Pharmaceutical compositions containing (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile and methods of use thereof

Abstract

Provided herein are pharmaceutical compositions (e.g., oral dosage 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, tautomers, isotopomers, or pharmaceutically acceptable salt thereof, and a carrier or diluent. Also provided herein are methods of preparing and using the pharmaceutical compositions.

Description

[0001] 1. Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 048,998, filed on July 7, 2020, the entire contents of which are incorporated herein by reference. 2. Technical field

[0004] Provided herein are pharmaceutical compositions 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, tautomers, isotopomers, or pharmaceutically acceptable salt thereof, and a carrier or diluent. Also provided herein are methods of using such pharmaceutical compositions to treat, prevent, and manage various disorders. 3. Background technology

[0006] Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells can lead to bone pain and fractures, anemia, infection, and other complications. Multiple myeloma is the second most common hematological malignancy, but the exact cause of multiple myeloma remains unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin, except in some patients (estimated to be 1% to 5%) whose myeloma cells do not secrete these proteins (called non-secretory myeloma). M protein (short for monoclonal protein, also called paraprotein) is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all multiple myeloma patients (except those with non-secretory myeloma or those whose myeloma cells produce both immunoglobulin light and heavy chains).

[0007] Skeletal symptoms, including bone pain, are one of 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 be lost from the bones, leading to lytic lesions; hypercalcemia is another symptom. Osteoclast-stimulating factors, also known as cytokines, can prevent myeloma cells from apoptosis or death. Fifty percent of patients have radiologically detectable myeloma-related bone lesions at the time of diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infection, and renal insufficiency.

[0008] Current treatments for multiple myeloma may involve one or more of surgery, stem cell transplantation, chemotherapy, immunotherapy, and / or radiation therapy to eliminate the patient's multiple myeloma cells. All current treatment approaches have significant disadvantages for the patient.

[0009] Over the past decade, new therapeutic agents (particularly immunomodulatory drugs such as lenalidomide and pomalidomide) have significantly improved response rates and prolonged progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma. However, in many patients with multiple myeloma, even after these patients have achieved a complete response (CR), there is persistent level of residual disease below the sensitivity of bone marrow (BM) morphology, immunofixation protein electrophoresis, and light chain quantification, which eventually leads to disease relapse. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is being considered as an alternative trial endpoint to improve the identification of effective treatments (particularly first-line trials), which currently require 5 to 10 years of follow-up to identify survival differences. Therefore, monitoring minimal residual disease (MRD) in patients with multiple myeloma provides prognostic value for predicting PFS and OS and making treatment decisions. A threshold of 0.01% after treatment (10 -4 ) detects minimal residual disease (MRD) in myeloma, that is, multiple myeloma cells are considered to account for 10% of total bone marrow mononuclear cells. -4 cells or fewer are MRD-negative and have 10 -4 10 cells or more are considered MRD positive. -4 MRD thresholds were originally based on technical capabilities but are now determined by flow cytometry at 10 -5 And through high-throughput sequencing in 10 -6 Quantitative MRD detection is possible under the condition of VDJ. (Rawstron et al., Blood 2015; 125(12): 1932-1935). Methods for measuring MRD include DNA sequencing of VDJ, polymerase chain reaction (PCR) (including allele-specific PCR, ASO PCR) and multiparameter flow cytometry (MPF). MRD assays based on, for example, clonotype characteristic measurements are also described in U.S. Pat. No. 8,628,927 to Faham et al., which is incorporated herein by reference.

[0010] There is a great need for safe and effective compounds and methods for treating, preventing, and managing multiple myeloma, including for patients with newly diagnosed multiple myeloma or who are refractory to standard therapies, while reducing or avoiding toxicities and / or side effects associated with conventional therapies.

[0011] The various possible pharmaceutical compositions (e.g., oral dosage formulations containing different excipients) create potential differences in the physical and chemical properties for a given drug compound. The discovery and selection of pharmaceutical compositions is very important for developing effective, stable and marketable drug products. 4. Summary of the invention

[0013] Certain pharmaceutical compositions comprising Compound 1 were previously described in U.S. Application No. 16 / 737,721, the entire contents of which are incorporated herein by reference.

[0014] Provided herein are pharmaceutical compositions (e.g., oral dosage formulations) comprising: 1) a hydrobromide salt of Compound 1:

[0015]

[0016] 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.

[0017] Also provided herein are pharmaceutical compositions (e.g., oral dosage formulations) comprising: 1) Compound 1:

[0018]

[0019] 2) a mixture of mannitol and starch, 3) sodium stearyl fumarate, and 4) optionally fumaric acid.

[0020] The chemical name of Compound 1 is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. Also provided herein is a method for preparing a pharmaceutical composition.

[0021] The pharmaceutical compositions provided herein are useful formulations for use in animals or humans. Thus, the embodiments herein encompass the use of these pharmaceutical compositions as final drug products. Certain embodiments provide pharmaceutical compositions for preparing final dosage forms with improved properties, such as powder flowability, compactability, tableting, stability, and excipient compatibility required for manufacturing, processing, formulating, and / or storing the final drug product.

[0022] Also provided are pharmaceutical compositions that are formulated for administration by appropriate routes and modes, containing an effective concentration of Compound 1 provided herein. In one embodiment, the pharmaceutical composition is an oral dosage formulation. In one embodiment, the pharmaceutical composition is an immediate release (IR) oral dosage formulation.

[0023] In one embodiment, the pharmaceutical composition delivers an amount effective to treat multiple myeloma. In one embodiment, the pharmaceutical composition delivers an amount effective to prevent multiple myeloma. In one embodiment, the pharmaceutical composition delivers an amount effective to alleviate multiple myeloma.

[0024] In one embodiment, provided herein are methods for treating multiple myeloma, which methods include administering a pharmaceutical composition provided herein. Also provided herein are combination therapies, which use a combination of a pharmaceutical composition provided herein and a therapy (e.g., another agent with activity for multiple myeloma or its symptoms). Examples of therapies within the scope of these methods include, but are not limited to, surgery, chemotherapy, radiotherapy, biotherapy, stem cell transplantation, cell therapy, and combinations thereof.

[0025] A pharmaceutical package or test kit is further provided, comprising one or more containers containing one or more ingredients of a pharmaceutical composition. Optionally, associated with such one or more containers may be a notice in a form prescribed by a governmental agency that manages the manufacture, use or sale of a drug or biological product, the notice reflecting the agency's permission to manufacture, use or sell for human administration. The package or test kit may be labeled with information on mode of administration, order of drug administration (e.g., separate, sequentially or concurrently), etc.

[0026] These and other aspects of the subject matter described herein will become apparent upon reference to the following detailed description. 5. Description of the drawings

[0028] Figure 1A and Figure 1B Total chemical impurity and chiral impurity levels from excipient compatibility testing are shown separately.

[0029] Figure 2A and Figure 2B Total chemical impurity and chiral impurity levels of prototype formulations prepared by the RC process are shown separately.

[0030] Figure 3A , Figure 3B and Figure 3C Hydrolytic degradant No. 1, hydrolytic degradant No. 2, and chiral impurity levels of the prototype formulation prepared by the RC process are shown, respectively.

[0031] Figure 4A and Figure 4B Total chemical impurity and chiral impurity levels are shown, respectively, for prototype formulations prepared by the HSWG process.

[0032] Figure 5A , Figure 5B and Figure 5CHydrolytic degradant No. 1, hydrolytic degradant No. 2, and chiral impurity levels are shown for the prototype formulation prepared by the HSWG process, respectively.

[0033] Fig. 6A and Figure 6B The effect of stearic acid on chemical purity and chiral purity based on exposure and under storage conditions are shown, respectively.

[0034] Figure 7 Shown is the dissolution profile of the prototype formulation prepared by the HSWG process.

[0035] Figure 8 Dissolution release profiles of the excipient range DoE batches at pH 4.5 at T=0 are shown.

[0036] Fig. 9 The effect of SSG performed using a prototype formulation on the dissolution performance is shown.

[0037] Fig. 10A A comparison of the stability (chirality / chemistry) properties of DPs made using various fabrication processes (DB vs. RC vs. HSWG) is shown; Fig. 10B Comparison of dissolution profiles is shown.

[0038] Fig.11 Dissolution release profiles of the excipient range DoE batches at pH 2.0 are shown (T=0).

[0039] Fig. 12A and Fig. 12B Relevant hydrolytic impurity and chiral impurity levels are shown separately for the excipient range DoE batches.

[0040] Fig.13 Shown is a comparison of the multi-media dissolution profiles of DB free base formulation and HSWG free base formulation with 3% FA at pH 1.2, 2.0, 4.5, and 6.8 using the 2 mg dosage strength.

[0041] Fig.14 A two-stage dissolution test using DB free base formulation with 3% FA and HSWG free base formulation at 0.5 mg dosage strength is shown to evaluate the impact on the risk of drug precipitation.

[0042] Fig.15 Shown is a comparison of the dissolution performance of a DB free base formulation with 3% FA and HSWG free base formulations (without fumaric acid, with 1% and 3% FA) at pH 4.5 using a 2 mg dosage strength.

[0043] Fig.16Mean monkey PK data using 2.0 mg of DB free base formulation with 3% FA and HSWG free base formulation are shown.

[0044] Fig.17 The in vitro dissolution performance of DB free base formulations with 3% FA, HSWG free base formulations with and without fumaric acid, and formulations with HBr salt at pH 4.5 are shown.

[0045] Fig.18 Mean monkey PK data using 0.5 mg of DB free base formulation with 3% FA and HSWG free base formulation are shown.

[0046] Fig.19 A representative X-ray powder diffraction (XRPD) pattern of Form K of the free base of Compound 1 is provided.

[0047] Fig. 20 A representative XRPD pattern of Form K' of the free base of Compound 1 is provided.

[0048] Fig.21 A representative XRPD pattern of Form A of the hydrobromide salt of Compound 1 is provided. 6. Specific implementation methods

[0050] 6.1 Definitions

[0051] As used herein and in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0052] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the mentioned claimed features or components, but not excluding the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used to replace the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0053] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components of its stated composition. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent description, except those that are not necessary for the technical effect to be achieved.

[0054] As used herein, the term "or" should be interpreted as an inclusive "or", meaning any one or any combination. Thus, "A, B or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B and C". Exceptions to this definition will only occur when a combination of elements, functions, steps or acts are inherently mutually exclusive in some way.

[0055] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form means a dose, amount, or weight percentage recognized by one of ordinary skill in the art as providing a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. In certain embodiments, when used in this context, the terms "about" and "approximately" contemplate doses, amounts, or weight percentages within 30%, within 20%, within 15%, within 10%, or within 5% of a specified dose, amount, or weight percentage.

[0056] As used herein and unless otherwise indicated, when used in conjunction with a numerical value or range of values ​​provided to characterize a particular solid form (e.g., a particular temperature or temperature range such as, for example, describing a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content expressed, for example, in mass or percentage; or a peak position in an analysis such as, for example, by IR or Raman spectroscopy or XRPD), the terms "about" and "approximately" indicate that the value or range of values ​​may deviate to an extent that one of ordinary skill in the art considers reasonable while still describing a particular solid form. For example, in a particular embodiment, when used in this context, the terms "about" and "approximately" indicate that a 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 recited value or range of values. For example, in some embodiments, the values ​​of XRPD peak positions can vary by as much as ±0.2 degrees 2θ while still describing a specific XRPD peak.As used herein, a tilde (ie, "~") preceding a value or range of values ​​indicates "about" or "approximately."

[0057] Unless otherwise stated, the terms "X-ray powder diffraction," "powder X-ray diffraction," "PXRD," and "XRPD" are used interchangeably in this application.

[0058] As used herein and unless otherwise indicated, the term "solid form" and related terms refer to a physical form that is not primarily in a liquid or gaseous state. As used herein, the terms "solid form" and "solid forms" encompass semisolids. A solid form can be crystalline, amorphous, partially crystalline, partially amorphous, or a mixture of multiple forms.

[0059] As used herein and unless otherwise indicated, the term "crystalline" and related terms used herein, when used to describe a substance, component, product or form, means that the substance, component, product or form is substantially crystalline, for example, as determined by X-ray diffraction. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

[0060] As used herein and unless otherwise specified, the terms "amorphous", "amorphous form" and related terms used herein mean that the substance, component or product in question is not substantially 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 certain embodiments, the amorphous form of a substance may be substantially free of other amorphous forms and / or crystalline forms. In other embodiments, the amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphous forms and / or crystalline forms based on weight. In certain embodiments, the amorphous form of a substance may be physically and / or chemically pure. In certain 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 certain embodiments, the amorphous form of a substance may contain additional components or ingredients (e.g., additives, polymers, or excipients that may be used to further stabilize the amorphous form). In certain embodiments, the amorphous form may be a solid solution.

[0061] As used herein and unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, relatively non-toxic acids, including inorganic and organic acids. In certain embodiments, suitable acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, citric acid, dihydrogenphosphoric acid, vinylsulfonic 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, monohydrogencarbonic acid, monohydrogenphosphoric acid, monohydrogensulfuric acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, suberic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, and the like (see, e.g., SM Berge et al., J. Pharm. Sci., 66: 1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use [Handbook of Pharmaceutical Salts: Properties, Selection and Use], PH Stahl and CG Wermuth, eds., (2002), Wiley [Wiley Publishing House], Weinheim City (Weinheim)). In certain embodiments, suitable acids are strong acids (e.g., pKa less than about 1), including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, pyridinesulfonic acid or other substituted sulfonic acids. Also included are salts of other relatively non-toxic compounds having acidic characteristics (including amino acids (such as aspartic acid, etc.) and other compounds (such as aspirin, ibuprofen, saccharin, etc.). Acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid (neat acid or in a suitable solvent). As a solid, the salt can exist in a crystalline or amorphous form, or a mixture thereof. The salt can also exist in polycrystalline form.

[0062] As used herein, "multiple myeloma" refers to a hematologic disorder characterized by malignant plasma cells and includes the following disorders: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk, and high-risk multiple myeloma; newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; smoldering (indolent) 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 translocation (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20);), MMSET translocation (e.g., t(4;14)(p16;q32)), MAF translocation (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 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy, and gain(1q)).

[0063] As used herein and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to alleviating or lessening the severity of the symptoms associated with the disease or disorder (eg, multiple myeloma) being treated.

[0064] The term "prevention" includes suppressing the symptoms of a particular disease or disorder (e.g., multiple myeloma). In some embodiments, patients with a family history of multiple myeloma are candidates for a preventive regimen. In general, the term "preventing" refers to administering a drug before symptoms occur, particularly to patients at risk for multiple myeloma.

[0065] As used herein and unless otherwise indicated, the term "managing" encompasses preventing a patient who has had a particular disease or disorder (such as multiple myeloma) from having the disease or disorder relapse, prolonging the time a patient with the disease or disorder remains in remission, reducing the mortality rate of a patient, and / or maintaining a reduction in the severity of or avoiding the occurrence of symptoms associated with the disease or condition being managed.

[0066] As used herein, a "subject" or "patient" is an animal, typically a mammal, including a human, such as a human patient.

[0067] The term "relapse" refers to the reappearance of myeloma cells and / or a decrease in normal blood cells in the bone marrow of a patient whose multiple myeloma has been in remission following therapy.

[0068] The term "refractory or resistant" refers to a situation in which myeloma cells remain in the bone marrow and / or normal cells decrease even after intensive treatment.

[0069] As used herein, "induction therapy" refers to the first treatment given for a disease, or the first treatment given with the intent to induce complete remission of a disease (such as cancer). When used alone, induction therapy is a recognized best available treatment. If residual cancer is detected, the patient is treated with another therapy (called re-induction). If the patient is in complete remission after induction therapy, additional consolidation and / or maintenance therapy is given to prolong the remission period or potentially cure the patient.

[0070] As used herein, "consolidation therapy" refers to treatment given for a disease after remission has first been achieved. For example, consolidation therapy for cancer is treatment given after the cancer is gone after initial treatment. Consolidation therapy can include radiation therapy, stem cell transplantation, or treatment with cancer drug therapy. Consolidation therapy is also called enhancement therapy and post-remission therapy.

[0071] As used herein, "maintenance therapy" refers to treatment given to a disease after achieving remission or best response in order to prevent or delay relapse. Maintenance therapy may include chemotherapy, hormone therapy, or targeted therapy.

[0072] As used herein, "remission" is a reduction or disappearance of signs and symptoms of cancer (e.g., multiple myeloma). In a partial remission, some but not all signs and symptoms of the cancer disappear. In a complete remission, all signs and symptoms of the cancer disappear, although the cancer may still be in the body.

[0073] As used herein, "transplantation" refers to high-dose therapy with stem cell rescue. Hematopoietic (blood) or bone marrow stem cells are not used for treatment, but are used to save patients after high-dose therapy (e.g., high-dose chemotherapy and / or radiotherapy). Transplantation includes "autologous" stem cell transplantation (ASCT), which refers to harvesting the patient's own stem cells and using them as replacement cells. In some embodiments, transplantation also includes tandem transplantation or multiple transplantations.

[0074] As used herein and unless otherwise indicated, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease (e.g., multiple myeloma), or to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0075] The terms "co-administered" and "in combination with..." include administering one or more therapeutic agents (e.g., a compound provided herein and another anti-multiple myeloma agent, anticancer agent, or supportive care agent) simultaneously, concurrently, or sequentially (without particular time limits). In one embodiment, these agents are present in cells or in the patient's body at the same time, or exert their biological or therapeutic effects at the same time. In one embodiment, these therapeutic agents are in the same composition or unit dosage form. In another embodiment, these therapeutic agents are in separate compositions or unit dosage forms.

[0076] The term "supportive care agent" refers to any substance that treats, prevents, or manages an adverse effect from treatment with Compound 1, or an enantiomer or mixture of enantiomers, tautomers, isotopomers, or pharmaceutically acceptable salt thereof.

[0077] The term "biological therapy" refers to the administration of biological therapeutic agents, such as umbilical cord blood, stem cells, growth factors, etc.

[0078] In the context of cancer (such as multiple myeloma), inhibition can be assessed by: inhibiting disease progression, inhibiting tumor growth, reducing primary tumors, alleviating tumor-related symptoms, inhibiting tumor secretion 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 down or reducing the severity of secondary effects of the disease, preventing tumor growth and tumor regression, increasing time to progression (TTP), increasing progression-free survival (PFS), increasing overall survival (OS), etc. As used herein, OS means the time from the start of treatment to death from any cause. As 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 dose of compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate will be calculated using Kaplan-Meier estimation. Event-free survival (EFS) means the time from the start of treatment to any treatment failure (including disease progression, discontinuation of treatment for any reason, or death). In one embodiment, the overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment, ORR means the sum of the percentages of patients who achieve a complete response and a partial response. In one embodiment, according to the IMWG unified response criteria, ORR means the percentage of patients with the best response ≥ partial response (PR). In one embodiment, the duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one embodiment, DoR is the time from achieving a response ≥ partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from the first recorded response to the first recorded disease progression or death. In one embodiment, DoR is the time from the first recorded response ≥ partial response (PR) to the first recorded disease progression or death. In one embodiment, the response time (TTR) means the time from the first dose of compound to the first recorded response. In one embodiment, TTR means the time from the first dose of compound to the first recorded response ≥ partial response (PR). In extreme cases, complete inhibition is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes preventing the onset of clinically evident cancer altogether, or preventing the onset of cancer at a preclinically evident stage. The definition is also intended to cover preventing transformation to malignant cells or halting or reversing the progression of precancerous cells to malignant cells. This includes preventive treatment of those at risk of developing cancer.

[0079] In certain embodiments, treatment of multiple myeloma can be assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions shown below:

[0080]

[0081]

[0082] Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response.

[0083] a All response categories require two serial assessments at any time prior to initiation of any new therapy; all categories also do not require known evidence of progressive or new bone lesions if radiographic studies are performed. Radiographic studies are not required to meet these response requirements.

[0084] b No repeat bone marrow biopsy is required for confirmation.

[0085] c The presence / absence of clonal cells is based on the κ / λ ratio. An abnormal κ / λ ratio by immunohistochemistry and / or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of an abnormal clone is κ / λ >4:1 or <1:2.

[0086] d Measurable disease defined by at least one of the following measurements: bone marrow plasma cells ≥30%; serum M-protein ≥1 g / dl (≥10 gm / l) [10 g / l]; urine M-protein ≥200 mg / 24 h; serum FLC assay: affected FLC level ≥10 mg / dl (≥100 mg / l); conditional on abnormal serum FLC ratio.

[0087] As used herein, ECOG status refers to the 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 follows:

[0088]

[0089] Unless otherwise stated, in the event of a discrepancy between a depicted chemical structure of a compound provided herein and the chemical name of a compound provided herein, the chemical structure shall control.

[0090] 6.2 Pharmaceutical compositions comprising Compound 1

[0091] In certain embodiments, provided herein are pharmaceutical compositions (e.g., oral dosage formulations) comprising Compound 1:

[0092]

[0093] or an enantiomer, a mixture of enantiomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof, and a carrier or a diluent.

[0094] In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration to patients. In one embodiment, the pharmaceutical compositions provided herein exhibit favorable physical and / or pharmacological properties. Such properties include, but are not limited to, ease of determination, content uniformity, fluidity for manufacture, dissolution and bioavailability and stability. In one embodiment, the pharmaceutical compositions provided herein have a shelf life of at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months without refrigeration. In certain embodiments, "no refrigeration" refers to a temperature of 20 ° C or above. In one embodiment, the pharmaceutical compositions provided herein are stored under refrigerated conditions. In one embodiment, the pharmaceutical compositions provided herein have a shelf life of at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months when stored under refrigerated conditions. In one embodiment, the properties of the pharmaceutical compositions provided herein make them suitable for immediate release (IR).

[0095] The pharmaceutical compositions provided herein can be formulated into suitable pharmaceutical formulations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs (for oral administration) or sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch formulations and dry powder inhalers. Typically, the above compounds are formulated 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 compositions provided herein are oral dosage forms. In one embodiment, the oral dosage unit form is a tablet. In one embodiment, the oral dosage unit form is a caplet. In one embodiment, the pharmaceutical compositions provided herein are immediate release capsules. In one embodiment, the pharmaceutical compositions provided herein are immediate release (IR) capsule blends (BIC) (blend in capsule).

[0096] Tablets, caplets and capsules typically contain about 50 mg to about 500 mg of the pharmaceutical composition (i.e., active ingredient and one or more excipients). Capsules can be of any size. Examples of standard sizes include 000, 00, 0, 1, 2, 3, 4 and 5. See, for example, Remington's Pharmaceutical Sciences, pp. 1658-1659 (Alfonso Gennaro, ed., Mack Publishing Company, Easton Pennsylvania, 18th ed., 1990), which is incorporated by reference. In some embodiments, the size of the capsules provided herein is No. 1 or larger, No. 2 or larger, No. 3 or larger, or No. 4 or larger.

[0097] In the composition, effective concentrations of one or more compounds or pharmaceutically acceptable salts are mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective for delivering an amount that treats, prevents, or alleviates one or more symptoms and / or progression of multiple myeloma after administration.

[0098] (a) Form of Compound 1

[0099] The chemical name of Compound 1 is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. Methods for preparing Compound 1 have been described in U.S. Pat. No. 10,357,489, which is incorporated herein by reference in its entirety.

[0100] In one embodiment, Compound 1 or its enantiomer, mixture of enantiomers, tautomers, isotopomers, or pharmaceutically acceptable salt is provided in a solid form in a pharmaceutical composition. Solid forms of Compound 1 or its enantiomer, mixture of enantiomers, tautomers, isotopomers, or pharmaceutically acceptable salts have been described in U.S. Application No. 16 / 737,739, which is incorporated herein by reference in its entirety.

[0101] 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 anhydrate. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is non-solvated.

[0102] Solid forms can be characterized using a variety of methods known to those skilled in the art, including but not limited to single crystal X-ray diffraction, X-ray powder diffraction (PXRD), microscopy (e.g., optical microscopy, scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy), dynamic vapor sorption (DVS), spectroscopy (e.g., infrared, Raman, and nuclear magnetic resonance), high performance liquid chromatography (HPLC). The particle size and size distribution of the solid forms provided herein can be determined by conventional methods (e.g., laser scattering techniques).

[0103] In one embodiment, the pharmaceutical composition comprises Compound 1 (i.e., as a free base). As used herein and unless otherwise indicated, "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 forms and crystalline forms.

[0104] In one embodiment, the pharmaceutical composition comprises a salt of compound 1. In one embodiment, the salt is hydrochloride, methanesulfonate, hydrobromide, benzenesulfonate, glycolate, L-malate, naphthalene disulfonate, sulfate, toluenesulfonate, oxalate, isethionate, maleate, phosphate, malonate, gentisate, L-tartrate, fumarate, citrate, R-mandelate, L-ascorbate, succinate, nitrate, salicylate, edisylate, cyclamate, ethanesulfonate, 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 forms and crystalline forms.

[0105] In one embodiment, the pharmaceutical composition comprises the hydrochloride salt of Compound 1. In one embodiment, the pharmaceutical composition comprises the methanesulfonate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises the hydrobromide salt of Compound 1. In one embodiment, the pharmaceutical composition comprises the benzenesulfonate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises the glycolate salt of Compound 1. In one embodiment, the pharmaceutical composition comprises the L-malate salt of Compound 1.

[0106] 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, or an intermediate form between Form K and Form K′, or a mixture thereof.

[0107] In one embodiment, Form K is a channel hydrate of the free base of Compound 1. In one embodiment, Form K is a monohydrate of the free base of Compound 1. In one embodiment, Form K' is a dehydrated hydrate of Form K. In one embodiment, without being limited by a particular theory, Form K' is converted to Form K as humidity increases, and Form K is converted to Form K' as humidity decreases. Therefore, depending on the humidity, there are intermediate forms between Form K and Form K'. In one embodiment, when the water activity is not higher than about 0.11, Form K is converted to Form K'. In one embodiment, when the water activity is not lower than about 0.17, Form K' is converted to Form K'.

[0108] In one embodiment, the pharmaceutical compositions provided herein comprise Form K, Form K', or an intermediate form between Form K and Form K' of the free base of Compound 1, or a mixture thereof, characterized in that the XRPD pattern comprises 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 compositions provided herein comprise Form K of the free base of Compound 1, characterized in that the XRPD pattern further comprises at least one peak at approximately 14.2, 18.6, or 20.3 ° 2θ. In one embodiment, a pharmaceutical composition provided herein comprises Form K' of the free base of Compound 1, wherein Form K' is characterized in that the XRPD pattern further comprises at least one peak at about 18.0 or 18.8 degrees 2-theta.

[0109] Fig.19 A representative XRPD pattern of Form K is provided in .

[0110] In one embodiment, a pharmaceutical composition provided herein comprises a free base of Compound 1 in a solid form characterized by 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 the peaks located at approximately 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 compositions provided herein comprise a free base of Compound 1 in a solid form characterized by 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 the peaks located at approximately: 8.59, 10.78, 1 2θ. In one embodiment, the solid form is characterized by 3 of these peaks. In one embodiment, the solid form is characterized by 5 of these peaks. In one embodiment, the solid form is characterized by 7 of these peaks. In one embodiment, the solid form is characterized by 9 of these peaks. In one embodiment, the solid form is characterized by 11 of these peaks. In one embodiment, the solid form is characterized by all of these peaks.

[0111] 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 comprising peaks at approximately 14.2, 14.6, 18.2, and 18.3 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 22.3, 23.1, and 24.5 ° 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, 14.2, 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.

[0112] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, and the free base of compound 1 is in a solid form characterized by an XRPD pattern comprising peaks at 14.2, 14.6, 18.2, and 18.3 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.21, 14.60, 18.21, and 18.34°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.04 ° 2θ.

[0113] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, and the free base of compound 1 is in a solid form characterized by an XRPD pattern comprising peaks at 14.2, 14.6, 18.2, and 18.3 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.21, 14.60, 18.21, and 18.34°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.02 ° 2θ.

[0114] 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 comprising peaks at 14.2, 14.6, 18.2, and 18.3 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ. In one embodiment, the XRPD pattern comprises 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 comprising peaks at 14.21, 14.60, 18.21, and 18.34 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87 ° 2θ. In one embodiment, the XRPD pattern comprises 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° 2-theta.

[0115] 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 comprising peaks at approximately 14.6, 18.2, 18.3, and 18.6 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 22.3, 23.1, and 24.5 ° 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, 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.

[0116] 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 comprising peaks at 14.6, 18.2, 18.3, and 18.6 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.60, 18.21, 18.34, and 18.62°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.04 ° 2θ.

[0117] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, and the free base of compound 1 is in a solid form characterized by an XRPD pattern comprising peaks at 14.6, 18.2, 18.3, and 18.6 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.60, 18.21, 18.34, and 18.62°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.02 ° 2θ.

[0118] 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 comprising peaks at 14.6, 18.2, 18.3, and 18.6 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ. In one embodiment, the XRPD pattern comprises 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 comprising peaks at 14.60, 18.21, 18.34, and 18.62 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87 ° 2θ. In one embodiment, the XRPD pattern comprises 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° 2-theta.

[0119] 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 comprising peaks at approximately 14.6, 18.2, 18.3, and 20.3 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 22.3, 23.1, and 24.5 ° 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, 20.3, 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.

[0120] 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 comprising peaks at 14.6, 18.2, 18.3, and 20.3 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.60, 18.21, 18.34, and 20.25°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.04°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.04 ° 2θ.

[0121] 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 comprising peaks at 14.6, 18.2, 18.3, and 20.3 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.60, 18.21, 18.34, and 20.25°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87°2θ±0.02°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 18.02 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.75 ° 2θ ± 0.02 ° 2θ.

[0122] 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 comprising peaks at 14.6, 18.2, 18.3, and 20.3 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.3, 23.1, and 24.5 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.5 and 20.9 ° 2θ. In one embodiment, the XRPD pattern comprises 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 comprising peaks at 14.60, 18.21, 18.34, and 20.25 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 22.28, 23.05, and 24.54 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.47 and 20.87 ° 2θ. In one embodiment, the XRPD pattern comprises 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° 2-theta.

[0123] In one embodiment, the pharmaceutical composition provided herein comprises a free base of Compound 1, wherein the free base of Compound 1 is characterized by an XRPD pattern similar to Fig.19 The XRPD pattern presented in matches the solid form.

[0124] Fig. 20 A representative XRPD pattern of Form K' is provided in .

[0125] In one embodiment, a pharmaceutical composition provided herein comprises a free base of Compound 1 in a solid form characterized by 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 peaks located at approximately 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 compositions provided herein comprise a free base of Compound 1 in a solid form characterized by 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 peaks located at approximately: 8.65, 10.79, 14. 2θ. In one embodiment, the solid form is characterized by 3 of these peaks. In one embodiment, the solid form is characterized by 5 of these peaks. In one embodiment, the solid form is characterized by 7 of these peaks. In one embodiment, the solid form is characterized by 9 of these peaks. In one embodiment, the solid form is characterized by 11 of these peaks. In one embodiment, the solid form is characterized by all of these peaks.

[0126] 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 comprising peaks at approximately 14.6, 18.0, 18.3, and 18.4 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.9, 22.4, and 23.2 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 16.6 and 20.5 ° 2θ. In one embodiment, the XRPD pattern comprises 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° 2-theta.

[0127] 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 comprising peaks at 14.6, 18.0, 18.3, and 18.4 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in 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 includes peaks at 20.92, 22.36, and 23.19°2θ±0.04°2θ. In one embodiment, the XRPD pattern further includes peaks at 16.55 and 20.52°2θ±0.04°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 14.21 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25 ° 2θ ± 0.04 ° 2θ.

[0128] In one embodiment, the pharmaceutical composition provided herein comprises a free base of compound 1, and the free base of compound 1 is in a solid form characterized by an XRPD pattern comprising peaks at 14.6, 18.0, 18.3, and 18.4 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.63, 18.02, 18.25, and 18.40°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.92, 22.36, and 23.19°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.55 and 20.52°2θ±0.02°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 14.21 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25 ° 2θ ± 0.02 ° 2θ.

[0129] 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 14.6, 18.0, 18.3, and 18.4 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.63, 18.02, 18.25, and 18.40 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.92, 22.36, and 23.19 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.55 and 20.52 ° 2θ. In one embodiment, the XRPD pattern comprises 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° 2-theta.

[0130] In one embodiment, the pharmaceutical composition provided herein comprises the free base of Compound 1, which is in a solid form characterized by an XRPD pattern comprising peaks at approximately 14.6, 18.3, 18.4, and 18.8° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.9, 22.4, and 23.2° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 16.6 and 20.5° 2θ. In one embodiment, the XRPD pattern comprises 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.

[0131] 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 comprising peaks at 14.6, 18.3, 18.4, and 18.8 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in 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 comprises peaks at 20.92, 22.36, and 23.19°2θ±0.04°2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.55 and 20.52°2θ±0.04°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 14.21 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62 ° 2θ ± 0.04 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25 ° 2θ ± 0.04 ° 2θ.

[0132] 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 comprising peaks at 14.6, 18.3, 18.4, and 18.8 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in a solid form characterized by an XRPD pattern comprising peaks at 14.63, 18.25, 18.40, and 18.75°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.92, 22.36, and 23.19°2θ±0.02°2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.55 and 20.52°2θ±0.02°2θ. In one embodiment, the XRPD pattern comprises 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 contain a peak at 14.21 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 18.62 ° 2θ ± 0.02 ° 2θ. In one embodiment, the XRPD pattern does not contain a peak at 20.25 ° 2θ ± 0.02 ° 2θ.

[0133] 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 14.6, 18.3, 18.4, and 18.8 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 20.9, 22.4, and 23.2 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at 16.6 and 20.5 ° 2θ. In one embodiment, the XRPD pattern comprises 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 in 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 includes peaks at 20.92, 22.36, and 23.19 ° 2θ. In one embodiment, the XRPD pattern further includes peaks at 16.55 and 20.52 ° 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. 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° 2-theta.

[0134] In one embodiment, the pharmaceutical composition provided herein comprises a free base of Compound 1, wherein the free base of Compound 1 is characterized by an XRPD pattern similar to Fig. 20 The XRPD pattern presented in matches the solid form.

[0135] In one embodiment, without being bound by any particular theory, the XRPD peaks of Form K' are slightly shifted to higher °2θ values ​​compared to Form K, indicating that Form K' has a slightly contracted lattice.

[0136] In certain embodiments, pharmaceutical compositions provided herein comprise Form A of the hydrobromide salt of Compound 1.

[0137] In one embodiment, the molar ratio of Compound 1 to hydrobromic acid in Form A is about 1:1. In one embodiment, Form A is a monohydrobromide salt of Compound 1. In one embodiment, Form A is a non-solvated form of the hydrobromide salt of Compound 1. In one embodiment, Form A is an anhydrate of the hydrobromide salt of Compound 1.

[0138] Fig.21 A representative XRPD pattern of Form A of the hydrobromide salt of Compound 1 is provided in .

[0139] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of Compound 1 in a solid form characterized by 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 of the peaks located at about 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 3 of these peaks. In one embodiment, the solid form is characterized by 5 of these peaks. In one embodiment, the solid form is characterized by 7 of these peaks. In one embodiment, the solid form is characterized by 9 of these peaks. In one embodiment, the solid form is characterized by 11 of these peaks. In one embodiment, the solid form is characterized by all of these peaks.

[0140] In one embodiment, a pharmaceutical composition provided herein comprises a hydrobromide salt of Compound 1 in solid form characterized by 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 peaks located at approximately 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 of these peaks. In one embodiment, the solid form is characterized by 5 of these peaks. In one embodiment, the solid form is characterized by 7 of these peaks. In one embodiment, the solid form is characterized by 9 of these peaks. In one embodiment, the solid form is characterized by 11 of these peaks. In one embodiment, the solid form is characterized by all of these peaks.

[0141] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of Compound 1 in a solid form characterized by an XRPD pattern comprising peaks at approximately 10.3, 19.3, and 24.0 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 17.1 and 20.7 ° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 12.8 and 15.6 ° 2θ. In one embodiment, the XRPD pattern comprises 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.

[0142] In one embodiment, the pharmaceutical composition provided herein comprises a hydrobromide salt of Compound 1, wherein the hydrobromide salt of Compound 1 is characterized by an XRPD pattern similar to Fig.21 The XRPD pattern presented in matches the solid form.

[0143] In one embodiment, the XRPD pattern is obtained using Cu Ka radiation.

[0144] (b) Compound 1 hydrobromide pharmaceutical composition

[0145] In one embodiment, provided herein is a pharmaceutical composition comprising 1) a hydrobromide salt of Compound 1:

[0146]

[0147] 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.

[0148] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) a hydrobromide salt 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; and wherein the carrier or diluent is a mixture of mannitol and cellulose or a mixture of mannitol and starch.

[0149] In one embodiment, the hydrobromide salt of Compound 1 is a crystalline hydrobromide salt of Compound 1. In one embodiment, the hydrobromide salt of Compound 1 is characterized by an XRPD pattern comprising peaks at approximately 10.3, 19.3, and 24.0 degrees 2θ.

[0150] In one embodiment, the amount of the hydrobromide salt 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 the hydrobromide salt of Compound 1 is about 0.1 to about 1.5% w / w. In one embodiment, the amount of the hydrobromide salt of Compound 1 is about 0.16 to about 0.65% w / w.

[0151] In one embodiment, the amount of the hydrobromide salt of 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. In one embodiment, the amount is about 0.5%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, 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, or about 3% w / w. In one embodiment, the amount is about 0.16% w / w. In one embodiment, the amount is about 0.65% w / w.

[0152] In one embodiment, component 2) is a mixture of mannitol and cellulose. In one embodiment, the cellulose is microcrystalline cellulose (MCC).

[0153] In one embodiment, component 2) is a mixture of mannitol and starch. In one embodiment, the starch is partially pregelatinized starch.

[0154] 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.

[0155] 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 about 85.35% w / w. In one embodiment, the amount is about 85.84% w / w.

[0156] In one embodiment, 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. In one embodiment, 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. In one embodiment, the amount of mannitol is about 65 to about 66% w / w, and the amount of cellulose or starch is about 20% w / w.

[0157] In one embodiment, the amount of mannitol is about 35, about 40, about 45, about 50, about 55, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 75, about 80, about 85, about 90, or about 93% w / w. In one embodiment, the amount is about 65.35% w / w. In one embodiment, the amount is about 65.84% w / w.

[0158] 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.

[0159] In one embodiment, the amount of starch 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.

[0160] In one embodiment, the weight ratio of cellulose or starch to mannitol is about 1:1 to about 1:20. In one embodiment, the weight ratio of cellulose or starch to mannitol is about 1:1.3 to about 1:15. In one embodiment, the weight ratio of cellulose or starch to mannitol is about 1:1.7 to about 1:8. In one embodiment, the weight ratio of cellulose or starch to mannitol is about 1:2 to about 1:4. In one embodiment, the weight ratio of cellulose or starch to mannitol is about 1:3.3.

[0161] In one embodiment, the HPMC is HPMC E5.

[0162] 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.

[0163] 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.

[0164] In one embodiment, the SSG is a low pH SSG.

[0165] In one embodiment, the amount of SSG is about 0.5 to about 10% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of SSG is about 1 to about 9% w / w. In one embodiment, the amount of SSG is about 2 to about 8% w / w. In one embodiment, the amount of SSG is about 3 to about 7% w / w. In one embodiment, the amount of SSG is about 4 to about 6% w / w.

[0166] 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.

[0167] In one embodiment, the pH of the pharmaceutical composition (e.g., slurry pH) is about 4.2 to about 5.8. 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.

[0168] 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.

[0169] 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.

[0170] In one embodiment, the average particle size of the pharmaceutical composition is about 100 to about 250 μM. In one embodiment, the D10 of the pharmaceutical composition is about 15 to about 100 μM. In one embodiment, the D10 of the pharmaceutical composition is about 30 to about 100 μM. In one embodiment, the D50 of the pharmaceutical composition is about 80 to about 250 μM. In one embodiment, the D50 of the pharmaceutical composition is about 100 to about 250 μM. In one embodiment, the D90 of the pharmaceutical composition is about 180 to about 650 μM. In one embodiment, the D90 of the pharmaceutical composition is about 280 to about 650 μM.

[0171] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) a hydrobromide salt of Compound 1 (e.g., Form A) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 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, provided herein is a pharmaceutical composition comprising: 1) a hydrobromide salt of Compound 1 (e.g., Form A) in an amount of about 0.16% w / w; 2) mannitol in an amount of about 65.84% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) HPMC E5 in an amount of about 5% w / w; 4) low pH SSG in an amount of about 5% w / w; and 5) stearic acid in an amount of about 4% w / w. In one embodiment, the total weight of the pharmaceutical composition is about 70 to about 280 mg, and in one embodiment, a dosage strength equivalent to about 0.1 to about 0.4 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 70 mg. In one embodiment, the pharmaceutical composition is contained in a No. 4 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 140 mg. In one embodiment, the pharmaceutical composition is contained in a No. 2 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 210 mg. In one embodiment, the total weight of the pharmaceutical composition is about 280 mg.

[0172] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) a hydrobromide salt 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, provided herein is a pharmaceutical composition comprising: 1) a hydrobromide salt of Compound 1 (e.g., Form A) in an amount of about 0.65% w / w; 2) mannitol in an amount of about 65.35% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) HPMC E5 in an amount of about 5% w / w; 4) low pH SSG in an amount of about 5% w / w; and 5) stearic acid in an amount of about 4% w / w. In one embodiment, the total weight of the pharmaceutical composition is about 70 to about 280 mg, and in one embodiment, a dosage strength equivalent to about 0.4 to about 1.6 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 70 mg. In one embodiment, the pharmaceutical composition is contained in a No. 3 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 140 mg. In one embodiment, the total weight of the pharmaceutical composition is about 210 mg. In one embodiment, the total weight of the pharmaceutical composition is about 280 mg.

[0173] (c) Compound 1 free base pharmaceutical composition

[0174] In one embodiment, provided herein is a pharmaceutical composition comprising 1) Compound 1:

[0175]

[0176] 2) a mixture of mannitol and starch, 3) sodium stearyl fumarate, and 4) optionally fumaric acid.

[0177] In one embodiment, provided herein is a pharmaceutical composition 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.

[0178] In one embodiment, Compound 1 is crystalline Compound 1. In one embodiment, Compound 1 is characterized by an XRPD pattern comprising peaks at approximately 14.6, 18.2, and 18.3 degrees 2-theta.

[0179] 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.

[0180] In one embodiment, the amount of 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 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0. In one embodiment, the amount is about 0.13% w / w. In one embodiment, the amount is about 0.27% w / w. In one embodiment, the amount is about 0.5% w / w. In one embodiment, the amount is about 0.67% w / w. In one embodiment, the amount is about 1.33% w / w. In one embodiment, the amount is about 2.67% w / w.

[0181] In one embodiment, the starch is a partially pregelatinized starch.

[0182] In one embodiment, the amount of the mixture of mannitol and starch is about 90 to about 99.5% w / w (of the total weight of the pharmaceutical composition). In one embodiment, the amount of the mixture of mannitol and starch is about 95 to about 99% w / w. In one embodiment, the amount of the mixture of mannitol and starch is about 97 to about 99% w / w.

[0183] In one embodiment, the amount of the mixture of mannitol and starch 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 about 98.5% w / w. In one embodiment, the amount is about 98.73% w / w. In one embodiment, the amount is about 98.87% w / w.

[0184] In one embodiment, 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. In one embodiment, the amount of mannitol is about 77 to about 79% w / w, and the amount of starch is about 20% w / w.

[0185] In one embodiment, the amount of mannitol is about 60, about 65, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, or about 89% w / w. In one embodiment, the amount is about 78% w / w. In one embodiment, the amount is about 79% w / w. In one embodiment, the amount is about 77.67% w / w. In one embodiment, the amount is about 78.5% w / w. In one embodiment, the amount is about 78.73% w / w. In one embodiment, the amount is about 78.87% w / w.

[0186] In one embodiment, the amount of starch is about 10, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, or about 30% w / w. In one embodiment, the amount is about 20% w / w.

[0187] In one embodiment, the weight ratio of starch to mannitol is about 1:2 to about 1:9. In one embodiment, the weight ratio of starch to mannitol is about 1:2.5 to about 1:6. In one embodiment, the weight ratio of starch to mannitol is about 1:3 to about 1:4.5. In one embodiment, the weight ratio of starch to mannitol is about 1:3.9.

[0188] 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.

[0189] 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.

[0190] In one embodiment, the pharmaceutical composition does not contain fumaric acid.

[0191] 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.

[0192] 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.

[0193] In one embodiment, the pH of the pharmaceutical composition (e.g., slurry pH) is about 2.1 to about 8.7. 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.

[0194] In one embodiment, the average particle size of the pharmaceutical composition is about 70 to about 250 μM. In one embodiment, the average particle size of the pharmaceutical composition is about 120 to about 200 μM. In one embodiment, the D10 of the pharmaceutical composition is about 30 to about 100 μM. In one embodiment, the D10 of the pharmaceutical composition is about 60 to about 90 μM. In one embodiment, the D50 of the pharmaceutical composition is about 110 to about 280 μM. In one embodiment, the D50 of the pharmaceutical composition is about 130 to about 250 μM. In one embodiment, the D90 of the pharmaceutical composition is about 240 to about 580 μM. In one embodiment, the D90 of the pharmaceutical composition is about 350 to about 560 μM.

[0195] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1 (e.g., Form K) in an amount of about 0.1 to about 0.2% w / w; 2) mannitol in an amount of about 78 to about 79% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; and 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1 (e.g., Form K) 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. In one embodiment, the total weight of the pharmaceutical composition is about 75 to about 300 mg, and in one embodiment, a dosage strength of about 0.1 to about 0.4 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0196] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1 (e.g., Form K) in an amount of about 0.2 to about 0.3% w / w; 2) mannitol in an amount of about 78 to about 79% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; and 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1 (e.g., Form K) 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. In one embodiment, the total weight of the pharmaceutical composition is about 75 to about 300 mg, and in one embodiment, a dosage strength of about 0.2 to about 0.8 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0197] In one embodiment, provided herein is a pharmaceutical composition comprising: 1) an amount of about 0.4 to about 0.6% w / w of Compound 1 (e.g., Form K); 2) an amount of about 78 to about 79% w / w of mannitol and an amount of about 19 to about 21% w / w of partially pregelatinized starch; and 3) an amount of about 0.5 to about 1.5% w / w of sodium stearyl fumarate. In one embodiment, provided herein is a pharmaceutical composition comprising: 1) an amount of about 0.5% w / w of Compound 1 (e.g., Form K); 2) an amount of about 78.5% w / w of mannitol and an amount of about 20% w / w of partially pregelatinized starch; and 3) an amount of about 1% w / w of sodium stearyl fumarate. In one embodiment, the total weight of the pharmaceutical composition is about 80 to about 300 mg, and in one embodiment, a dosage strength of about 0.4 to about 1.5 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 80 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0198] In one embodiment, provided herein is a pharmaceutical composition 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 77 to about 78% w / w and partially pregelatinized starch in an amount of about 19 to about 21% w / w; and 3) sodium stearyl fumarate in an amount of about 0.5 to about 1.5% w / w. In one embodiment, provided herein is a pharmaceutical composition comprising: 1) Compound 1 (e.g., Form K) 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. In one embodiment, the total weight of the pharmaceutical composition is about 75 to about 300 mg, and in one embodiment, a dosage strength of about 1 to about 4 mg of Compound 1 (free base) is provided. In one embodiment, the total weight of the pharmaceutical composition is about 75 mg. In one embodiment, the pharmaceutical composition is contained in a size 4 capsule. In one embodiment, the total weight of the pharmaceutical composition is about 300 mg. In one embodiment, the pharmaceutical composition is contained in a size 1 capsule.

[0199] In one embodiment, provided herein is a pharmaceutical composition 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 one embodiment, provided herein is a pharmaceutical composition 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.

[0200] In one embodiment, provided herein is a pharmaceutical composition 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 one embodiment, provided herein is a pharmaceutical composition 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.

[0201] In one embodiment, provided herein is a pharmaceutical composition 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 one embodiment, provided herein is a pharmaceutical composition 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.

[0202] (d) Other Examples of Pharmaceutical Compositions

[0203] In one embodiment, the pharmaceutical composition provided herein may optionally further comprise one or more additional excipients. Additional excipients include, but are not limited to, wetting agents, solubilizers, crystal stabilizers, anti-adhesive agents, and precipitation inhibitors.

[0204] In one embodiment, the pharmaceutical composition provided herein optionally further comprises one or more of 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.

[0205] In one embodiment, the pharmaceutical composition provided herein is formulated into a capsule. In one embodiment, the capsule is a HPMC capsule. In one embodiment, the capsule is a gelatin capsule.

[0206] Typically, the composition is formulated for single-dose administration. In order to formulate the composition, a certain weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration that reduces or alleviates the condition being treated. Pharmaceutical carriers or vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a particular mode of administration.

[0207] In addition, the compound can be formulated as the only pharmaceutically active ingredient in the composition, or can be combined with other active ingredients. Liposomal suspensions (including liposomes targeting tissues, such as lipids targeting tumors) can 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 as known in the art. In short, liposomes (such as multilamellar vesicles (MLV)) can be formed by the following: egg yolk phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) are dried inside a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, centrifuged and granulated, and then resuspended in PBS.

[0208] The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient. The therapeutically effective concentration can be determined empirically by testing the compound in the in vitro and in vivo systems described herein, and then extrapolating the dosage for humans therefrom.

[0209] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, metabolism and excretion rate of the active compound, the physicochemical characteristics of the compound, the dosage regimen and the amount administered, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to alleviate one or more symptoms of cancer (including solid tumors and hematogenous tumors).

[0210] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical applications may include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol, dimethylacetamide or other synthetic solvents; antimicrobial agents, such as benzyl alcohol and methyl paraben; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampoules, pens, disposable syringes or single-dose or multi-dose vials made of glass, plastic or other suitable materials.

[0211] In the case where the compound exhibits insufficient solubility, methods for solubilizing the compound may be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as ), or dissolved in aqueous sodium bicarbonate.

[0212] After mixing or adding one or more compounds, the resulting mixture can be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate the symptoms of the disease, disorder or condition being treated and can be determined empirically.

[0213] Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms containing an appropriate amount of a compound or a pharmaceutically acceptable salt thereof, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions. Pharmaceutical therapeutic active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. As used herein, unit dosage forms refer to physically discrete units that are suitable for human and animal subjects and are individually packaged as known in the art. Each unit dose contains a predetermined amount of therapeutically active compounds associated with a desired pharmaceutical carrier, vehicle, or diluent sufficient to produce a desired therapeutic effect. Examples of unit dosage forms include ampoules and syringes and independently packaged tablets or capsules. Unit dosage forms can be administered in fractions or multiples thereof. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, tablet or capsule bottles, or pint or gallon bottles. Therefore, multiple dosage forms are multiples of unit doses that are not separately packaged.

[0214] Dosage forms or compositions containing active ingredients in the range of 0.005% to 100% can be prepared (the balance is made up by non-toxic carriers). For oral administration, pharmaceutically acceptable non-toxic compositions are formed by incorporating any commonly used excipients, such as, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, cross-linked sodium carboxymethyl cellulose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as but not limited to implants and microencapsulated delivery systems, and biodegradable biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, etc. Methods for preparing these compositions are known to those skilled in the art.

[0215] The active compound or pharmaceutically acceptable salt can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a time release formulation or coating.

[0216] These compositions can include other active compounds to obtain a desired combination of properties. The compounds provided herein or pharmaceutically acceptable salts thereof as described herein may also be advantageously administered with another pharmacological agent for therapeutic or preventive purposes, which is known in the art to be valuable in treating one or more of the above-mentioned diseases or medical conditions (such as diseases associated with oxidative stress). It should be understood that such combination therapies constitute additional aspects of the compositions and methods of treatment provided herein.

[0217] (e) Process for preparing dosage form

[0218] The pharmaceutical compositions (dosage forms) provided herein can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with an excipient constituting one or more essential ingredients. Typically, the composition is prepared by uniformly mixing the active ingredient with a liquid excipient or a finely divided solid excipient or both (e.g., directly blending), and then (if necessary) forming the product into the desired presentation form (e.g., by using roller compaction (RC), HSWG, compaction, and / or encapsulation processes). If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0219] The dosage forms provided herein can be prepared by compression or molding (optionally with one or more auxiliary ingredients). Compressed tablets can be prepared by compacting the active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, and the active ingredient is optionally mixed with an excipient and / or a surfactant or a dispersant as above. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. The encapsulation of the dosage forms provided herein can be carried out using capsules of hydroxypropyl methylcellulose, calcium alginate or gelatin.

[0220] In some embodiments, active ingredient and excipient are directly blended and loaded into, for example, capsules, or directly compressed into tablets. In some cases, directly blended dosage forms may be more advantageous than compacted (e.g., rolled) dosage forms. In some embodiments, directly blended dosage forms may be more advantageous than compacted (e.g., rolled) dosage forms because direct blending processes may result in better stability of molecules that are sensitive to degradation under mechanical stress (e.g., compaction). In some embodiments, direct blending also helps minimize the degradation of active ingredient.

[0221] In certain embodiments, the roller compaction process involves mixing the intragranular ingredients in a blender, using a comil to deagglomerate, and passing through a roller compactor and a mill to produce particles. In the roller compaction process, the compacted material is usually ground into smaller particles for further processing. The purpose of this step in the manufacture is to reduce the particle size of the material. The ground material is then blended with other ingredients, and the final dosage form is then manufactured.

[0222] In some embodiments, the high shear wet granulation (HSWG) process involves pre-blending the ingredients within the granule, adding water for mixing, wet massing, fluid bed drying, co-grinding, final lubrication, and encapsulation.

[0223] For some active ingredients, particularly for compounds with low solubility, the particle size of the active ingredient is reduced to a fine powder to help increase the dissolution rate of the active ingredient. An increase in the dissolution rate is usually necessary for the active ingredient to be effectively absorbed in the gastrointestinal tract. However, for fine powders that are directly blended and loaded onto capsules, the excipient should preferably provide certain features that make the ingredients suitable for direct blending processes. Examples of such features include, but are not limited to, acceptable flow characteristics. Therefore, in one embodiment, the present invention provides the use of excipients and compositions comprising excipients that can provide features that make the resulting mixture suitable for direct blending processes, such as good flow characteristics.

[0224] 6.3 Usage

[0225] In one embodiment, provided herein is a method for treating multiple myeloma, the method comprising administering to a patient a pharmaceutical composition provided herein. In one embodiment, provided herein is a pharmaceutical composition provided herein for use in a method for treating multiple myeloma, wherein the method comprises administering to a patient the pharmaceutical composition.

[0226] In one embodiment, provided herein is a method for preventing multiple myeloma, the method comprising administering to a patient a pharmaceutical composition provided herein. In one embodiment, provided herein is a pharmaceutical composition provided herein for use in a method for preventing multiple myeloma, wherein the method comprises administering to a patient the compound.

[0227] In one embodiment, provided herein is a method for managing multiple myeloma, the method comprising administering to a patient a pharmaceutical composition provided herein. In one embodiment, provided herein is a pharmaceutical composition provided herein for use in a method for managing multiple myeloma, wherein the method comprises administering to a patient the compound.

[0228] In one embodiment, the present invention also provides a method for inducing a therapeutic response in a patient, wherein the therapeutic response is assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau JL, Miguel JS et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7), comprising administering to a patient suffering from multiple myeloma an effective amount of a pharmaceutical composition provided herein. In another embodiment, the present invention provides a method for achieving a stringent complete response, a complete response, or a very good partial response (as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC)) in a patient, comprising administering to a patient suffering from multiple myeloma an effective amount of a pharmaceutical composition provided herein. In another embodiment, the present invention provides a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient suffering from multiple myeloma an effective amount of a pharmaceutical composition provided herein. In another embodiment, provided herein are methods for achieving an increase in total survival in a patient, including administering an effective amount of a pharmaceutical composition provided herein to a patient with multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in progression-free survival in a patient, including administering an effective amount of a pharmaceutical composition provided herein to a patient with multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in event-free survival in a patient, including administering an effective amount of a pharmaceutical composition provided herein to a patient with multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in progression time in a patient, including administering an effective amount of a pharmaceutical composition provided herein to a patient with multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in disease-free survival in a patient, including administering an effective amount of a pharmaceutical composition provided herein to a patient with multiple myeloma.

[0229] Also provided herein are methods for treating patients who have previously received multiple myeloma treatment but have not responded to standard therapy, as well as patients who have not previously received treatment. Also contemplated are methods for treating patients who have undergone surgery for the treatment of multiple myeloma, as well as those who have not undergone surgery. Also provided herein are methods for treating patients who have previously received transplantation therapy, as well as those who have not received transplantation therapy.

[0230] The methods provided herein include treating relapsed, refractory or resistant multiple myeloma. The methods provided herein include preventing relapsed, refractory or resistant multiple myeloma. The methods provided herein include managing relapsed, refractory or resistant multiple myeloma. In some such embodiments, myeloma is first, second, third, fourth or fifth relapsed multiple myeloma. In one embodiment, the methods provided herein reduce, maintain or eliminate minimal residual disease (MRD). In one embodiment, the methods provided herein encompass treating, preventing, or managing various types of multiple myeloma, such as monoclonal gammopathy of undetermined significance (MGUS), low-risk, intermediate-risk, and high-risk multiple myeloma, newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma), transplant eligible and transplant ineligible multiple myeloma, smoldering (indolent) 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, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma, by administering a therapeutically effective amount of a pharmaceutical composition provided herein. In another embodiment, the methods provided herein encompass treating, preventing, or managing multiple myeloma characterized by a genetic abnormality, such as a cyclin D translocation (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32; or t(6;20);), a MMSET translocation (e.g., t(4;14)(p16;q32)), a MAF translocation (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 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy, and gain (1q)) by administering a therapeutically effective amount of a compound described herein.

[0231] In some embodiments, the methods include administering a therapeutically effective amount of a pharmaceutical composition provided herein as an induction therapy. In some embodiments, the methods include administering a therapeutically effective amount of a pharmaceutical composition provided herein as a consolidation therapy. In some embodiments, the methods include administering a therapeutically effective amount of a pharmaceutical composition provided herein as a maintenance therapy.

[0232] In a specific embodiment of the methods described herein, the multiple myeloma is a plasma cell leukemia.

[0233] In one embodiment of the methods described herein, multiple myeloma is high-risk multiple myeloma. In some such embodiments, high-risk multiple myeloma is relapsed or refractory. In one embodiment, high-risk multiple myeloma is a multiple myeloma that relapses within 12 months after the first treatment. In yet another embodiment, high-risk multiple myeloma is a multiple myeloma characterized by genetic abnormalities (e.g., one or more of del (17 / 17p) and t (14; 16) (q32; q32)). In some such embodiments, high-risk multiple myeloma is relapsed or refractory to one, two or three previous treatments.

[0234] In one embodiment, the 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 a 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 an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

[0235] In one embodiment, multiple myeloma is characterized by homozygous deletion of p53. In one embodiment, multiple myeloma is characterized by homozygous deletion of wild-type p53.

[0236] In one embodiment, the multiple myeloma is characterized by wild-type p53.

[0237] In one embodiment, multiple myeloma is characterized by the activation of one or more oncogenic drivers. In one embodiment, the 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.

[0238] 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 translocation is 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 translocation is t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocation is t(14;16) and t(16;22). In one embodiment, the chromosomal translocation is t(14;20) and t(11;14).

[0239] In one embodiment, multiple myeloma is characterized by Q331 p53 mutation, activation of C-MAF, and chromosomal translocation at t(14; 16). In one embodiment, multiple myeloma is characterized by homozygous deletion of p53, activation of C-MAF, and chromosomal translocation at t(14; 16). In one embodiment, multiple myeloma is characterized by K132N p53 mutation, activation of MAFB, and chromosomal translocation at t(14; 20). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of FGFR3 and MMset, and chromosomal translocation at t(4; 14). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of C-MAF, and chromosomal translocation at t(14; 16). In one embodiment, multiple myeloma is characterized by homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocation at t(4; 14) and t(14; 16). In one embodiment, multiple myeloma is characterized by homozygous loss of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by 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 E286K p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by R175H p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by 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, and chromosomal translocations at t(14; 20) and t(11; 14). In one embodiment, multiple myeloma is characterized by A161T p53 mutation, activation of cyclin D, and chromosomal translocations at t(11; 14).

[0240] In some embodiments of the methods described herein, the multiple myeloma is newly diagnosed multiple myeloma that is eligible for transplantation. In another embodiment, the multiple myeloma is newly diagnosed multiple myeloma that is not eligible for transplantation.

[0241] In yet other embodiments, multiple myeloma is characterized by early progression (e.g., less than 12 months) after initial treatment. In still other embodiments, multiple myeloma is characterized by early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is refractory to lenalidomide. In 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 3 or more treatments, and is exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide or avadomide), or is double refractory to a proteasome inhibitor and an immunomodulatory compound. In still other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibedomide, or avalidomide), or is double refractory to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In still other embodiments, the multiple myeloma is triple refractory, e.g., the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprezomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibedomide, or avalidomide), and one other active agent as described herein.

[0242] In certain embodiments, provided herein are methods for treating, preventing, and / or managing multiple myeloma (relapsed / refractory multiple myeloma) or symptoms thereof in patients with impaired renal function, comprising administering to a patient with relapsed / refractory multiple myeloma who has impaired renal function a therapeutically effective amount of a pharmaceutical composition provided herein.

[0243] In certain embodiments, provided herein are methods for treating, preventing and / or managing multiple myeloma (including relapsed or refractory multiple myeloma) or its symptoms in frail patients, comprising administering a therapeutically effective amount of a pharmaceutical composition provided herein to a frail patient suffering from multiple myeloma. In some such embodiments, the frail patient is characterized by not meeting the induction therapy conditions or being intolerant to dexamethasone treatment. In some such embodiments, the frail patient is an elderly person, for example, over 65 years old.

[0244] In certain embodiments, provided herein are methods of 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.

[0245] In certain embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein as an induction therapy, wherein the multiple myeloma is newly diagnosed transplant eligible multiple myeloma.

[0246] In certain embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein as maintenance therapy following other therapy or transplantation, wherein prior to the other therapy or transplantation, the multiple myeloma was newly diagnosed multiple myeloma eligible for transplantation.

[0247] In certain embodiments, provided herein are methods for treating, preventing or managing multiple myeloma, which methods include administering to a patient a therapeutically effective amount of a pharmaceutical composition provided herein as a maintenance therapy after other therapies or transplantation. In some embodiments, before other therapies and / or transplantation, the multiple myeloma is a newly diagnosed multiple myeloma that meets transplantation conditions. In some embodiments, other therapies before transplantation are treatments with chemotherapy or compound 1.

[0248] In certain embodiments, provided herein are methods of 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 relapsed or high-risk multiple myeloma refractory to one, two, or three prior therapies.

[0249] In certain embodiments, provided herein are methods of 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 multiple myeloma that is not eligible for transplantation.

[0250] In certain embodiments, the therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 25 mg / day, from about 0.01 to about 10 mg / day, from about 0.01 to about 5 mg / day, from about 0.01 to about 2 mg / day, from about 0.01 to about 1 mg / day, from about 0.01 to about 0.5 mg / day, from about 0.01 to about 0.25 mg / day, from about 0.1 to about 25 mg / day, from about 0.1 to about 10 mg / day, from about 0.1 to about 5 mg / day, from about 0.1 to about In one embodiment, the therapeutic or preventive effective amount of Compound 1 is about 0.1 mg / day to about 0.4 mg / day.

[0251] In certain embodiments, the therapeutically or prophylactically effective amount 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 / day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, or about 0.7 mg / day.

[0252] In one embodiment, for the conditions described herein, the recommended daily dose range of Compound 1 is in the range of about 0.1 mg to about 25 mg / day, preferably in a single dose once a day or divided doses throughout the day. In other embodiments, the dosage range is about 0.1 to about 10 mg / day. Specific doses per day 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 / day. More specific doses per day include 0.1, 0.2, 0.3, 0.4 or 0.5 mg / day.

[0253] In a particular embodiment, the recommended starting dose can be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 25 mg / day. In another embodiment, the recommended starting dose can be 0.1, 0.2, 0.3, 0.4 or 0.5 mg / day. The dose can be increased to 1, 2, 3, 4 or 5 mg / day.

[0254] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.001 to about 5 mg / kg / day, about 0.001 to about 4 mg / kg / day, about 0.001 to about 3 mg / kg / day, about 0.001 to about 2 mg / kg / day, about 0.001 to about 1 mg / kg / day, about 0.001 to about 0.05 mg / kg / day, about 0.001 to about 0.04 mg / kg / day, about 0.001 to about 0.03 mg / kg / day, about 0.001 to about 0.02 mg / kg / day, about 0.001 to about 0.01 mg / kg / day, or about 0.001 to about 0.005 mg / kg / day.

[0255] The dosage for administration may also be expressed in units other than mg / kg / day. For example, a dosage for parenteral administration may be expressed as mg / m 2 / day. A person of ordinary skill in the art would readily know how to convert the dosage from mg / kg / day to mg / m 2 / 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 equivalent to 38 mg / m 2 / sky.

[0256] In certain embodiments, the patient to be treated with one of the methods provided herein has not received multiple myeloma therapy treatment before administering the pharmaceutical composition provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has received multiple myeloma therapy treatment before administering the pharmaceutical composition provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has developed resistance to multiple myeloma therapy. In some such embodiments, the patient has developed resistance to one, two or three anti-multiple myeloma therapies, wherein these therapies are 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, ibedomide, or avadomide).

[0257] The methods provided herein encompass treating patients regardless of the patient's age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the subject is less than 65 years of age. In other embodiments, the subject is over 65 years of age. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject over 65 years of age. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject over 75 years of age.

[0258] Depending on the state of the disease to be treated and the condition of the subject, the pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or external (e.g., transdermal or topical) administration. The pharmaceutical compositions provided herein can be formulated into suitable dosage units alone or with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles suitable for each administration route.

[0259] In one embodiment, the pharmaceutical compositions provided herein are administered orally. In another embodiment, the pharmaceutical compositions provided herein are administered parenterally. In yet another embodiment, the pharmaceutical compositions provided herein are administered intravenously.

[0260] The pharmaceutical compositions provided herein can be delivered in a single dose (e.g., a single bolus), or an oral tablet or pill; or delivered over time, such as a continuous infusion over time or a divided bolus dose over time. If necessary, the compounds as described herein can be repeatedly administered, for example, until the patient experiences stable or regressed disease, or until the patient experiences disease progression or unacceptable toxicity. Disease stability or the lack thereof is determined by methods known in the art, such as assessing the patient's symptoms, physical examination, visualization of tumors using X-ray, CAT, PET or MRI scan imaging, and other generally accepted assessment modalities.

[0261] The pharmaceutical composition provided herein can be applied once a day (QD or qd), or divided into multiple daily doses, such as twice a day (BID or bid), three times a day (TID or tid) and four times a day (QID or qid). In addition, the application can be continuous (that is, daily or daily for several consecutive days), intermittent, for example, periodic application (that is, including a few days, weeks or months of drug-free rest). As used herein, the term "daily" is intended to mean, for example, once a day or more than once a therapeutic compound is applied over a period of time. The term "continuously" is intended to mean that the therapeutic compound is applied every day, and the uninterrupted time period of at least 7 days to 52 weeks is continued. As used herein, the term "intermittent" or "intermittently" is intended to mean to stop and start at regular or irregular intervals. For example, the intermittent application of the pharmaceutical composition provided herein is applied one to six days a week, applied in cycles (for example, applied daily for two to eight consecutive weeks, and then not applied for a rest period of up to one week), or applied every other day. As used herein, the term "cycle" is intended to mean that the therapeutic compound is applied every day or continuously, but there is a rest period. In some such embodiments, administration is once daily for two to six days, followed by a rest period of no administration for five to seven days.

[0262] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain 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 a 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.

[0263] In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 20 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 15 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 10 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 7 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 5 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 4 days, followed by a rest period. In one embodiment, a therapeutically effective amount of a pharmaceutical composition provided herein is administered in a treatment cycle, and the treatment cycle includes an administration period of up to 3 days, followed by a rest period.

[0264] 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.

[0265] In one embodiment, the rest period is about 2 days to up to about 11 days. In one embodiment, the rest period is about 2 days to up to about 10 days. In one embodiment, the rest period is about 2 days. In one embodiment, the rest period is about 3 days. In one embodiment, the rest period is about 4 days. In one embodiment, the rest period is about 5 days. In one embodiment, the rest period is about 6 days. In another embodiment, the rest period is about 7 days. In another embodiment, the rest period is about 8 days. In another embodiment, the rest period is about 9 days. In another embodiment, the rest period is about 10 days. In another embodiment, the rest period is about 11 days.

[0266] In one embodiment, the treatment cycle includes an administration period of up to 15 days, followed by a rest period of about 2 days to up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of about 2 days to up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days, followed by a rest period of about 2 days to up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of about 2 days to up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 10 days to up to about 15 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 3 days to up to about 15 days.

[0267] In one embodiment, the treatment cycle includes an administration period of up to 15 days, followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of 4 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of 3 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of 2 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days, followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of 11 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of 9 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of 2 days. In another embodiment, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of 4 days.

[0268] In one embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 5th day of a 28-day cycle. In another embodiment, the treatment cycle includes applying a pharmaceutical composition provided herein on the 1st to 10th day of a 28-day cycle. In one embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 21st day of a 28-day cycle. In another embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 5th day of a 7-day cycle. In another embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 7th day of a 7-day cycle. In one embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 10th day and the 15th to 24th day of a 28-day cycle (referred to herein as a 20 / 28 dosing cycle). In one embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 3rd day and the 15th to 18th day of a 28-day cycle. In one embodiment, the treatment cycle includes applying a therapeutically effective amount of a pharmaceutical composition provided herein on the 1st to 7th day and the 15th to 21st day of a 28-day cycle (referred to herein as a 14 / 28 dosing cycle). In one embodiment, the treatment cycle includes administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 5 and days 15 to 19 of a 28-day cycle (referred to herein as a 10 / 28 dosing cycle). In one embodiment, the treatment cycle includes administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 3 and days 15 to 17 of a 28-day cycle (referred to herein as a 6 / 28 dosing cycle).

[0269] In one embodiment, the treatment cycle includes administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 14 of a 21-day cycle. In another embodiment, the treatment cycle includes administering a therapeutically effective amount of a 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 administering a therapeutically effective amount of a 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 administering a therapeutically effective amount of a 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 administering a therapeutically effective amount of a 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 administering a therapeutically effective amount of a 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 administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 4, 8 to 10, and 15 to 17 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 3 and 8 to 11 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of a pharmaceutical composition provided herein on days 1 to 3 and 11 to 13 of a 21-day cycle.

[0270] Any treatment cycle described herein may be repeated for at least 2, 3, 4, 5, 6, 7, 8 or more cycles. In some cases, the treatment cycle described herein includes 1 to about 24 cycles, about 2 to about 16 cycles or about 2 to about 4 cycles. In some cases, the treatment cycle described herein includes 1 to about 4 cycles. In certain embodiments, the 1st to 4th cycles are all 28-day cycles. In certain embodiments, the pharmaceutical composition provided herein for the treatment of an effective amount is administered for 1 to 13 28-day cycles (e.g., about 1 year). In some cases, cyclic therapy is not limited to the number of cycles, and therapy continues until disease progression. In some cases, the cycle may include changing the duration of the administration period and / or rest period described herein.

[0271] In one embodiment, the treatment cycle includes applying the pharmaceutical composition provided herein once a day with a dosage 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, the treatment cycle includes applying the pharmaceutical composition provided herein once a day with a dosage 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 applying the pharmaceutical composition provided herein once a day with a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on the 1st to 10th day of a 28-day cycle. In some such embodiments, the treatment cycle includes applying the pharmaceutical composition provided herein once a day at a dosage 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 applying the pharmaceutical composition provided herein once a day at a dosage 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 applying the pharmaceutical composition provided herein twice a day at a dosage of about 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 applying the pharmaceutical composition provided herein twice a day at a dosage of about 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 applying the pharmaceutical composition provided herein twice a day with a dosage of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on the 1st to 3rd and 15th to 17th day of a 28-day cycle. In other embodiments, the treatment cycle includes applying the pharmaceutical composition provided herein twice a day with a dosage of about 0.2 mg on the 1st to 3rd and 15th to 17th day of a 28-day cycle. In one such embodiment, the pharmaceutical composition is applied on the 1st to 3rd day (morning and evening), the 14th day (evening), the 15th and 16th day (morning and evening), and the 17th day (morning only) of a 28-day cycle (e.g., in the 1st cycle).

[0272] For reasons of clarity, it should be noted that, unless otherwise stated, the dosages of Compound 1 mentioned herein refer to the amount of Compound 1 in the form of the free base. In case, for example, a pharmaceutically acceptable salt of Compound 1 is used, the amounts given above need to be adjusted accordingly.

[0273] 6.4 Combination Therapy with a Second Active Agent

[0274] The pharmaceutical compositions provided herein can also be combined or used in combination with conventional therapies (e.g., before, during, or after conventional therapies), including but not limited to surgery, biological therapy (including immunotherapy, such as the use of checkpoint inhibitors), radiotherapy, chemotherapy, stem cell transplantation, cell therapy, or other non-drug-based therapies currently used to treat, prevent, or manage multiple myeloma. The combination of the compounds provided herein with conventional therapies can provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that when given in parallel with conventional therapies, the pharmaceutical compositions provided herein can provide an additive or synergistic effect.

[0275] As discussed elsewhere herein, this article encompasses methods for reducing, treating and / or preventing adverse or undesirable effects associated with conventional therapies (including but not limited to surgery, chemotherapy, radiotherapy, biological therapy and immunotherapy). Pharmaceutical compositions and other active ingredients provided herein can be administered to patients before, during or after the occurrence of adverse reactions associated with conventional therapies.

[0276] The pharmaceutical compositions provided herein may also be combined or used in combination with other therapeutic agents used to treat and / or prevent multiple myeloma as described herein.

[0277] In one embodiment, provided herein is a method of treating, preventing, or managing multiple myeloma, comprising administering to a patient a combination of a pharmaceutical composition provided herein and one or more second active agents, optionally in combination with radiation therapy, blood transfusion, or surgery.

[0278] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as a pharmaceutical composition provided herein) can be administered 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 before) administering the second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein, as well as quadruple therapy. In one embodiment, the second therapy is dexamethasone.

[0279] The pharmaceutical compositions provided herein and one or more second active agents can be administered to a patient simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally and does not decompose before entering the bloodstream).

[0280] The route of administration of the pharmaceutical composition provided herein is independent of the route of administration of the second therapy. In one embodiment, the pharmaceutical composition provided herein is administered orally. In another embodiment, the pharmaceutical composition provided herein is administered intravenously. Therefore, according to these embodiments, the pharmaceutical composition provided herein is administered orally or intravenously, and can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, through liposomes, via inhalation, vaginally, intraocularly, via local delivery, subcutaneously, intrafatally, intraarticularly, intrathecally or with a slow release dosage form by a catheter or stent. In one embodiment, the pharmaceutical composition provided herein and the second therapy are administered by the same mode of administration (orally or by IV). In another embodiment, the pharmaceutical composition provided herein is administered by a mode of administration (e.g., by IV), and the second agent (anti-multiple myeloma agent) is administered by another mode of administration (e.g., oral).

[0281] In one embodiment, the second active agent is administered intravenously or subcutaneously once or twice daily in an amount 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 active agent will depend on the specific agent 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 optional additional active agent administered concurrently to the patient.

[0282] One or more second active ingredients or agents can be used in the methods and compositions provided herein together with the pharmaceutical compositions provided herein. The second active agent can be a macromolecule (e.g., protein), a small molecule (e.g., a synthetic inorganic molecule, an organometallic molecule, or an organic molecule) or a cell therapy (e.g., a CAR cell).

[0283] Examples of second active agents that can be used in the methods and compositions described herein include one or more of the following: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, obinutuzmab, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprazomib, 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, BI 894999, 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-(methylsulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313 and EP11336), BCL2 inhibitors (e.g., venetoclax or navitoclax), MCL-1 inhibitors (e.g., AZD5991, AMG176, MIK665, S64315 or S63845), LSD-1 inhibitors ( For example, ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof), a corticosteroid (e.g., prednisone), dexamethasone; an antibody (e.g., a CS1 antibody such as elotuzumab; a CD38 antibody such as daratumumab or isatuximab; or a BCMA antibody or antibody-conjugate such as GSK2857916 or BI836909), a checkpoint inhibitor (as described herein) or a CAR cell (as described herein).

[0284] In one embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is dexamethasone.

[0285] In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 10, 15, and 22 of the 1st cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of the 1st cycle.

[0286] In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 10, 15, and 22 of the 1st cycle. In some embodiments, dexamethasone is administered at a dose 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 the 1st cycle.

[0287] In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 10, 15, and 22 of the 1st cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 3, 14, and 17 of the 1st cycle.

[0288] In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 10, 15, and 22 of the 1st cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 3, 14, and 17 of the 1st cycle.

[0289] In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 10, 15, and 22 of the 1st cycle. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered on Days 1, 3, 14, and 17 of Cycle 1 at a dose of 40 mg.

[0290] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is bortezomib. In yet another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is daratumumab. In some such embodiments, the methods further comprise administering dexamethasone. In some embodiments, the methods comprise administering the pharmaceutical compositions provided herein with a proteasome inhibitor as described herein, a CD38 inhibitor as described herein, and a corticosteroid as described herein.

[0291] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is panobinostat. In some such embodiments, the methods further comprise administering dexamethasone.

[0292] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is ACY241. In some such embodiments, the methods further comprise administering dexamethasone.

[0293] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is vincristine. In some such embodiments, the methods further comprise administering dexamethasone.

[0294] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is cyclophosphamide. In some such embodiments, the methods further comprise administering dexamethasone.

[0295] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is etoposide. In some such embodiments, the methods further comprise administering dexamethasone.

[0296] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is doxorubicin. In some such embodiments, the methods further comprise administering dexamethasone.

[0297] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is venetoclax. In some such embodiments, the methods further comprise administering dexamethasone.

[0298] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is AMG 176. In some such embodiments, the methods further comprise administering dexamethasone.

[0299] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is MIK665. In some such embodiments, the methods further comprise administering dexamethasone.

[0300] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is GSK525762A. In some such embodiments, the methods further comprise administering dexamethasone.

[0301] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is OTX015. In some such embodiments, the methods further comprise administering dexamethasone.

[0302] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one. In some such embodiments, these methods further comprise administering dexamethasone.

[0303] In another embodiment, the second active agent used in the methods and compositions described herein with the pharmaceutical compositions provided herein is 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof (e.g., benzenesulfonate). In some such embodiments, these methods additionally comprise administering dexamethasone.

[0304] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with checkpoint inhibitors. In one embodiment, in conjunction with the methods provided herein, a checkpoint inhibitor and a pharmaceutical composition provided herein are used in combination. In another embodiment, in conjunction with the methods provided herein, two checkpoint inhibitors and a pharmaceutical composition provided herein are used in combination. In yet another embodiment, in conjunction with the methods provided herein, three or more checkpoint inhibitors and a pharmaceutical composition provided herein are used in combination.

[0305] As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" refers to a molecule that completely or partially reduces, inhibits, interferes with, or modulates one or more checkpoint proteins. Without being limited by a particular theory, checkpoint proteins regulate the activation or function of T cells. Many 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 [Natural Cancer Review] 2012, 12, 252-264). These proteins appear to be responsible for the co-stimulatory or inhibitory interactions of T cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

[0306] 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 in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as tremelimumab 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 TM sell.

[0307] In one embodiment, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-1 / 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 PCT Patent Application Publication Nos. WO 2003042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400, and WO 2011161699, all of which are incorporated herein in their entirety.

[0308] 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, SCH 900475, or rambrolizumab). 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. TM 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 TM For sale. In yet another embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. CT-011 alone did not show a response in the treatment of relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is the fusion protein AMP-224. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody that is specifically designed for its ability to bind to Fcγ receptor I, and the monoclonal antibody has unique binding characteristics to PD-1, with high affinity and excellent target specificity.

[0309] 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 (Duvalumab). 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 ).

[0310] 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.

[0311] In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is a soluble Ig fusion protein IMP321 (Brignone et al., J. Immunol. [Journal of Immunology], 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0312] 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).

[0313] 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).

[0314] 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.

[0315] 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.

[0316] 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 urerulumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

[0317] 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.

[0318] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0319] 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.

[0320] 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 categories). In addition, 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 described herein and understood in the art.

[0321] In certain embodiments, the pharmaceutical compositions provided herein may be used in combination with one or more immune cells (e.g., modified immune cells) expressing one or more chimeric antigen receptors (CAR) on their own surface. Typically, CAR comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain from a first protein (e.g., an antigen binding protein). In certain embodiments, once the extracellular domain is bound to a target protein (such as a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA)), a signal is generated via an intracellular signaling domain of an activated immune cell, for example, to target and kill cells expressing the target protein.

[0322] Extracellular domain: The extracellular domain of the CAR binds to the antigen of interest. In certain embodiments, the extracellular domain of the CAR comprises a receptor or a portion of a receptor that binds to the antigen. In certain embodiments, the extracellular domain comprises or is an antibody or an antigen-binding portion thereof. In particular embodiments, the extracellular domain comprises or is a single-chain Fv (scFv) domain. The single-chain Fv domain may comprise, for example, a V domain connected to a V domain by a flexible linker. H V L , where V L and V H from antibodies that bind to the antigen.

[0323] In certain embodiments, the antigen recognized by the extracellular domain of the polypeptide described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is but not limited to Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calreticulin, 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), prostate-specific protein (prostein ), TARP (T cell receptor gamma variable reading frame protein), Trp-p8, STEAPI (prostate six transmembrane epithelial antigen 1), chromogranin, cytokeratin, desmin, glial fibrillary acid protein (GFAP), 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, pyruvate kinase M2 isozyme (tumor M2-PK) dimer form, abnormal ras protein or abnormal p53 protein. In certain other embodiments, the TAA or TSA recognized by the extracellular domain of CAR is integrin αvβ3 (CD61), prolactin or Ral-B.

[0324] In certain embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a cancer / testis (CT) antigen, e.g., 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.

[0325] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a carbohydrate or ganglioside, for example, fuc-GMI, GM2 (carcinoembryonic antigen-immunogenicity-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, etc.

[0326] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of CAR is α-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, β-catenin, CA 125, CA 15-3 (CA 27.29\BCAA), CA195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-1, dek-can fusion protein, EBNA, EF2, Epstein-Barr II (Epstein Barr) virus antigen, ETV6-AML1 fusion protein, HLA-A2, HLA-All, hsp70-2, KIAA0205, Mart2, Mum-1, Mum-2 and Mum-3, new PAP, class I myosin, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Gage 3, Gage 4, Gage 5, Gage 6, Gage7, GnTV, Herv-K-mel, Lage-1, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, MAGE-1, 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, MYL-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, CA 19-9, CA 72-4, CAM 17.1, 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.

[0327] In various particular embodiments, the tumor-associated antigen or tumor-specific antigen is an AML-associated tumor antigen as described in S. Anguille et al., Leukemia (2012), 26, 2186-2196.

[0328] Other tumor-associated and tumor-specific antigens are known to those skilled in the art.

[0329] Receptors, antibodies and scFvs that bind to TSAs and TAAs, and nucleotide sequences encoding them are useful in constructing chimeric antigen receptors and are known in the art.

[0330] In certain specific embodiments, the antigen recognized by the extracellular domain of the chimeric antigen receptor is an antigen that is not generally considered to be a TSA or TAA, but it is still associated with tumor cells or tumor-induced damage. In certain embodiments, for example, the antigen is, for example, a growth factor, cytokine or interleukin, for example, a growth factor, cytokine or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines or interleukins may include, for example, 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 produce a hypoxic environment locally in the tumor. Therefore, in other specific embodiments, 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 local damage to normal tissues, resulting in the release of molecules called damage-associated molecular pattern molecules (DAMPs, also known as alarmins). Therefore, in certain other specific embodiments, the antigen is a DAMP, for example, heat shock protein, chromatin-associated protein high mobility group protein 1 (HMGB 1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be deoxyribonucleic acid, adenosine triphosphate, uric acid or heparin sulfate.

[0331] Transmembrane domain: In certain embodiments, the extracellular domain of CAR is connected to the transmembrane domain of the polypeptide via a linker, a spacer or a hinge polypeptide sequence (e.g., a sequence from CD28 or a sequence from CTLA4). The transmembrane domain can 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 a particular embodiment, the transmembrane domain may be obtained from or derived from, for example, CD8, CD16, cytokine receptors, and interleukin receptors, or growth factor receptors, etc.

[0332] Intracellular signaling domain: In certain embodiments, the intracellular domain of CAR is or is contained in an intracellular domain or motif of a protein expressed on the surface of a T cell and triggering activation and / or proliferation of the T cell. Such a domain or motif is capable of transmitting a primary antigen binding signal, which is required for activation of T lymphocytes in response to the binding of an antigen to the extracellular portion of CAR. Typically, this domain or motif contains or is an ITAM (immunoreceptor tyrosine-based activation motif). Suitable ITAM-containing polypeptides for CAR include, for example, ζCD3 chain (CD3ζ) or its ITAM-containing portion. In a particular embodiment, the intracellular domain is a CD3ζ intracellular signaling domain. In other particular embodiments, the intracellular domain is from a lymphocyte receptor chain, a TCR / CD3 complex protein, an Fc receptor subunit, or an IL-2 receptor subunit. In certain embodiments, CAR additionally comprises one or more costimulatory domains or motifs, for example, as part of the intracellular domain of a polypeptide. The one or more co-stimulatory domains or motifs can be, or can comprise, one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, or a co-stimulatory induced T cell co-stimulation (ICOS) polypeptide sequence, or other co-stimulatory domains or motifs, or any combination thereof.

[0333] CAR can also include a T cell survival motif. The T cell survival motif can be any polypeptide sequence or motif that promotes the survival of T lymphocytes after antigen stimulation. In certain embodiments, the T cell survival motif is or is derived from the intracellular signaling domain of CD3, CD28, IL-7 receptor (IL-7R), the intracellular signaling domain of IL-12 receptor, the intracellular signaling domain of IL-15 receptor, the intracellular signaling domain of IL-21 receptor, or the intracellular signaling domain of transforming growth factor β (TGFβ) receptor.

[0334] The modified immune cells expressing CAR can be, for example, T lymphocytes (T cells, such as 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 can be initial T lymphocytes or MHC-restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In certain embodiments, T lymphocytes have been separated from tumor biopsies, or have been expanded from T lymphocytes separated from tumor biopsies. In certain other embodiments, T cells have been separated from peripheral blood, cord blood, or lymph, or expanded from T lymphocytes separated from peripheral blood, cord blood, or lymph. Immune cells for generating modified immune cells expressing CAR can be separated using conventional methods accepted by the prior art, such as blood collection, followed by single collection and optionally antibody-mediated cell separation or sorting.

[0335] The modified immune cells are preferably autologous to the individuals to whom the modified immune cells will be administered. In certain other embodiments, the modified immune cells are allogeneic to the individuals to whom the modified immune cells will be administered. When allogeneic T lymphocytes or NK cells are used to prepare the modified T lymphocytes, it is preferred to select T lymphocytes or NK cells that will reduce the possibility of graft-versus-host disease (GVHD) in the individuals. For example, in certain embodiments, virus-specific T lymphocytes are selected to prepare the modified T lymphocytes; it is expected that the native ability of such lymphocytes to bind to any receptor antigen will be greatly reduced, thereby being activated by any receptor antigen. In certain embodiments, by co-administering one or more immunosuppressants (such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, etc.) to the host, the rejection of receptor-mediated allogeneic T lymphocytes can be reduced.

[0336] T lymphocytes (e.g., unmodified T lymphocytes, or T lymphocytes expressing CD3 and CD28, or T lymphocytes comprising a polypeptide comprising a CD3 zeta signaling domain and a CD28 co-stimulatory domain) can be expanded using antibodies against CD3 and CD28, such as antibodies attached to beads; see, e.g., U.S. Pat. Nos. 5,948,893, 6,534,055, 6,352,694, 6,692,964, 6,887,466, and 6,905,681.

[0337] The modified immune cells (e.g., modified T lymphocytes) may optionally contain a "suicide gene" or "safety switch" that, when desired, can kill substantially all of the modified immune cells. For example, in certain embodiments, the modified T lymphocytes may contain an HSV thymidine kinase gene (HSV-TK) that causes the modified T lymphocytes to die when contacted with gancyclovir. In another embodiment, the modified T lymphocytes contain an inducible caspase, such as inducible caspase 9 (i-caspase 9), such as a fusion protein between caspase 9 and human FK506 binding protein, which allows dimerization using special small molecule drugs. See Straathof et al., Blood 1 05(11):4247-4254 (2005).

[0338] In certain embodiments, a combination of a pharmaceutical composition provided herein and a chimeric antigen receptor (CAR) T cell is administered to a patient with multiple myeloma of various types or stages. In certain embodiments, the CAR T cell in the combination targets B cell maturation antigen (BCMA), and in more specific embodiments, the CAR T cell is bb2121 or bb21217. In certain embodiments, CAR-T cells are JCARH125.

[0339] 7. Examples

[0340] Certain embodiments of the invention are illustrated by the following non-limiting examples.

[0341] Development of Compound 1HBr Formulation

[0342] 7.1 Drug-excipient compatibility studies

[0343] Binary drug-excipient compatibility studies were performed to identify suitable excipients for capsule formulations. The following table lists the excipients of various functional categories evaluated. Considering low-dose formulations where the diluent accounts for the majority of the composition, the API to diluent ratio is 1:400; for other excipients, the ratio is 1:50.

[0344] Table 1: List of samples evaluated for compatibility with drug substances

[0345]

[0346] The drug substance and excipients were distributed in a predetermined ratio, mixed using a vortex mixer for 30 seconds, and then distributed into the required number of vials for stability studies. These vials (open conditions) were exposed to 50°C / 0% RH and 50°C / 75% RH conditions for 2 weeks and 4 weeks, respectively. The control samples were stored in a refrigerator at 5°C. After 2 weeks, the chemical degradation products and chiral purity loss (S-isomer conversion to R-isomer) of the selective samples were tested. After 4 weeks, samples showing>3% chemical degradation were excluded from the test.

[0347] The following are the main degradation pathways that may limit shelf life: (1) hydrolysis, (2) oxidation, and (3) loss of chiral purity. The levels of total chemical impurities and chiral impurities in samples after 2 and 4 weeks of stress were compared with those in the control sample, which were Figure 1A and Figure 1B as shown in .

[0348] Compound 1 HBr drug substance: The control sample showed 0.2% chemical impurities and 0.3% chiral impurities. After 2 weeks of exposure to 50°C / 75% RH conditions, the chemical impurity level increased to 0.35% and increased to 0.77% after 4 weeks of exposure. After 4 weeks under this condition, the chiral impurity only increased to 0.4%. No significant changes in chemical or chiral impurities were observed under dry conditions (50°C).

[0349] 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; the degradation profile was similar to that of the drug substance itself. For the remaining three, starch was more compatible than MCC, followed by lactose. Starch showed slightly better compatibility than MCC under dry conditions, and at 50°C / 75% RH, starch was better than MCC. Of the four diluents, lactose degraded the most in both chemical and chiral terms and at both 50°C and 50°C / 75% RH conditions. Overall, the diluents were ranked from most compatible to least compatible as follows: mannitol>starch>MCC>lactose.

[0350] Disintegrants: Cross-linked sodium carboxymethylcellulose (2-week 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 the API itself. After 2 weeks at 50°C / 75% RH, sodium starch glycolate type A exhibited the lowest chemical compatibility (6% impurities) and was excluded from further evaluation. Cross-linked polyvinylpyrrolidone showed the second highest level of chemical degradation and the highest chiral impurities. Under dry conditions, all four disintegrants showed stability similar to that of the pure API. Overall, the disintegrant ranking is as follows: Cross-linked sodium carboxymethylcellulose ≈ sodium starch glycolate type B > cross-linked polyvinylpyrrolidone >> sodium starch glycolate type A.

[0351] Binders: Among the polymers evaluated as binders and crystallization stabilizers, PVP K90 and HPC EXF resulted in significant decreases in chiral purity and increases in total relative impurities, with only HPMC E5 proving to be compatible.

[0352] Glidants / Anti-blocking Agents: Precipitated silica was shown to catalyze chemical degradation and also result in loss of chiral purity. However, fumed silica was found to have good compatibility.

[0353] Lubricants: All three lubricants evaluated showed excellent compatibility with no significant increase in total relative and chiral impurities. In particular, stearic acid showed the least amount of total related impurities (chemical degradants) compared to the other two lubricants.

[0354] Among the evaluated excipients for drug-excipient compatibility studies, nine excipients were shortlisted based on their impact on chemical and chiral degradation risk of the drug substance for formulation and process design considerations. In summary, microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, stearic acid, HPMC E5, sodium glycolate B starch, fumed silica, and sodium stearyl fumarate were selected for further evaluation in blends.

[0355] 7.2 Prototype formulation development through RC process

[0356] The prototype batches listed in the table below were manufactured using the RC process. The batch size was 500 g. The blend was compacted under the predicted rolling force (4-4.5 kN) to achieve a SF of about 0.75, a rolling speed of 1 rpm, and a rolling gap of 2 mm. The capsules were exposed to accelerated open conditions (50°C / 0% RH and 50°C / 75% RH) and evaluated for chemical and chiral stability after 2 and 4 weeks. In this study, the HSWG formulation of the free base was used as a baseline.

[0357] Table 2: Composition of prototype batches made using RC as a potential manufacturing platform to evaluate chemical and chiral stability

[0358]

[0359] *Based on a theoretical potency of 0.8752

[0360] Chemical stability results are summarized in Figure 2AFormulation PD02-247B did not exhibit the best chemical stability. However, the presence of starch in this formulation improved stability compared to formulation PD02-247A and formulation PD02-247F containing MCC. Although colloidal silica showed excellent compatibility in the binary study, formulation PD02-247C containing silica exhibited the worst chemical stability. Among all the prototype formulations evaluated, formulation PD02-247E using stearic acid as a lubricant showed significantly better chemical stability properties. Figure 2B The chiral stability properties of the formulations followed similar trends as shown in . Formulation PD02-247E with mannitol, starch and stearic acid was selected for further evaluation.

[0361] 7.3 Selection of pilot prototype formulations for RC process

[0362] The effect of adding disintegrants and binders on the stability of 0.15% DL formulations (0.1 mg capsules) was evaluated, which may have an impact on the reliability, stability and dissolution of granulation. As shown in the table below, batches PD02-292A2, PD02-292B and PD02-292C were manufactured without disintegrants, with cross-linked sodium carboxymethyl cellulose (CCS) and with low pH sodium starch glycolate (low pH SSG), respectively. In addition, in order to evaluate the effect of binders, formulation PD02-332 was manufactured with HPMC E5 and CCS. In order to evaluate the effect of disintegrants on capsule dissolution, formulations without disintegrants, formulations with CCS and a third formulation (2 mg capsules) with CCS and HPMC E5 were prepared at 1.5% DL. All of these batches were manufactured using a rolling process. The capsules were exposed to 50°C / 0% RH and 50°C / 75% RH open conditions to conduct stability and dissolution studies.

[0363] Table 3: Prototype batches manufactured for stability assessment

[0364]

[0365]

[0366] Hydrolytic degradation and chiral degradation are summarized in Figure 3A , Figure 3B and Figure 3CIn. Comparing formulation PD02-292A2 without any disintegrant and formulation PD02-292B with cross-linked sodium carboxymethylcellulose, similar degradation was observed at the four-week time point. Comparing formulation PD02-292B with cross-linked sodium carboxymethylcellulose (CCS) and formulation PD02-292C with sodium starch glycolate-type B (SSG), the formulation with SSG-type B exhibited significantly better stability properties. The seven weeks of PD02-292C at 50°C and 50°C / 75% RH were even comparable to the four weeks of PD02-292B at 50°C and 50°C / 75% RH. Finally, comparing formulation PD02-292B with CCS and formulation PD02-332 containing both CCS and HPMC, the presence of HPMC exhibited similar chemical and chiral stability at 50°C and 50°C / 75% RH for two weeks.

[0367] The slurry pH of selected prototype formulations was measured to assess the microenvironmental pH and to confirm the disproportionation tendency of the HBr salt in the formulation (pKa 6.62, pH max As shown in the table below, the presence of low pH SSG in formulation (PD02-292C) resulted in the lowest slurry pH (4.65), which is close to the pH of the salt. max However, the slurry pH of formulations without disintegrant, with CCS, or with CCS and HPMC E5 was 5.61 or higher.

[0368] Table 4: Slurry pH of prototype formulations evaluated using RC process

[0369] Batch number Slurry pH PD02-292A1 - Final blend (without disintegrant) 5.61 PD02-292B-Final Blend (CCS) 5.64 PD02-292C-Final blend (SSG-B) 4.65 PD02-332-Final blend (CCS and HPMC) 5.73

[0370] Based on hydrolytic and chiral stability and slurry pH, a formulation containing mannitol, starch, low pH SSG, HPMC E5 and stearic acid was selected as a lead prototype formulation for roller compaction process.

[0371] 7.4 Manufacturability Evaluation of RC Process

[0372] The RC process is used to manufacture the lead prototype formulation PD02-366 as shown in the table below to evaluate the manufacturability of the formulation. The theoretical batch size is 5kg. All the intragranular ingredients are mixed in a blender, agglomerated using a granulator, and produced by a roller compactor and a mill. For batch PD02-366, approximately half of the ground particles are then mixed with an extragranular lubricant to obtain a final blend, which is then encapsulated in a Vcaps Plus HPMC capsule shell. For batch PD02-366A, the remaining half is mixed with extragranular mannitol and a lubricant to obtain a final blend, which is then encapsulated in a Vcaps Plus HPMC capsule shell. Layered capsule samples are collected for CU testing.

[0373] Table 5: Prototype batches manufactured to evaluate RC as a potential manufacturing platform

[0374]

[0375] The fluidity of the final blend of PD02-366 and PD02-366A with 15% extragranular mannitol SD100 was tested. The FFc values ​​of PD02-366 and PD02-366A were found to be 4.8 and 5.9, respectively, indicating that the additional granular mannitol improved the flow of the final blend. The slurry pH of PD02-366 was 4.54. Compared with PD02-366 (%RSD ranged from 1.65% to 2.84%), the capsule weight control of PD02-366A was more stringent, with a %RSD range of 1.17% to 1.68%.

[0376] The extra granules formulation PD02-366A had a low AV and tighter %RSD, which may be due to the incorporation of extra granules (15% w / w) mannitol 100SD improving flow properties. The table below indicates the average labeled amount (%LC), %RSD and acceptance value (AV).

[0377] Table 6: Average Labeled Content (%LC) and Acceptable Value (AV) of Prototype RC Batches

[0378]

[0379] In summary, roller compaction was found to be a feasible manufacturing process that meets the critical quality attributes of the drug product. PD02-366A was selected as the lead prototype formulation for roller compaction. The drug loading can be varied from 0.164% to 0.653% to obtain capsules with a strength of 0.1-1.6 mg. PD02-366A capsules were batch packaged as 7 capsules / 100cc HDPE bottles with 2g of desiccant for ICH stability studies.

[0380] 7.5 Prototype formulation development via HSWG process

[0381] 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. The manufacturing process consisted of pre-blending the intragranular ingredients in a granulator bowl, adding water to mix, wet massing, fluidized bed drying, co-grinding, final lubrication, and encapsulation. The chemical and chiral stabilities of these capsule batches were evaluated using open stability at the following storage conditions: 50°C / 0% RH and 50°C / 75% RH for two weeks and four weeks, respectively.

[0382] Table 7: Small-scale prototype batches manufactured to evaluate HSWG as a potential manufacturing platform

[0383]

[0384]

[0385] *Based on a theoretical potency of 0.8752

[0386] Based on a small-scale prototype stability study ( Figure 4A and Figure 4B ), the following observations were made and summarized as follows: Comparing PD02-248A and 248B (with HPMC), the formulation with HPMC as a binder greatly 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 showed the best overall chemical and chiral stability characteristics. In the initial prototype formulation screening, mannitol, starch, MCC, SSG-B type, HPMC and SSF were selected for further evaluation.

[0387] 7.6 Selection of pilot prototype formulations for HSWG process

[0388] In this study, the role of binders and disintegrants in selected HSWG formulations was evaluated. Prototype batches as indicated in the table below were manufactured and evaluated for chemical and chiral stability, content uniformity, and dissolution. The batch size was 3 kg. The manufacturing steps included the following: bag blending of intragranular excipients for 2 minutes, premixing in a granulator, granulation (addition of water 100 g / min), fluid bed drying, co-grinding, final blending / lubrication, and packaging.

[0389] Table 8: Prototype batches manufactured for stability assessment

[0390]

[0391]

[0392] Hydrolytic degradation and chiral degradation are summarized in Figure 5A , Figure 5B and Figure 5C As can be seen in PD02-248A, the formulation without any disintegrant showed a higher amount of degradation. Comparing PD02-248F (SSG-B type) and PD02-314 (CCS), SSG-B type again showed better stability. The degradation of PD02-314 at 50°C / 75% RH at 11 days was higher than that of PD02-248F at 14 days. Similar observations were seen for PD02-315 (SSG-B type) compared to PD02-316 (CCS), with CCS causing higher degradation of the PD02-316 formulation. Again, MCC as a diluent (PD02-314) provided slightly better stability than the formulation with starch (PD02-316).

[0393] In order to evaluate the effect of stearic acid compared to SSF as a lubricant on the stability of selected prototype formulations, PD02-373 and PD02-373A were manufactured. The batch size was 500 g. The manufacturing process consisted of pre-blending the intra-granular ingredients in a granulator bowl, followed by adding water to mix for granulation, wet massing, fluidized bed drying, co-grinding, lubrication, and packaging. The composition is shown in the table below.

[0394] Table 9: Prototype formulations made to evaluate stearic acid for stability

[0395]

[0396]

[0397] Based on Fig. 6A Based on the open stability data shown in , stearic acid provides acceptable chemical and chiral stability. PD02-373A was also packaged as 7 pellets in 100 mL HDPE bottles (with and without 2 g of desiccant) for development of ICH stability studies. The one-month and three-month stability results are summarized in Figure 6BThe formulation showed excellent stability under all 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 under both 25°C / 60% RH and 40°C / 75% RH conditions. Chiral impurities only increased slightly at 40°C / 75% RH, and the impurity level was not affected by the desiccant. In addition, stearic acid has been shown from the RC process to greatly improve the stability of the formulation. Finally, stearic acid also minimizes the risk of salt disproportionation. Therefore, stearic acid was selected as a lubricant for further evaluation.

[0398] To determine the effect of disintegrants and binders on the dissolution of the formulations, 2 mg capsules (lots PD02-323, 324, 328 and 329) were tested for in vitro dissolution using pH 4.5 citrate buffer as the medium. Dissolution testing was performed at T = 0 and after being subjected to 50 ° C / 0% RH and 50 ° C / 75% RH for 2 weeks. Figure 7 As shown in the , formulation PD02-324 (without disintegrant) showed the slowest release, approximately 80% at 45 min. Formulations PD02-323 (CCS as disintegrant) and PD02-328 (with SSG-B type) showed very comparable dissolution profiles, indicating that there was no significant difference between CCS and SSG-B type as disintegrants. HPMC (PD02-329) added as a binder solution improved drug release kinetics, releasing around 94% at the 45 min time point. For all batches, no significant differences in dissolution stability performance were found at T = 0 or after storage for 2 weeks at 50 ° C / 75% RH.

[0399] Finally, the slurry pH of selected prototype formulations was measured to assess the microenvironmental pH and confirm the disproportionation tendency of the HBr salt in the formulation (pKa 6.62, pH max As shown in the table below, the presence of low pH SSG in formulations PD02-315 and PD02-328 resulted in lower slurry pH, 4.67 and 4.65, respectively. The slurry pH of formulations without disintegrant or with CCS was above 5.4.

[0400] Table 10: Slurry pH of prototype formulations evaluated using the HSWG process

[0401] Batch number Slurry pH PD02-314(MNT / ST / CCS) 5.61 PD02-315(MNT / ST / SSG-B) 4.67 PD02-316(MNT / ST / CCS) 5.58 PD02-323(MNT / ST / CCS) 5.66 PD02-324(MNT / MCC) 5.44 PD02-328(MNT / MCC / SSG-B) 4.65 PD02-373A(MNT / MCC / SSG-B) 4.52

[0402] Based on hydrolytic and chiral stability, dissolution 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.

[0403] 7.7 Manufacturability Evaluation of HSWG Process

[0404] In addition to evaluating stability and dissolution, the particle properties and capsule weight variability of batches PD02-314, PD02-315, PD02-316, PD02-323, PD02-324, PD02-328, and PD02-329 were characterized. Capsules from batches PD02-314, 316, 328, and 329 were evaluated for the assay.

[0405] The physical properties of the final blends such as particle size, volume and tap density and in-process capsule weight %RSD are shown in the table below. All batches showed good particle growth and the D 50 Varying between 120 and 250 μm. All particles showed good flowability (Hausner ratio will be less than 1.29) and also showed good capsule weight control. Overall, the capsule weight RSD in the process was less than 1.5%. The potency values ​​of selected batches (PD02-314, 316, 328 and 329) were acceptable and in the range of 96.9%-103.0%.

[0406] Table 11: Particle size distribution, density and in-process weight variation (%RSD) of final blends of prototype HSWG batches

[0407]

[0408]

[0409] In summary, based on the acceptable open stability and fast dissolution release profiles, as well as the acceptable assay data presented above, the HSWG process was found to be a feasible manufacturing process that meets the critical quality attributes of the drug product.

[0410] 7.8 Excipient Range Study for Compound 1HBr Formulation

[0411] To identify the quantitative composition of the Compound 1HBr drug product for the pivotal study, the effects of selected intragranular excipient levels on the manufacturability and quality attributes of the capsules were determined. 3 Full factorial DoE and 2 center point batches were constructed as shown in the table below. The three variables in the study were MCC, HPMC and SSG levels. The API level was fixed at 0.653% w / w to obtain capsule strength (0.4-1.6 mg) by varying the fill weight. The extragranular stearic acid level was also fixed at 4% w / w in this study. The mannitol level was adjusted to add up to 100%.

[0412] Table 12: Study Design for Excipient Range Study

[0413]

[0414]

[0415] The particle size distribution of the milled particles and the bulk density and tap density of the final blend are listed in the table below. In general, batches containing a higher proportion of HPMC as a binder resulted in larger average particle sizes of particles; while batches containing the highest level of MCC and the lowest level of HPMC combined had the lowest average particle sizes (PD02-404 and PD02-408), respectively. Trend analysis showed that all variables evaluated had a statistically significant effect on the physical properties of the particles, with p-values ​​of 0.00038 and 0.00302 for MCC and HPMC, respectively. For the individual components, the level of MCC was negatively correlated with PSD and density, where increasing MCC levels were found to produce smaller particles with lower density. In contrast, a positive correlation was established for density and PSD as HPMC levels increased. Similarly, the SSG levels studied had no substantial effect on PSD, but did on density, with a P-value of 0.026.

[0416] Table 13: Particle size distribution of milled particles and density of final blend

[0417]

[0418] Adhesion evaluation of selected final blends indicated that the final blends had a low tendency to adhere to the tamping pin face during the encapsulation process.

[0419] All batches of final blends were evaluated for flow using a ring shear cell tester. Flow data indicated that all batches met the free-flowing regime (ffc>10). Powder flow is expected to have very little effect on capsule weight variability.

[0420] To confirm the risk of salt disproportionation to free base in the formulation, the slurry pH of the final blend was measured. The slurry pH of all blends ranged from 4.43 to 4.72. Theoretically, the degree of disproportionation could be about 1% (API pKa of 6.62) when the microenvironment pH range of the formulation was 4.43-4.72.

[0421] To evaluate the homogeneity of the granulation, a sieve cut assay was performed on selected batches of milled granules. The average sieve cut assay values ​​for the tested batches varied between approximately 93%-98% and the RSD was less than 15%. Based on the results, the tested granules exhibited acceptable homogeneity and the CU risk was considered low.

[0422] Capsules were sampled at regular time intervals during the encapsulation process for layered content uniformity testing. All batches exhibited good capsule weight control; the average capsule weights of these batches were within the range of 100% ± 1%, and the %RSD varied between 0.95% and 2.45%. All batches exhibited acceptable content uniformity; the average CU values ​​varied within the range of 100% ± 2%, the RSD was 4.7% or less, and the AV values ​​were less than 7 except for batch PD02-405 (AV 11.4, RSD4.7%). The individual capsule potency of all batches varied within 93%-107%. The high CU variability of batch PD02-405 can be attributed to its relatively high weight variability (RSD2.45%). After weight correction, the CU RSD value decreased from 4.7% to 3%. Optimization of encapsulation parameters will further improve the variability of capsule weight, and thereby improve the variability of CU. Trend analysis indicated that formulation variables (levels of MCC, HPMC, or SSG) did not significantly affect the weight-corrected CU means and RSDs.

[0423] The dissolution performance of 1.6 mg capsules of batches PD02-403, 406, and 407 was evaluated using a USP Type II dissolution apparatus at 50 rpm at pH 4.5 (media volume 500 mL). Figure 8 ) showed that the dissolution profiles of the three batches were similar, but the extreme batch PD02-407 with the lowest MCC and HPMC levels and the highest low pH SSG level exhibited an overall faster dissolution when compared to the other two batches.

[0424] A two-week open accelerated stability study was conducted at 50°C / 0% RH and 50°C / 75% RH to evaluate the effects of formulation variables on chemical and chiral stability. Three batches were evaluated: PD02-401, 402, 403. The data indicated that the range of excipient levels evaluated in this study did not affect the chemical or chiral stability of the formulation.

[0425] Excipient Range The DoE study showed that the excipient levels evaluated in this study had no real impact on product quality attributes such as CU, dissolution, and chemical and chiral stability. The center point batches were reproducibly manufactured 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) studies. The drug substance level can be varied between 0.164% and 0.653%, and the mannitol level will be adjusted accordingly. Possible capsule strengths of 0.1 mg to 1.6 mg can be achieved by varying the capsule fill weight between 70-280 mg.

[0426] Table 14: Selection of formulation compositions for human BA studies based on excipient range DoE study selections for optimization by HSWG process

[0427]

[0428] 7.9 Description of the manufacturing process

[0429] The API, mannitol, MCC, low pH SSG and HPMC components in the granules are distributed according to the bill of materials and loaded into the granulator bowl. The materials are dry mixed and granulated by adding a predetermined amount of water to the powder bed in the granulator bowl. The wet granules are then conveyed to a fluid bed dryer and dried at a preset inlet air temperature. The inlet air volume is adjusted to maintain an acceptable fluid bed height. The dried granules are passed through a granulator, and the ground granules are further mixed with pre-screened stearic acid in a box blender to obtain the final blend. The final blend is then filled into the Vcaps Plus HPMC capsule shell at a predetermined fill weight. The capsules are finally dusted and weight sorted.

[0430] Development of free base formulation of compound 1

[0431] The following Compound 1 free base formulations were previously described in U.S. Application No. 16 / 737,721, the entire contents of which are incorporated herein by reference. For ease of reference, these formulations are hereinafter referred to as direct blend (DB) free base (FB) formulations with fumaric acid (FA) in some examples.

[0432] Table 15: Composition of free base formulations of 0.13%, 0.5% and 1% DL obtained by direct blending process

[0433]

[0434] ICH stability studies combined with ASAP modeling show that when packaged in HDPE bottles with 2g of desiccant, 0.1 and 0.5 mg capsules of the free base formulation manufactured by the direct blending process all have acceptable stability. Surprisingly, the 2 mg strength capsules with higher DL and higher Aerosil 200 levels (as an anti-adhesive (or glidant)) show the worst stability. This observation is counterintuitive and appears to be caused by the Aerosil level in the formulation. In addition, the Aerosil grade used in the 0.1 mg capsule does not have global market acceptability.

[0435] Several studies were performed to evaluate the effect of excipients or their levels on product quality (stability, dissolution, etc.) or manufacturability (e.g., adhesion) and to identify potential alternative excipients.

[0436] 7.10 Evaluating the Effects of Colloidal Silica

[0437] To evaluate the feasibility of removing Aerosil from the formulation, the manufacturability of a batch without Aerosil was evaluated. In the absence of Aerosil in the formulation, powder sticking to the tamping pin was observed during the encapsulation process and the capsule assay was low. In an accelerated exposure study, the alternative anti-blocking agent Cab-O-Sil M5P did not improve the stability properties.

[0438] 7.11 Evaluation of Alternative Lubricants

[0439] To mitigate potential adhesion issues for formulations without Aerosil, the manufacturability of formulations with more efficient lubricants such as SSF and magnesium stearate was evaluated. As an alternative, the adhesion evaluation of formulations with the highest (2.56% w / w) expected drug load of 4% SA, 4% SSF or 2% magnesium stearate was performed using a compaction simulator. Higher levels of SA (8% w / w) were also evaluated. The compositions are indicated in the table below.

[0440] Table 16: Prototype Free Base Formulations with Fumaric Acid by Direct Blending Process - Evaluation of Adhesion Potential of Alternative Lubricants

[0441]

[0442] To evaluate adhesion / filming potential, 10 compacts were made in succession using a 9 mm flat tool at each compaction force (100 N, 500 N, and 2500 N). The punch faces were examined under a magnifying glass and ranked for filming or adhesion based on the following criteria: no haze, looked essentially clean (rating 0); light dust (very slight haze / powder, strongly reflective) (rating 1); light haze (slightly diffuse reflective) (rating 2); moderate haze (particularly diffuse and reduced reflective) (rating 3); heavy haze (effectively no light reflective) (rating 4); slight waxy buildup (<1 mm 2 )(Grade 5); Moderate wax accumulation (1-2mm 2 )(rating 6); extensive waxy buildup in multiple depressed areas (rating 7); buildup covering most of the depressions (rating 8); depressions not visible (rating 9); and sticking affecting tablet weight (rating 10). The ranking of sticking / filming observations is summarized in the table below. The results indicate that 4% SSF appears to be only slightly better than the other three compositions.

[0443] Table 17: Summary of adhesion / film formation trends after compaction of 10 consecutive compacts using prototype formulations

[0444]

[0445] In the open accelerated stability study, 0.1 mg strength capsules of the prototype formulations with SSF (PD01-405A) or Mg stearate (PD01-405B) manufactured by the direct blending process showed better stability than the 0.1 mg direct blended capsules (Cap-16) with Aerosil 972. However, as mentioned before, the latter formulations and the 0.5 mg direct blended capsules with Aerosil 200 had good stability in the packaged configuration. The stability results indicate that any of the three lubricants can be used in the direct blended formulations with the appropriate packaging configuration.

[0446] Table 18: Prototype free base formulations (PD01-405-A / B) at 0.14% DL obtained by DB process using alternative lubricants

[0447]

[0448]

[0449] *Pearlitol Flash is a co-processed blend of mannitol and pregelatinized starch (approximately 80%-20% w / w).

[0450] 7.12 Evaluating the Acidifier Level

[0451] Prototype free base formulations with different levels (0-4% w / w) of FA were made using a dry blending process. The formulation compositions are listed in the table below. These formulations contained Pearlitol flash as a diluent and 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 exposure studies, the overall stability of formulations containing up to 3% FA was superior to the directly blended free base formulation Cap-16, even under conditions of high temperature and humidity. The compositions are shown in the table below.

[0452] Table 19: Prototype Freebase Formulations Made by Direct Blending - Evaluated FA Levels

[0453]

[0454] *Pearlitol Flash is a co-processed blend of mannitol and pregelatinized starch (approximately 80%-20% w / w).

[0455] 7.13 Evaluation of Alternative Diluents

[0456] During clinical batch manufacturing, the DB process was found to be not robust due to CU variations, especially for low drug loading (0.13% w / w) batches. Considering the inherent CU risk of manufacturing low-dose products by direct blending process, one or more alternative manufacturing platforms (such as HSWG, FBG, RC) were evaluated to mitigate the potential CU risk.

[0457] Alternative diluents that are beneficial to the manufacturing process, such as mannitol, MCC, starch, and co-processed mannitol / starch combinations (Pearlitol flash), were evaluated. The formulation compositions evaluated are listed in the table below. Batch PD01-403A with Pearlitol flash was manufactured using a direct compaction process, while batch PD01-596 containing mannitol 50C, MCC PH101, and pregelatinized starch was manufactured by the HSWG process. Despite the different manufacturing processes, diluents, and even lubricants, both formulations showed good stability.

[0458] Table 20: Prototype Freebase Compositions Made by Direct Blending and HSWG Processes - Evaluation of Alternative Diluents

[0459]

[0460] *Pearlitol Flash is a co-processed blend of mannitol and pregelatinized starch (approximately 80%-20% w / w).

[0461] The in vitro dissolution of batch PD01-596 containing MCC was evaluated. In pH 2.0 media, drug release was incomplete, with only about 85% to 90% released at 60 minutes for the initial capsule samples and after storage for three months at 40°C / 75% RH. Incomplete drug release from formulations containing MCC could potentially affect bioperformance.

[0462] 7.14 Evaluation of SSG as a Disintegrant

[0463] To reduce incomplete dissolution of formulations containing MCC, the effect of SSG as a disintegrant on capsule dissolution was evaluated because it is compatible with compound 1 free base. The following table shows the composition of the four formulations evaluated in this study. Batches PD01-597, 597A, 660, and 660A were manufactured without SSG, with only extragranular SSG, with both intragranular and extragranular SSG, and with only intragranular SSG. The drug loading was 2.72% to obtain capsules of 2 mg strength for dissolution studies. All batches were manufactured by the HSWG process.

[0464] Table 21: Prototype Free Base Formulations Manufactured by the HSWG Process - Evaluation of the Impact of Disintegrant

[0465]

[0466] Fig. 9 The dissolution profiles of all four batches in pH 2 medium are shown in . The dissolution of the batch without SSG (PD0-597) was incomplete, with an overall release of only about 80% at the 60-minute time point. Incorporation of extragranular SSG alone did not improve the dissolution profile (PD01-597A). In contrast, the addition of intragranular SSG alone (PD01-660A) and the addition of both intragranular and extragranular SSG (PD01-660) significantly improved the release rate; the overall release at 60 minutes was about 93%. The results show that if a formulation containing MCC is to be developed, SSG can be added at least intragranularly to improve the dissolution profile.

[0467] 7.15 Manufacturing Process Development

[0468] In order to identify a suitable manufacturing process that is not only scalable but also must preserve all critical quality attributes of the drug product, different manufacturing platforms, namely direct blending, roller compaction, and high shear wet granulation, were evaluated. Fig. 10A As shown in, for the HSWG / FBD and DB processes, the chemical and chiral stability of the free base formulations using the same composition (see table below) for each process was found to be significantly better when compared to the RC process. Manufacturability (high assay recovery and tight CU control) can be achieved using the HSWG / FBD process when compared to the DB or RC process. Fig. 10B As shown in Figure 2, formulations with higher drug loading (see table below) showed better and complete in vitro dissolution when manufactured using HSWG / FBD process. The overall ranking of manufacturing platforms was HSWG / FBD>DB>RC.

[0469] Table 22: Composition of free base formulations for DB / RC / HSWG process evaluation

[0470] HSWG batch number PD01-511 PD01-599 RC Batch Number PD01-521A / B PD01-522 A / B DB Batch No. PD01-521C PD01-522C Element Amount(%w / w) Amount(%w / w) Compound 1 0.13 2.7 Mannitol 76.87 74.3 starch 20 20 SSF 3 3 total 100 100

[0471] A = low force, B = high force

[0472] 7.16 Excipient Range Finding Studies

[0473] As discussed above, a combination of high shear wet granulation (HSWG) and fluidized bed drying (FBD) was identified as a viable manufacturing process for Compound 1 capsules. The drug load in the formulation ranged from approximately 0.13 to 2.7% w / w to achieve the expected dosage range of 0.1 mg to 10 mg capsule strength, with capsule size no larger than size 0.

[0474] In order to optimize the formulation for the HSWG / FBD process, a prototype formulation consisting of MNT / starch / SSF and a MNT / starch / MCC / SSF formulation with a batch size of 3 kg were further evaluated. Factors such as the type of granulation fluid (water or 15% starch slurry), the level of granulation fluid, the spray rate and the wet massing time were also evaluated. During the final blending, the SSF (lubricant) level of all evaluated formulations was kept constant at 1%. The obtained granules had good quality and good flowability, which in turn resulted in strict weight variability of the capsules. During encapsulation, no adhesion to the tamping pin surface was observed. Both formulations (MNT / starch and MNT / starch / MCC) produced good CU; however, the average labeled value of the manufactured batches was about 5%-8% higher. At T=0, the dissolution of the MNT / starch formulation was faster than that of the formulation containing MCC. Open stability studies showed that both evaluated formulations had good chemical and chiral stability. Spraying water or starch slurry also had no effect on the obtained granules. From the preliminary results, it was found that MCC was not important for granulation growth or controlling the granulation endpoint. In addition, it had a negative impact on the in vitro dissolution performance. Based on the above findings, the MNT / starch / SSF-based formulation was selected as the lead prototype formulation for the HSWG / FBD process.

[0475] In order to identify the quantitative composition of MNT / starch / SSF based formulations by HSWG process, the effect of excipient levels on product quality attributes was evaluated. The detailed excipient range study composition is listed in the table below. Batches were manufactured at 3 kg scale using HSWG / FBD process with spray water as granulation fluid.

[0476] Table 23: Formulation composition for excipient range study for HSWG process

[0477]

[0478]

[0479] * Remove purified water after drying

[0480] The granules obtained were found to be of good quality with flow properties ranging between easy flowing and free flowing. A summary of the physical characterization of the final blends is listed in the table below.

[0481] Table 24: Summary of physical characterization of DoE formulations using excipient ranges for final blends

[0482]

[0483] All batches of encapsulation produced capsules with tight control of capsule weight. As listed in the table below, the CU averages for all investigated batches were slightly higher (101.6% - 104.3%), although the CU RSD was tight and all AV values ​​were within acceptable ranges.

[0484] Table 25: Summary of content uniformity of DoE batches across a range of formulations

[0485]

[0486]

[0487] like Fig.11 As shown in , all manufactured batches also exhibited a rapid and complete release profile at pH 2.0 (T = 0). Fig. 12A ) and chirality ( Fig. 12B ) stability demonstrated stable drug product after 3 and 7 days of storage, respectively. In addition, drug stability was linearly correlated with drug loading, with higher DL formulations showing better chemical and chiral stability. However, the 0.13% DL batch with 30% w / w starch exhibited a relatively high level of RRT 0.41 impurity characteristic.

[0488] From the excipient range DoE study it can be inferred that none of the parameters evaluated showed any significant impact on the product attributes (CU, dissolution and RI / chiral stability); however, the batch with 10% starch provided a narrow granulation endpoint window when compared to the batches with 20% w / w or 30% w / w starch. Based on these observations, the formulation with 20% starch was selected for further development.

[0489] 7.17 Composition of free base preparations

[0490] Based on prototype formulation screening and formulation range-finding studies, a composition consisting of mannitol-starch-SSF was selected for further study, with 0.13%, 0.26%, 0.5% and 1.33% DL available in different dosage strengths, such as listed in the table below.

[0491] Table 26: Unit formulations of compound 1 with drug loadings of 0.13%, 0.27%, 0.5% and 1.33%

[0492]

[0493]

[0494] * Remove purified water after drying

[0495] 7.18 Multi-media Dissolution Studies

[0496] The goal of the study was to develop an in vitro predictive tool that could predict in vivo performance by changes in formulation components (hereinafter referred to as HSWG free base formulation for ease of reference) and its manufacturing process compared to the free base formulation manufactured using a direct blending (DB) process. In vitro multi-media dissolution studies were performed at pH 2.0, 4.5, and 6.8.

[0497] To evaluate the effect of multiple dissolution media, a 2 mg dose strength was evaluated. Fig.13 The results of this study are presented in . At pH 2.0, both DB and HSWG free base formulations were found to be comparable, whereas when the pH was shifted to 4.5 and 6.8, the dissolution profile of the HSWG free base formulation was found to be slower compared to the DB formulation.

[0498] A two-stage dissolution test was also performed to evaluate the risk of precipitation after the physiological pH shift from 1.2 in the stomach (0 to 30 minutes) to 6.8 in the intestine (30 to 90 minutes). Capsules of both DB and HSWG free base formulations were evaluated at a 0.5 mg dose. Fig.14 From the results of the two-stage dissolution test shown in , it can be inferred that the risk of precipitation is expected to be low.

[0499] 7.19 Prototype Free Base Formulation with Fumaric Acid

[0500] As discussed above, the proposed HSWG free base formulation was found to be slow in biorelevant dissolution media. Alternative formulations with 1% and 3% fumaric acid were manufactured for 2 mg dosage strength. The compositions are listed in the table below. The rationale for adding fumaric acid in the formulation was to maintain the microenvironmental pH in the acidic range since the drug substance is soluble at lower pH due to its pH dependent dissolution properties. The in vitro dissolution performance was evaluated at pH 4.5 as it was found to have the greatest discrimination compared to other dissolution media.

[0501] Table 27: Composition of HSWG free base formulation with FA for 2 mg dose strength used in monkey PK study

[0502]

[0503] like Fig.15 As shown in, the dissolution release performance of HSWG FB formulations with 1% and 3% FA was found to be significantly faster and higher when compared to DB FB formulation with FA or HSWG FB formulation without FA. This study confirms the hypothesis that the incorporation of fumaric acid contributes to higher drug dissolution by maintaining a favorable microenvironment pH that favors higher drug solubility.

[0504] 7.20 Animal PK Study-I

[0505] Animal PK studies were conducted in male monkeys to find out if there is any correlation between pH 4.5 dissolution and PK profile in monkeys. Each group was dosed with 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.

[0506] The crossover study design included 4 male monkeys / group (with at least 1 week washout period) receiving different formulations. In addition, the monkeys were fasted overnight and fasted for 4 hours after administration. PK samples were collected up to 24 hours after dosing. Fig.16 As shown in , the HSWG FB formulation without FA showed 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 showed similar and significantly higher exposures.

[0507] Likewise, the in vitro dissolution rank order was found to be similar to the in vivo AUC rank order, qualitatively indicating a good in vitro-in vivo correlation. Based on the in vitro dissolution and in vivo monkey AUC data at pH 4.5, the rank order of the formulations was as follows: HSWG FB formulation with 3% FA ≥ HSWG FB formulation with 1% FA >>> DB FB formulation (3% FA) > HSWG FB formulation (without FA).

[0508] 7.21 Evaluation of hydrobromide options as an alternative HSWG formulation

[0509] To evaluate the effect of the HBr salt of Compound 1 on in vitro performance, an alternative HSWG formulation of HBr saline without fumaric acid was made. The composition of the HSWG HBr formulation of the 0.5 mg dosage strength is listed in the table below.

[0510] Table 28: Composition of 0.5 mg capsules for monkey PK study-2: DB FB formulation, HSWG FB formulation, and HSWG FB formulation with 3% FA, and HSWG HBr formulation

[0511]

[0512] The composition of HSWG HBr was not optimized, but a head-on comparison of the drug substance forms (free base vs. HBr salt) was performed, with the composition and manufacturing process remaining unchanged.

[0513] like Fig.17 As shown in , the dissolution performance of HSWG HBr formulations at a 0.5 mg dosage strength was evaluated at pH 4.5 for DB FB and HSWG FB formulations, as well as a HSWGFB formulation with 3% FA.

[0514] In pH 4.5 media, the HSWG HBr formulation exhibited faster and almost complete dissolution when compared to the DB FB formulation, or the HSWG FB formulation, or the HSWG FB formulation with 3% FA.

[0515] 7.22 Animal PK Study-II

[0516] Another monkey PK study was designed for the 0.5 mg dose strength and contained the following four cohorts (four monkeys / cohort): DB FB formulation, HSWG FB formulation, HSWG FB formulation with 3% FA, and HSWG HBr formulation. The composition of all formulations has been specified in the previous section.

[0517] In this study, HSWG HBr formulation and HSWG FB formulation with 3% FA showed much higher absorption than DB FB formulation and HSWG FB formulation; among all formulations, HSWG HBr formulation showed the highest AUC. Fig.18 As shown in , it was observed that both DB FB formulation and HSWG FB formulation exhibited comparable bioperformance. The rank order of formulations based on AUC was as follows: HSWG HBr formulation>HSWG FB formulation with 3% FA>>>DB FB formulation with 3% FA=HSWG FB formulation.

[0518] Table 29: Summary of PK data in monkeys (males) following oral administration of 0.5 mg dose strength

[0519]

[0520]

[0521] The embodiments provided herein are not limited in scope by the specific embodiments provided in the examples, which are intended as illustrations of several aspects of the embodiments provided, and the disclosure encompasses any functionally equivalent embodiments. Indeed, various modifications of the embodiments provided herein, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0522] A number of references are cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. A pharmaceutical composition comprising 1) a hydrobromide salt of compound 1: 2) a mixture of mannitol and microcrystalline cellulose or a mixture of mannitol and starch, 3) hydroxypropyl methylcellulose (HPMC), 4) sodium starch glycolate (SSG), and 5) stearic acid.

2. The pharmaceutical composition of claim 1, comprising: 1) a hydrobromide salt 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; and wherein the carrier or diluent is a mixture of mannitol and microcrystalline cellulose or a mixture of mannitol and starch.

3. The pharmaceutical composition of claim 2, wherein the hydrobromide salt of Compound 1 is a crystalline hydrobromide salt of Compound 1.

4. The pharmaceutical composition of claim 2, wherein the hydrobromide salt of Compound 1 is characterized by an XRPD pattern comprising peaks at approximately 10.3, 19.3, and 24.0° 2θ.

5. The pharmaceutical composition of claim 2, wherein the amount of the hydrobromide salt of Compound 1 is about 0.1 to about 1.5% w / w.

6. The pharmaceutical composition of claim 5, wherein the amount of the hydrobromide salt of Compound 1 is about 0.16 to about 0.65% w / w.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the component 2) is a mixture of mannitol and microcrystalline cellulose.

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

9. The pharmaceutical composition of claim 8, wherein the starch is partially pregelatinized starch.

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

11. The pharmaceutical composition of claim 10, wherein the amount of the mixture of mannitol and microcrystalline cellulose or the mixture of mannitol and starch is about 85 to about 86% w / w.

12. The pharmaceutical composition of any one of claims 1 to 6, wherein the amount of the mannitol is about 35 to about 93% w / w, and the amount of the microcrystalline cellulose or starch is about 5 to about 35% w / w.

13. The pharmaceutical composition of claim 12, wherein the amount of mannitol is about 50 to about 80% w / w, and the amount of microcrystalline cellulose or starch is about 10 to about 30% w / w.

14. The pharmaceutical composition of claim 13, wherein the amount of mannitol is about 65 to about 66% w / w, and the amount of microcrystalline cellulose or starch is about 20% w / w.

15. The pharmaceutical composition of any one of claims 1 to 6, wherein the weight ratio of the microcrystalline cellulose or starch to the mannitol is about 1:1 to about 1:

20.

16. The pharmaceutical composition of claim 15, wherein the weight ratio of the microcrystalline cellulose or starch to the mannitol is about 1:1.7 to about 1:

8.

17. The pharmaceutical composition of claim 16, wherein the weight ratio of the microcrystalline cellulose or starch to the mannitol is about 1:3.

3.

18. The pharmaceutical composition of any one of claims 1 to 6, wherein the HPMC is HPMC E5.

19. The pharmaceutical composition of any one of claims 1 to 6, wherein the amount of HPMC is about 3 to about 7% w / w.

20. The pharmaceutical composition of claim 19, wherein the amount of HPMC is about 5% w / w.

21. The pharmaceutical composition of any one of claims 1 to 6, wherein the SSG is a low pH SSG.

22. The pharmaceutical composition of any one of claims 1 to 6, wherein the amount of SSG is about 3 to about 7% w / w.

23. The pharmaceutical composition of claim 22, wherein the amount of SSG is about 5% w / w.

24. The pharmaceutical composition of any one of claims 1 to 6, wherein the amount of stearic acid is about 2 to about 6% w / w.

25. The pharmaceutical composition of claim 24, wherein the amount of stearic acid is about 4% w / w.

26. The pharmaceutical composition of claim 1, comprising: 1) a hydrobromide salt of Compound 1 in an amount of about 0.16% w / w; 2) mannitol in an amount of about 65.84% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) HPMC E5 in an amount of about 5% w / w; 4) low pH SSG in an amount of about 5% w / w; and 5) stearic acid in an amount of about 4% w / w.

27. The pharmaceutical composition of claim 26, having a total weight of about 70 mg.

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

29. The pharmaceutical composition of claim 26, wherein the total weight of the pharmaceutical composition is about 140 mg.

30. The pharmaceutical composition of claim 29, contained in a size 2 capsule.

31. The pharmaceutical composition of claim 1, comprising: 1) a hydrobromide salt of Compound 1 in an amount of about 0.65% w / w; 2) mannitol in an amount of about 65.35% w / w and microcrystalline cellulose in an amount of about 20% w / w; 3) HPMC E5 in an amount of about 5% w / w; 4) low pH SSG in an amount of about 5% w / w; and 5) stearic acid in an amount of about 4% w / w.

32. The pharmaceutical composition of claim 31, wherein the total weight of the pharmaceutical composition is about 70 mg.

33. The pharmaceutical composition of claim 32, contained in a size 3 capsule.

34. A pharmaceutical composition comprising 1) Compound 1: 2) a mixture of mannitol and starch, 3) sodium stearyl fumarate, and 4) optionally fumaric acid.

35. A pharmaceutical composition as described in claim 34, 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.

36. The pharmaceutical composition of claim 35, wherein Compound 1 is crystalline Compound 1.

37. The pharmaceutical composition of claim 36, wherein Compound 1 is characterized by an XRPD pattern comprising peaks at approximately 14.6, 18.2, and 18.3 degrees 2θ.

38. The pharmaceutical composition of claim 35, wherein the amount of Compound 1 is about 0.1 to about 2% w / w.

39. The pharmaceutical composition of claim 38, wherein the amount of Compound 1 is about 0.13 to about 1.33% w / w.

40. The pharmaceutical composition of any one of claims 34 to 39, wherein the starch is a partially pregelatinized starch.

41. The pharmaceutical composition of any one of claims 34 to 39, wherein the amount of the mixture of mannitol and starch is about 95 to about 99% w / w.

42. The pharmaceutical composition of claim 41, wherein the amount of the mixture of mannitol and starch is about 97 to about 99% w / w.

43. The pharmaceutical composition of any one of claims 34 to 39, wherein the amount of the mannitol is about 60 to about 89% w / w, and the amount of the starch is about 10 to about 30% w / w.

44. The pharmaceutical composition of claim 43, wherein the amount of mannitol is about 77 to about 79% w / w, and the amount of starch is about 20% w / w.

45. The pharmaceutical composition of any one of claims 34 to 39, wherein the weight ratio of the starch to the mannitol is about 1:2 to about 1:

9.

46. ​​The pharmaceutical composition of claim 45, wherein the weight ratio of the starch to the mannitol is about 1:3.

9.

47. The pharmaceutical composition of any one of claims 34 to 39, wherein the amount of sodium stearyl fumarate is from about 0.5 to about 2% w / w.

48. The pharmaceutical composition of claim 47, wherein the amount of sodium stearyl fumarate is about 1% w / w.

49. A pharmaceutical composition as described in any one of claims 34 to 39, which does not contain fumaric acid.

50. The pharmaceutical composition of any one of claims 34 to 39, wherein the amount of fumaric acid is from about 0.1 to about 10% w / w.

51. The pharmaceutical composition of claim 50, wherein the amount of fumaric acid is about 1 to about 3% w / w.

52. The pharmaceutical composition of claim 34, 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.

53. The pharmaceutical composition of claim 52, having a total weight of about 75 mg.

54. The pharmaceutical composition of claim 53, contained in a size 4 capsule.

55. The pharmaceutical composition of claim 52, wherein the total weight of the pharmaceutical composition is about 300 mg.

56. The pharmaceutical composition of claim 55, contained in a size 1 capsule.

57. The pharmaceutical composition of claim 34, 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.

58. The pharmaceutical composition of claim 57, having a total weight of about 75 mg.

59. The pharmaceutical composition of claim 58, contained in a size 4 capsule.

60. The pharmaceutical composition of claim 57, wherein the total weight of the pharmaceutical composition is about 300 mg.

61. The pharmaceutical composition of claim 60, contained in a size 1 capsule.

62. The pharmaceutical composition of claim 34, 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.

63. The pharmaceutical composition of claim 62, wherein the total weight of the pharmaceutical composition is about 80 mg.

64. The pharmaceutical composition of claim 63, contained in a size 4 capsule.

65. The pharmaceutical composition of claim 62, wherein the total weight of the pharmaceutical composition is about 300 mg.

66. The pharmaceutical composition of claim 65, contained in a size 1 capsule.

67. The pharmaceutical composition of claim 34, 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.

68. The pharmaceutical composition of claim 67, having a total weight of about 75 mg.

69. The pharmaceutical composition of claim 68, contained in a size 4 capsule.

70. The pharmaceutical composition of claim 67, wherein the total weight of the pharmaceutical composition is about 300 mg.

71. The pharmaceutical composition of claim 70, contained in a size 1 capsule.

72. A pharmaceutical composition as described in claim 34, comprising: 1) Compound 1 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.

73. A pharmaceutical composition as described in claim 34, comprising: 1) Compound 1 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.

74. A pharmaceutical composition as described in claim 34, comprising: 1) Compound 1 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.

75. Use of a therapeutically effective amount of a pharmaceutical composition as described in any one of claims 1 to 74 in the preparation of a medicament for treating multiple myeloma in a patient in need thereof.

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