Methods for treating estrogen receptor-mediated disorders

Abstract

The present disclosure provides a method for treating an estrogen receptor-mediated disease, disorder, or condition in a subject, comprising administering to the subject a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with ribociclib, or a pharmaceutically acceptable salt thereof. JPEG2025533900000017.jpg46165

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Application No. 63 / 413,475, filed October 5, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Breast cancer is the most frequently diagnosed cancer in women. Approximately 5–10% of cases are metastatic at the time of diagnosis, and nearly 30% of patients with early-stage disease will relapse and develop metastatic disease. (Reinert, T., & Barrios, CH, Therapeutic Advances in Medical Oncology, 7(6), 304–320 (2015); Sini, V., Cinieri, S., Conte, P., Laurentiis, MD, Leo, AD, Tondini, C., & Marchetti, P., Critical Reviews in Oncology / Hematology, 100, 57–68 (2016). Endocrine therapy is the first-line treatment for advanced estrogen receptor-positive cancer. However, most patients develop resistance to endocrine therapy over time. Alternative treatments, such as the selective estrogen receptor degrader fulvestrant, exist, but their potential is limited due to poor bioavailability. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Reinert, T., & Barrios, CH, Therapeutic Advances in Medical Oncology, 7(6), 304-320(2015) [Non-patent document 2] Sini, V., Cinieri, S., Conte, P., Laurentiis, MD, Leo, AD, Tondini, C., & Marchetti, P., Critical Reviews in Oncology / Hematology, 100, 57-68 (2016) Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides, inter alia, methods for treating, stabilizing, or reducing the severity or progression of estrogen receptor-mediated diseases, disorders, and conditions through the administration of orally bioavailable estrogen receptor antagonists and orally bioavailable CDK4 / 6 inhibitors. In some embodiments, the present disclosure provides a method of treating an estrogen receptor mediated disease in a subject, comprising administering Compound 1, [ka] or a pharmaceutically acceptable salt thereof, in combination with a composition comprising ribociclib or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the present disclosure provides Compound 1, [ka] or a pharmaceutically acceptable salt thereof and a composition comprising ribociclib or a pharmaceutically acceptable salt thereof, optionally the kit comprising a label indicating that Compound 1 and ribociclib are useful for the treatment of estrogen receptor-mediated diseases, disorders, and conditions. [Brief explanation of the drawings]

[0006] [Figure 1A]1 is a plot illustrating the mean (SD) Compound 1 plasma concentration versus time profiles following a single oral dose of 30 mg Compound 1 as monotherapy and in combination with 600 mg ribociclib.

[0007] [Figure 1B] 1 is a plot illustrating the mean (SD) Compound 1 plasma concentration vs. time profiles following a single oral dose of 60 mg Compound 1 as monotherapy and in combination with 600 mg ribociclib.

[0008] [Figure 1C] 1 is a plot illustrating the mean (SD) Compound 1 plasma concentration versus time profiles following a single oral dose of 120 mg Compound 1 as monotherapy and in combination with 600 mg ribociclib.

[0009] [Figure 2A] 1 is a plot illustrating the steady-state Compound 1 plasma concentration vs. time profile of 30 mg of Compound 1 in combination with 600 mg of ribociclib, and the mean (SD) Compound 1 steady-state plasma concentration vs. time profile of 30 mg of Compound 1 as monotherapy.

[0010] [Figure 2B] 1 is a plot illustrating the steady-state Compound 1 plasma concentration vs. time profile of 60 mg of Compound 1 in combination with 600 mg of ribociclib, and the mean (SD) Compound 1 steady-state plasma concentration vs. time profile of 60 mg of Compound 1 as monotherapy.

[0011] [Figure 3] FIG. 1 is a plot illustrating the geometric mean (SD) ribociclib plasma pharmacokinetic parameters following a single oral dose of 600 mg ribociclib as monotherapy and in combination with three different doses of Compound 1.

[0012] [Figure 4]FIG. 1 is a plot illustrating steady-state geometric mean (SD) ribociclib plasma dose-normalized pharmacokinetic parameters of 600 mg of ribociclib as monotherapy and in combination with two different doses of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure provides, inter alia, a method for treating an estrogen receptor-mediated disease in a subject, comprising administering a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a composition comprising ribociclib, or a pharmaceutically acceptable salt thereof. In particular, the present disclosure encompasses the insight that certain synergistic effects may be achieved when combining Compound 1 and ribociclib when treating an estrogen receptor-mediated disease, compared to administering Compound 1 or ribociclib alone.

[0014] definition About: As used herein, the term "about" refers to a value that is similar relative to a reference value. Generally, a person skilled in the art familiar with the context will understand the degree of variation encompassed by "about" in that context. For example, in some embodiments, the term "about" can encompass a range of values ​​that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value. In some embodiments, "about" refers to ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the reference value.

[0015] Administration: As used herein, the term "administration" typically refers to administering a composition to a subject or system, e.g., to effect delivery of an agent that is, is contained in, or is otherwise delivered by the composition.

[0016] Agent: As used herein, the term "agent" refers to an entity (e.g., a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or a complex, combination, mixture, or system thereof [e.g., cell, tissue, organism]), or a phenomenon (e.g., heat, current or electric field, magnetic force or field, etc.).

[0017] Antagonist: As used herein, the term "antagonist" may refer to an agent or condition whose presence, level, degree, type, or form is associated with a decrease in the level or activity of a target. Antagonists may include any chemical class of agent, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or other entities that exhibit relevant inhibitory activity. In some embodiments, an antagonist may be a "direct antagonist" in that it binds directly to its target, and in some embodiments, an antagonist may be an "indirect antagonist" in that it affects its target by means other than direct binding (e.g., by interacting with a modulator of the target such that the level or activity of the target is altered). In some embodiments, an "antagonist" may be referred to as an "inhibitor."

[0018] Associated: As used herein, two events or entities are "associated" with one another when the presence, level, degree, and / or form of one correlates with that of the other. For example, a particular entity (e.g., a polypeptide, gene signature, metabolite, microorganism, etc.) is considered associated with a particular disease, disorder, or condition when its presence, level, and / or form correlates (e.g., across a relevant population) with the occurrence and / or susceptibility of the disease, disorder, or condition. In some embodiments, two or more entities are physically "associated" with one another when they are in physical proximity to one another and / or interact, directly or indirectly, to remain in physical proximity. In some embodiments, two or more entities that are physically associated with one another are covalently bound to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently bound to one another but are non-covalently associated by, for example, hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0019] Biological sample: As used herein, the term "biological sample" typically refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture), as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample is or includes a biological tissue or biological fluid. In some embodiments, the biological sample can be or include bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing body fluids, suspended nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural effusion, feces, lymph, gynecological fluids, skin swabs, vaginal swabs, oral swabs, nasal swabs, washings or lavage fluids, such as ductal lavage or bronchoalveolar lavage, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other body fluids, secretions, and / or excretions, and / or cells derived therefrom, and the like. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells derived from the individual from whom the sample is obtained. In some embodiments, a sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, a primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, stool, etc.), and the like. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components thereof and / or adding one or more agents thereto), such as filtration using a semipermeable membrane. Such a "processed sample" may comprise, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0020] Biomarker: The term "biomarker" is used herein, consistent with its usage in the art, to refer to an entity (or a form thereof) whose presence or level correlates with a particular biological event or condition of interest such that it is considered a "marker" for that event or condition. To give just a few examples, in some embodiments, a biomarker may be or include a marker of a particular disease state, or a marker of the likelihood that a particular disease, disorder, or condition may develop, occur, or recur. In some embodiments, a biomarker may be or include a marker of a particular disease or treatment outcome, or the likelihood thereof. Thus, in some embodiments, a biomarker has predictive capabilities of a relevant biological event or condition of interest; in some embodiments, a biomarker has prognostic capabilities; and in some embodiments, a biomarker has diagnostic capabilities.

[0021] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); and in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents, or active portions thereof, may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0022] Comparability: As used herein, the term "comparability" refers to two or more agents, entities, circumstances, sets of conditions, etc. that may not be identical to one another, but are sufficiently similar to permit comparisons between them, so that one of skill in the art will understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, a comparable set of conditions, circumstances, individuals, or populations is characterized by multiple substantially identical characteristics and one or a few different characteristics. One of skill in the art will understand, in context, the degree of identity required for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered comparable in any given situation. For example, one of skill in the art will understand that sets of circumstances, individuals, or populations are comparable to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicate variations in the different characteristics.

[0023] Corresponding: As used herein, the phrase "corresponding" refers to a relationship between two entities, events, or phenomena that share sufficient characteristics to be reasonably similar, such that the "corresponding" attribute is apparent. For example, in some embodiments, the term may be used with respect to a compound or composition to designate the location and / or identity of a structural element in the compound or composition through comparison to an appropriate reference compound or composition. For example, in some embodiments, a monomer residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as "corresponding" to a residue in an appropriate reference polymer. For example, those skilled in the art will understand that, for simplicity's sake, residues in polypeptides are often designated using a standard numbering system based on a reference related polypeptide, such that an amino acid "corresponding" to, for example, residue 190 need not actually be the 190th amino acid in a particular amino acid chain, but rather corresponds to the residue found at position 190 in the reference polypeptide. Those skilled in the art will readily understand how to identify "corresponding" amino acids. For example, one of skill in the art will recognize a variety of sequence alignment strategies, including, for example, software programs such as BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE, which can be utilized to identify "corresponding" residues in polypeptides and / or nucleic acids according to the disclosure.

[0024] Dosage form or unit dosage form: Those of skill in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a unit dosage (or an entire fraction thereof) appropriate for administration according to a dosing regimen that has been determined to correlate with a desired or beneficial outcome (i.e., a therapeutic dosing regimen) when administered to a relevant population. Those of skill in the art will understand that the total amount of a therapeutic composition or agent to be administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0025] Dosing regimen or treatment regimen: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a set of (typically more than one) unit doses, typically separated by a period of time, administered individually to a subject. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by periods of the same length, and in some embodiments, a dosing regimen includes multiple doses and at least two different periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose in a first dosage amount, followed by one or more additional doses in a second dosage amount that is different from the first dosage amount. In some embodiments, the dosing regimen comprises a first dose in a first dosage amount, followed by one or more additional doses in a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0026] Excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0027] Improved, increased, or reduced: As used herein, the terms "improved," "increased," or "reduced," or grammatical equivalents thereof, refer to a value relative to a comparable reference measurement. For example, in some embodiments, an assessment achieved with an agent of interest may be "improved" compared to an assessment obtained with a comparable reference agent. Alternatively, or additionally, in some embodiments, an assessment achieved in a subject or system of interest may be "improved" compared to an assessment obtained in the same subject or system under different conditions (e.g., before or after an event such as administration of the agent of interest), or in a different comparable subject (e.g., in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or in a comparable subject or system different from the subject or system of interest that has previously been exposed to a condition, agent, etc.).

[0028] Oral: As used herein, the phrases "oral administration" and "orally administered" have their art-recognized meaning to refer to administration of a compound or composition by mouth.

[0029] Parenteral: As used herein, the phrases "parenteral administration" and "parenterally administered" have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, intrathecal, intrathecal, and intrasternal injection and infusion.

[0030] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions are or can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0031] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a therapeutic regimen to a relevant subject (e.g., in an amount demonstrated to exhibit a statistically significant probability of achieving a predetermined therapeutic effect when administered) or in a different comparable subject (e.g., in a comparable subject or system different from the subject or system of interest, in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or previously exposed to a condition, agent, etc.). In some embodiments, the term comparable refers to a statistically relevant difference (e.g., a difference of sufficient generality and / or magnitude to achieve statistical relevance). One of skill in the art will recognize or be able to readily determine the degree and / or generality of difference necessary or sufficient to achieve such statistical significance in a given context.

[0032] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic compatible substances used in pharmaceutical formulations.

[0034] The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable salt: a salt of such a compound that is suitable for use in a pharmaceutical context, i.e., a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. In some embodiments, pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0035] Prevent or Prophylaxis: As used herein, the terms "prevent" or "prevention," when used in the context of the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete when the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0036] Reference: As used herein, the term "reference" refers to a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as understood by those of skill in the art, a reference or control is determined or characterized under conditions or circumstances comparable to those to be evaluated. Those of skill in the art will understand when there is sufficient similarity to justify reliance on and / or comparison to a particular reference or control considered.

[0037] Small molecule: As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, 2 kD, or 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0038] In some embodiments, the small molecule does not comprise a polymer moiety. In some embodiments, the small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, the small molecule is not and / or does not comprise a polysaccharide (e.g., in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, the small molecule is not a lipid.

[0039] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0040] Those of skill in the art will understand, upon reading this disclosure, that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms, such as, for example, crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0041] Those skilled in the art will appreciate that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer, or geometric isomer, or in the form of a mixture of stereoisomers; in some embodiments, such small molecules may be utilized in accordance with the present disclosure in the form of a racemic mixture.

[0042] Those skilled in the art will recognize that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in individual tautomeric forms or in forms that interconvert between tautomeric forms.

[0043] Those skilled in the art will appreciate that certain small molecule compounds may contain isotopic substitutions (e.g., 2 H or 3 H (for H), 11 C. 13 C, or 14 C( 12 Regarding C), 13 N or 15 N( 14 N), 17 O or 18 O( 16 Regarding O), 36 Cl( 35 / 37 Cl), 18 F( 19 Regarding F), 131 I( 127It will be understood that such small molecules have a structure that allows for isotopically modified forms, such as for I. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0044] In some embodiments, a reference to a particular small molecule compound may refer to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., an acid addition or base addition salt form, depending on the compound), and in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0045] In some embodiments, if a small molecule compound is naturally occurring or found in nature, the compound may be provided and / or utilized in accordance with the present disclosure in a form that differs from the form in which it naturally occurs or is found in nature. One of skill in the art will understand that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound or a particular form thereof (e.g., with respect to other components of the preparation, including other forms of the compound) that differs from the absolute or relative amount of the compound or form present in a reference preparation of interest (e.g., a primary sample from a source of interest, such as a biological or environmental source) will be distinct from the compound as it is present in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered a different form of the compound from a racemic mixture of the compound, a particular salt of a small molecule compound may be considered a different form of the compound from another salt form of the compound, a preparation containing only a form of the compound that contains one conformer of the double bond ((Z) or (E)) may be considered a different form of the compound from one that contains the other conformer of the double bond ((E) or (Z)), a preparation in which one or more atoms are isotopes different from those present in a reference preparation may be considered a different form, etc.

[0046] Therapeutic Agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that induces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by various criteria, such as a particular age group, sex, genetic background, pre-existing clinical condition, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay the onset, reduce the severity, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is a drug that has been, or needs to be, approved by a government agency before it can be commercially available for administration to humans. In some embodiments, a "therapeutic agent" is a drug that requires a pharmaceutical prescription for administration to humans.

[0047] Treat: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who show only early signs of the disease, disorder, and / or condition, for example, to reduce the risk of developing pathology associated with the disease, disorder, and / or condition.

[0048] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. As will be appreciated by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cell or tissue. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorate, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0049] The compounds referred to herein may contain deuterium ( 2 It will be understood by one of ordinary skill in the art that the compound may be enriched with one or more isotopes such as, but not limited to, H or D.

[0050] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain chiral centers, which may be in either the (R) or (S) configuration, or may include mixtures thereof, unless otherwise specified. Accordingly, the present application includes, where applicable, stereoisomers of the compounds described herein, individually or mixed in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials or by separating isomers of the compounds of the present application.

[0051] Methods for treating estrogen receptor-mediated diseases The present disclosure relates to, inter alia, methods of treating estrogen receptor mediated diseases, disorders, and conditions, comprising administering to a patient in need of treatment Compound 1, [ka] or a pharmaceutically acceptable salt thereof, and ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 and ribociclib are administered to a patient as separate compositions, each comprising one or more suitable pharmaceutically acceptable excipients.

[0052] The present disclosure encompasses the insight that certain synergistic effects may be achieved when Compound 1 and ribociclib are administered together to patients suffering from an estrogen receptor-mediated disease, disorder, or condition. The claimed methods may offer advantages over currently available treatments, such as fulvestrant, because both Compound 1 and ribociclib are orally bioavailable and can be administered to patients in any suitable form, including as a capsule or tablet.

[0053] Estrogen receptors ("ER") are involved in a variety of biological processes, such as those related to the development of the female reproductive system, the maintenance of bone mass, and the protection of cardiovascular and / or central nervous system components (see, e.g., Pearce & Jordan Crit. Rev. Onc / Hem 50:3, 2004; Heldring Phys. Rev. 87:905, 2007). ERs are involved in a variety of cancers. Many tumors express estrogen receptors (i.e., ER tumors, also referred to herein as hormone-positive or HR+ tumors). +In tumors (e.g., breast tumors), active ERα signaling has been demonstrated to cause cell proliferation (although it has been reported that ERβ signaling can achieve tumor-suppressive effects; see, e.g., Nilsson & Gustafson Clin. Pharmacol. Ther. 89:44, 2011). Typically, tumors (e.g., breast tumors) in which only 1% of cells stain positive for ER are considered to be "ER-positive." + Therapies that target ER are classified as + It is the standard treatment for many patients with tumors (see, e.g., Cardoso et al. Annals Onc. https: / / doi.org / 10.1093 / announc / mdmx036, 2017; Rugo et al. J. Clin. Oncol. 34:3069, 2016; Senkus et al. Annal Onc. 26:v8, 2015; Sareddy & Vadlamudi Clin. J Nat. Med, 13:801, 2015). For example, for patients with early-stage breast cancer, the recommended therapy typically involves tumor resection followed by ER-targeted therapy (e.g., as discussed below). For advanced breast cancer, including metastatic breast cancer, ER-targeted therapy is the primary treatment.

[0054] In particular, the presence or expression of certain ER mutations has been reported to affect the efficacy of various ER-targeted therapies (see, e.g., Jeselsohn et al. Nature Rev. Clin. Onc. 12, 573, 2015; Gelsomino et al. Breast Cancer Res. Treat 157:253, 2016; Toy et al. 2013). Some particularly problematic mutations are those that "activate" one or more aspects of ER expression and / or function, and some activating mutations have been reported to render ER ligand-independent (i.e., constitutively active). For example, certain mutations in the ER ligand-binding domain, including D538G and Y537S, have been demonstrated to constitutively activate ER, and other mutations, including deletions and / or fusions that remove the ligand-binding domain, may have similar effects (see, e.g., Li et al. Cell Replicates 4:1116, 2013; Veeraraghavan et al. Breast Cancer Research and Treatment 158, 219-232, 2016; Veeraraghavan, et al. Nature Comms 5:4577, 2014). Some reports indicate that as many as 50% of women with metastatic breast cancer may have activating ER mutations detectable in circulating tumor DNA.

[0055] Nevertheless, regardless of the mechanism of action of a particular agent, clinical experience to date has demonstrated that incomplete efficacy (e.g., within individual patients and / or across patient populations) and / or the development of resistance remain problems.

[0056] In some embodiments described herein, the estrogen receptor-mediated disease is cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer (e.g., breast cancer) has metastasized to another organ (e.g., brain, bone, lung, and / or liver). In some embodiments, the organ with the metastasis is the subject's brain. In some embodiments, the organ with the metastasis is the subject's bone. In some embodiments, the organ with the metastasis is the subject's lung. In some embodiments, the organ with the metastasis is the subject's liver.

[0057] In some embodiments, the subject has HR+ / HER2- metastatic breast cancer. In some embodiments, the subject has cancer that has metastasized to another organ (e.g., brain, lung, liver, and / or bone). In some embodiments, the subject has histologically or cytologically confirmed advanced or metastatic breast cancer (e.g., for which no standard cure exists).

[0058] In some embodiments, the subject suffering from the disease described herein has previously received endocrine therapy. In some embodiments, the subject has received at least six months of previous continuous endocrine therapy for locally advanced or metastatic breast cancer. In some embodiments, the subject has received no more than two previous hormone regimens for advanced or metastatic disease.

[0059] In some embodiments, the subject suffering from a disease described herein has previously received chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease). In some embodiments, the subject has previously received no more than one chemotherapy regimen for locally advanced or metastatic breast cancer.

[0060] In some embodiments, the subject has previously received at least one of a CDK4 / 6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.

[0061] compound 1 In some embodiments, the present disclosure recognizes the particular utility of Compound 1, which is a complete estrogen receptor antagonist. In some embodiments, a "complete estrogen receptor antagonist," as that term is used herein, is characterized by complete antagonism of the estrogen receptor, with no or minimal residual estrogen receptor agonist activity. For example, a complete estrogen antagonist is understood to be a drug (e.g., a small molecule compound) that exhibits ER antagonism but not ER agonism in one or more of the following assays: ERα protein level assay, MCF-7 cell line assay, Ishikawa cell line assay (measuring wild-type ER and certain mutants, including mutants lacking the AF1 and / or AF2 domains), and rodent uterine weight gain assay. Generally, see WO2017 / 059139. Alternatively or additionally, in some embodiments, a full estrogen receptor antagonist has three characteristics: (1) it inhibits both activating function 1 (AF1) and activating function 2 (AF2), because full anti-estrogen activity requires inactivation of both AF1 and AF2, (2) it promotes ER degradation, and (3) it lacks the partial ER agonist activity observed with certain other agents. Without being bound by theory, it is understood that full inhibition of both AF1 and AF2 is required for full estrogen receptor activity because activating mutations in the gene encoding estrogen receptor 1 allow activation of both AF1 and AF2 even in the absence of estrogen.

[0062] Given the importance of ER signaling in many cancers, as well as certain cardiovascular, inflammatory, and neurodegenerative diseases, significant efforts have been invested in the development of ER-targeting therapeutic agents and modalities. While there is some fluidity / flexibility in the terminology used to describe ER-targeting agents, a variety of agents with different mechanisms are being developed and / or investigated.

[0063] Currently, fulvestrant is the only approved therapy that possesses each of the characteristics of a full estrogen receptor antagonist described above, but fulvestrant suffers from a number of drawbacks, including low oral bioavailability and an inability to cross the blood-brain barrier.

[0064] compound 1 [ka] is an orally bioavailable complete estrogen receptor antagonist ("CERAN") that overcomes the shortcomings of fulvestrant. Compound 1 is described in WO 2017 / 059139 as Compound B, otherwise known as (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The synthesis and certain attributes of Compound 1 are reported in WO 2017 / 059139.

[0065] Compound 1 potently competes with the endogenous activating estrogen ligand 17-β estradiol for binding in the ligand-binding pocket. Compound 1 blocks estrogen-driven transcriptional activity, inhibits estrogen-driven breast cancer cell proliferation, and induces ER degradation. Compound 1, as CERAN, completely inactivates the ER by both completely inactivating the ER and degrading it, as well as by inactivating both activating function 1 (AF1) and activating function 2 (AF2) transcriptional activation functions. Compound 1 robustly degrades estrogen receptors in ER+ cell lines. In vivo studies demonstrated that compound 1 has no agonist activity in the uterus of immature ovariectomized mice and blocks estrogen-driven uterine weight gain. Previous therapies, such as traditional selective estrogen receptor degraders (SERDs), which degrade only the ER, or selective estrogen receptor modulators (SERMs), which have mixed agonist and antagonist effects, are unable to achieve the complete estrogen receptor antagonism achieved by Compound 1.

[0066] Unless otherwise indicated, as used herein, "Compound 1" refers to Compound 1 in any available form, such as, for example, a salt form and / or solid form. Accordingly, reference to an amount of Compound 1 (e.g., in mg) will be understood to mean the amount of Compound 1 in free base form. Thus, Compound 1 may be provided and / or utilized, for example, as a salt form of Compound 1, such that the amount of salt (or other form) is an amount corresponding to the "free base equivalent" of Compound 1.

[0067] In some embodiments, a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof further comprises one or more pharmaceutically acceptable carriers or excipients. For example, the pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is customary, additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0068] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.

[0069] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings (i.e., buffers), and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, i.e., preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0070] In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 90 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg.

[0071] In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 360 mg (QD) per day. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 360 mg (QD) per day. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 300 mg (QD) per day. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 120 mg (QD) per day. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg to about 120 mg (QD) per day. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 90 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg QD.

[0072] In some embodiments, Compound 1 is administered to a subject in a unit dosage form. In some embodiments, the unit dosage form is a capsule or a tablet. In some embodiments, the unit dosage form comprises about 15 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form comprises about 15 mg to about 100 mg of Compound 1. In some embodiments, the unit dosage form comprises about 60 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form comprises about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of Compound 1. In some embodiments, the unit dosage form comprises about 15 mg of Compound 1. In some embodiments, the unit dosage form comprises about 30 mg of Compound 1. In some embodiments, the unit dosage form comprises about 60 mg of Compound 1. In some embodiments, the unit dosage form comprises about 90 mg of Compound 1. In some embodiments, the unit dosage form comprises about 120 mg of Compound 1. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0073] In some embodiments, the total daily dose of Compound 1 administered to a subject is about 15 mg to about 360 mg QD per day. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg to about 360 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg to about 300 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg to about 120 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 60 mg to about 120 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 15 mg to about 100 mg QD. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg QD. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 60 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 90 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 120 mg.

[0074] In some embodiments, Compound 1 is administered to a subject once daily for a 28-day cycle. In some embodiments, Compound 1 is administered to a subject once daily for two 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily for three, four, five, or more 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily for six, seven, eight, nine, ten, eleven, twelve, or more 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily until disease symptoms are no longer measurable. In some embodiments, Compound 1 is administered for the lifetime of the subject. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a drug holiday. As used herein, a "drug holiday" refers to a period during which a drug (e.g., Compound 1) is not administered to a subject. In some embodiments, the drug holiday is one day, one week, or one 28-day cycle. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a drug holiday, after which administration of Compound 1 resumes once daily at the same dose level as before the drug holiday.

[0075] Ribociclib Ribociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Ribociclib has the following structure: [ka] Ribociclib is also known as 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. Ribociclib is approved for the treatment of hormone receptor-positive (e.g., HR+ or ER+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with (i) an aromatase inhibitor as initial endocrine therapy or (ii) fulvestrant as initial endocrine therapy or after disease progression on endocrine therapy in postmenopausal women or men. Full prescribing information for ribociclib can be found in the KISQALI® labeling at www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 209092s008lbl.pdf, which is incorporated herein by reference in its entirety.

[0076] Ribociclib is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. These kinases are activated upon binding to D-cyclins and play a key role in signaling pathways leading to cell cycle progression and cell proliferation. The cyclin D-CDK4 / 6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib reduced pRb phosphorylation, leading to G1 cell cycle arrest and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single-agent ribociclib in rat xenograft models bearing human tumor cells led to a reduction in tumor volume, which correlated with the inhibition of pRb phosphorylation. In a study using a patient-derived estrogen receptor-positive breast cancer xenograft model, the combination of ribociclib and antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared with each drug alone. Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor-positive breast cancer xenograft model.

[0077] In some embodiments, a composition comprising ribociclib or a pharmaceutically acceptable salt thereof may be provided and / or utilized in any suitable pharmaceutical composition or dosage form. In some embodiments, a composition comprising ribociclib or a pharmaceutically acceptable salt thereof may further comprise one or more pharmaceutically acceptable carriers or excipients. For example, the pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions.

[0078] In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is provided and / or utilized in a film-coated tablet for oral use. In some embodiments, tablets containing ribociclib or a pharmaceutically acceptable salt thereof also contain one or more of colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, magnesium stearate, or microcrystalline cellulose. In some embodiments, tablets containing ribociclib or a pharmaceutically acceptable salt thereof are coated with a film coating comprising one or more of black iron oxide, red iron oxide, lecithin (soy), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and xanthan gum.

[0079] Unless otherwise indicated, as used herein, "ribociclib" refers to ribociclib in any available form, such as, for example, a salt form and / or solid form. Accordingly, references to an amount of ribociclib (e.g., in mg) will be understood to mean the amount of ribociclib in free base form. Thus, ribociclib may be provided and / or utilized, for example, as a salt form of ribociclib, such that the amount of the salt (or other form) is an amount corresponding to the "free base equivalent" of ribociclib.

[0080] In some embodiments, ribociclib is provided and / or utilized in salt form. For example, in some embodiments, ribociclib is provided as ribociclib succinate: [ka] provided and / or used as. Ribociclib succinate is also known as butanedioic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1).

[0081] In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg to about 800 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 500 mg to about 700 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 600 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 400 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg.

[0082] In some embodiments, ribociclib is administered to a subject in an amount that is about 200 mg to about 800 mg QD per day. In some embodiments, ribociclib is administered to a subject in an amount that is about 500 mg to about 700 mg QD per day. In some embodiments, ribociclib is administered to a subject in an amount that is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg QD per day. In some embodiments, ribociclib is administered to a subject in an amount that is about 600 mg QD. In some embodiments, ribociclib is administered to a subject in an amount that is about 400 mg QD. In some embodiments, ribociclib is administered to a subject in an amount that is about 200 mg QD.

[0083] In some embodiments, ribociclib is administered to a subject in a unit dosage form. In some embodiments, the unit dosage form is a capsule or a tablet. In some embodiments, the unit dosage form contains about 150 mg to about 250 mg of ribociclib. In some embodiments, the unit dosage form contains about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg of ribociclib. In some embodiments, the unit dosage form contains about 200 mg of ribociclib. In some embodiments, the unit dosage form contains about 254.4 mg of ribociclib succinate. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0084] In some embodiments, the total daily dose of ribociclib administered to a subject is about 200 mg to about 800 mg. In some embodiments, the total daily dose of ribociclib administered to a subject is about 500 mg to about 700 mg. In some embodiments, the total daily dose of ribociclib administered to a subject is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, the total daily dose of ribociclib administered to a subject is about 600 mg. In some embodiments, the total daily dose of ribociclib administered to a subject is about 400 mg. In some embodiments, the total daily dose of ribociclib administered to a subject is about 200 mg.

[0085] In some embodiments, ribociclib is administered to a subject once daily for 21 days of a 28-day cycle (i.e., once daily for 21 days followed by a 7-day drug holiday).

[0086] Combination therapy The present disclosure recognizes that certain drug combinations can be beneficially used to completely antagonize estrogen receptors. Thus, in some embodiments, the present disclosure provides a method for treating a subject suffering from an ER-related disorder (e.g., cancer or breast cancer), comprising administering Compound 1 or a pharmaceutically acceptable salt thereof in combination with ribociclib or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the present disclosure provides a combination therapy comprising administration of Compound 1 and ribociclib. In some embodiments, the present disclosure encompasses the insight that certain synergistic effects may be achieved when combining Compound 1 and ribociclib when treating estrogen receptor-mediated diseases compared to administration of Compound 1 or ribociclib administered alone.

[0088] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject, once daily, about 15 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 200 mg to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject, once daily, about 30 mg to about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject, once daily, about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject once daily about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject once daily about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject once daily about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof in combination with about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, Compound 1 is administered daily for a 28-day cycle and ribociclib is administered daily for 21 days of the 28-day cycle (i.e., the same 28-day cycle). In some embodiments, Compound 1 and ribociclib are administered for 1, 2, 3, 4, 5, or more 28-day cycles.

[0090] It is understood that Compound 1 and ribociclib can be administered simultaneously or separately. For example, in some embodiments, Compound 1 and ribociclib are administered simultaneously. In some embodiments, Compound 1 and ribociclib are administered at approximately the same time each day (e.g., for the first 21 days of a 28-day cycle). In some embodiments, ribociclib is administered before administration of Compound 1. In some embodiments, ribociclib is administered after administration of Compound 1.

[0091] In some embodiments, the present disclosure provides methods comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to a subject who has received or is receiving ribociclib (e.g., according to a regimen provided herein). In some embodiments, the present disclosure provides methods comprising administering ribociclib to a subject who has received or is receiving Compound 1 (e.g., according to a regimen provided herein).

[0092] In some embodiments, the disclosure provides an improved method of treating a disease, disorder, or condition comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, and ribociclib in combination, wherein the improvement comprises administering about 30 mg to about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement further comprises administering about 600 mg of ribociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement comprises administering 30 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement comprises administering 60 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement comprises administering 90 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement comprises administering 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the methods described herein further comprise administering letrozole or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein further comprise administering about 2.5 mg of letrozole or a pharmaceutically acceptable salt thereof.

[0094] kit In some embodiments, the disclosure provides a kit comprising one or more compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more compositions comprising ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising about 30 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 200 mg to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises a composition comprising about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit comprises packaging material comprising a label indicating that Compound 1 and ribociclib can be used to treat an estrogen receptor-mediated disease, disorder, or condition. [Example]

[0095] Example 1. A Phase 1b, Open-Label, Multicenter Study of Compound 1 in Combination with the CDK4 / 6 Inhibitor Ribociclib in Adult Subjects with Advanced and / or Metastatic HR-Positive, HER2-Negative Breast Cancer This example provides a Phase 1b, open-label, two-part study of Compound 1 in combination with ribociclib.

[0096] This study was designed to determine dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), and / or recommended phase 2 doses (RP2Ds), and to characterize the safety and pharmacokinetic (PK) profile of Compound 1 in combination with ribociclib in adult subjects with hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Subjects will receive treatment and be evaluated in 28-day cycles.

[0097] This embodiment includes two parts.

[0098] Part 1 (Dose Escalation): This part will evaluate the safety and pharmacokinetics of a range of doses of Compound 1 administered PO QD to subjects in combination with 600 mg of ribociclib administered orally (PO) once daily (QD) to determine the (RP2D). The dose escalation study design will include cohorts of 3-6 evaluable subjects who will be consecutively enrolled and monitored for DLTs during the first cycle of study treatment. In the cohort safety review, PK and safety events will be reviewed, and DLT observations may be extended for up to two cycles.

[0099] Part 2 (Dose Expansion): This part of the study further evaluates the safety and pharmacology of compound 1 at the RP2D in combination with ribociclib and provides a preliminary estimate of the antitumor activity of the combination.

[0100] The objectives of Part 1 (dose escalation) of this study are as follows: Main Objective • To identify dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and / or RP2D of Compound 1 when administered in combination with ribociclib. To evaluate the safety and tolerability of Compound 1 when administered in combination with ribociclib. To evaluate the PK of Compound 1 and ribociclib when administered in each combination. Secondary Objectives To preliminarily evaluate the antitumor activity (ORR, defined as confirmed complete response [CR] + confirmed partial response [PR]) of compound 1 when administered in combination with ribociclib, as assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). To estimate the CBR (CR+PR+SD≥24 weeks) of Compound 1 when administered in combination with ribociclib. To estimate the duration of response (DoR) of Compound 1 in subjects with HR+ / HER2- metastatic or locally advanced breast cancer without evidence of CNS metastasis who have progressed after receiving at least one hormonal therapy regimen in the metastatic or locally advanced setting. Preliminary Purpose To evaluate the pharmacodynamic effects of treatment with compound 1 on biomarkers in plasma and ctDNA. • To correlate biomarkers of ERα and PR expression with the clinical activity of Compound 1.

[0101] The objectives of the second part of the study (dose expansion) are as follows: Main Objective To characterize the safety and tolerability of Compound 1 at the RP2D when administered in combination with ribociclib. To characterize the PK of compound 1 and ribociclib at RP2D. Secondary Objectives To exploratory evaluate the antitumor activity (ORR, defined as confirmed complete response [CR] + confirmed partial response [PR]) of Compound 1 when administered in combination with ribociclib, as assessed by the investigator using RECIST v1.1. To estimate the CBR of Compound 1 in subjects with HR+ / HER2- metastatic or locally advanced breast cancer without evidence of CNS metastases who have progressed after receiving at least one hormonal therapy regimen in the metastatic or locally advanced setting. To estimate the duration of response (DoR) of Compound 1 in subjects with HR+ / HER2- metastatic or locally advanced breast cancer without evidence of CNS metastasis who have progressed after receiving at least one hormonal therapy regimen in the metastatic or locally advanced setting. Preliminary Purpose To evaluate the pharmacodynamic effects of treatment with compound 1 on biomarkers in plasma and ctDNA. • To correlate biomarkers of ERα and PR expression with the clinical activity of Compound 1.

[0102] The endpoints for Part 1 (dose escalation) of the study were: Primary endpoint • Incidence and severity of DLTs. • The MTD and / or RP2D of Compound 1 when administered in combination with ribociclib. Incidence and severity of TEAEs and SAEs, assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v5.0). ●Maximum concentration (C max ), minimum concentration (C min ), time to maximum concentration (T max ), area under the curve (AUC), half-life (t 1 / 2 ), and plasma levels of Compound 1 (and potential metabolites) and ribociclib at predetermined intervals to establish PK parameters, including trough concentrations of Compound 1 at steady state. Secondary endpoints - ORR as assessed by Tumor Response Assessment using RECIST 1.1. • CBR defined by the proportion of subjects with CR+PR+SD ≥ 24 weeks in subjects without evidence of CNS metastases. Duration of response (DoR) and DoR compared with previous endocrine therapy. Preliminary endpoints • Searching for candidate biomarkers (such as mutESR1, PIK3CA variants, and others) in pre- and post-therapy ctDNA. Preliminary analyses of metabolites of Compound 1 in plasma may also be performed, in which case the results of those analyses will be reported separately by the sponsor. • Percentage of Ki67 in archived or fresh biopsy samples obtained before C1D1. • Quantitative ERα and PR (percentage and Allred score) in biopsy samples obtained in archived or fresh biopsy samples before C1D1.

[0103] The endpoints for the second part of the study (dose expansion) were: Primary endpoint Incidence and severity of TEAEs and SAEs assessed using NCI CTCAE v5.0. Maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), area under the curve (AUC), half-life ( t 1 / 2), and plasma levels of Compound 1 (and potential metabolites) and ribociclib at predetermined intervals to establish PK parameters, including trough concentrations of Compound 1 at steady state. Secondary endpoints ORR as assessed by Tumor Response Assessment using RECIST 1.1 CBR defined as the proportion of subjects with CR+PR+SD ≥ 24 weeks in subjects without evidence of CNS metastases DoR, time to progression, and progression-free survival (PFS) in subjects without evidence of CNS metastases Preliminary endpoints • To explore candidate biomarkers (such as mutESR1, PIK3CA variants, and others) in ctDNA before and after therapy with compound 1. • Preliminary analyses of metabolites of Compound 1 in plasma may also be performed, in which case the results of those analyses will be reported separately by the sponsor. • Percentage of Ki67 in archived or fresh biopsy samples obtained before C1D1. • Quantitative ERα and PR (percentage and Allred score) in biopsy samples obtained in archived or fresh samples before C1D1. Selection Criteria

[0104] Subjects eligible to participate in the study must meet all of the following criteria: 1. Female or male aged ≥ 18 years. 2. Willing and able to participate, comply with all study requirements, and provide signed and dated informed consent prior to the initiation of any study procedures. 3. Histologically or cytologically confirmed locally advanced or MBC for which no standard curative measures exist. 4. HR+ / HER2- disease as determined on a most recently obtained archived tumor tissue sample from a metastatic site using locally accepted criteria according to local pathology reporting. 5. Evaluable disease (measurable and non-measurable). Measurable disease, i.e., at least one measurable lesion by RECIST 1.1 (lesions in previously irradiated sites may only be counted as target lesions if there is clear evidence of progression since irradiation). 6. Received at least 6 months of prior continuous endocrine therapy for locally advanced or metastatic disease. 7. Life expectancy ≥ 6 months as determined by the investigator. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 8.0 or 1. 9. Women of childbearing potential must be willing to adhere to highly effective contraception. Highly effective methods of contraception include: i. Total abstinence (if this is consistent with the subject's preferred usual lifestyle). Cyclic abstinence (e.g., calendar, ovulation, symptom-temperature, post-ovulation methods) and pull-out are not acceptable methods of contraception. ii. Female sterilization (having undergone surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy or tubal ligation at least 6 weeks prior to receiving study treatment. In the case of oophorectomy alone, only if the woman's reproductive status has been confirmed by follow-up hormone level assessment. iii. Sterilization of male partner (at least 6 months prior to screening). For female subjects in the study, the vasectomized male partner should be the subject's only partner, and the success of the vasectomy must be medically confirmed according to local practice. iv. Placement of a non-hormonal intrauterine device (IUD). b. Additionally, a woman of childbearing potential must meet all of the following criteria: i. Not being pregnant, as confirmed by a negative serum pregnancy test (β-human chorionic gonadotropin) prior to starting study treatment. ii. Not breastfeeding c. Female subjects are considered to be of childbearing potential unless: i. Age ≥ 60 ii. Have undergone hysterectomy, bilateral tubal ligation, or bilateral oophorectomy iii. Medically confirmed ovarian insufficiency (with serum estradiol and follicle-stimulating hormone levels) iv. Perimenopause (amenorrhea ≥ 12 months) while not using drugs that interfere with ovarian function 10. Male subjects must be willing to adhere to highly effective contraception. A highly effective method of contraception must include one of the following criteria: A successful vasectomy b. For subjects who have not had a successful vasectomy and are the partner of a female of childbearing potential, the partner adheres to one of the following: i. Use of hormonal contraception + spermicide condoms for men ii. IUD (hormonal or non-hormonal) iii. Use of Depo Provera+ male spermicide condoms 11. Premenopausal or perimenopausal female subjects must be willing to take a luteinizing hormone-releasing hormone (LHRH) agonist ≥ 2 weeks prior to the first study drug. 12. Free of proton pump inhibitor (PPI) use for 7 days prior to first study drug dose and agrees to abstain from PPI therapy for the duration of the study. 13. Subject must not have received any previous endocrine or targeted therapy ≤ 2 weeks prior to the first study drug dose. 14. Subject must not have received fulvestrant, chemotherapy, antibody therapy, targeted therapy, or investigational therapy ≤ 4 weeks prior to the first study drug dose. 15. Prior radiation therapy must have been completed at least 2 weeks prior to the first study drug dose with resolution of toxicity ≤ Grade 1 (excluding alopecia). 16. Major surgery with recovery must have been completed at least 4 weeks prior to administration of the first dose of study drug. 17. Any toxicity from prior therapy, except for alopecia, must have resolved to ≤ Grade 1 as defined by NCI CTCAE v5.0 or baseline prior to the first study drug dose. 18. Subjects with brain metastases are eligible for the study if they meet all of the following criteria: Brain metastases are treated or do not require treatment at the time of study enrollment or are unlikely to require treatment during the study. b. Not taking dexamethasone or taking a stable dose of ≤2 mg dexamethasone daily (or an alternative steroid dosed at a level equivalent to ≤2 mg daily) for 4 weeks prior to the first study drug dose. 19. Have any of the following laboratory values ​​within 28 days prior to the first dose of study drug: a. Serum creatinine ≤ upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m 2 It has. b. Total bilirubin ≤ 1.5 x ULN unless there is a history of Gilbert's syndrome, in which case total bilirubin is ≤ 3.0 x ULN or direct bilirubin is ≤ 1.5 x ULN. c. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN if due to tumor-related liver damage. d. No need for red blood cell (RBC) transfusion within the last 4 weeks prior to administration of the first dose of study drug, hemoglobin ≥ 9.0 g / dL. e. Platelet count ≥ 100 × 10 9 cells / L. f. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 cells / L (no use of hematopoietic growth factors within 3 weeks prior to administration of the first dose). g. Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. If receiving chronic anticoagulation therapy, PT and aPTT must be within the therapeutic range. 20. Standard 12-lead ECG values ​​defined as the average of three ECGs. a. QTcF (QT interval corrected for heart rate using Fridericia's correction) <450 msec at screening. b. Average resting heart rate (determined from ECG) of 50 to 90 beats per minute (bpm). 21. Have received ≤2 prior hormonal regimens for advanced or metastatic disease. Prior hormonal regimens in combination with a CDK4 / 6 inhibitor are permitted. 22. Have received ≤1 prior chemotherapy regimen for locally advanced or metastatic disease. 23. The following laboratory values ​​within normal range or corrected to within normal range with supplementation within 24 hours of the first dose of study drug: Potassium B. Magnesium c. Total calcium (corrected for serum albumin) 24. Left ventricular ejection fraction greater than 50% as determined by MUGA or echocardiography.

[0105] Exclusion criteria Subjects who meet any of the following exclusion criteria are ineligible to participate in either the dose escalation or dose expansion portions of the study. 1. Prior or concurrent malignancy whose natural history or treatment may interfere with safety or efficacy evaluation of the investigational regimen, as determined by the medical monitor. 2. Clinically significant uncontrolled cardiac disease and / or cardiac repolarization abnormalities, including any of the following: Myocardial infarction, angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to the first dose of study drug. b. Confirmed cardiomyopathy. c. Long QT syndrome, or family history of idiopathic sudden death or congenital long QT syndrome, or risk factors for torsade de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia, history of heart failure, or clinically significant / symptomatic bradycardia. d. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular block (e.g., bifascicular block, Mobitz type II, and third-degree atrioventricular block). e. Uncontrolled systolic blood pressure >160 or <90mmHg. 3. History of cerebrovascular disease within 6 months prior to the first dose of study drug. 4. History of pulmonary embolism or deep vein thrombosis within the past 6 months, or subject at increased risk for thrombosis as determined by the investigator. (Subjects receiving chronic anticoagulation regimens are permitted.) 5. History of pneumonia or interstitial lung disease (ILD). (Chest computed tomography [CT] scans performed prior to the start of study treatment for tumor evaluation should be reviewed to ensure the absence of relevant pulmonary complications.) 6. Leptomeningeal disease or spinal cord compression. 7. History or ongoing gastrointestinal (GI) disorder that may affect absorption of oral therapeutic agents (such as active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper GI surgery including gastrectomy, and difficulty swallowing capsules). 8. Known human immunodeficiency virus (HIV) infection. 9. Known clinically significant history of liver disease consistent with Child-Pugh class B or C, including active viral or other hepatitis (e.g., hepatitis B or C virus), current alcohol abuse, or cirrhosis. 10. History of severe skin reactions such as Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, or drug reactions accompanied by eosinophilia and systemic symptoms. 11. Active infection requiring antimicrobial therapy or that is clinically significant. 12. Have a clinically significant comorbidity such as an active infection, psychiatric illness, or any other condition that may affect the subject's ability to participate in this study or otherwise confound the study results. 13. Currently receiving any of the following medications and cannot discontinue them 7 days before the start of treatment: Concomitant medications, herbal supplements, grapefruit and its juice, and / or bitter orange and its juice are strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 / 5. b. Drugs with a narrow therapeutic range that are metabolized primarily through CYP3A4 / 5. 14. History of allergic reaction caused by compounds with a similar chemical composition to any investigational drug. 15. Currently receiving or have received systemic corticosteroids ≤ 2 weeks prior to starting study drug or have not fully recovered from the adverse effects of such treatment. a. Note: The following uses of corticosteroids are permitted: i. Short-duration (<5 days) systemic corticosteroids. ii. Topical application of any duration (e.g., rash). iii. Inhalation sprays (e.g., for obstructive airway diseases). iv. Eye drops or local injection (e.g., intra-articular). 16. Currently receiving concomitant medication(s) known to cause TdP that has a known risk of prolonging the QT interval and / or cannot be discontinued or replaced by a safe alternative (e.g., within 5 half-lives or 7 days before starting the study drug). 17. Subject's QTcF cannot be determined.

[0106] Number of planned targets The number of subjects planned for each section is provided below.

[0107] Part 1 (Dose Escalation): Approximately 9-18 subjects are planned to be enrolled, with the exact number of subjects enrolled depending on the dose level at which DLT is seen. Subjects who discontinue Part 1 (Dose Escalation) of the study before completing Cycle 1 (C1) for reasons other than DLT will be replaced.

[0108] Part 2 (Dose Expansion): Twelve subjects will be enrolled in the dose expansion portion of the study. Subjects who discontinue Part 2 (Dose Expansion) of the study before completing at least two cycles of therapy and at least one post-baseline response assessment will be replaced.

[0109] Therefore, a maximum of 30 subjects will be enrolled in this study.

[0110] research treatment All subjects will receive Compound 1 in combination with ribociclib in this study.

[0111] Subjects will take Compound 1 capsules PO QD at approximately the same time on an empty stomach. Subjects should fast for 2 hours before administration of Compound 1 and remain fasted until 1 hour after dosing, except for water, which will be allowed to take the study drug. The cycle will be repeated every 4 weeks (28 days) with continuous dosing of Compound 1.

[0112] Part 1 (dose escalation) Cohorts of 3 to 6 subjects will be enrolled at each Compound 1 dose level, with each subject participating in only one cohort. Subjects at each dose level will be treated and observed for DLTs until the end of the first cycle. Cohort safety reviews will review PK and safety events, and DLT observations may be extended for up to two cycles.

[0113] Given the DLT observed in Cycle 1, a 3+3 dose escalation will follow. Cohorts of 3 to 6 subjects will be treated at each dose level. Three subjects may be enrolled simultaneously at each dose level of the study. The decision to enroll a new subject at the current dose level, the next highest dose level, or the next lowest dose level will be made based on data available at the time of enrollment of the new subject. If two or more DLTs are observed at a given dose level, the dose level will be de-escalated. The decision to escalate to the next highest dose level will be made by the participating investigators and a representative from the sponsor at a cohort review meeting after at least three subjects have completed Cycle 1. Intra-subject dose escalation is not permitted.

[0114] Compound 1 will be administered up to a maximum dose of 120 mg QD.

[0115] Dose escalation of Compound 1 will be performed according to the following dosing schedule: [Table 5]

[0116] Dose-limiting toxicity During C1, subjects will be evaluated for the occurrence of DLTs, which are protocol-defined TEAEs graded by the investigator according to NCI CTCAE v5.0 and deemed by the investigator to be at least possibly related to Compound 1. For each dose group, TEAEs meeting the definition of DLT will be documented separately. During dose escalation cohort safety reviews, PK and safety events will be reviewed, and DLT observation may be extended for up to two cycles.

[0117] Multiple concurrent TEAEs in an individual subject meeting the definition of a DLT will be considered a single DLT.

[0118] Subjects must receive at least 75% of the planned dose of Compound 1 in C1 (at least 21 of 28 doses) to be evaluated for DLT determination. Subjects who receive less than 75% of the planned dose for reasons other than DLT will be replaced. (Subjects who receive <75% of the planned dose in C1 will be evaluated in the overall safety analysis, but not for the purpose of dose escalation.) In such cases, a replacement subject may be enrolled to receive the same starting dose of Compound 1 as the subject who withdrew early.

[0119] Definition of MTD or R2PD For purposes of defining the MTD and / or RP2D of Compound 1, subjects will be evaluated according to their actual starting dose of Compound 1 in C1. For most subjects, this will be the dose cohort to which they were assigned.

[0120] The MTD is defined as the highest feasible dose tested at which <33% (ie, ≦1 in 6) subjects experienced a DLT.

[0121] The RP2D will be determined after review of all available safety and PK data.

[0122] At least one laboratory or vital sign measurement obtained following at least one dose of study drug is required for inclusion in the analysis of specific safety parameters. A baseline measurement is also required to assess change from baseline.

[0123] Duration of treatment In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive study treatment for up to one year at the investigator's discretion, and beyond one year with the investigator and sponsor's consent. Subjects who discontinue Compound 1 must also discontinue ribociclib within the context of this protocol.

[0124] Reference therapy, dose, route, and regimen Ribociclib All subjects will receive Compound 1 in combination with a fixed dose of 600 mg QD ribociclib for the first 21 consecutive days of a 28-day cycle, according to the prescribing information. Subjects should take their ribociclib dose at approximately the same time each day following administration of Compound 1.

[0125] Criteria for evaluation Safety: Safety and tolerability will be assessed by clinical review of all relevant parameters, including AEs, DLTs, laboratory values, ECG results, and vital signs.

[0126] Pharmacokinetics: Pharmacokinetic parameters will be determined for each analyte (Compound 1 and ribociclib) in the PK analysis set using standard compartmental or non-compartmental methods.

[0127] Pharmacodynamics: Pharmacodynamic evaluation will be performed by assessing pre- and post-treatment ctDNA. ctDNA will be assessed for ESR1 mutations and other pathways important for ER activity.

[0128] Efficacy: Radiographic and / or physical assessments of malignancies will be performed at screening / baseline (within 28 days prior to the first study drug dose) and every two cycles. Subjects determined to have achieved clinical benefit from study treatment after the C8 radiological assessment may have the frequency of radiographic and physical assessments reduced to every three months. ORR and CBR, as determined by the subject's best tumor response, duration of response, and time to progression, will be assessed by the investigator using RECIST v1.1. Additional imaging studies and tumor measurements will be performed in subjects who achieve a PR or CR on a second exam ≥ 4 weeks after the initial response determination.

[0129] statistical methods Data collected in this study will be presented using summary tables, data listings, and graphs. Categorical data will be summarized using contingency tables (frequencies and percentages). For continuous data, summary statistics of mean, standard deviation, median, minimum, and maximum will be presented. Baseline will be defined as the last assessment before the first dose of study treatment.

[0130] Safety Analysis: Safety data from Part 1 (dose escalation) will be summarized by dose cohort. Safety data will also be summarized for Part 2 (dose expansion). Safety will be assessed through summaries of AEs, clinical laboratory results, vital signs, and ECOG PS.

[0131] Adverse events will be classified by system organ and preferred term using MedDRA, with severity classified using CTCAE 5.0 criteria. All collected AE data will be listed. All SAEs will also be listed. All TEAEs will be summarized by cohort, regardless of attribution. Hematology, chemistry, and other laboratory changes will be summarized narratively for each scheduled protocol assessment time point. Vital sign results (blood pressure, pulse, respiration, and temperature) will be summarized narratively for each scheduled protocol assessment time point. ECOG performance status shift tables will be provided by cohort and scheduled visit. Analysis of ECG results will be based on subjects in the safety analysis set with baseline and on-treatment ECG data.

[0132] Preliminary Efficacy Analyses: Efficacy and biomarker analyses will be performed on the FAS and efficacy analysis set populations. Results of these analyses will be presented for the overall cohort, by mutESR1 status, and whether the subject received prior CDK4 / 6 inhibitor therapy. For Phase 1, narrative summaries will be presented by cohort. ORR (CR + PR) will be estimated in the dose expansion portion. ORR estimates will be accompanied by two-sided 95% strict confidence intervals. ORR will be determined using RECIST v1.1. CBR (CR + PR + SD > 24 weeks) will be estimated with two-sided 95% strict confidence intervals. All CRs and PRs included in ORR and CBR are confirmed responses. Duration of objective response will be calculated for subjects achieving CR or PR. For such subjects, duration of objective response is defined as the number of days from the start date of PR or CR (first achieved of either response) to the first date of objectively confirmed progressive disease. Disease progression will be determined by the investigator using RECIST v1.1.

[0133] Pharmacokinetic Analysis: Pharmacokinetic parameters will be determined for each analyte (Compound 1 and ribociclib) in the PK analysis set using standard compartmental or non-compartmental methods. Analyte concentrations will be summarized for each cohort per cycle and per day using appropriate descriptive statistics (e.g., N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation [CV] %, geometric mean, and CV related to the geometric mean).

[0134] Biomarker analysis: Descriptive statistics will be primarily used to summarize the biomarker data generated in this study. For continuous variables, the number of subjects with non-missing data, the mean, either standard error or standard deviation, median, 25th percentile (1st quartile), 75th percentile (3rd quartile), minimum, and maximum will be presented. For discrete data, frequency and percentage distributions will be presented.

[0135] Example 2. Data from a Phase 1b, Open-Label, Multicenter Study of Compound 1 in Combination with the CDK4 / 6 Inhibitor Ribociclib in Adult Subjects with Advanced and / or Metastatic HR-Positive, HER2-Negative Breast Cancer This example reports a Phase 1b, open-label, two-part study of Compound 1 in combination with ribociclib. This example included participants with evaluable HR+, HER2- advanced or metastatic breast cancer who had received ≤2 prior endocrine therapies (prior CDK4 / 6 inhibitors were permitted) and ≤1 prior line of chemotherapy. Participants received escalating doses of Compound 1, 30, 60, and 120 mg, orally (PO) once daily (QD) in combination with the approved dose of ribociclib 600 mg QD (days 1-21 of a 28-day cycle) in a 3+3 design to identify the recommended Phase 2 dose (RP2D). The dose-expansion phase will evaluate additional safety and PK parameters, as well as the antitumor activity of Compound 1 in combination with ribociclib.

[0136] safety Eleven participants were enrolled at dose levels of 30 mg (n=3), 60 mg (n=3), and 120 mg (n=3) in the dose-escalation phase and n=2 in the dose-expansion phase of Compound 1 in combination with ribociclib. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached.

[0137] Treatment-emergent adverse reactions (TEAEs) that occurred in two or more participants are shown in Table 1. The most common TEAE was neutropenia, mostly attributable to ribociclib. Other TEAEs that occurred in ≥2 participants were grade 1 or 2. There was no increase in the incidence or intensity of TEAEs with increasing dose of Compound 1. QT duration (corrected according to the Fredericia formula, QTcF) was monitored. There were no increases in QTcF greater than grade 2 (one participant had a grade 2 increase) or increases in QTcF duration requiring dose reduction or discontinuation of study treatment. The recommended Compound 1 dose for expansion in combination with ribociclib (600 mg PO QD, days 1–21 of a 28-day cycle) was 120 mg. [Table 1A]

[0138] Pharmacokinetics Objectives and Endpoints Pharmacokinetic parameters were determined for each analyte (Compound 1, ribociclib). Analyte concentrations were summarized for each cohort per cycle and per day using appropriate descriptive statistics (e.g., N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation [CV] %, geometric mean, and CV related to the geometric mean). The primary PK endpoints established were the following PK parameters: AUC 0~6 , AUC 0~24 , C max , and T max .

[0139] Pharmacokinetic Analysis Considerations Subject Treatment: The PK data included in this example were based on plasma concentrations of Compound 1 and ribociclib from nine female subjects with metastatic breast cancer (MBC) who received 600 mg ribociclib tablets in a fasted state, three subjects who received 30 mg Compound 1 capsules, three subjects who received 60 mg capsules, and three subjects who received 120 mg capsules. No subjects withdrew or terminated early. Two subjects were removed from the study after Cycle 2. When incomplete sampling affected PK parameters, results were excluded from the descriptive and inferential statistics.

[0140] PK Sampling: Blood samples for PK analysis of Compound 1 in plasma were obtained from all subjects at the following times during Cycle 1: pre-dose on C1D1 and 0.5 hours (±15 minutes), 1 hour (±15 minutes), 2 hours (±30 minutes), 4 hours (±30 minutes), 6 hours (±30 minutes), optionally 8 hours (±30 minutes), and 24 hours (±2 hours) after dosing (pre-dose on C1D2), and pre-dose on C1D8 and C1D15. Blood samples for plasma PK analysis of Compound 1 were obtained from six of the nine subjects at the following times: pre-dose at C2D1, pre-dose at C2D15, 0.5 hours (± 15 minutes), 1 hour (± 15 minutes), 2 hours (± 30 minutes), 4 hours (± 30 minutes), and 6 hours (± 30 minutes) after administration (pre-dose at C2D16), optionally 8 hours (± 30 minutes), and 24 hours (± 2 hours). Samples were also collected pre-dose at C3D1 and C3D15, and pre-dose at C5D1, C7D1, and C9D1. Blood samples for plasma PK analysis of ribociclib were obtained from all subjects at the same time points as Compound 1 for C1D1, C1D2, C1D8, C1D15, C2D15, and C2D16, and collected for C3D15.

[0141] Pharmacokinetic results Pharmacokinetic profile of Compound 1: A summary of the key pharmacokinetic parameters of Compound 1 after administration in combination with ribociclib is presented in Table 2 (Day 1) and Table 3 (steady state). Mean plasma Compound 1 concentration vs. time plots after administration in combination with ribociclib are presented in Figures 1A, 1B, and 1C (Day 1) and 2A and 2B (steady state).

[0142] Pharmacokinetic profile of ribociclib: A summary of the key pharmacokinetic parameters of ribociclib after administration in combination with Compound 1 is presented in Table 4 (Day 1) and Table 5 (steady state). Dot plots of the geometric mean (geometric SD) of plasma ribociclib pharmacokinetic parameters after administration in combination with Compound 1 are presented in Figure 3 (Day 1) and Figure 4 (steady state). [Table 1] [Table 2] [Table 3] [Table 4]

[0143] Pharmacokinetic Considerations and Conclusions compound 1 Single Dose: Single Dose Exposure Parameter AUC of Compound 1 When Administered in Combination with 600 mg Ribociclib 0~6 , AUC 0~24 , and C max The T of Compound 1 given alone or in combination with ribociclib was similar to that of Compound 1 when administered as a single agent. max Median values ​​were also similar across the dose levels studied for single doses. These results suggest that to date, there have been no clear DDIs following coadministration of single doses of 30, 60, and 120 mg of Compound 1 with 600 mg of ribociclib. PK parameters for the 120 mg Compound 1 combination were within the 90% confidence intervals of the geometric means of Compound 1 monotherapy.

[0144] Steady State: Single Dose: Steady State Exposure Parameter AUC of Compound 1 when Administered in Combination with 600 mg Ribociclib 0~6 , AUC 0~24 , and C max The T of Compound 1 given alone or in combination with ribociclib was similar to that of Compound 1 when administered as a single agent. max Median values ​​were also similar across dose levels of 30 and 60 mg Compound 1. These results suggest that to date, there have been no significant DDIs for the 30 and 60 mg Compound 1 doses following coadministration with 600 mg ribociclib.

[0145] The PK of Compound 1 was dose proportional within the dose range of 30 to 120 mg when Compound 1 was dosed in combination with 600 mg of ribociclib.

[0146] Ribociclib Single Dose: Single-Dose Exposure Parameter AUC of Ribociclib When Administered in Combination with 30, 60, or 120 mg of Compound 1 0~24 and C max was similar to that of ribociclib when administered as a single agent (Novartis Pharmaceuticals Canada Inc. 2023. Available at www.ask.novartispharma.ca / download.htm?res=kisqali_scrip_e.pdf&resTitleId=1439 (accessed September 26, 2023)). The T of ribociclib administered alone or in combination with 30, 60, or 120 mg QD of Compound 1 max Median values ​​were similar for the single doses. These results suggest that to date, there have been no clear DDIs for single-dose ribociclib following coadministration with 30, 60, or 120 mg QD Compound 1.

[0147] Steady State: Steady-State Exposure Parameter AUC of Ribociclib When Dosed in Combination with 30 or 60 mg Compound 1 QD 0~6 , AUC 0~24 , and C max were similar to those of ribociclib when administered as a single agent (Novartis Pharmaceuticals Canada Inc. 2023. Available at www.ask.novartispharma.ca / download.htm?res=kisqali_scrip_e.pdf&resTitleId=1439 (accessed September 26, 2023)). These preliminary results suggest that, to date, there have been no clear DDIs following coadministration of 600 mg QD ribociclib 3 weeks on / 1 week off with 30 or 60 mg QD Compound 1.

Claims

1. A pharmaceutical composition for treating estrogen receptor-mediated diseases, disorders, or conditions in a subject, wherein the pharmaceutical composition comprises compound 1, 【Transformation 7】 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition contains about 15 mg to about 360 mg of compound 1, The pharmaceutical composition is characterized by being administered in combination with a composition comprising approximately 200 to approximately 800 mg of ribociclib or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is administered in an amount of about 30 mg to about 120 mg of compound 1.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered in an amount of about 30 mg of compound 1.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered in an amount of about 60 mg of compound 1.

5. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered in an amount of about 90 mg of compound 1.

6. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered in an amount of about 120 mg of compound 1.

7. The pharmaceutical composition according to claim 1 or 2, characterized in that the composition containing ribociclib is administered in an amount of about 500 to about 700 mg of ribociclib.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that the composition containing ribociclib is administered in an amount of approximately 600 mg of ribociclib.

9. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition is administered once a day.

10. The pharmaceutical composition according to claim 1 or 2, characterized in that the composition comprising ribociclib is administered once daily for 21 days, followed by a 7-day drug-free period.

11. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutical composition and the composition containing ribociclib are administered simultaneously.

12. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a capsule or a tablet.

13. The pharmaceutical composition according to claim 12, wherein the composition comprising ribociclib or a pharmaceutically acceptable salt thereof is in the form of a capsule or tablet.

14. The pharmaceutical composition according to claim 1 or 2, wherein the estrogen receptor-mediated disease, disorder, or condition is cancer.

15. The pharmaceutical composition according to claim 14, wherein the cancer is breast cancer.

16. The pharmaceutical composition according to claim 15, wherein the cancer is HR+ / HER2- breast cancer.

17. The pharmaceutical composition according to claim 14, wherein the cancer has metastasized to another organ.

18. The pharmaceutical composition according to claim 17, wherein the cancer has metastasized to the brain, bones, lungs, or liver.

19. The pharmaceutical composition according to claim 1 or 2, wherein the subject has previously received at least one of a CDK4 / 6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.

20. Compound 1 in approximately 30 mg to approximately 360 mg, 【Chemistry 9】 A kit comprising a composition containing either or a pharmaceutically acceptable salt thereof, and a composition containing about 200 to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof.

21. The kit according to claim 20, wherein the kit comprises about 30 mg of compound 1 or a pharmaceutically acceptable salt thereof.

22. The kit according to claim 20, wherein the kit comprises about 60 mg of compound 1 or a pharmaceutically acceptable salt thereof.

23. The kit according to claim 20, wherein the kit comprises about 90 mg of compound 1 or a pharmaceutically acceptable salt thereof.

24. The kit according to claim 20, wherein the kit comprises about 120 mg of compound 1 or a pharmaceutically acceptable salt thereof.

25. The kit according to any one of claims 20 to 24, wherein the kit comprises about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof.

26. The kit according to any one of claims 20 to 24, comprising packaging material including a label indicating that compound 1 and ribociclib can be used to treat an estrogen receptor-mediated disease, disorder, or condition.

27. The kit according to claim 26, wherein the estrogen receptor-mediated disease, disorder, or condition is cancer.

28. The kit according to claim 27, wherein the cancer is breast cancer.

29. The kit according to claim 28, wherein the cancer is HR+ / HER2- breast cancer.

30. The kit according to claim 27, wherein the cancer has metastasized to another organ.

31. The kit according to claim 30, wherein the cancer has metastasized to the brain, bones, lungs, or liver.

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