3) on the inside of a flask. A solution of the compound provided herein in phosphate-buffered saline (PBS) lacking the divalent cation is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelletized by centrifugation, and then resuspended in PBS.

[0162] The active compound is contained in a pharmaceutically acceptable carrier in an amount sufficient to impart a therapeutically beneficial effect to the treated patient without the presence of undesirable side effects. The therapeutically effective concentration can be empirically determined by testing the compound in the in vitro and in vivo systems described herein, and then extrapolated therefrom to the human dose.

[0163] The concentration of the active compound in a pharmaceutical composition depends on the absorption, tissue distribution, inactivation, metabolic and excretion rates of the active compound, the physicochemical characteristics of the compound, the administration schedule and dosage, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to improve one or more symptoms of cancer, such as solid tumors and hematological malignancies.

[0164] Liquids or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain any of the following components: sterile diluents, e.g., water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol and methylparaben; antioxidants, e.g., ascorbic acid, sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid (EDTA); buffers, e.g., acetates, citrates, phosphates; and agents for adjusting isotonicity, e.g., sodium chloride or dextrose. Parenteral formulations may be encapsulated in ampoules, pens, disposable syringes, or single-dose or multi-dose vials made of glass, plastic, or other suitable materials.

[0165] If a compound exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of a cosolvent, such as dimethyl sulfoxide (DMSO), a surfactant, such as TWEEN®, or elution in aqueous sodium bicarbonate.

[0166] When compounds are mixed or added, the resulting mixture may be a solution, suspension, or emulsion. The form of the resulting mixture depends on numerous factors, such as the intended administration method and the degree of elution of the compound in the selected carrier or vehicle. The effective concentration is one that is sufficient to improve the symptoms of the disease, disorder, or condition being treated and can be determined empirically.

[0167] Pharmaceutical compositions are provided for administration to humans and animals in the form of tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, as well as oral liquids or suspensions and water-in-oil emulsions, containing unit dosage forms, such as suitable amounts of a compound or a pharmaceutically acceptable salt thereof. The pharmaceutically active compounds and their salts are formulated and administered in unit dosage forms or multi-dose forms. As used herein, unit dose forms refer to physically distinct units suitable for human and animal subjects, and are individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutic active compound sufficient to produce the desired therapeutic effect, accompanied by the required pharmaceutical carrier, vehicle, or diluent. Examples of unit dose forms include ampoules and syringes, and individually packaged tablets or capsules. Unit dose forms may be administered in part or in multiple doses. Multi-dose forms are multiple identical unit dosage forms packaged in a single container, to be administered in divided unit dose forms. Examples of multi-dose forms include vials, tablets, or capsules in bottles, or pint or gallon bottles. Therefore, a multi-dose form is a set of multiple unit doses that are not divided in the packaging.

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

[0169] The active compound or pharmaceutically acceptable salt can be prepared using a carrier, such as a sustained-release formulation or coating, to protect the compound from rapid elimination from the body.

[0170] The composition may contain other active compounds to obtain a desired combination of properties. The compounds provided herein or their pharmaceutically acceptable salts described herein may also be advantageously administered for therapeutic or prophylactic purposes in combination with other pharmacological agents known in the general art to be beneficial in treating one or more of the diseases or medical conditions mentioned above, such as diseases related to oxidative stress. It should be understood that such combination therapies constitute further embodiments of the compositions and treatment methods provided herein.

[0171] (e) Method for preparing dosage forms The pharmaceutical compositions (dosage forms) provided herein may be prepared by any of the compounding methods, all of which include the step of associating the active ingredient with excipients constituting one or more required components. Generally, compositions are prepared by uniformly mixing (e.g., direct blending) the active ingredient with a liquid excipient or a finely ground solid excipient or both, and then, if necessary, shaping the product into a desired form (e.g., by using roller compression (RC), HSWG, compression and / or encapsulation processes). Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0172] The dosage forms provided herein can be prepared by compression or molding using one or more optional adjuncts. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine and mixing it with the above-mentioned excipients and / or surfactants or dispersants, which may be optional. Wet tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Encapsulation of the dosage forms provided herein can be carried out using hydroxypropyl methylcellulose, calcium alginate, or gelatin capsules.

[0173] In some embodiments, the active ingredient and excipients are directly blended and then, for example, filled into capsules or compressed directly into tablets. In some examples, a directly blended dosage form may be more advantageous than a compressed (e.g., roller compressed) dosage form. In some embodiments, a directly blended dosage form may be more advantageous than a compressed (e.g., roller compressed) dosage form because the directly blending process may result in better stability of molecules that are susceptible to degradation under mechanical stress (e.g., compression). In some embodiments, direct blending also helps minimize the degradation of the active ingredient.

[0174] In some embodiments, the roller compression process includes mixing the granular components in a blender, deaggregating them using a co-mill, passing them through a roller compressor, and grinding them to produce granules. In the roller compression process, the compressed material is often ground into smaller particles for further processing. The purpose of this step in manufacturing is to reduce the particle size of the material. The ground material is then blended with other components to produce the final dosage form.

[0175] In some embodiments, the high-shear wet granulation (HSWG) process includes pre-blending of granular components, addition of water while mixing, wet agglomeration, fluidized bed drying, co-milling, final smoothing, and encapsulation.

[0176] For certain active ingredients, particularly compounds with low elution rates, reducing the particle size of the active ingredient to a fine powder helps increase the rate of elution. An increased rate of elution is often necessary for the effective absorption of the active ingredient in the gastrointestinal tract. However, for direct blending of fine powders and filling into capsules, the excipient should preferably provide certain characteristics that make the components suitable for the direct blending process. Examples of such characteristics, but not limited to, include acceptable flow characteristics. Therefore, in one embodiment, this specification provides the use of an excipient capable of providing characteristics that make the resulting mixture suitable for the direct blending process, such as good flow characteristics, and a composition containing the same.

[0177] 6.3 How to use In one embodiment, a method for treating multiple myeloma is provided herein, comprising administering a pharmaceutical composition provided herein to a patient. In one embodiment, a pharmaceutical composition provided herein for use in a method for treating multiple myeloma is provided herein, the method comprising administering the pharmaceutical composition to a patient.

[0178] In one embodiment, a method for preventing multiple myeloma is provided herein, comprising administering a pharmaceutical composition provided herein to a patient. In one embodiment, a pharmaceutical composition provided herein for use in a method for preventing multiple myeloma is provided herein, the method comprising administering the compound to a patient.

[0179] In one embodiment, a method for managing multiple myeloma is provided herein, comprising administering a pharmaceutical composition provided herein to a patient. In one embodiment, a pharmaceutical composition provided herein for use in a method for managing multiple myeloma is provided herein, the method comprising administering the compound to a patient.

[0180] In one embodiment, a method is also provided herein for inducing a therapeutic response evaluated using the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient (see Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10)10:1-7), comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, a method is provided herein for achieving a strict complete response, complete response, or best partial response in a patient as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC), comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, this specification provides a method for achieving an increase in overall survival, progression-free survival, event-free survival, progression-free survival, or disease-free survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, this specification provides a method for achieving an increase in overall survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, this specification provides a method for achieving an increase in progression-free survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, this specification provides a method for achieving an increase in event-free survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma.In another embodiment, a method is provided herein for achieving an increase in progression-free survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma. In another embodiment, a method is provided herein for achieving an increase in disease-free survival in a patient, comprising administering an effective amount of the pharmaceutical composition provided herein to a patient having multiple myeloma.

[0181] This specification also provides methods for treating patients who have been previously treated for multiple myeloma but are unresponsive to standard therapy, as well as patients who have not been previously treated. Further encompassing methods for treating patients who have undergone surgery for multiple myeloma, as well as patients who have not undergone surgery. This specification also provides methods for treating patients who have undergone transplant therapy, as well as patients who have not undergone transplant therapy.

[0182] The methods provided herein include the treatment of relapsed, refractory, or resistant multiple myeloma. The methods provided herein include the prevention of relapsed, refractory, or resistant multiple myeloma. The methods provided herein include the management of relapsed, refractory, or resistant multiple myeloma. In some such embodiments, the myeloma is primary, secondary, tertiary, quaternary, or quintuple relapsed multiple myeloma. In one embodiment, the methods provided herein reduce, maintain, or eliminate minimal residual disease (MRD). In one embodiment, the method provided herein includes treating, preventing, or managing various types of multiple myeloma, such as monoclonal gammaglobulinemia of unspecified significance (MGUS), low-risk, intermediate-risk, and high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk, and high-risk multiple myeloma), transplant-eligible and ineligible multiple myeloma, smoldering (low-grade) multiple myeloma (including low-risk, intermediate-risk, and high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, nonsecretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma, by administering a therapeutically effective amount of the pharmaceutical composition provided herein. In another embodiment, the methods provided herein include treating, preventing, or managing multiple myeloma characterized by genetic abnormalities, such as cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (e.g., t(4;14)(p16;q32)); MAF translocations (e.g., t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (e.g., 17p13 or deletion of chromosome 13; del(17 / 17p), non-hyperdiploidy and amplification (1q)), by administering a therapeutically effective amount of the pharmaceutical composition provided herein.

[0183] In some embodiments, the method includes administering a therapeutically effective amount of the pharmaceutical composition provided herein as induction therapy. In some embodiments, the method includes administering a therapeutically effective amount of the pharmaceutical composition provided herein as consolidation therapy. In some embodiments, the method includes administering a therapeutically effective amount of the pharmaceutical composition provided herein as maintenance therapy.

[0184] In a particular embodiment of the method described herein, multiple myeloma is a plasma cell leukemia.

[0185] In one embodiment of the method described herein, the multiple myeloma is a high-risk multiple myeloma. In some such embodiments, the high-risk multiple myeloma is relapsing or refractory. In one embodiment, the high-risk multiple myeloma is a multiple myeloma that relapses within 12 months of initial treatment. In yet another embodiment, the high-risk multiple myeloma is a multiple myeloma characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some such embodiments, the high-risk multiple myeloma is relapsing or refractory to one, two, or three prior treatments.

[0186] In one embodiment, multiple myeloma is characterized by a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is an R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is an R337 mutation. In one embodiment, the p53 mutation is an R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is an S261 mutation. In one embodiment, the p53 mutation is an S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is an R175 mutation. In one embodiment, the p53 mutation is an R175H mutation. In one embodiment, the p53 mutation is the E258 mutation. In one embodiment, the p53 mutation is the E258K mutation. In one embodiment, the p53 mutation is the A161 mutation. In one embodiment, the p53 mutation is the A161T mutation.

[0187] In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53. In one embodiment, multiple myeloma is characterized by a homozygous deletion of wild-type p53.

[0188] In one embodiment, multiple myeloma is characterized by wild-type p53.

[0189] In one embodiment, multiple myeloma is characterized by the activation of one or more oncogenic drivers. In one embodiment, one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In one embodiment, multiple myeloma is characterized by the activation of C-MAF. In one embodiment, multiple myeloma is characterized by the activation of MAFB. In one embodiment, multiple myeloma is characterized by the activation of FGFR3 and MMset. In one embodiment, multiple myeloma is characterized by the activation of C-MAF, FGFR3, and MMset. In one embodiment, multiple myeloma is characterized by the activation of cyclin D1. In one embodiment, multiple myeloma is characterized by the activation of MAFB and cyclin D1. In one embodiment, multiple myeloma is characterized by the activation of cyclin D.

[0190] In one embodiment, multiple myeloma is characterized by one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocations are t(14;16) and t(16;22). In one embodiment, the chromosomal translocations are t(14;20) and t(11;14).

[0191] In one embodiment, multiple myeloma is characterized by a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by an R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by a W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, multiple myeloma is characterized by an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22).In one embodiment, multiple myeloma is characterized by activation of wild-type p53, MAFB, and cyclin D1, as well as chromosomal translocations at t(14;20) and t(11;14). In another embodiment, multiple myeloma is characterized by an A161T p53 mutation, activation of cyclin D, and chromosomal translocation at t(11;14).

[0192] In some embodiments of the method described herein, the multiple myeloma is a newly diagnosed multiple myeloma that is eligible for transplantation. In another embodiment, the multiple myeloma is a newly diagnosed multiple myeloma that is ineligible for transplantation.

[0193] In yet another embodiment, multiple myeloma is characterized by early progression after initial treatment (e.g., less than 12 months). In yet another embodiment, multiple myeloma is characterized by early progression after autologous stem cell transplantation (e.g., less than 12 months). In yet another embodiment, multiple myeloma is refractory to lenalidomide. In yet another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, multiple myeloma is relapsed or refractory to three or more treatments and has been exposed to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), or is birefractory to proteasome inhibitors and immunomodulatory compounds. In yet another embodiment, multiple myeloma is relapsed or refractory to three or more prior treatments, e.g., CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide or avadomide), or is double refractory to proteasome inhibitors or immunomodulatory compounds and CD38 mAbs. In further embodiments, multiple myeloma is triple-refractory, for example, multiple myeloma is refractory to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), and one other activator, as described herein.

[0194] In one embodiment, the Specified provides a method for treating, preventing and / or managing multiple myeloma, e.g., relapsed / refractory multiple myeloma, in patients with renal impairment or symptoms thereof, comprising administering a therapeutically effective amount of the pharmaceutical composition provided herein to a patient with relapsed / refractory multiple myeloma accompanied by renal impairment.

[0195] In some embodiments, this specification provides a method for treating, preventing and / or managing multiple myeloma, e.g., relapsed or refractory multiple myeloma or its symptoms in a frail patient, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to a frail patient having multiple myeloma. In some such embodiments, the frail patient is characterized by ineligibility for induction therapy or intolerance to dexamethasone treatment. In some such embodiments, the frail patient is, for example, an elderly person over 65 years of age.

[0196] In one embodiment, the Specified provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein, wherein the multiple myeloma is fourth-line relapsed / refractory multiple myeloma.

[0197] In one embodiment, the Specified provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein as induction therapy, wherein the multiple myeloma is newly diagnosed transplant-eligible multiple myeloma.

[0198] In one embodiment, the Specified provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein as maintenance therapy after other treatment or transplantation, wherein the multiple myeloma is newly diagnosed transplant-eligible multiple myeloma prior to other treatment or transplantation.

[0199] In some embodiments, this specification provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition provided herein as maintenance therapy after other treatment or transplantation. In some embodiments, the multiple myeloma is transplant-eligible multiple myeloma newly diagnosed before other treatment and / or transplantation. In some embodiments, the other treatment before transplantation is chemotherapy or treatment with compound 1.

[0200] In one embodiment, the Specified provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein, wherein the multiple myeloma is a high-risk multiple myeloma that has relapsed or refractory to one, two, or three prior treatments.

[0201] In one embodiment, the Specified provides a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein, wherein the multiple myeloma is newly diagnosed, transplant-ineligible multiple myeloma.

[0202] In one embodiment, the therapeutic or prophylactic effective dose of the compound is approximately 0.01 to 25 mg per day, approximately 0.01 to 10 mg per day, approximately 0.01 to 5 mg per day, approximately 0.01 to 2 mg per day, approximately 0.01 to 1 mg per day, approximately 0.01 to 0.5 mg per day, approximately 0.01 to 0.25 mg per day, approximately 0.1 to 25 mg per day, approximately 0.1 to 10 mg per day, approximately 0.1 to 5 mg per day, approximately 0.1 to The dosage is approximately 2 mg, approximately 0.1 to 1 mg per day, approximately 0.1 to 0.5 mg per day, approximately 0.1 to 25 mg per day, approximately 0.5 to 25 mg per day, approximately 0.5 to 10 mg per day, approximately 0.5 to 5 mg per day, approximately 0.5 to 2 mg per day, approximately 0.5 to 1 mg per day, approximately 1 to 25 mg per day, approximately 1 to 10 mg per day, approximately 1 to 5 mg per day, approximately 1 to 2.5 mg per day, or approximately 1 to 2 mg per day. In one embodiment, the therapeutic or prophylactic effective dose of compound 1 is approximately 0.1 mg to approximately 0.4 mg per day.

[0203] In some embodiments, the therapeutic or prophylactic effective dose is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, or about 25 mg per day. In some such embodiments, the therapeutic or prophylactic effective dose is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, or about 0.7 mg per day.

[0204] In one embodiment, the recommended daily dose range of compound 1 for the conditions described herein is preferably in the range of about 0.1 mg to about 25 mg per day, administered as a single once-daily dose or in divided doses throughout the day. In other embodiments, the dose is in the range of about 0.1 to about 10 mg per day. Specific daily doses include 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per day. More specific daily doses include 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day.

[0205] In specific embodiments, the recommended starting dose may be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 25 mg per day. In another embodiment, the recommended starting dose may be 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day. The dose can be gradually increased up to 1, 2, 3, 4, or 5 mg per day.

[0206] In one embodiment, the therapeutic or prophylactic effective dose is approximately 0.001 to 5 mg / kg / day, approximately 0.001 to 4 mg / kg / day, approximately 0.001 to 3 mg / kg / day, approximately 0.001 to 2 mg / kg / day, approximately 0.001 to 1 mg / kg / day, approximately 0.001 to 0.05 mg / kg / day, approximately 0.001 to 0.04 mg / kg / day, approximately 0.001 to 0.03 mg / kg / day, approximately 0.001 to 0.02 mg / kg / day, approximately 0.001 to 0.01 mg / kg / day, or approximately 0.001 to 0.005 mg / kg / day.

[0207] The administered dose can also be expressed in units other than mg / kg / day. For example, the dose for parenteral administration can be expressed as mg / m² / day. Those skilled in the art will readily understand how to convert a dose for a given height, weight, or both from mg / kg / day to mg / m² / day (see www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg person is approximately equal to 38 mg / m² / day.

[0208] In some embodiments, a patient to be treated with one of the methods provided herein has not been treated with multiple myeloma therapy prior to administration of the pharmaceutical composition provided herein. In some embodiments, a patient to be treated with one of the methods provided herein has been treated with multiple myeloma therapy prior to administration of the pharmaceutical composition provided herein. In some embodiments, a patient to be treated with one of the methods provided herein has developed drug resistance to anti-multiple myeloma therapy. In some such embodiments, the patient has developed resistance to one, two, or three anti-multiple myeloma therapies, and the treatment is selected from CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide or abadomide).

[0209] The methods provided herein encompass treating patients regardless of their age. In some embodiments, the subjects are 18 years of age or older. In other embodiments, the subjects are 18, 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years of age. In other embodiments, the subjects are under 65 years of age. In other embodiments, the subjects are over 65 years of age. In one embodiment, the subjects are elderly multiple myeloma subjects, for example, over 65 years of age. In one embodiment, the subjects are elderly multiple myeloma subjects, for example, over 75 years of age.

[0210] Depending on the state of the disease to be treated and the target pathological condition, the pharmaceutical compositions provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, intranasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. The pharmaceutical compositions provided herein may be formulated alone or together in suitable dosage units having pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0211] In one embodiment, the pharmaceutical composition provided herein is administered orally. In another embodiment, the pharmaceutical composition provided herein is administered parenterally. In yet another embodiment, the pharmaceutical composition provided herein is administered intravenously.

[0212] The pharmaceutical compositions provided herein can be delivered as a single dose, for example, as a single bolus injection or as an oral tablet or pill; or over time, for example, as a continuous infusion over time or as a divided bolus administration over time. The compounds described herein may be administered repeatedly, if necessary, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease progression or unacceptable toxicity. Disease stabilization or lack thereof is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged using X-ray, CAT, PET or MRI scans, and other generally accepted evaluation modalities.

[0213] The pharmaceutical compositions provided herein may be administered once daily (QD or qd) or divided into multiple daily doses, such as twice daily (BID or bid), three times daily (TID or tid), and four times daily (QID or qid). In addition, administration may be continuous (i.e., daily as consecutive days or every day), intermittent, or cyclical (i.e., including drug-free breaks of several days, weeks, or months). As used herein, the term “daily” means, for example, administering the therapeutic compound once or twice daily for a period of time. The term “continuous” means administering the therapeutic compound daily for an uninterrupted period of at least 7 days to 52 weeks. As used herein, the terms “intermittent” or “intermittently” mean stopping and starting at either equal or unequal intervals. For example, intermittent administration of the pharmaceutical compositions provided herein may be administration 1 to 6 days per week, administration in a cycle (e.g., daily administration for 2 to 8 consecutive weeks, followed by a drug-free rest period of up to 1 week), or administration every other day. As used herein, the term “cycling” means daily or consecutive administration of the therapeutic compound, but accompanied by a drug-free period. In some such embodiments, administration may be once daily for 2 to 6 days, followed by a drug-free rest period of 5 to 7 days.

[0214] In some embodiments, the frequency of administration ranges from approximately once a day to approximately once a month. In some embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the pharmaceutical composition provided herein is administered once a day. In another embodiment, the pharmaceutical composition provided herein is administered twice a day. In yet another embodiment, the pharmaceutical composition provided herein is administered three times a day. In yet another embodiment, the pharmaceutical composition provided herein is administered four times a day.

[0215] In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 20 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 15 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 10 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 7 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 5 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 4 days followed by a rest period. In one embodiment, a therapeutically effective amount of the pharmaceutical composition provided herein is administered in a treatment cycle including an administration period of up to 3 days followed by a rest period.

[0216] In one embodiment, the treatment cycle includes an administration period of up to 14 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 4 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period.

[0217] In one embodiment, the drug-free period is approximately 2 days to a maximum of approximately 11 days. In one embodiment, the drug-free period is approximately 2 days to a maximum of approximately 10 days. In one embodiment, the drug-free period is approximately 2 days. In one embodiment, the drug-free period is approximately 3 days. In one embodiment, the drug-free period is approximately 4 days. In one embodiment, the drug-free period is approximately 5 days. In one embodiment, the drug-free period is approximately 6 days. In another embodiment, the drug-free period is approximately 7 days. In another embodiment, the drug-free period is approximately 8 days. In another embodiment, the drug-free period is approximately 9 days. In another embodiment, the drug-free period is approximately 10 days. In another embodiment, the drug-free period is approximately 11 days.

[0218] In one embodiment, the treatment cycle includes an administration period of up to 15 days followed by a rest period of approximately 2 to 10 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of approximately 2 to 10 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period of approximately 2 to 10 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of approximately 2 to 10 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of approximately 10 to 15 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of approximately 3 to 15 days.

[0219] In one embodiment, the treatment cycle includes an administration period of up to 15 days followed by a 7-day rest period. In another embodiment, the treatment cycle includes an administration period of up to 10 days followed by a 5-day rest period. In yet another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a 9-day rest period. In another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a 2-day rest period. In yet another embodiment, the treatment cycle includes an administration period of up to 3 days followed by a 4-day rest period.

[0220] In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 5 of a 28-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 10 of a 28-day cycle. In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 21 of a 28-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 5 of a 7-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 7 of a 7-day cycle. In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 10 and 15 to 24 of a 28-day cycle (referred to herein as a 20 / 28 administration cycle). In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 3 and 15 to 18 of a 28-day cycle. In one embodiment, a treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-7 and 15-21 of a 28-day cycle (referred to herein as a 14 / 28 administration cycle). In one embodiment, a treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-5 and 15-19 of a 28-day cycle (referred to herein as a 10 / 28 administration cycle). In one embodiment, a treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-3 and 15-17 of a 28-day cycle (referred to herein as a 6 / 28 administration cycle).

[0221] In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 14 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of the pharmaceutical composition provided herein on days 1 to 4 and 8 to 11 of a 21-day cycle. In one embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 5 and 8 to 12 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 5 and 11 to 15 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1 to 4, 8 to 11 and 15 to 18 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-4, 8-10, and 15-17 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-3 and 8-11 of a 21-day cycle. In another embodiment, the treatment cycle includes administration of a therapeutically effective amount of the pharmaceutical composition provided herein on days 1-3 and 11-13 of a 21-day cycle.

[0222] Any treatment cycle described herein can be repeated at least two, three, four, five, six, seven, or eight times. In some examples, a treatment cycle described herein includes one to about 24 cycles, two to about 16 cycles, or two to about 4 cycles. In some examples, a treatment cycle described herein includes one to about 4 cycles. In some embodiments, cycles 1 to 4 are all 28-day cycles. In some embodiments, a therapeutically effective amount of the pharmaceutical composition provided herein is administered for one to thirteen 28-day cycles (e.g., about one year). In some examples, the cycling therapy is not limited by the number of cycles, and the treatment continues until disease progression. In some examples, cycles may include variations in the duration of administration and / or rest periods described herein.

[0223] In one embodiment, a treatment cycle includes administering the pharmaceutical composition provided herein once daily at a dose of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 5.0 mg / day, or 10 mg / day. In one embodiment, a treatment cycle includes administering the pharmaceutical composition provided herein once daily at a dose of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, or 0.8 mg / day. In some such embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein once daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 of a 28-day cycle. In some such embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein once daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 and 15 to 24 of a 28-day cycle. In some such embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein once daily at a dose of about 0.1 mg on days 1 to 10 and 15 to 24 of a 28-day cycle. In other embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein twice daily at doses of approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 of a 28-day cycle. In other embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein twice daily at doses of approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 19 of a 28-day cycle. In other embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein twice daily at doses of approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 17 of a 28-day cycle.In other embodiments, the treatment cycle includes administering the pharmaceutical composition provided herein twice daily at a dose of approximately 0.2 mg on days 1-3 and 15-17 of a 28-day cycle. In such an embodiment, the pharmaceutical composition is administered on days 1-3 (morning and night), day 14 (night only), day 15 and 16 (morning and night), and day 17 (morning only) of a 28-day cycle, for example, cycle 1.

[0224] For clarity, unless otherwise specified, the dose of Compound 1 referred to herein refers to the amount of Compound 1 in its free base form. For example, if a pharmaceutically acceptable salt of Compound 1 is used, the above given amounts must be adapted accordingly.

[0225] 6.4 Combination therapy with a second activator The pharmaceutical compositions provided herein may be used in combination with or in conjunction with conventional treatments, including, but not limited to, surgery, biotherapy (e.g., immunotherapy with checkpoint inhibitors), radiotherapy, chemotherapy, stem cell transplantation, cell therapy, or other non-drug-based treatments currently used to treat, prevent, or manage multiple myeloma (e.g., before, during, or after such treatments). The combined use of the compounds provided herein and conventional treatments may provide a unique treatment regimen that is unexpectedly effective in a particular patient. Without being limited by theory, the pharmaceutical compositions provided herein may provide additive or synergistic effects when administered simultaneously with conventional treatments.

[0226] As discussed elsewhere in this specification, conventional treatments include, but are not limited to, methods for reducing, treating, and / or preventing adverse or undesirable effects associated with surgery, chemotherapy, radiotherapy, biotherapy, and immunotherapy. The pharmaceutical compositions and other active ingredients provided herein may be administered to patients before, during, or after the occurrence of adverse effects associated with conventional treatments.

[0227] The pharmaceutical compositions provided herein may be used in combination with, or in combination with, other therapeutic agents useful for the treatment and / or prevention of multiple myeloma as described herein.

[0228] In one embodiment, a method for treating, preventing or managing multiple myeloma is provided herein, comprising administering to a patient a pharmaceutical composition provided herein in combination with one or more second activators and optionally in combination with radiotherapy, blood transfusion, or surgery.

[0229] As used herein, the term “in combination” includes the use of two or more therapeutic agents (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term “in combination” does not limit the order in which therapeutic agents (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. The first therapeutic agent (e.g., prophylactic or therapeutic agent, e.g., a pharmaceutical composition provided herein) may be administered to the subject before (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) or simultaneously with its administration. It can be administered after the administration (for example, 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). In this specification, triple therapy is intended in the same way as quadruple therapy. In one embodiment, the second therapeutic agent is dexamethasone.

[0230] The administration of the pharmaceutical compositions provided herein and one or more second activators to a patient may be carried out in parallel or sequentially via the same or different routes of administration. The suitability of a particular route of administration used for a particular activator depends on the activator itself (for example, whether it can be administered orally without being broken down before entering the bloodstream).

[0231] The route of administration of the pharmaceutical composition provided herein is independent of the route of administration of the second therapeutic agent. In one embodiment, the pharmaceutical composition provided herein is administered orally. In another embodiment, the pharmaceutical composition provided herein is administered intravenously. Accordingly, according to these embodiments, the pharmaceutical composition provided herein is administered orally or intravenously, and the second therapeutic agent can be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via liposome, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intrafatally, intra-articularly, intrathecally, or in sustained-release form. In one embodiment, the pharmaceutical composition provided herein and the second therapeutic agent are administered orally or intravenously by the same method of administration. In another embodiment, the pharmaceutical composition provided herein is administered by a certain method of administration, for example intravenously, while the second drug (anti-multiple myeloma agent) is administered by a different method of administration, for example, orally.

[0232] In one embodiment, the second activator is administered intravenously or subcutaneously once or twice daily in amounts of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. The specific amount of the second activator depends on the specific drug used, the type of multiple myeloma being treated or managed, the severity and stage of the disease, and the amount of the pharmaceutical composition provided herein and any additional activators of any choice administered concurrently to the patient.

[0233] One or more second active ingredients or activators may be used in conjunction with the pharmaceutical compositions provided herein in the methods and compositions provided herein. The second activator may be a macromolecule (e.g., a protein), a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule), or a cell therapy product (e.g., CAR cells).

[0234] Examples of second activators that can be used in the methods and compositions described herein include melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, obinutuzumab, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (e.g., GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI894999, GS-5829, GSK1210151A(I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinoline-1(2H)-O 4-[2-(4-amino-piperidine-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6 Examples include one or more of the following: oxo-1,6-dihydropyrimidine-4-yl]-2-fluorobenzonitrile or a salt thereof, corticosteroids (e.g., prednisone), dexamethasone; antibodies (e.g., CS1 antibodies, e.g., elotuzumab; CD38 antibodies, e.g., daratumumab or isatuximab; or BCMA antibodies or antibody conjugates, e.g., GSK2857916 or BI836909); checkpoint inhibitors (as described herein); or CAR cells (as described herein).

[0235] In one embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is dexamethasone.

[0236] In some embodiments, dexamethasone is administered in doses of 4 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered in doses of 4 mg on days 1, 4, 8 and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered in doses of 4 mg on days 1, 8 and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in doses of 4 mg on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered in doses of 4 mg on days 1, 8, 15 and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in doses of 4 mg on days 1, 10, 15 and 22 of cycle 1. In some embodiments, dexamethasone is administered in doses of 4 mg on days 1, 3, 15 and 17 of a 28-day cycle. In this embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of cycle 1.

[0237] In some other embodiments, dexamethasone is administered in doses of 8 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered in doses of 8 mg on days 1, 4, 8 and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered in doses of 8 mg on days 1, 8 and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in doses of 8 mg on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered in doses of 8 mg on days 1, 8, 15 and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in doses of 8 mg on days 1, 10, 15 and 22 of cycle 1. In some embodiments, dexamethasone is administered in doses of 8 mg on days 1, 3, 15 and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 3, 14, and 17 of cycle 1.

[0238] In some embodiments, dexamethasone is administered in doses of 10 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered in doses of 10 mg on days 1, 4, 8 and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered in doses of 10 mg on days 1, 8 and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in doses of 10 mg on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered in doses of 10 mg on days 1, 8, 15 and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in doses of 10 mg on days 1, 10, 15 and 22 of cycle 1. In some embodiments, dexamethasone is administered in doses of 10 mg on days 1, 3, 15 and 17 of a 28-day cycle. In this embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 3, 14, and 17 of cycle 1.

[0239] In some embodiments, dexamethasone is administered in doses of 20 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered in doses of 20 mg on days 1, 4, 8 and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered in doses of 20 mg on days 1, 8 and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in doses of 20 mg on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered in doses of 20 mg on days 1, 8, 15 and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in doses of 20 mg on days 1, 10, 15 and 22 of cycle 1. In some embodiments, dexamethasone is administered in doses of 20 mg on days 1, 3, 15 and 17 of a 28-day cycle. In this embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 3, 14, and 17 of cycle 1.

[0240] In some embodiments, dexamethasone is administered in doses of 40 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered in doses of 40 mg on days 1, 4, 8 and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered in doses of 40 mg on days 1, 8 and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered in doses of 40 mg on days 1, 10, 15 and 22 of cycle 1. In some other embodiments, dexamethasone is administered in doses of 40 mg on days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. In other such embodiments, dexamethasone is administered in doses of 40 mg on days 1, 8, 15 and 22 of a 28-day cycle. In other such embodiments, dexamethasone is administered in doses of 40 mg on days 1, 3, 15 and 17 of a 28-day cycle. In this embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 3, 14, and 17 of cycle 1.

[0241] In another embodiment, in the method and composition described herein, the second activator used with the pharmaceutical composition provided herein is bortezomib. In yet another embodiment, in the method and composition described herein, the second activator used with the pharmaceutical composition provided herein is daratumumab. In some such embodiments, the method further comprises the administration of dexamethasone. In some embodiments, the method comprises the administration of the pharmaceutical composition provided herein using the proteasome inhibitor described herein, the CD38 inhibitor described herein, and the corticosteroid described herein.

[0242] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is panobinostat. In some such embodiments, the method further comprises the administration of dexamethasone.

[0243] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is ACY241. In some such embodiments, the method further comprises the administration of dexamethasone.

[0244] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is vincristine. In some such embodiments, the method further comprises the administration of dexamethasone.

[0245] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is cyclophosphamide. In some such embodiments, the method further comprises the administration of dexamethasone.

[0246] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is etoposide. In some such embodiments, the method further comprises the administration of dexamethasone.

[0247] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is doxorubicin. In some such embodiments, the method further comprises the administration of dexamethasone.

[0248] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is venetoclax. In some such embodiments, the method further comprises the administration of dexamethasone.

[0249] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is AMG176. In some such embodiments, the method further comprises the administration of dexamethasone.

[0250] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is MIK665. In some such embodiments, the method further comprises the administration of dexamethasone.

[0251] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is GSK525762A. In some such embodiments, the method further comprises the administration of dexamethasone.

[0252] In another embodiment, in the method and composition described herein, the second activator used in conjunction with the pharmaceutical composition provided herein is OTX015. In some such embodiments, the method further comprises the administration of dexamethasone.

[0253] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinoline-1(2H)-one. In some such embodiments, the method further comprises the administration of dexamethasone.

[0254] In another embodiment, in the methods and compositions described herein, the second activator used in conjunction with the pharmaceutical compositions provided herein is 4-[2-(4-amino-piperidine-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-yl]-2-fluorobenzonitrile or a salt thereof (e.g., besylate). In some such embodiments, the method further comprises the administration of dexamethasone.

[0255] In one embodiment, the pharmaceutical composition provided herein is administered in combination with a checkpoint inhibitor. In one embodiment, in relation to the method provided herein, one checkpoint inhibitor is used in combination with the pharmaceutical composition provided herein. In another embodiment, in relation to the method provided herein, two checkpoint inhibitors are used in combination with the pharmaceutical composition provided herein. In yet another embodiment, in relation to the method provided herein, three or more checkpoint inhibitors are used in combination with the pharmaceutical composition provided herein.

[0256] As used herein, the terms “immune checkpoint inhibitor” or “checkpoint inhibitor” refer to molecules that reduce, inhibit, interfere with, or modulate one or more checkpoint proteins, either entirely or partially. While not limited by any particular theory, checkpoint proteins modulate the activation or function of T cells. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). These proteins are thought to be responsible for co-stimulatory or inhibitory interactions in the T cell response. Immune checkpoint proteins are thought to regulate and maintain self-tolerance and the duration and extent of physiological immune responses. Immune checkpoint inhibitors may contain or be derived from antibodies.

[0257] In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in U.S. Patent Nos. 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein by reference as a whole. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as tisilimumb or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name Yervoy®.

[0258] In one embodiment, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-I / PD-L1 inhibitors include, but are not limited to, those described in U.S. Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149; and the PCT Patent Application Publications International Publication Nos. 2003042402, 2008156712, 2010089411, 2010036959, 2011066342, 2011159877, 2011082400, and 2011161699, all of which are incorporated herein by reference as a whole.

[0259] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), or pembrolizumab (also known as MK-3475, SCH900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is marketed under the trade name Opdivo®. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda®. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. CT-011 administered alone has not shown efficacy in treating relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In yet another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind to Fc gamma receptor I has been specifically artificially removed, giving it a unique binding signature to PD-1 with high affinity and excellent target specificity.

[0260] In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®).

[0261] In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.

[0262] In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is the soluble Ig fusion protein IMP321 (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0263] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is the anti-B7-H3 antibody MGA271 (Loo et al., Clin. Cancer Res., 2012, 3834).

[0264] In one embodiment, the checkpoint inhibitor is a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).

[0265] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

[0266] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.

[0267] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

[0268] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

[0269] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0270] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod.

[0271] In certain embodiments, the combination therapies provided herein include two or more of the checkpoint inhibitors described herein (including checkpoint inhibitors of the same or different classes). Further, the combination therapies described herein can be used in combination with one or more second active agents described herein, where appropriate for the treatment of diseases understood in the art.

[0272] In one embodiment, the pharmaceutical compositions provided herein can be used in combination with one or more immune cells (e.g., modified immune cells) expressing one or more chimeric antigen receptors (CARs) on their surface. Generally, a CAR comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain from a first protein (e.g., an antigen-binding protein). In one embodiment, when the extracellular domain binds to a target protein, such as a tumor-associated antigen (TAA) or tumor-specific antigen (TSA), a signal is generated via the intracellular signaling domain, which activates immune cells to target and kill, for example, cells expressing the target protein.

[0273] Extracellular domain: The extracellular domain of the CAR binds to the target antigen. In some embodiments, the extracellular domain of the CAR includes a receptor or a portion of a receptor that binds to the antigen. In some embodiments, the extracellular domain includes or is an antibody or its antigen-binding moiety. In specific embodiments, the extracellular domain includes or is a single-chain Fv(scFv) domain. The single-chain Fv domain may include, for example, a VL linked to a VH by a flexible linker, where the VL and VH are from an antibody that binds to the antigen.

[0274] In some embodiments, the antigen recognized by the extracellular domain of the polypeptide described herein is a tumor-associated antigen (TAA) or tumor-specific antigen (TSA). In various specific embodiments, the tumor-associated antigen or tumor-specific antigen may be, but are not limited to, Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, B-cell maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-24-associated antigen (MAGE), CD19, CD22, CD27, CD30, CD34, CD45, CD70, CD99, CD117, EGFRvIII (epidermal growth factor variant III), mesothelin, PAP (prostatic acid phosphatase), prostain, or TARP (T-cell receptor gamma surrogate). These include Leading Frame Protein (CRP), Trp-p8, STEAPI (prostate 6-transmembrane epithelial antigen 1), chromogranin, cytokeratin, desmin, glial cell fibrous acidic protein (GFAP), total cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-I), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, dimeric form of pyruvate kinase isozyme M2 (tumor M2-PK), abnormal ras protein, or abnormal p53 protein. In another embodiment, the TAA or TSA recognized by the extracellular domain of CAR is integrin αvβ3 (CD61), galactin, or Ral-B.

[0275] In one embodiment, the TAA or TSA recognized by the extracellular domain of CAR is a cancer / testis (CT) antigen, such as BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ES0-1, NY-SAR-35, OY-TES-1, SPANXBI, SPA17, SSX, SYCPI, or TPTE.

[0276] In another embodiment, the TAA or TSA recognized by the extracellular domain of the CAR is a sugar or ganglioside, such as fuc-GMI, GM2 (carcinoembryonic antigen-immunogenic-1, OFA-I-1), GD2 (OFA-I-2), GM3, GD3, etc.

[0277] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of CAR is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, beta-catenin, CA125, CA15-3 (CA27, 29\BCAA), CA195, CA242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-l, dek-can fusion protein, EBNA, EF2, Epstein-Barr virus antigen, ETV6-AML1 fusion protein Protein, HLA-A2, HLA-All, hsp70-2, KIAA0205, Mart2, Mum-1, 2 and 3, neo-PAP, Class I myosin, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, triose phosphate isomerase, Gage3, 4, 5, 6, 7, GnTV, Herv-K-mel, Lage-1, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, gp100(Pmel17), tyrosinase, TRP-1, TR P-2, MAGE-l, MAGE-3, RAGE, GAGE-1, GAGE-2, p15(58), RAGE, SCP-1, Hom / Mel-40, PRAME, p53, HRas, HER-2 / neu, E2A-PRL, H4-RET, IGH-IGK, M YL-RAR, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA19-9, C A72-4, CAM17.1, NuMa, K-ras, 13-catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, C0-029, FGF-5, G250, Ga733(EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-C0-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP or TPS.

[0278] In various specific embodiments, the tumor-related or tumor-specific antigen is the AML-related tumor antigen described in S. Anguille et al, Leukemia (2012), 26, 2186-2196.

[0279] Other tumor-associated antigens and tumor-specific antigens are known to those skilled in the art.

[0280] Receptors, antibodies, and scFvs that bind to TSA and TAA, which are useful for constructing chimeric antigen receptors, are known in the art, as are their encoding nucleotide sequences.

[0281] In one specific embodiment, the antigen recognized by the extracellular domain of the chimeric antigen receptor is not generally considered to be either a TSA or a TAA, but is nevertheless an antigen associated with tumor cells or damage caused by the tumor. In one embodiment, for example, the antigen is a growth factor, cytokine, or interleukin, such as a growth factor, cytokine, or interleukin associated with angiogenesis or angiogenesis. Examples of such growth factors, cytokines, or interleukins include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), or interleukin-8 (IL-8). Tumors can also create a tumor-local hypoxic environment. Therefore, in another specific embodiment, the antigen is a hypoxia-related factor, such as HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF-3α, or HIF-3β. Tumors can also cause localized damage to normal tissue, leading to the release of molecules known as damage-associated molecular pattern molecules (DAMPs; also known as alarmins). Therefore, in some other specific embodiments, the antigen may be DAMPs, such as heat shock proteins, chromatin-associated protein high mobility group box 1 (HMGB1), S100A8 (MRP8, cargranulin A), S100A9 (MRP14, cargranulin B), serum amyloid A (SAA), or deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparin sulfate.

[0282] Transmembrane domain: In some embodiments, the extracellular domain of the CAR is bound to the transmembrane domain of the polypeptide by a linker, spacer, or hinge polypeptide sequence, such as a sequence from CD28 or a sequence from CTLA4. The transmembrane domain may be obtained from or derived from the transmembrane domain of any transmembrane protein, and may include all or part of such a transmembrane domain. In specific embodiments, the transmembrane domain may be obtained from or derived from, for example, CD8, CD16, cytokine receptors and interleukin receptors or growth factor receptors.

[0283] Intracellular signaling domain: In some embodiments, the intracellular domain of a CAR is or includes an intracellular domain or motif of a protein expressed on the surface of a T cell that induces activation and / or proliferation of the T cell. Such a domain or motif can transmit a primary antigen-binding signal necessary for T lymphocyte activation in response to antigen binding to the extracellular portion of the CAR. Typically, this domain or motif includes or includes an ITAM (immune receptor tyrosine-based activation motif). Suitable ITAM-containing polypeptides for CARs include, for example, the zeta CD3 chain (CD3ζ) or its ITAM-containing portion. In specific embodiments, the intracellular domain is a CD3ζ intracellular signaling domain. In other specific embodiments, the intracellular domain is from a lymphocyte receptor chain, a TCR / CD3 complex protein, an Fe receptor subunit, or an IL-2 receptor subunit. In some embodiments, the CAR further includes one or more co-stimulatory domains or motifs, for example, as part of the intracellular domain of the polypeptide. One or more costimulatory domains or motifs may be or include one or more of the following: costimulatory CD27 polypeptide sequences, costimulatory CD28 polypeptide sequences, costimulatory OX40 (CD134) polypeptide sequences, costimulatory 4-1BB (CD137) polypeptide sequences, or costimulatory-inducible T cell costimulatory (ICOS) polypeptide sequences, or any combination thereof.

[0284] CARs may also include T cell survival motifs. T cell survival motifs can be any polypeptide sequence or motif that promotes the survival of T lymphocytes after antigen stimulation. In some embodiments, the T cell survival motif is or is derived from the intracellular signaling domains of CD3, CD28, the IL-7 receptor (IL-7R), the IL-12 receptor, the IL-15 receptor, the IL-21 receptor, or the transforming growth factor β (TGFβ) receptor.

[0285] Modified immune cells expressing CARs may be, for example, T lymphocytes (T cells, e.g., CD4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTLs), or natural killer (NK) cells. The T lymphocytes used in the compositions and methods provided herein may be naive T lymphocytes or MHC-restricted T lymphocytes. In some embodiments, the T lymphocytes are tumor-infiltrating lymphocytes (TILs). In some embodiments, the T lymphocytes are isolated from a tumor biopsy or augmented from T lymphocytes isolated from a tumor biopsy. In other embodiments, the T cells are isolated from peripheral blood, umbilical cord blood, or lymph, or augmented from T lymphocytes isolated therefrom. The immune cells to be used to generate modified immune cells expressing CARs can be isolated using standard methods acceptable in the art, such as blood collection and subsequent apheresis and, optionally, antibody-mediated cell isolation or sorting.

[0286] The modified immune cells are preferably autologous to the individual to whom the modified immune cells are to be administered. In certain other embodiments, the modified immune cells are allogeneic to the individual to whom the modified immune cells are to be administered. When using allogeneic T lymphocytes or NK cells to prepare modified T lymphocytes, it is preferred to select T lymphocytes or NK cells that reduce the likelihood of graft-versus-host disease (GVHD) in the individual. For example, in certain embodiments, virus-specific T lymphocytes are selected for the preparation of modified T lymphocytes; such lymphocytes are predicted to have a greatly reduced natural ability to bind to any recipient antigen and thus be activated by that antigen. In certain embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by co-administering to the host one or more immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, and the like.

[0287] T lymphocytes, such as unmodified T lymphocytes or T lymphocytes expressing CD3 and CD28 or comprising a polypeptide containing a CD3ζ signaling domain and a CD28 co-stimulatory domain, can be expanded using antibodies against CD3 and CD28, such as antibodies attached to beads; see, for example, U.S. Patent Nos. 5,948,893; 6,534,055; 6,352,694; 6,692,964; 6,887,466; and 6,905,681.

[0288] Modified immune cells, such as modified T lymphocytes, may optionally contain “suicide genes” or “safety switches” that enable substantially all killing of the modified immune cells, as needed. For example, in one embodiment, modified T lymphocytes may contain an HSV thymidine kinase gene (HSV-TK) that causes the death of modified T lymphocytes upon contact with ganciclovir. In another embodiment, modified T lymphocytes may contain an inducible caspase, such as inducible caspase 9 (i-caspase 9), a fusion protein of caspase 9 and human FK506-binding protein, for example, one that enables dimerization by the use of a specified small molecule drug. See Straathof et al., Blood 105(11):4247-4254 (2005).

[0289] In some embodiments, the pharmaceutical compositions provided herein are administered in combination with chimeric antigen receptor (CAR) T cells to patients with various types or stages of multiple myeloma. In some embodiments, the CAR T cells in the combination target B cell maturation antigen (BCMA), and in more specific embodiments, the CAR T cells are bb2121 or bb21217. In some embodiments, the CAR T cells are JCARH125. [Examples]

[0290] One embodiment of the present invention is illustrated by the following non-limiting examples.

[0291] Development of an HBr formulation of compound 1 7.1 Drug-excipient compatibility testing Two-component drug-excipient compatibility tests were conducted to identify suitable excipients for capsule formulations. A list of excipients from various functional classes evaluated is provided in the table below. Considering low-dose formulations where the diluent constitutes the majority of the composition, the API-to-diluent ratio was 1:400; for other excipients, the ratio was 1:50.

[0292] [Table 3]

[0293] The drug substance and excipients were dispensed in predetermined ratios, mixed for 30 seconds using a vortex mixer, and then dispensed into the required number of vials for stability testing. These vials (open-dish conditions) were exposed to 50°C / 0%RH and 50°C / 75%RH conditions for 2 and 4 weeks, respectively. Control samples were stored in a refrigerator at 5°C. Selected samples were tested for chemical degradation products and loss of chiral purity (conversion from S-isomer to R-isomer) after 2 weeks. Samples showing >3% chemical degradation were excluded from testing after 4 weeks.

[0294] The following are the main degradation pathways that can limit the shelf life: (1) hydrolysis; (2) oxidation; and (3) loss of chiral purity. The total chemical impurity and chiral impurity levels of the samples after 2 weeks and 4 weeks of stress are compared with the control samples shown in Figures 1A and 1B, respectively.

[0295] HBr drug substance (or active pharmaceutical ingredient) of Compound 1: The control sample showed 0.2% chemical impurities and 0.3% chiral impurities. Chemical impurity levels increased to 0.35% after 2 weeks and 0.77% after 4 weeks of exposure under 50°C / 75%RH conditions. Chiral impurities increased to only 0.4% after 4 weeks under these conditions. Under dry conditions (50°C), no significant changes were observed in either chemical or chiral impurities.

[0296] Diluents: Microcrystalline cellulose, mannitol, partially pregelatinized starch, and lactose monohydrate were evaluated as diluents or carriers. Mannitol was the most compatible based on chemical and chiral impurity levels; its degradation profile was similar to that of the drug substance itself. Of the remaining three, starch was more compatible than MCC, followed by lactose. Under dry conditions, starch showed slightly better compatibility than MCC, and at 50°C / 75%RH, starch was better than MCC. Of the four diluents, lactose showed the greatest degradation both chemically and chirally, and under both 50°C and 50°C / 75%RH conditions. In summary, the diluents were ranked from best to worst compatibility as follows: mannitol > starch > MCC > lactose.

[0297] Disintegrants: Croscarmellose sodium (2 and 4-week data) and low-pH sodium starch glycolate (2-week data) showed the best compatibility; chemical and chiral impurity levels were similar to or better than those of the drug substance itself. Sodium starch glycolate type A showed the lowest chemical compatibility (6% impurities) after 2 weeks at 50°C / 75%RH and was excluded from further evaluation. Crospovidone showed the second-highest level of chemical degradation and the highest level of chiral impurities. Under dry conditions, all four disintegrants showed similar stability to the undiluted drug substance. In summary, the disintegrants were ranked as follows: Croscarmellose sodium ≈ Sodium starch glycolate type B > Crospovidone >> Sodium starch glycolate type A.

[0298] Binders: Of the polymers evaluated as binders and crystallization stabilizers, PVP K90 and HPC EXF caused a significant decrease in chiral purity and a significant increase in total relative impurities, while only HPMC E5 was demonstrated to be suitable.

[0299] Flow accelerators / fluidizing aids: Precipitated silicon dioxide was shown to catalyze chemical decomposition and also resulted in a loss of chiral purity. However, fumed silicon dioxide was found to have good compatibility.

[0300] Lubricants: All three lubricants evaluated demonstrated excellent compatibility without significant increases in total relative impurities or chiral impurities. In particular, stearic acid was shown to have the lowest amount of total related impurities (chemical decomposition products) compared to the other two lubricants.

[0301] Nine excipients evaluated for drug-excipient compatibility testing were shortlisted for formulation and process design studies based on their impact on the risk of chemical and chiral degradation of the drug substance. In summary, microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, stearic acid, HPMC E5, sodium starch glycolate type B, fumed silicon dioxide, and sodium stearyl fumarate were selected for further evaluation in blends.

[0302] 7.2 Development of prototype formulations using the RC process The prototype batches listed in the table below were manufactured using the RC process. The batch size was 500 g. The blend was compressed at a predicted roller force (4–4.5 kN) to achieve approximately 0.75 SF, a roll speed of 1 rpm, and a roll gap of 2 mm. The capsules were exposed to accelerated open-dish conditions (50°C / 0%RH and 50°C / 75%RH), and their chemical and chiral stability was evaluated after 2 and 4 weeks. In this study, the HSWG formulation for free bases was used as the baseline.

[0303] [Table 4]

[0304] The chemical stability results are summarized in Figure 2A. Formulation PD02-247B did not exhibit the best chemical stability. However, the presence of starch in this formulation improved stability compared to formulations PD02-247A and MCC-containing formulation PD02-247F. Colloidal silicon dioxide showed excellent compatibility in the two-component test, but formulation PD02-247C, which contains silicon dioxide, showed the poorest chemical stability. Formulation PD02-247E, which has stearic acid as a lubricant, showed a significantly better chemical stability profile than all the evaluated prototype formulations. As shown in Figure 2B, the chiral stability profiles of the formulations followed similar trends. Formulation PD02-247E, which has mannitol, starch, and stearic acid, was selected for further evaluation.

[0305] 7.3 Selection of Lead Prototype Formulations for the RC Process The effects of disintegrants and binders on the stability of formulations in 0.15% DL (0.1 mg capsules), which can affect granulation robustness, stability, and dissolution, were evaluated. As shown in the table below, batches PD02-292A2, PD02-292B, and PD02-292C were prepared without a disintegrant, with croscarmellose sodium (CCS), and with low pH sodium starch glycolate (low pH SSG), respectively. Furthermore, to evaluate the effect of binders, formulation PD02-332 was prepared with HPMC E5 and CCS. To evaluate the effect of disintegrants on capsule dissolution, formulations without a disintegrant, formulations with CCS, and a third formulation with CCS and HPMC E5 were prepared in 1.5% DL (2 mg capsules). All of these batches were prepared using a roller compression process. For both stability and dissolution testing, the capsules were exposed to open-dish conditions at 50°C / 0%RH and 50°C / 75%RH.

[0306] [Table 5]

[0307] Hydrolysis and chiral degradation are summarized in Figures 3A, 3B, and 3C. Comparing formulation PD02-292A2, which contains no disintegrants, and formulation PD02-292B, which contains croscarmellose sodium, similar degradation was observed at 4 weeks. Comparing formulation PD02-292B, which contains croscarmellose sodium (CCS), and formulation PD02-292C, which contains sodium starch glycolate type B (SSG), the formulation with SSG-B demonstrated a significantly better stability profile. The 7 weeks at 50°C and 50°C / 75%RH for PD02-292C were equivalent to the 4 weeks at 50°C and 50°C / 75%RH for PD02-292B. Finally, comparing formulation PD02-292B containing CCS with formulation PD02-332 containing both CCS and HPMC, the presence of HPMC demonstrated similar chemical and chiral stability over two weeks at 50°C and 50°C / 75%RH.

[0308] The slurry pH of the selected prototype formulations was measured to evaluate the microenvironment pH, and the disproportionate tendency of the HBr salt (pKa 6.62, pHmax 4.62) in the formulations was confirmed. As shown in the table below, the presence of low pH SSG in the formulation (PD02-292C) resulted in a minimum slurry pH of 4.65, which approximates the pHmax of the salt. On the other hand, the slurry pH of formulations without a disintegrant or containing CCS or CCS and HPMC E5 was 5.61 or higher.

[0309] [Table 6]

[0310] Based on hydrolysis, chiral stability, and slurry pH, a formulation containing mannitol, starch, low pH SSG, HPMC E5, and stearic acid was selected as the lead prototype formulation for the roller compression process.

[0311] 7.4 Manufacturability assessment of the RC process The lead prototype formulation PD02-366 was manufactured using the RC process as shown in the table below to evaluate its manufacturability. The theoretical batch size was 5 kg. All granular components were mixed in a blender, deaggregated using a co-mill, and passed through a roller compressor and mill to produce granules. For batch PD02-366, approximately half of the ground granules were then mixed with an extragranular lubricant to obtain the final blend, which was then encapsulated in Vcaps Plus HPMC capsule shells. For batch PD02-366A, the remaining half was mixed with extragranular mannitol and a lubricant to obtain the final blend, which was then encapsulated in Vcaps Plus HPMC capsule shells. Layered capsule samples were collected for CU testing.

[0312] [Table 7]

[0313] The fluidity of the final blends of PD02-366 and PD02-366A with 15% extragranular mannitol SD100 was tested. FFc values ​​of 4.8 and 5.9 were found for PD02-366 and PD02-366A, respectively, demonstrating that extragranular mannitol improved the final blend flow. PD02-366 had a slurry pH of 4.54. Capsule weight control was tighter for PD02-366A with a %RSD in the range of 1.17%–1.68% compared to PD02-366 with a %RSD in the range of 1.65%–2.84%.

[0314] The non-granulated formulation PD02-366A exhibited lower AV and tighter %RSD, potentially due to improved fluidity resulting from the incorporation of non-granulated (15% w / w) mannitol 100SD. The average labeled claim (%LC), %RSD, and threshold value (AV) are shown in the table below.

[0315] [Table 8]

[0316] In conclusion, the roller compression process was found to be a viable manufacturing process for meeting critical quality characteristics of drug products. PD02-366A was selected as the lead prototype formulation for the roller compression process. Drug loads could be varied from 0.164% to 0.653% to obtain capsules of strength from 0.1 to 1.6 mg. PD02-366A capsule batches were packaged at 7 counts per 100cc HDPE bottle and 2g desiccant for ICH stability testing.

[0317] 7.5 Development of prototype formulations using the HSWG process The small-scale prototype batches listed in the table below were manufactured using a high-shear wet granulation (HSWG) process. The batch size was 500 g. This manufacturing process consisted of: pre-blending of granular components in a granulator bowl, addition of water while mixing, wet agglomeration, fluidized bed drying, co-milling, final smoothing, and encapsulation. The chemical and chiral stability of these encapsulated batches was evaluated using the following storage conditions: open-dish stability at 50°C / 0%RH for 2 weeks and 4 weeks at 50°C / 75%RH, respectively.

[0318] [Table 9]

[0319] Based on small-scale prototype stability tests (Figures 4A and 4B), the following observations were made and summarized below: Comparing PD02-248A and 248B (with HPMC), the formulation with HPMC as a binder showed significantly improved stability. Comparing PD02-248B (with starch) and PD02-248C (with MCC), MCC as a diluent provided slightly better stability than the formulation with starch. Comparing PD02-248C and PD02-248F (with SSG-B type), the formulation with SSG-B type demonstrated the best overall chemical and chiral stability profile. From this initial prototype formulation screening, mannitol, starch, MCC, SSG-B type, HPMC, and SSF were selected for further evaluation.

[0320] 7.6 Selection of Lead Prototype Formulations for the HSWG Process In this study, the effects of binders and disintegrants in selected HSWG formulations were evaluated. Prototype batches shown in the table below were prepared and evaluated for chemical and chiral stability, content uniformity, and elution. The batch size was 3 kg. The manufacturing steps included: bag blending of granular excipients for 2 minutes, pre-mixing in a granulator, granulation (water added at 100 g / min), fluidized bed drying, co-grinding, final blending / smoothing, and encapsulation.

[0321] [Table 10]

[0322] Hydrolysis and chiral degradation are summarized in Figures 5A, 5B, and 5C. Formulations without any disintegrants showed considerably greater degradation, as can be seen in PD02-248A. Comparing PD02-248F (SSG-B type) and PD02-314 (CCS), the SSG-B type again showed considerably better stability. Degradation at 50°C / 75%RH for 11 days was already higher for PD02-314 than for PD02-248F at 14 days. Similar observations were made in the comparison between PD02-315 (SSG-B type) and PD02-316 (CCS), where CCS resulted in greater degradation in the PD02-316 formulation. Here again, MCC (PD02-314) as a diluent provided slightly better stability than the starch-containing formulation (PD02-316).

[0323] To evaluate the comparative effect of stearic acid and SSF as lubricants on the stability of selected prototype formulations, PD02-373 and PD02-373A were prepared. The batch size was 500 g. The manufacturing process consisted of pre-blending of granular components in a granulator bowl, followed by mixing with water, wet agglomeration, fluidized bed drying, co-grinding, lubrication, and encapsulation. The composition is shown in the table below.

[0324] [Table 11]

[0325] Stearic acid provided acceptable chemical and chiral stability based on open-dish stability data, as shown in Figure 6A. PD02-373A was also packaged as 7 counts with and without 2g of desiccant in 100mL HDPE bottles for development ICH stability testing. 1 and 3-month stability results are summarized in Figure 6B. The formulation exhibited excellent stability across stability conditions. Hydrolytic degradation products were slightly higher at 40°C / 75%RH than at 25°C / 60%RH. The presence of desiccant reduced the level of hydrolytic degradation products at both 25°C / 60%RH and 40°C / 75%RH conditions. Chiral impurities increased only slightly at 40°C / 75%RH, and impurity levels were not affected by the desiccant. Furthermore, stearic acid was demonstrated to significantly increase formulation stability from the RC process. Finally, stearic acid also minimizes the risk of salt disproportionation. Therefore, stearic acid was selected as a lubricant for further evaluation.

[0326] To determine the effect of disintegrants and binders on the dissolution of formulations, 2 mg capsules (batch PD02-323, 324, 328, and 329) were tested for in vitro dissolution using pH 4.5 citrate buffer as the medium. Dissolution tests were performed at T=0 and after 2 weeks of exposure at 50°C / 0%RH and 50°C / 75%RH. As shown in Figure 7, formulation PD02-324 (without disintegrant) showed the slowest release, with approximately 80% at 45 minutes. Formulations PD02-323 (with CCS as a disintegrant) and PD02-328 (with SSG-B type) showed very similar dissolution profiles, demonstrating no significant difference between CCS and SSG-B type as disintegrants. HPMC (PD02-329) added as a binder solution improved drug release kinetics, with approximately 94% release at 45 minutes. This elution stability performance was not found to differ significantly across all batches, either at T=0 or after 2 weeks of storage at 50°C / 75%RH.

[0327] Finally, the slurry pH of the selected prototype formulations was measured to evaluate the microenvironment pH and confirm the disproportionate trend of HBr salts (pKa 6.62, pHmax 4.62) in the formulations. As shown in the table below, the presence of low pH SSG in formulations PD02-315 and PD02-328 resulted in lower slurry pH values ​​of 4.67 and 4.65, respectively. On the other hand, the slurry pH of formulations without disintegrants or with CCS was greater than 5.4.

[0328] [Table 12]

[0329] Based on hydrolysis and chiral stability, elution performance, and slurry pH, a formulation containing mannitol, MCC, low pH SSG, HPMC, and stearic acid was selected as the lead prototype formulation for the HSWG process.

[0330] 7.7 Manufacturability assessment of the HSWG process In addition to evaluating stability and dissolution, batches PD02-314, PD02-315, PD02-316, PD02-323, PD02-324, PD02-328, and PD02-329 were characterized for granular properties and capsule weight variability. Capsules from batches PD02-314, 316, 328, and 329 were evaluated for assay.

[0331] The physical properties of the final blend, such as particle size, bulk and tap density, and in-process capsule weight %RSD, are shown in the table below. All batches demonstrated good granule growth, and the D50 of the final blend varied between 120 and 250 μm. All granules demonstrated good flowability (Hausner ratio less than 1.29) and similarly demonstrated good capsule weight control. In summary, the in-process capsule weight RSD was less than 1.5%. The potency values ​​of the selected batches (PD02-314, 316, 328, and 329) were acceptable, ranging from 96.9% to 103.0%.

[0332] [Table 13]

[0333] In conclusion, based on the acceptable open-dish stability and rapid elution / release profile demonstrated above, as well as the acceptable assay data, the HSWG process was found to be a viable manufacturing process for meeting critical quality characteristics of drug products.

[0334] 7.8 Excipient range setting test for HBr formulations of Compound 1 To identify the quantitative composition of the HBr drug product of compound 1 for estimation testing, the effects of selected granular excipient levels on capsule manufacturability and quality characteristics were determined. The test design included 23 full factorial DoEs using two center point batches, as shown in the table below. The three variables in the test were MCC, HPMC, and SSG levels. Capsule strength (0.4–1.6 mg) was obtained by varying the filling weight while fixing the API level at 0.653% w / w. The extragranular stearic acid level was also fixed at 4% w / w in this test. Mannitol levels were adjusted to total 100%.

[0335] [Table 14]

[0336] The particle size distribution of the ground granules and the bulk and tap densities of the final blend are listed in the table below. In general, batches containing a higher proportion of HPMC as a binder resulted in granules with larger average particle sizes, while batches containing the highest level of MCC and the lowest level of HPMC resulted in the lowest average particle sizes (PD02-404 and PD02-408), respectively. Trend analysis showed that all evaluated variables had a statistically significant effect on the physical properties of the granules, with p-values ​​of 0.00038 and 0.00302 for MCC and HPMC, respectively. For individual components, the level of MCC was found to have a negative correlation with PSD and density, with increasing levels of MCC resulting in smaller granules with lower density. In contrast, a positive correlation was established between increasing levels of HPMC and density and density. Similarly, the levels of SSG tested did not demonstrate a significant effect on PSD but did demonstrate a significant effect on density, with a p-value of 0.026.

[0337] [Table 15]

[0338] Adhesion evaluation of the selected final blend demonstrated a low tendency for the final blend to adhere to the tamping pin surface during the encapsulation process.

[0339] Flow evaluation of the final blend from all batches was performed using a ring shear cell tester. The flow data indicates that all batches fall within the free-flow regime (ffc > 10). The influence of powder flow on capsule weight variability was predicted to be extremely low.

[0340] To assess the risk of salt disproportionation relative to free bases in the formulation, the slurry pH of the final blend was measured. The slurry pH of all blends was in the range of 4.43–4.72. Theoretically, the degree of disproportionation could have been approximately 1% within the microenvironmental pH range of 4.43–4.72 for the formulation (API pKa is 6.62).

[0341] To evaluate the uniformity of the granules, a sieve-cut assay was performed on the ground granules of selected batches. The mean sieve-cut assay of the tested batches varied between approximately 93% and 98%, and the RSD was less than 15%. Based on these results, the tested granules demonstrated acceptable uniformity and were considered to have a low CU risk.

[0342] For stratified content uniformity testing, capsules were sampled at regular intervals during the encapsulation process. All batches showed good capsule weight control; the average capsule weight of each batch was within 100±1%, and the %RSD varied from 0.95% to 2.45%. All batches showed acceptable content uniformity; the average CU value varied from 100±2%, the RSD was less than 4.7%, and the AV value was less than 7, except for batch PD02-405 (AV 11.4, RSD 4.7%). The individual capsule potency of all batches varied within 93-107%. The high CU variability of batch PD02-405 may have been due to its relatively high weight variability (RSD 2.45%). After weight correction, the CU RSD value decreased by 4.7% to 3%. Optimization of encapsulation parameters will further improve capsule weight variability and therefore CU variability. Trend analysis demonstrated that the formulation variable (levels of MCC, HPMC, or SSG) did not significantly affect the weight-adjusted mean CU and RSD.

[0343] The dissolution performance of 1.6 mg capsules from batches PD02-403, 406, and 407 was evaluated using a USP II dissolution device at 50 rpm in a pH of 4.5 (500 mL medium volume). The results (Figure 8) show that the dissolution profiles of the three batches were similar, however, PD02-407, the extreme batch with the lowest levels of MCC and HPMC and the highest level of low pH SSG, demonstrated generally faster dissolution compared to the other two batches.

[0344] The effects of formulation variables on chemical and chiral stability were evaluated by conducting two-week open-dish accelerated stability tests at 50°C / 0%RH and 50°C / 75%RH. Three batches, PD02-401, 402, and 403, were evaluated. The data showed that the excipient level ranges evaluated in this test did not affect either the chemical or chiral stability of the formulation.

[0345] The Excipient Range (DoE) test demonstrated that the excipient levels evaluated in this test had no practical effect on product quality characteristics, such as CU, dissolution, and chemical and chiral stability. The center point batch was manufactured reproducibly and exhibited good stability and dissolution profiles. Based on these observations, the center point formulations listed in the table below were proposed as drug products for human bioavailability (BA) testing. Drug substance levels can vary between 0.164% and 0.653%, and mannitol levels are adjusted accordingly. Potential capsule strengths of 0.1 mg to 1.6 mg can be achieved by varying the capsule filling weight between 70 and 280 mg.

[0346] [Table 16]

[0347] 7.9 Description of the manufacturing process The granular components API, mannitol, MCC, low pH SSG, and HPMC were dispensed according to the materials list and loaded into the granulator bowl. The materials were dry-mixed and granulated by adding a predetermined amount of water to the powder bed in the granulator bowl. The wet granules were then transferred to a fluidized bed dryer and dried at a pre-set inlet air temperature. The inlet air volume was adjusted to maintain an acceptable fluidized bed height. The dried granules were passed through a cormill, and the pulverized granules were further mixed with pre-sieved stearic acid in a bin blender to obtain the final blend. The final blend was then filled into Vcaps Plus HPMC capsule shells at a predetermined filling weight. Finally, the capsules were dedusted and sorted by weight.

[0348] Development of Compound 1 Free Base Composition The following compound 1 free base formulations are already described in U.S. Patent Application Publication No. 16 / 737,721, which is incorporated herein by reference in whole. For convenience of reference, these formulations will be referred below, in some embodiments, to direct blend (DB) free base (FB) formulations having fumaric acid (FA).

[0349] [Table 17]

[0350] ICH stability testing, conducted in parallel with ASAP modeling, demonstrated that both 0.1 and 0.5 mg capsules of the free base formulation produced by the direct blending process exhibited acceptable stability when packaged in HDPE bottles with 2 g of desiccant. Surprisingly, the 2 mg strength capsules, with higher DL and higher Aerosil 200 levels as a flow aid (or flow enhancer), exhibited the poorest stability. This observation is counterintuitive and was attributed to the Aerosil level in the formulation. Furthermore, the Aerosil grade used in the 0.1 mg capsules is not acceptable in the global market.

[0351] Several tests were conducted to evaluate the impact of excipients or their levels on product quality (stability, elution, etc.) or manufacturability (e.g., tackiness), and potential alternative excipients were identified.

[0352] 7.10 Evaluation of the effects of colloidal silicon dioxide To assess the feasibility of removing Aerosil from the formulation, the manufacturability of batches without Aerosil was evaluated. In the absence of Aerosil in the formulation, powder adhesion to the tamping pin was observed during encapsulation, and the encapsulation assay was low. The alternative fluidizing agent Cab-O-Sil M5P did not improve the stability profile in the accelerated open-dish test.

[0353] 7.11 Evaluation of alternative lubricants To mitigate potential tackiness issues in formulations without Aerosil, the feasibility of formulations with more efficient lubricants, such as SSF and magnesium stearate, was evaluated. Alternatively, tackiness evaluation of formulations at the highest estimated drug load (2.56% w / w) with 4% SA, 4% SSF, or 2% magnesium stearate was performed using a compression simulator. Higher levels of SA (8% w / w) were also evaluated. The compositions are shown in the table below.

[0354] [Table 18]

[0355] To evaluate adhesion / filming potential, a 9mm flat tool was used for 10 consecutive compressions at each compression force (100N, 500N, and 2500N). The punched surface was tested under a magnifying lens and ranked for filming or adhesion based on the following criteria: no haze and substantially clean (Rank 0); light dust (minimal haze / powder, sharp reflection) (Rank 1); slight haze (slightly diffused reflection) (Rank 2); moderate haze (significantly diffused and reduced reflection) (Rank 3); severe haze (no effective light reflection) (Rank 4); slight waxy buildup (<1mm²) (Rank 5); moderate waxy buildup (1-2mm²) (Rank 6); widespread waxy buildup across multiple areas of the deboss (Rank 7); deboss largely covered by buildup (Rank 8); debossing not visible (Rank 9); adhesion affecting tablet weight (Rank 10). The ranking of adhesion / filming observations is summarized in the table below. The results suggested that the 4% SSF was only slightly better than the other three compositions.

[0356] [Table 19]

[0357] In open-dish accelerated stability tests, 0.1 mg strength capsules of the prototype formulations containing SSF (PD01-405A) or magnesium stearate (PD01-405B), manufactured by the direct blending process, showed better stability than 0.1 mg direct-blended capsules (Cap-16) containing Aerosil 972. However, as previously stated, the latter formulation and the 0.5 mg direct-blended capsules containing Aerosil 200 exhibit good stability in their packaged configurations. The stability results suggest that any one of these three lubricants can be used in direct-blended formulations with appropriate packaging configurations.

[0358] [Table 20]

[0359] 7.12 Evaluation of Acidifying Agent Levels Prototype free base formulations with varying levels of FA (0-4% w / w) were prepared using a dry blending process. The formulation compositions are listed in the table below. The formulations contained Pearlitol flash as a diluent but did not contain Aerosil. The slurry pH of the formulations ranged from 4.3 at 0% FA to 2.2 at 4% FA. In accelerated open-dish tests, the overall stability of formulations containing up to 3% FA was better than that of the directly blended free base formulation Cap-16, even under high temperature and high humidity conditions. The composition is shown in the table below.

[0360] [Table 21]

[0361] 7.13 Evaluation of alternative diluents During clinical batch manufacturing, the DB process was not found to be robust, particularly for low drug load batches (0.13% w / w), due to variations in CU (consumption of cereals). Considering the inherent CU risk of the direct blending process for producing low-dose products, alternative manufacturing platforms, e.g., HSWG, FBG, and RC, were evaluated to mitigate potential CU risks.

[0362] Alternative diluents that contribute to the manufacturing process, such as mannitol, MCC, starch, and co-processed mannitol / starch combinations (Pearlitol flash), were evaluated. The evaluated formulation compositions are listed in the table below. Batch PD01-403A containing Pearlitol flash was manufactured using a direct compression process, while batch PD01-596 containing mannitol 50C, MCC PH101, and pregelatinized starch was manufactured using the HSWG process. Both formulations showed good stability regardless of the differences in manufacturing process, diluents, and even lubricants.

[0363] [Table 22]

[0364] In vitro elution of MCCs containing batch PD01-596 was evaluated. In a pH 2.0 medium, drug release was incomplete, with only about 85%–90% released within 60 minutes of the initial capsule sample and after 3 months of storage at 40°C / 75%RH. Incomplete drug release from MCC-containing formulations may potentially affect bioperformance.

[0365] 7.14 Evaluation of SSG as a disintegrant To reduce the incomplete dissolution of MCC-containing formulations, the effect of SSG as a disintegrant on capsule dissolution was evaluated, as SSG was compatible with compound 1 free base. The compositions of the four formulations evaluated in this study are shown in the table below. Batch PD01-597, 597A, 660, and 660A were prepared without SSG, using only extragranular SSG, both intragranular and extragranular SSG, and intragranular SSG only, respectively. The drug load was 2.72% to obtain 2 mg strength capsules for the dissolution test. All batches were prepared using the HSWG process.

[0366] [Table 23]

[0367] Figure 9 shows the elution profiles for all four batches in pH2 media. Elution was incomplete in the batch without SSG (PD0-597), with overall release being only about 80% at 60 minutes. Incorporation of extragranular SSG alone did not improve the elution profile (PD01-597A). In contrast, the addition of intragranular SSG alone (PD01-660A) and both intragranular and extragranular SSG (PD01-660) significantly improved the release rate; overall release was about 93% at 60 minutes. The results suggest that when developing MCC-containing formulations, adding SSG at least intragranular can improve the elution profile.

[0368] 7.15 Manufacturing Process Development To identify a suitable manufacturing process that should maintain not only scalability but also all important quality characteristics of the drug product, different manufacturing platforms, namely direct blending, roller compression, and high-shear wet granulation, were evaluated. As shown in Figure 10A, the chemical and chiral stability of free base formulations using the same composition (see table below) was found to be significantly better for the HSWG / FBD and DB processes compared to the RC process. Manufacturability (high assay recovery and tight CU control) could be achieved using the HSWG / FBD process compared to either the DB or RC process. As shown in Figure 10B, in vitro elution of formulations with higher drug loads (see table below) was superior and complete when manufactured using the HSWG / FBD process. The overall ranking of the manufacturing platforms was HSWG / FBD > DB > RC.

[0369] [Table 24]

[0370] 7.16 Excipient Range Setting Test As described above, the combination of high-shear wet granulation (HSWG) with fluidized bed drying (FBD) was identified as a viable manufacturing process for compound 1 capsules. The drug load range in the formulation was approximately 0.13% to 2.7% w / w to achieve a predicted dose range of capsule strength from 0.1 mg to 10 mg for capsule sizes of size 0 or less.

[0371] To optimize formulations for the HSWG / FBD process, prototype formulations containing MNT / starch / SSF and MNT / starch / MCC / SSF formulations were further evaluated in 3 kg batch sizes. Factors such as granulation fluid type (water or 15% starch slurry), granulation fluid level, spray rate, and wet agglomeration time were also evaluated. For all evaluated formulations, the SSF (lubricant) level was kept constant at 1% during final blending. The resulting granules were of good quality and had good flow, which then resulted in capsules with tight weight variability. No adhesion to the surface of the tamping pin was observed during encapsulation. Both formulations (MNT / starch and MNT / starch / MCC) yielded good CU; however, the average label claim value was approximately 5-8% higher per production batch. Dissolution at T=0 was faster for the MNT / starch formulation than for the MCC-containing formulation. Open-dish stability tests showed good chemical and chiral stability for both evaluation formulations. Spraying with either water or starch slurry had no effect on the resulting granules. Preliminary results showed that MCC was not important for either granulation growth or granulation endpoint control. Furthermore, it negatively affected in vitro elution performance. Based on the above findings, the MNT / starch / SSF-based formulation was selected as the lead prototype formulation for the HSWG / FBD process.

[0372] To identify the quantitative composition of MNT / starch / SSF-based formulations using the HSWG process, the influence of excipient levels on product quality characteristics was evaluated. Detailed excipient range test compositions are listed in the table below. Batches were prepared on a 3 kg scale using the HSWG / FBD process, and water was sprayed as the granulation liquid.

[0373] [Table 25]

[0374] The resulting granules were found to be of good quality, with flow properties ranging from good flow to free flow. A summary of the physical characteristics of the final blend is listed in the table below.

[0375] [Table 26]

[0376] Encapsulation of all batches resulted in capsules with tight control over capsule weight. As listed in the table below, the mean CU for all surveyed batches was slightly high (101.6–104.3%), but the CU RSD was tight, and all AV values ​​were within acceptable limits.

[0377] [Table 27]

[0378] Leach release (T=0) at pH 2.0 for all manufacturing batches demonstrated a rapid and complete release profile, as shown in Figure 11. Open-dish chemical (Figure 12A) and chiral (Figure 12B) stability at 70°C / 0%RH and 60°C / 75%RH demonstrated stable drug products during 3 and 7 days of storage, respectively. Furthermore, the stability of the drug product followed a linear relationship with drug load, with higher DL formulations demonstrating better chemical and chiral stability. However, the 0.13% DL batch with 30% w / w starch demonstrated a relatively high level of impurity profile with an RRT of 0.41.

[0379] From the excipient range DoE (DoE) testing, it could be inferred that the evaluation parameters did not demonstrate any significant effect on product characteristics (CU, elution, and RI / chiral stability); however, batches with 10% starch provided a narrower granulation endpoint window compared to batches with either 20% w / w or 30% w / w starch. Based on these observations, the formulation with 20% starch was selected for further development.

[0380] 7.17 Free Base Composition Based on prototype formulation screening and formulation range setting tests, compositions containing mannitol-starch-SSF were selected for further testing using DL concentrations of 0.13%, 0.26%, 0.5%, and 1.33%, which can produce different dose intensities, as listed in the table below.

[0381] [Table 28]

[0382] 7.18 Multiple Media Elution Test The objective of this study was to develop an in vitro predictive tool that could predict in vivo performance by comparing the formulation components (hereinafter referred to as HSWG free base formulations for convenience of reference) with free base formulations produced using direct blending (DB) and variations in the manufacturing process. In vitro multi-media elution tests were performed at pH 2.0, 4.5, and 6.8.

[0383] To evaluate the effect of multiple elution media, the dose intensity of 2 mg was assessed. The results from this study are shown in Figure 13. At pH 2.0, both the DB and HSWG free base formulations were found to be equivalent. However, when the pH was shifted to 4.5 and 6.8, the elution profile of the HSWG free base formulation was found to be slower compared to the DB formulation.

[0384] A two-stage dissolution test was also performed to evaluate the risk of precipitation during the transition of physiological pH from 1.2 in the stomach (0-30 minutes) to 6.8 in the intestines (30-90 minutes). Both DB and HSWG free base formulations were evaluated at a dose of 0.5 mg. Based on the results from the two-stage dissolution test shown in Figure 14, it can be estimated that the risk of precipitation was predicted to be low.

[0385] 7.19 Prototype free base formulations containing fumaric acid As described above, the proposed HSWG free base formulation was found to be slow in bioelution media. Alternative formulations containing 1% and 3% fumaric acid were prepared at a dose intensity of 2 mg. The compositions are listed in the table below. The fundamental reason for adding fumaric acid to the formulation was to maintain the microenvironment pH in an acidic range, as the drug substance is soluble at lower pH due to its pH-dependent elution properties. In vitro elution performance was evaluated at pH 4.5 because it was found to incorporate the greatest discriminatory power against other elution media.

[0386] [Table 29]

[0387] As shown in Figure 15, the elution performance of HSWG FB formulations with 1% and 3% FA was found to be significantly faster and higher compared to both DB FB formulations with FA and HSWG FB formulations without FA. This study supports the hypothesis that fumarate uptake supports higher drug elution by maintaining a favorable microenvironment pH that contributes to higher drug solubility.

[0388] 7.20 Animal PK Test-I Animal PK studies were conducted in male monkeys to determine whether any correlation existed between pH 4.5 elution and the PK profile in the monkeys. Each cohort was administered 2 mg capsules of the following formulations: DB FB formulation (3% FA), HSWG FB formulation without FA, HSWG FB formulation with 1% FA, and HSWG FB formulation with 3% FA.

[0389] A crossover study design including four male monkeys per cohort (with a washout period of at least one week) received different formulations. Furthermore, the monkeys were fasted overnight and for four hours post-administration. PK samples were collected up to 24 hours after administration. As shown in Figure 16, the HSWG FB formulation without FA demonstrated the lowest exposure (AUC) and higher variability, followed by the DB FB formulation with 3% FA, while the HSWG FB formulations with 1% and 3% FA demonstrated similar and significantly higher exposures.

[0390] Similarly, the in vitro elution ranking was found to be similar to the in vivo AUC ranking, qualitatively demonstrating a good in vitro-in vivo correlation. Based on in vitro elution and in vivo monkey AUC data at pH 4.5, the formulations were ranked as follows: HSWG FB formulation with 3% FA ≥ HSWG FB formulation with 1% FA >>> DB FB formulation (3% FA) > HSWG FB formulation (no FA).

[0391] 7.21 Evaluation of the optional selection of hydrobromide as an alternative HSWG formulation. To evaluate the effect of the HBr salt of compound 1 on in vitro performance, alternative HSWG formulations without fumaric acid were prepared. The composition of the HSWG HBr formulations at a dose intensity of 0.5 mg is listed in the table below.

[0392] [Table 30]

[0393] The HSWG HBr composition was not optimized; instead, the composition and manufacturing process were kept unchanged to allow for a direct comparison of the drug substance forms (comparison between free base and HBr salt).

[0394] As shown in Figure 17, the dissolution performance of HSWG HBr formulations at a dose intensity of 0.5 mg was evaluated at pH 4.5 for DB FB and HSWG FB formulations, as well as for an HSWG formulation with 3% FA.

[0395] The HSWG HBr formulation demonstrates rapid and nearly complete elution in a pH 4.5 medium compared to DB FB, HSWG FB, or HSWG FB formulations with 3% FA.

[0396] 7.22 Animal PK Test-II The following four monkey cohorts (four monkeys per cohort): Another monkey PK study was designed for a dose intensity of 0.5 mg, containing DB FB, HSWG FB, HSWG FB with 3% FA, and HSWG HBr formulations. The composition of all formulations is as specified in the section above.

[0397] This study demonstrated that the HSWG HBr formulation and the HSWG FB formulation with 3% FA exhibited significantly higher absorption than the DB FB and HSWG FB formulations, while the HSWG HBr formulation demonstrated the highest AUC among all formulations. As shown in Figure 18, both the DB FB and HSWG FB formulations were observed to exhibit comparable bioperformance. The formulation ranking based on AUC is as follows: HSWG HBr formulation > HSWG FB formulation with 3% FA >>> DB FB formulation with 3% FA = HSWG FB formulation.

[0398] [Table 31]

[0399] The embodiments provided herein should not be limited in scope by specific embodiments provided in examples intended to describe some aspects of the provided embodiments, and any functionally equivalent embodiments are encompassed by this disclosure. In fact, in addition to those shown and described herein, various modifications to the embodiments provided herein will be apparent to those skilled in the art and are intended to be within the scope of the appended claims.

[0400] Numerous references are cited, and their disclosures are incorporated herein by reference as a whole.

Claims

1. 1) Compound 1: 【Chemistry 1】 A pharmaceutical composition comprising: 1) hydrobromide, 2) a mixture of mannitol and cellulose or a mixture of mannitol and starch, 3) hydroxypropyl methylcellulose (HPMC), 4) sodium starch glycolate (SSG), and 5) stearic acid, which is in the form of a tablet, capsule, pill, powder, or granule.

2. The pharmaceutical composition according to claim 1, comprising: 1) a hydrobromide of compound 1 in an amount of about 0.05 to about 3% w / w; 2) a carrier or diluent in an amount of about 70 to about 98% w / w; 3) HPMC in an amount of about 0.5 to about 10% w / w; 4) SSG in an amount of about 0.5 to about 10% w / w; and 5) stearic acid in an amount of about 0.5 to about 8% w / w, wherein the carrier or diluent is a mixture of mannitol and cellulose or a mixture of mannitol and starch.

3. The pharmaceutical composition according to claim 1 or 2, wherein the hydrobromide of compound 1 is a crystalline hydrobromide of compound 1, and optionally, the hydrobromide of compound 1 is characterized by an XRPD pattern including peaks at 10.3±0.2°2θ, 19.3±0.2°2θ, and 24.0±0.2°2θ.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of hydrobromide salt of compound 1 is about 0.1 to about 1.5% w / w, or about 0.16 to about 0.65% w / w.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the aforementioned component 2) is a mixture of mannitol and cellulose, and optionally the cellulose is microcrystalline cellulose (MCC).

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the aforementioned component 2) is a mixture of mannitol and starch, and optionally the starch is partially pregelatinized starch.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the amount of the mixture of mannitol and cellulose or the mixture of mannitol and starch is about 80 to about 90% w / w, or about 85 to about 86% w / w.

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the amount of mannitol is about 35 to about 93% w / w, and the amount of cellulose or starch is about 5 to about 35% w / w, optionally, the amount of mannitol is about 50 to about 80% w / w, and the amount of cellulose or starch is about 10 to about 30% w / w, optionally, the amount of mannitol is about 65 to about 66% w / w, and the amount of cellulose or starch is about 20% w / w.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight ratio of the cellulose or starch to the mannitol is about 1:1 to about 1:20, optionally, the weight ratio of the cellulose or starch to the mannitol is about 1:1.7 to about 1:8, optionally, the weight ratio of the cellulose or starch to the mannitol is about 1:3.

3.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the HPMC is HPMC E5, and optionally the amount of the HPMC is about 3 to about 7% w / w, and optionally the amount of the HPMC is about 5% w / w.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the SSG is a low pH SSG, optionally the amount of the SSG is about 3 to about 7% w / w, and optionally the amount of the SSG is about 5% w / w.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the amount of stearic acid is about 2 to about 6% w / w, and optionally, the amount of stearic acid is about 4% w / w.

13. The pharmaceutical composition according to claim 1, comprising: 1) about 0.16% w / w of hydrobromide of compound 1; 2) about 65.84% w / w of mannitol and about 20% w / w of microcrystalline cellulose; 3) about 5% w / w of HPMC E5; 4) about 5% w / w of low pH SSG; and 5) about 4% w / w of stearic acid, and optionally having a total weight of about 70 mg and optionally contained in a size 4 capsule, or having a total weight of about 140 mg and optionally contained in a size 2 capsule.

14. The pharmaceutical composition according to claim 1, comprising: 1) about 0.65% w / w of hydrobromide of compound 1; 2) about 65.35% w / w of mannitol and about 20% w / w of microcrystalline cellulose; 3) about 5% w / w of HPMC E5; 4) about 5% w / w of low pH SSG; and 5) about 4% w / w of stearic acid, optionally having a total weight of about 70 mg and optionally contained in a size 3 capsule.

15. 1) Compound 1: 【Chemistry 2】 A pharmaceutical composition comprising: 2) a mixture of mannitol and starch; 3) sodium stearyl fumarate; and 4) optionally fumaric acid, which is in the form of a tablet, capsule, pill, powder, or granule.

16. The pharmaceutical composition according to claim 15, comprising: 1) compound 1 in an amount of about 0.05 to about 4% w / w; 2) a mixture of mannitol and starch in an amount of about 90 to about 99.5% w / w; 3) sodium stearyl fumarate in an amount of about 0.1 to about 5% w / w; and 4) fumaric acid in an amount of about 0 to about 10% w / w.

17. The pharmaceutical composition according to claim 15 or 16, wherein compound 1 is a crystalline compound 1, and optionally, compound 1 is characterized by an XRPD pattern including peaks at 14.6±0.2°2θ, 18.2±0.2°2θ, and 18.3±0.2°2θ.

18. The pharmaceutical composition according to any one of claims 15 to 17, wherein the amount of compound 1 is about 0.1 to about 2% w / w, or about 0.13 to about 1.33% w / w.

19. The pharmaceutical composition according to any one of claims 15 to 18, wherein the starch is partially pregelatinized starch.

20. The pharmaceutical composition according to any one of claims 15 to 19, wherein the amount of the mixture of mannitol and starch is about 95 to about 99% w / w, optionally, the amount of the mixture of mannitol and starch is about 97 to about 99% w / w, or the amount of mannitol is about 60 to about 89% w / w and the amount of starch is about 10 to about 30% w / w, optionally, the amount of mannitol is about 77 to about 79% w / w and the amount of starch is about 20% w / w.

21. The pharmaceutical composition according to any one of claims 15 to 19, wherein the weight ratio of the starch to the mannitol is about 1:2 to about 1:9, and optionally, the weight ratio of the starch to the mannitol is about 1:3.

9.

22. The pharmaceutical composition according to any one of claims 15 to 21, wherein the amount of sodium stearyl fumarate is about 0.5 to about 2% w / w, and optionally, the amount of sodium stearyl fumarate is about 1% w / w.

23. A pharmaceutical composition according to any one of claims 15 to 22, wherein it does not contain fumaric acid, or the amount of fumaric acid is about 0.1 to about 10% w / w, or about 1 to about 3% w / w.

24. The pharmaceutical composition according to claim 15, comprising: 1) compound 1 in an amount of about 0.13% w / w; 2) mannitol in an amount of about 78.87% w / w and partially pregelatinized starch in an amount of about 20% w / w; and 3) sodium stearyl fumarate in an amount of about 1% w / w, optionally having a total weight of about 75 mg and optionally contained in a size 4 capsule, or having a total weight of about 300 mg and optionally contained in a size 1 capsule.

25. The pharmaceutical composition according to claim 15, comprising: 1) compound 1 in an amount of about 0.27% w / w; 2) mannitol in an amount of about 78.73% w / w and partially pregelatinized starch in an amount of about 20% w / w; and 3) sodium stearyl fumarate in an amount of about 1% w / w, optionally having a total weight of about 75 mg and optionally contained in a size 4 capsule, or having a total weight of about 300 mg and optionally contained in a size 1 capsule.

26. The pharmaceutical composition according to claim 15, comprising: 1) compound 1 in an amount of about 0.5% w / w; 2) mannitol in an amount of about 78.5% w / w and partially pregelatinized starch in an amount of about 20% w / w; and 3) sodium stearyl fumarate in an amount of about 1% w / w, optionally having a total weight of about 80 mg and optionally contained in a size 4 capsule, or having a total weight of about 300 mg and optionally contained in a size 1 capsule.

27. The pharmaceutical composition according to claim 15, comprising: 1) compound 1 in an amount of about 1.33% w / w; 2) mannitol in an amount of about 77.67% w / w and partially pregelatinized starch in an amount of about 20% w / w; and 3) sodium stearyl fumarate in an amount of about 1% w / w, optionally having a total weight of about 75 mg and optionally contained in a size 4 capsule, or having a total weight of about 300 mg and optionally contained in a size 1 capsule.

28. 1) Compound 1 in an amount of approximately 0.5% w / w; 2) Mannitol in an amount of approximately 75.5% w / w and partially pregelatinized starch in an amount of approximately 20% w / w; 3) Sodium stearyl fumarate in an amount of approximately 1% w / w; and 4) Fumaric acid in an amount of approximately 3% w / w; or 1) Compound 1 in an amount of approximately 1.33% w / w; 2) Mannitol in an amount of approximately 76.67% w / w and partially pregelatinized starch in an amount of approximately 20% w / w; 3) comprising about 1% w / w of sodium stearyl fumarate; and 4) about 1% w / w of fumaric acid; or the pharmaceutical composition according to claim 15, comprising about 1.33% w / w of compound 1; 2) about 74.67% w / w of mannitol and about 20% w / w of partially pregelatinized starch; 3) about 1% w / w of sodium stearyl fumarate; and 4) about 3% w / w of fumaric acid.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the pharmaceutical composition is in the form of a capsule.

30. A pharmaceutical composition according to any one of claims 1 to 29 for treating multiple myeloma.

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